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Anuj Ranjan, Tanu Jindal
Toxicology of Organophosphate Poisoning pp 79-89; https://doi.org/10.1007/978-3-030-79128-5_5

The publisher has not yet granted permission to display this abstract.
Corrigendum
Sheng-Feng Lin, Han-Hwa Hu, Bo-Lin Ho, Chih-Hung Chen, Lung Chan, Huey-Juan Lin, Yu Sun, Yung-Yang Lin, Po-Lin Chen, Shinn-Kuang Lin, et al.
Published: 17 September 2021
Frontiers in Neurology, Volume 12; https://doi.org/10.3389/fneur.2021.737437

Abstract:
A Corrigendum on Pre-treatment of Single and Double Antiplatelet and Anticoagulant With Intravenous Thrombolysis for Older Adults With Acute Ischemic Stroke: The TTT-AIS Experience by Lin, S.-F., Hu, H.-H., Ho, B.-L., Chen, C.-H., Chan, L., Lin, H.-J., Sun, Y., Lin, Y-Y., Chen, P-L., Lin, S-K., Wei, C-Y., Lin, Y-T., Lee, J-T., Chao, A-C., and Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) Study Group. (2021). Front. Neurol. 12:628077. doi: 10.3389/fneur.2021.628077 In the published article, there were errors in affiliations 1–5. Instead of “1 School of Public Health, College of Public Health, Taipei, Taiwan, 2 Beijing Tiantan Hospital, Capital Medical University, Beijing, China, 3 Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China, 4 Department of Neurology, Taipei Medical University-Shaung Ho Hospital, Taipei, Taiwan, 5 Department of Health Care Administration, Chung-Hwa University of Medical Technology, Tainan, Taiwan” it should be “1 School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan, 2 Department of Critical Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan, 3 Department of Clinical Pathology, Taipei Medical University, Taipei, Taiwan, 4 Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China, 5 Department of Neurology, Taipei Medical University-Shaung Ho Hospital, Taipei, Taiwan.” The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Keywords: aspirin, clopidogrel, stroke, intracranial hemorrhage, intravenous thrombolysis Citation: Lin S-F, Hu H-H, Ho B-L, Chen C-H, Chan L, Lin H-J, Sun Y, Lin Y-Y, Chen P-L, Lin S-K, Wei C-Y, Lin Y-T, Lee J-T, Chao A-C and Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) Study Group (2021) Corrigendum: Pre-treatment of Single and Double Antiplatelet and Anticoagulant With Intravenous Thrombolysis for Older Adults With Acute Ischemic Stroke: The TTT-AIS Experience. Front. Neurol. 12:737437. doi: 10.3389/fneur.2021.737437 Received: 07 July 2021; Accepted: 08 July 2021; Published: 17 September 2021. Approved by: Copyright © 2021 Lin, Hu, Ho, Chen, Chan, Lin, Sun, Lin, Chen, Lin, Wei, Lin, Lee, Chao and Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) Study Group. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: A-Ching Chao, [email protected]; Han-Hwa Hu, [email protected]
Abm Moniruddin, Salma Chowdhury, Tanvirul Hasan, Baikaly Ferdous, Rashed Khan
Published: 6 September 2021
KYAMC Journal, Volume 12, pp 101-106; https://doi.org/10.3329/kyamcj.v12i2.55444

Abstract:
Appendicitis has its acute, subacute, recurrent and chronic forms. Appendicitis is commonly predisposed to and precipitated by a single or a combination of multiple discrete factors like obstruction of lumen, ischemia from thromboembolic episodes, infection or idiopathic etc. Typically, it starts as umbilical or peri-umbilical or midline abdominal dull aching pain that soon gets localized in the right iliac region. Movements worsen the pain. Other typical features include nausea, vomiting, anorexia, pyrexia, preference to lie down with or without curling up, chills, constipation, diarrhea, fever, shaking etc. The atypical symptoms of appendicitis include a dull or sharp pain anywhere in the abdomen, back, rectum, painful urination, bloating, flatulence, generalized abdominal tenderness, distension simulating acute intestinal obstruction, enlarging abdominal mass with or without overlying skin erythema, normal bowel movements, normal vital signs and even with no pain, no nausea, no vomiting no pyrexia or no weight loss. These atypical symptoms very often misguide the primary care physicians and the surgeons resulting in failure of diagnosis putting the patients to the risks of life-endangering complications. Diagnosis of appendicitis in absence of typical features are to be made from pre-occupied knowledge and clinical suspicion with or without the help of biochemical and/or imaging studies. Early and timely diagnosis and appropriate treatment are essential to save the life and to reduce the morbidity as well. Appendicitis should be thought in all cases of abdominal pain irrespective of its type and location, as must meningitis be thought in all cases of headaches. KYAMC Journal.2021;12(02): 101-106
, Richard Love
Journal of Nepal Medical Association, Volume 59; https://doi.org/10.31729/jnma.6355

Abstract:
While the acute case burdens and deaths from the COVID-19 pandemic (in Nepal approaching 700,000 and 10,000 respectively) have been costly, the characteristics and potentially huge dimensions of the chronic disease sequelae of this infectious disease are only slowly becoming apparent. We reviewed Pub Med, major medical meeting and medical journal, and investigative journalist materials seeking to frame and describe COVID-19 chronic disease. The consequences of COVID-19 infections follow major organ damage, and induction of immunological and hormonal systems dysfunction. The first injuries are consequent to direct viral effects on tissues, and vasculitis, endothelialitis, thrombosis and inflammatory events. Pulmonary, cardiac, brain, and kidney tissues incur function-limiting damage, with dyspnea, arrythmias, decreased exercise capacity, cognitive dysfunction, and decreased glomerular filtration rates. The second process is characterized by immune dysregulation and autoimmunity, and dysfunction of hormonal regulation systems, with high, fluctuating levels of physical and mental fatigue, multiple-site pain and ache, and non-restorative sleep, in 10-30% of cases. This communication proposes evaluation and management of chronic COVID-19 patients with efficient assessment of commonest symptoms, targeted physical examination and organ function testing, and interventions based on specific organ functional status, and experience with similar chronic immune syndromes, such as myalgic encephalomyelitis.
, Irawati Dewi, Hamid Akhir Yani S
Annals of Clinical Hypertension, Volume 5, pp 008-011; https://doi.org/10.29328/journal.ach.1001027

Abstract:
Objective: This study discusses strategies to overcome hypertension patient compliance to manage self-care. The purpose of the study is to provide a summary of the importance of attention to managing hypertension. Method: a review of literature relevant to hypertension, policies, and management, both pharmacological and non-pharmacological, through cross-programs or sectors. Result: This study found that the ministry of health had compiled various policies to reduce the prevalence of hypertension, including technical guidelines for its implementation, but the strategy has not yet fully reached the minimum service standard, which is because it has not fully involved the relevant cross sectors. Conclusion: Improve the coordination system by “Joint Decree” between the Ministry of Health and the Ministry of Villages, PDT and Transmigration, the Ministry of Social Affairs, Indonesian National Army, police, and NGOs to carry out activities simultaneously to the community.
Ibrahim Chikowe, Andrew G. Mtewa, David Tembo, Dallas Smith, Edna Ibrahim, Bonface Mwamatope, Justin Nkhungulu, Peter Kumpalume, Alfred Maroyi
Malawi Medical Journal, Volume 33, pp 85-107; https://doi.org/10.4314/mmj.v33i2.4

Abstract:
The Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered an international pandemic that has led to significant public health problems. To date, limited evidence exists to suggest that drugs are effective against the disease. As possible treatments are being investigated, herbal medicines have shown potential for producing novel antiviral agents for the COVID-19 disease. Aim This review explored the potential of Malawi’s traditional medicinal plants for the management of COVID-19. MethodsThe authors searched on PubMed and Google scholar for medicinal plants that are used in Malawi and published in openly available peer reviewed journals. Plants linked with antiviral treatment, anti-COVID-19 activity or COVID-19 symptoms management were targeted. These included activity against pneumonia, inflammation, cough, difficulty in breathing, pain/aches, fever, diarrhoea, rheumatism, fatigue, asthma, immunocompromised and cardiovascular diseases.Results11 studies were found with 306 plant species. 127 plant species had at least one COVID-19 related pharmacological activity. Of these plant species, the number of herbal entities used for each indication was: pain/aches (87), fever (2), pneumonia (9), breathing/asthma problems (5), coughing (11), diarrhoea (1), immunosuppression (8), blood issues (10), fatigue (2), heart problems (11), inflammation (8), rheumatism (10) and viral diseases (12). Thirty (30) species were used for more than one disease and Azedarachta indica topped the list (6 of the 13 COVID-19 related diseases). The majority of the species had phytochemicals known to have antiviral activity or mechanisms of actions linked to COVID-19 and consequent diseases’ treatment pathways.ConclusionMedicinal plants are a promising source of compounds that can be used for drug development of COVID-19 related diseases. This review highlights potential targets for the World Health Organization and other research entities to explore in order to assist in controlling the pandemic.
Laura E. Tanner
The Elusive Everyday in the Fiction of Marilynne Robinson pp 66-90; https://doi.org/10.1093/oso/9780192896360.003.0003

Abstract:
The cultural force of Gilead stems from its powerful unveiling of how dying complicates the sensory and psychological dynamics of human perception, expelling Robinson’s aging and ailing narrator from the ordinary world his prose so beautifully illuminates. In his journal to his son, Ames uses language to compensate for his anticipated absence; however, the reader’s experience of this first-person narrative may achieve an aesthetic transcendence that belies the aching apprehension of loss that functions as its scaffolding. Gilead localizes Ames’s psychic struggle with his own imminent death in acts of perceptual processing that it both depicts and thematizes. Combining physiological, sociological, and psychological approaches to aging with phenomenology and cognitive theories of perception, this chapter explores how the novel pushes existential concerns into the realm of the everyday to explore the way that the lived experience of dying traps Robinson’s protagonist uncomfortably in the collapsing space between perception and representation.
Bibo Lu, Qing Ye, , Jiachun Lu, Lu Li, Yuxuan Peng, Min He, Weiyin Chen, Xueping Yang
Abstract:
Background: Myasthenia gravis (MG) is an autoimmune antibody-mediated disorder caused by dysfunction at the neuromuscular junction spreads. The main clinical features of this disease are fluctuating fatigue, and weakness of the skeletal muscles of the eyes and limbs. At present, the tonifying the spleen and replenishing the kidney method in traditional Chinese medicine has been widely used for MG. The present study was conducted to evaluate the efficacy and safety of the tonifying the spleen and replenishing the kidney method in traditional Chinese medicine for MG. Methods: The following 10 databases were searched from inception to March 2021: PubMed, Cochrane Library, EMBASE, Web of Science, Springer, China National Knowledge Infrastructure (CNKI), Wan fang, VIP Chinese Science and Technique Journals Database, the Chinese Bio Medical Database (CBM), and Baidu Scholar. The language was limited to the Chinese and English language. Merely randomized controlled trials (RCTs) were included. The Cochrane Collaboration risk-of-bias tool was used for the methodological quality assessment and risk of bias. The meta-analysis was assessed using the Cochrane RevMan 5.3 software. Results: In the present study, a meta-analysis was conducted, and RCTs that met the eligibility criteria were included. Furthermore, the different outcome indicators of different methods were objectively compared. The main outcome indicators included the effective rate, quantitative myasthenia gravis (QMG) scores, adverse events, and quality of life (QOL). The secondary outcome indicators included AchRAb, serum-related immune cells (such as CD3+CD4+cells and CD4+/CD8+cells), the traditional Chinese medicine syndrome score scale (TCMSSS), the serum interleukin-6 level, the level of IFN-γ and its mRNA, and the clinical score that contains the clinical absolute score (CAS) and clinical relative score (CRS). Conclusion: This study would provide credible evidence to determine whether the tonifying the spleen and replenishing the kidney method in traditional Chinese medicine is an effective treatment method for MG. Trial registration number: INPLASY202110097
Bibo Lu, Qing Ye, Yuting Pan, Jiachun Lu, Lu Li, Yuxuan Peng, Min He, Weiyin Chen, Xueping Yang
Published: 28 May 2021
Medicine, Volume 100

The publisher has not yet granted permission to display this abstract.
Daria B. Kokh, Rebecca C. Wade
Published: 26 May 2021
by Zenodo
Abstract:
Data and Python scripts used for generation and analysis of RAMD dissociation trajectories for several GPCR complexes (including example showing generation of the Protein-Ligand Interaction Fingerprints, IFP, for several representative RAMD trajectories), reported in the manuscript "G-Protein Coupled Receptor-Ligand Dissociation Rates and Mechanisms from tRAMD Simulations" "G-Protein Coupled Receptor-Ligand Dissociation Rates and Mechanisms from tauRAMD Simulations" by Daria B. Kokh, Rebecca C. Wade submitted to the Journal of Chemical Theory and Computation 1. README.txt - instruction for script usage 2. PDBs.zip - PDB structures of complexes in water box used in the analysis, ligand PDB and mol2 structures 3. tauRAMD_v2.py - Python sctipt for estimation relative residence times from Gromacs-RAMD output 4. IFP_preprocess_Gromacs.py and IFP_SL-B2AR-WB-EX.py - Python scripts for preprocessing of RAMD trajectories and generation of IFPs 5. Scripts.zip - additional python functions 6. IXO-CHL.zip, IXO-ALO-CHL.zip, ACh-CHL.zip, b2AR.zip - Protein-Ligand Interaction Fingerprints (PL IFPs) generated from RAMD trajectories for mAChR M2 with iperoxo, mAChR M2 with iperoxo and PAM, mAChR M2 with ACh, and β2AR with alprenolol . 7. Topology.zip - Gromacs topology, index.ndx, and coordinate gro files for all four systems 8. Example_b2AR-alprenolol.zip - a set of data for a test example showing how IFP can be generated from RAMD trajectories (including several representative trajectories) 9. Gromacs-IFP-GPCR.ipynb - Jupyter Notebook for analysis of trajectories using generated IFP data 10. Auxi-Plots-GPCR.ipynb - Jupyter Notebook for generation additional plots from the paper 11. Waters.zip - number of water molecules in the binding pocket in dissociation trajectories of the β2AR - alprenolol system 12. GPCR.yml - JN environment file
Daria B. Kokh, Rebecca C. Wade
Published: 26 May 2021
by Zenodo
Abstract:
Data and Python scripts used for generation and analysis of RAMD dissociation trajectories for several GPCR complexes (including example showing generation of the Protein-Ligand Interaction Fingerprints, IFP, for several representative RAMD trajectories), reported in the manuscript "G-Protein Coupled Receptor-Ligand Dissociation Rates and Mechanisms from tRAMD Simulations" "G-Protein Coupled Receptor-Ligand Dissociation Rates and Mechanisms from tauRAMD Simulations" by Daria B. Kokh, Rebecca C. Wade submitted to the Journal of Chemical Theory and Computation 1. README.txt - instruction for script usage 2. PDBs.zip - PDB structures of complexes in water box used in the analysis, ligand PDB and mol2 structures 3. tauRAMD_v2.py - Python sctipt for estimation relative residence times from Gromacs-RAMD output 4. IFP_preprocess_Gromacs.py and IFP_SL-B2AR-WB-EX.py - Python scripts for preprocessing of RAMD trajectories and generation of IFPs 5. Scripts.zip - additional python functions 6. IXO-CHL.zip, IXO-ALO-CHL.zip, ACh-CHL.zip, b2AR.zip - Protein-Ligand Interaction Fingerprints (PL IFPs) generated from RAMD trajectories for mAChR M2 with iperoxo, mAChR M2 with iperoxo and PAM, mAChR M2 with ACh, and β2AR with alprenolol . 7. Topology.zip - Gromacs topology, index.ndx, and coordinate gro files for all four systems 8. Example_b2AR-alprenolol.zip - a set of data for a test example showing how IFP can be generated from RAMD trajectories (including several representative trajectories) 9. Gromacs-IFP-GPCR.ipynb - Jupyter Notebook for analysis of trajectories using generated IFP data 10. Auxi-Plots-GPCR.ipynb - Jupyter Notebook for generation additional plots from the paper 11. Waters.zip - number of water molecules in the binding pocket in dissociation trajectories of the β2AR - alprenolol system 12. GPCR.yml - JN environment file
Chaoying Liu, Peng Liu, Mei Ma, Hongxia Yang, Guoyan Qi
Abstract:
Objectives: To evaluate the efficacy of double-filtration plasmapheresis (DFPP) treatment of myasthenia gravis (MG) through a systematic review and meta-analysis. Methods: PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), and Wanfang databases were searched for randomized controlled trials (RCTs) and clinical controlled trials (CCTs) on DFPP for MG from database establishment to June 2019. Two researchers independently screened the articles, extracted the data, and cross checked the results. RevMan 5.3 was used for statistical analyses. Results: Seven RCTs and 2 CCTs were found comprising 329 patients. The results showed that clinical MG remission rate after DFPP treatment was significantly higher (OR = 4.33; 95% confidence interval [CI], 1.97–9.53; P < .001) and the serum levels of antititin antibody was significantly decreased (standardized mean difference [SMD] = 9.30; 95% CI, 7.51–11.08; P < .001). In addition, the quantitative MG (QMG) score, hospital stay and time to remission of MG symptoms, and acetylcholine receptor antibody (AchRAb) decreased in the DFPP treatment group; however, these outcomes had high heterogeneity among the studies. Only one study has reported on the adverse effects, including hypotension and hematoma. Conclusion: This meta-analysis suggests that DFPP can be recommended for the short-term mitigation of MG. Because our review was limited by the quantity and quality of the included studies, the above conclusions should be verified by additional high-quality studies.
Khushboo, Abhishek Kumar, Bechan Sharma
Mini-Reviews in Medicinal Chemistry, Volume 21, pp 1-1; https://doi.org/10.2174/1389557521666210415112601

Abstract:
Background: Depression is a most common mental disorder. The symptoms of depression include loss of energy, changes in appetite, more or less sleep, anxiety, low concentration, uncertainty, restlessness, feelings of worthlessness, guilt, or despair, and thoughts of self-harm or suicide. In order to provide safe, efficient and cost-effective medication, the plants based principles in isolation or in combination with traditional antidepressants are attracting increasing attention for depression therapy. Method: The information regarding the present review and its contents such as collected from published literature materials in different international journals. We have used different search engines such as PubMed, Medline, ResearchGate Google Semantic Scholar and ScienceDirect. For this purpose, the data obtained were properly organized and suitably analyzed to include in this article. Results: Most of the phytomolecules isolated from the medicinal plants display antidepressant effect through the synaptic regulation of levels of neurotransmitters such as dopamine, serotonin, and noradrenaline in different parts of the brain. The mechanism of action of phytomolecules also involves negative regulation of the activities of monoamine oxidase (MAO) and acetylcholinesterase (AChE) and prevention of hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis. In addition, the strong antioxidative and antiinflamatory potential of these phytochemicals offer synergy to their antidepressant as well as antipsychosomatic functions. Conclusion: The application of phytochemicals has proved it to be a safe, cost effective and efficient therapeutic agent to treat the patients suffering from mild to severe state of depression and other psychiatric disorders. The potential phytochemicals may be further optimized using in silico tools to develop better antidepressants and antisychotic agents in future.
Gang Zong, Shiliang Liu, Zunling Chen, Yulei Hu
Abstract:
Background: Myasthenia gravis is a common autoimmune disease in clinic. Although there are various ways and drugs for the treatment of myasthenia gravis in Western medicine, there are still a variety of adverse reactions. Studies have shown that Buzhong Yiqi decoction combined with Western medicine has a certain efficacy in the treatment of myasthenia gravis, but there is a lack of evidence-based medicine. The research carried out in this scheme is to systematically evaluate the efficacy and safety of Buzhong Yiqi decoction combined with Western medicine in the treatment of myasthenia gravis, and to provide reliable evidence for guiding clinical practice. Methods: English databases (the Cochrane Library, PubMed, Web of Science, Embase) and Chinese databases (China Biomedical Database, China Science and Technology Journal Database, China National Knowledge Infrastructure, Wanfang) will be searched by computer. In addition, Baidu Academic and Chinese Clinical Trial Registration Center will be searched manually. A randomized controlled clinical trial of Buzhong Yiqi decoction combined with Western medicine in the treatment of myasthenia gravis will be conducted from the establishment of the database to December 2020. The 2 researchers independently carry out data extraction and literature quality evaluation on the quality of the included study, and meta-analysis of the included literature will be carried out by using RevMan 5.3 software. Results: This study will evaluate the efficacy and safety of Buzhong Yiqi decoction combined with Western medicine in the treatment of myasthenia gravis by Quantitive MGscore, the number of Tregs cells and the content of anti-acetylcholine receptor antibody (AchR-Ab). Conclusion: This study will provide reliable evidence-based evidence for the clinical application of Buzhong Yiqi decoction combined with Western medicine in the treatment of myasthenia gravis. Ethics and dissemination: Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval was not required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences. OSF Registration number: DOI 10.17605/OSF.IO/MXUPK.
Monique Allewaert
Published: 1 January 2021
Abstract:
ExtractMonique Allewaert [E]ach wind is self-registering. THOREAU, JOURNAL, NOVEMBER 3, 1861 (last journal entry) Henry David Thoreau’s late, unfinished manuscript Dispersion of Seeds advances the theory of cross-species figuration and interpretation he slowly developed in his Journal. Thoreau’s Journal, which a number of Thoreau’s finest critics have argued was his primary work (Cameron; Walls; Arsić) , is a massive compendium of natural historical events occurring in and near Concord from 1837 through 1861. While occasionally entries to the Journal offer philosophical and literary mediations that scholars have excerpted as parts of larger analyses, more than anything it chronicles details that can only seem mind-numbingly incidental and without any taxonomizing principle. The unfinished Dispersion of Seeds, which Thoreau primarily wrote in late 1860 and revised in the fall of 1861 and into early 1862, was to offer the theory for registering and interpreting this surfeit of natural historical detail that he...
, Yan Zhou, Guozhen Yuan, Jingjing Shi, Shuai Shi, Limei Zhang, Ruoning Chai, Yihang Du, Chenglin Duan, Yuanhui Hu
Published: 1 January 2021
Channels, Volume 15, pp 298-309; https://doi.org/10.1080/19336950.2021.1882113

Abstract:
To explore the research status, hotspots, and trends in research on nicotinic acetylcholine receptor (nAChR) channel. The Web of Science core collection database from 2000 to 2020 was used as the data source. The visual analysis software VOSviewer1.6.16 and Citespace5.7 R3 were used to visualize the studies of the nAChR channel. The national/institutional distribution, journal distribution, authors, and related research were discussed. A total of 5,794 articles were obtained. The USA and the Utah System of Higher Education were the most productive country and institution for nAChR channel research. Journal of Biological Chemistry was the most productive journal (212) and the most productive researcher was McIntosh, J. Michael. The first highly co-cited article was “Refined structure of the nicotinic acetylcholine receptor at 4A resolution.” The most researched area was neurosciences neurology. The hot spots of nAChR channel research were “subunit and structure of nAChR,” “activation/agonist of nAChR channel,” and “Changes in nAChRs With Alzheimer’s Disease.” The top three research frontiers of nAChR channel research were “neuropathic pain,” “neuroinflammation,” and “α7 nACHR.” The study provides a perspective to visualize and analyze hotspots and emerging trends in the nAChR channel.
Saif Khan, Rahman Sz
Bangladesh Journal of Medical Science, Volume 20, pp 11-16; https://doi.org/10.3329/bjms.v20i1.50339

Abstract:
Dengue fever is one of the major public health problem in the tropical and subtropical countriesacross the globe with around 50-100 million cases occurring annually. It is a mosquito bornedisease caused by dengue virus of Flaviviridae family. There are four known serotypes ofdengue virus found worldwide. Aedesaegypti mosquito is the principal vector of transfer ofdengue virus in humans. Dengue clinically presents with high grade fever, chills, head-ache,retro orbital and severe back ache and sometimes with hemorrhagic manifestations whichcan occur without plasma leakage and also with plasma leakage as dengue hemorrhagic fever(DHF) and Dengue shock syndrome (DSS). Oral bleeding is one of the important hemorrhagicmanifestations of dengue clinically manifesting as petechiaes, ecchymosis, gingival bleedingand hematomas .The dentist is sometimes the first person who encounters these types of cases.Therefore, timely diagnosis and prompt referral can prevent morbidity and mortality. This paperdiscusses about the clinical and diagnostic perspectives which a dentist should know in order todiagnose a case of dengue fever presenting with oral bleeding. Bangladesh Journal of Medical Science Vol.20(1) 2021 p.11-16
Javier Jérez Escobar, Alfonso Martínez Visbal
Revista Ciencias Biomédicas, Volume 6, pp 118-129; https://doi.org/10.32997/rcb-2015-2990

Abstract:
Introducción: los receptores nicotínicos de acetilcolina (nAChR) en el estudio y entendimiento del dolor se han evaluado ampliamente en las últimas dos décadas. Se consideran piezas importantes para el desarrollo de analgésicos.Objetivo: identificar conceptos y avances acerca de los nAChR y su papel en la modulación del dolor.Metodología: se realizó búsqueda en PubMed, MEDLINE, ScienceDirect, Scielo, OvidSP, EBSCOhost y en la Biblioteca Cochrane (incluyendo la base de datos Cochrane de revisiones sistemáticas y Cochrane controlled trials register). También en las plataformas de las Revistas JAMA, Lancet, New England Journal of Medicine y Anesthesiology. Lasbúsquedas se limitaron a los idiomas inglés y español, así como documentos publicados entre 1970 y 2015.Resultados: los nAChR son canales iónicos transmisores que constan de diferentes subtipos, cada uno de los cuales tiene una farmacología y fisiología específica, con diferente distribución anatómica en el cerebro. No se limitan solo a sitios postsinápticos, también se localizan a nivel pre, peri y extrasinápticos donde pueden modular la función neuronal por una variedad de acciones. Los nAChR neuronales difieren de los nAChR periféricos, ya que no tienen las subunidades γ, δ, ε o, en su confección y constan de varios complementos de α2–α9 y subunidades β2–β4. Actualmente, seis α (α2-α7) y tres β (β2-β4) subunidades se han identificado y clonado a partir de cerebro humano. Los nAChRs son interesantes para develar los mecanismos inherentes al dolor y desarrollar nuevos analgésicos. Los ligandos a nAChR α4β2 siguen siendo la estrategia más atractiva para explicar el dolor neuropático e inflamatorio. Subunidades nicotínicas α5 reducen los estados de dolor e inflamación sobre todo neuropática. La activación central y periférica del nAChR α7, reduce la nocicepción y el dolor inflamatorio agudo.Conclusión: se observan avances en el conocimiento de los nAChR en los mecanismos del dolor. Amplios estudios se realizan a nivel preclínico para desarrollar nuevas estrategias terapéuticas y antiinflamatorias. Rev.cienc.biomed. 2015;6(1):118-129
Published: 19 November 2020
Postdigital Science and Education, Volume 3, pp 36-47; https://doi.org/10.1007/s42438-020-00202-8

The publisher has not yet granted permission to display this abstract.
Aisha Zakaria Hashem Mostafa, Fatimah Saud Alshammari, Motieah Hathal Alshammari, Nada Nasser Almansour, Beshaeir Klaeif AlBalwi, Lamia Nafea Alshammari, Malak Farraj AlTwalah, Fatima Sultana
Saudi Journal of Oral and Dental Research, Volume 5, pp 538-545; https://doi.org/10.36348/sjodr.2020.v05i11.003

Abstract:
©2020|Published by Scholars Middle East Publishers, Dubai, United Arab Emirates538Saudi Journal of Oral and Dental ResearchAbbreviated Key Title: Saudi J Oral Dent ResISSN 2518-1300(Print)|ISSN 2518-1297(Online)Scholars Middle East Publishers, Dubai, United Arab EmiratesJournal homepage:https://saudijournals.com/sjodrOriginal ResearchArticleElucidating the Awareness of Dental Doctors in Following Dental Protocol by M.O.H about the COVID-19 Pandemic in KSADr. Aisha Zakaria Hashem Mostafa*, Fatimah Saud AlShammari, Motieah Hathal AlShammari, Nada Nasser AlMansour, Beshaeir Klaeif Albalwi, Lamia Nafea AlShammari, Malak Farraj Altwalah, Fatima SultanaDepartment of Dentistry, Hail University, Hail, Saudi ArabiaDOI:10.36348/sjodr.2020.v05i11.003| Received:03.11.2020| Accepted:15.11.2020| Published:19.11.2020*Corresponding author:Dr. Aisha Zakaria Hashem MostafAbstractThe causative organism for the COVID-19 is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)virus. The common symptoms of the COVID-19 are: fever, dry cough and fatigue while the less common symptoms are: aches and pain, sore throat, diarrhoea, conjunctivitis, headache, loss of taste and smell, rash on skin, and discolouration of fingers and toes.Several studies reported that person of any age can be infected by the virus, but elderly patients with systemic diseases were more vulnerable to the virus. According to the World Health Organization (WHO), dentistry is the profession with high mode of exposure to the Covid-19 virus. The statistics as recorded on 20thOctober, 2020 shows that there are a total of 342,968 confirmed cases of COVID-19 in Saudi Arabia, with 5,217 deaths and 329,270 recovered cases. The Ministry of Health (MOH) of Saudi Arabia proposed a dental emergency protocol during the COVID-19 pandemic on 13thApril, 2020. This dental emergency protocol guides the triage, assessment and provision of the emergency dental treatment during the current COVID-19 pandemic. The dental care was divided into 4 by the Ministry of Health in Saudi Arabia in this dental emergency protocol as: Emergent dental care, urgent dental care, non-urgent dental care and Advice and self-care. The main aim of this study is to assess the awareness of dental doctors in following dental protocol by M.O.H about the covid-19 in Kingdom of Saudi Arabia. A pre-designed questionnaire is circulated online using Google form to record the results of the survey of elucidating the awareness of dental doctors in following dental protocol by M.O.H about the covid-19 in Saudi Arabia. The data that iscollected from the questionnaire is analysedusing the computer software Statistical package for social sciences that is SPSS 16.The protocol included all the information about the type of orofacial problem and the recommended management related to it. Nearly about 70 to 80 percent of the dental doctors that participated in this survey are aware about all the guidelines provided by the Ministry of Health. Every dental doctor practising in the Kingdom of Saudi Arabia is to be made aware of all the guidelines and protocol to be followed during the emergency dental care.
, Jodi Woan-Fei Law, Loh Teng-Hern Tan, Hooi-Leng Ser, Vengadesh Letchumanan
Published: 18 November 2020
by BMJ
Abstract:
Background The human microbiome comprises of microbes that live on or within various sites of the human body. These diverse microbes have the potential to impact our physiology, both in health and disease. Recently, several autoimmune diseases have been associated with the alterations in patients’ microbiota, including myasthenia gravis. Thus, this study aims to understand the role of gut microbiome in myasthenia gravis (MG) development, as well as obtaining clues on the regulation of gut microbiome to modulate the disease. Methods A systematic search was conducted using predefined MeSH terms ‘myasthenia gravis’ and ‘gut microbiome’ or ‘microbiota’ in three databases (Pubmed, Ovid Medline, Scopus; from database inception to December 2019). All the journal titles and abstracts were screened based on inclusion and exclusion criteria. Studies reporting gut microbiome data in relation to gut microbiome effects were included. Studies without myasthenia gravis and/or gut microbiome data were excluded along with conference abstracts, reviews, systematic reviews, meta-analyses, and comments. Results The systematic search identified 19 articles based on the MeSH term. The duplicate records were removed and 13 articles were accessed. Three studies were eligible for the qualitative analysis according to the inclusion criteria. All the studies reported changes in the microbiota composition as compared to control groups, with significantly lower in phyla Firmicutes and Actinobacteria. MG patients were found to harbour increased of the phylum Bacteroidetes and the family of Desulfovibrionaceae. The ratio of Firmicutes/Bacteroidetes in MG patients describes an inflammatory microbiota which might cause damage to the intestinal epithelium, subsequently trigger an immune response that contributes to the immunological imbalance characteristic of autoimmune disorder. It is reported that some of these microbes were linked with acetylcholine receptor (AchR) antibody, suggesting the gut microbiome influence the onset of myasthenia gravis through classical pathogenic pathways. Conclusions These findings provide vital insight and knowledge on MG gut microbiome that could enhance the potential for future microbial-based therapies to improve the clinical outcome of MG. Figure 1 illustrates the dysbiosis of the gut microbiome in myasthenia gravis patients.
International Journal of Research in Pharmaceutical Sciences, Volume 11, pp 6089-6094; https://doi.org/10.26452/ijrps.v11i4.3280

Abstract:
Cussonia natalensis Sond. and C. zuluensis Strey have a long history of medicinal use in southern Africa. The aim of this study was to review the medicinal uses and pharmacological properties of the two species. Results of this study are based on data derived from several online databases such as Scopus, Google Scholar, PubMed and Science Direct, and pre-electronic sources such as scientific publications, books, dissertations, book chapters and journal articles. The bark, fruits and roots of C. natalensis and C. zuluensis are used as emetic, purgative and protective charm, and traditional medicine for diarrhoea, fever, stomach ache and swellings. This study showed that pentacyclic triterpene acids, cardiac glycosides, flavonoids, polyphenols, saponins and steroids have been identified from the leaves, roots and twigs of the species. The leaf extracts and compounds isolated from C. natalensis and C. zuluensis exhibited antibacterial, antifungal, antimalarial, antiprotozoal and cytotoxicity activities. Documentation of the medicinal uses, phytochemistry and pharmacological properties of C. natalensis and C. zuluensis is important as this information provides baseline data required for future research and development of health-promoting and pharmaceutical products. There is need for extensive phytochemical, pharmacological and toxicological studies of crude extracts of C. natalensis and C. zuluensis to establish the safety profiles of different preparations of the two species.
International Journal of Research in Pharmaceutical Sciences, Volume 11, pp 5089-5096; https://doi.org/10.26452/ijrps.v11i4.3106

Abstract:
Maerua edulis (Gilg & Gilg-Ben.) DeWolf is collected from the wild for its edible fruits and also used as traditional medicine. This study is aimed at evaluating the ethnomedicinal uses, phytochemistry and pharmacological properties of M. edulis. Results of the current study are based on data derived from several online databases such as Scopus, Google Scholar, PubMed and Science Direct, and pre-electronic sources such as scientific publications, books, dissertations, book chapters and journal articles. This study revealed that the bark, fruit, leaf, root and tuber infusion and decoction of M. edulis are mainly used as a thirst quencher and ethnoveterinary medicine, and traditional medicine for eye infections, stomach ache, infertility in women, wounds, fungal infections, rheumatic swellings, cough and tuberculosis and sexually transmitted diseases. Phytochemical compounds identified from the species include agmatine, betaines, cardiac glycosides, fatty acids, flavonoids and quaternary ammonium compounds. Ethnopharmacological research revealed that M. edulis extracts and compounds isolated from the species have acaricidal, anthelmintic, antibacterial, antimycobacterial, antifungal, antiproliferative and insecticidal activities. Future research on M. edulis should focus on the possible biochemical mechanisms of both the crude extracts and identified phytochemical compounds including toxicological, in vivo and clinical studies to corroborate the traditional medicinal applications of the species.
Yanan Li, Ruying Fang, Zehua Liu, Luping Jiang, Jingdong Zhang, , ,
Published: 4 September 2020
The publisher has not yet granted permission to display this abstract.
Published: 26 August 2020
Frontiers in Microbiology, Volume 11; https://doi.org/10.3389/fmicb.2020.01905

Abstract:
Worldwide, the Coronavirus disease 2019 (COVID-19) pandemic has led to health and economic damage that cannot yet be accurately predicted. First clinical studies of hospitalized patients have shown that there are risk factors majorly contributing to the outcome of COVID-19 infection. However, a complete picture of disease pathogenesis and underlying mechanisms is still missing. Therefore, new theories that lead to a better understanding of COVID-19 are urgently needed. The understanding will lead to new diagnostic and of course therapeutic possibilities to target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here it is hypothesized that lowered concentrations or altered composition of pulmonary surfactant is a critical risk factor for COVID-19. As we continue to learn more about the virus, there are still many key questions that scientists are urgently try to answer: 1. Age: Children seem to be a less susceptible to COVID-19 and disease severity at young age is lower than in adults (Lee et al., 2020). Why? 2. Obesity/diabetes: Obesity (high body mass index) and diabetes seems to be a risk factor for poor adverse outcomes of COVID-19 (Malavazos et al., 2020). Why? 3. Smoking: The estimated prevalence of current smoking among hospitalized patients with COVID-19 is rather low (Farsalinos et al., 2020a). Why? 4. Blood pressure: Hypertension and intake angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) increase risk of developing severe and fatal COVID-19 (Fang et al., 2020). Why? 5. Coagulation: Hypercoagulability is associated with disease severity (Liu et al., 2020). Why? 6. Gender: Men with COVID-19 are more at risk for worse outcomes and death (Jin et al., 2020). Why? 7. Infection: The coronavirus by no means affects all persons, some seems to be resistant. Why? 8. Immunity: Do COVID-19 patients develop long-term immunity? 9. Diagnosis: The presence of virus in patients is verified in sputum, salvia, or a swab from deep in the nasal passages using antigen-based methods and RT-PCR tests. Serological tests are used to demonstrate previous infections with SARS-CoV-2. Can diagnosis be improved and/or simplified? 10. Therapy: Several vaccines, neutralizing antibodies and drugs are in the pipeline for COVID-19 therapy. Are there better alternatives? Experts from all over the world are presently discussing these topics and a number of plausible theories arose. In regard to age, suggested reasons are a more active innate immune response, healthier respiratory tracts, differences in the distribution/maturation/function of viral receptors, fewer outdoor activities and less international travel making younger persons less likely to contract the virus (Lee et al., 2020). The propensity of people with obesity to develop more serious complications if exposed to a virus is attributed to multiple factors, such as a chronic inflammatory status and delayed and ineffective immune response (Malavazos et al., 2020). Regarding smoking, a preliminary hypothesis assumes that the virus enters the body through neurons of the olfactory systems. In this scenario, nicotine inhibits the respective receptor (nAChR) explaining the low frequencies of smokers in the COVID-19 cohorts and suspecting nicotine or other pharmaceutical nicotine products as therapeutic agents to target COVID-19 (Farsalinos et al., 2020b; Kloc et al., 2020). It is suggested that there is a complex interplay between COVID-19 and the renin-angiotensin-aldosterone system (RAS), in which SARS-CoV-2 has a spike protein receptor-binding domain with high affinity for human angiotensin-converting enzyme 2 (ACE2) (Andersen et al., 2020), which regulate both the cross-species and human-to-human transmission of the virus. The virus likely recognizes ACE2 orthologous from many other species, except mouse and rat (Wan et al., 2020). It was found that the expression of this receptor is very low in healthy young persons, while it increases in patients with vascular diseases (Singh et al., 2020). ACE and ARBs increase expression of the metallopeptidase ACE2, which is expressed primarily in alveolar epithelial type II cells and serves as a viral reservoir and functional entry receptor of SARS-CoV (Li et al., 2003). Therefore, these drugs were proposed to increase viral uptake and risk of developing severe and fatal COVID-19 (Fang et al., 2020). In line, it was proposed that the SARS-CoV-2 spike protein activates RAS in the lung, thereby promoting platelet adhesion and aggregation and increasing the risk for pulmonary embolism, hypertension and fibrosis. On the contrary, anticoagulation agents improve the clinical outcome of COVID-19 (Liu et al., 2020). The risk factor “male gender” and the higher dying rate of men in COVID-19 is supposed to be consequence of the general demographic fact of a general shorter expectancy in men compared to women (Jin et al., 2020). However, there is already clear indication that there exist sex differences in surfactant biosynthesis putatively be ascribed to the stimulating effects of estrogens. This “male disadvantage” has been recognized clinically and in many experimental models (Torday and Nielsen, 1987; McCoy et al., 1999). Genetic host resistance to coronaviruses is assumed to occur at three levels, namely genetic control of the level of cellular entry receptors, genetic control at the level of macrophage activity, and genetic control at the level of acquired immunity (Buschman and Skamene, 1995). Resistance as a host response to coronavirus infection is predominantly mediated by adaptive immunity comprising humoral and cell-mediated immunity (Li et al., 2020). A different susceptibility to COVID-19 might therefore be evoked by many factors related to the innate or adaptive immune system. It should be mentioned, that the human population has a small pre-existing immunity against SARS-CoV-2 and the T cell response to the structural proteins S, M, and N of the SARS virus are long-lasting and persistent (Grifoni et al., 2020). However, these findings do not mean that persons that were infected are protected from reinfection. Reliable laboratory diagnostic for COVID-19 is required to prevent false negative and positive results which both have fatal consequences. Presently, RT-PCR is used as a diagnostic tool using nasal swab, tracheal aspirate or bronchoalveolar lavage (BAL) samples. However, they don't provide data about disease outcome and have only an estimated sensitivity rate around 66–80% (Pascarella et al., 2020). Simple analysis of most common COVID19-related symptoms such as fever (98%), cough (77%), and dyspnea (63.5%) are suitable to estimate mortality of critically ill patients (Yang et al., 2020). Similarly, the combination of three biomarkers (lactic dehydrogenase, high-sensitivity C-reactive protein, and lymphocyte count) identified by machine learning tools were shown to predict the mortality of individual patients more than 10 days in advance with more than 90% accuracy, suggesting that the combination of clinical symptoms and biomarkers can reflect the entire spectrum of disease from the earliest manifestations to the terminal stages (Yan et al., 2020). Currently, there are no effective vaccine or approved specific antiviral COVID-19 agents available. However, convalescent plasma therapy was effective to achieve serum SARS-CoV-2 RNA negativity in severe COVID-19 patients (Duan et al., 2020). So there are already promising strategies to limit or delay the spread of COVID-19 in the near future. Certainly, increasing funding in the research area “Corona” will further drive discovery providing the basis for successful targeting SARS-CoV-2. Undoubtedly, biased or unbiased biomarker discovery will be one important piece in the puzzle to target the COVID-19 pandemic. Although never working in the field of Corona, I would highlight several features of pulmonary surfactant rendering this surface-active lipoprotein complex relevant for the pathogenesis, diagnostics or therapy of COVID-19. Pulmonary surfactant is composed primarily of phospholipids and four surfactant-associated proteins, namely SP-A, SP-B, SP-C, and SP-D. This lipid-protein complex is essential for the biophysical function of the lung. It stabilizes the delicate structure of the mammalian alveoli along with successive compression-expansion respiratory cycles by reducing surface tension at the air-liquid interface (Autilio and Pérez-Gil, 2019). In addition, this mixture of lipids and proteins constitute a first barrier to the access of pathogens to the rest of the organism via the large respiratory surface, preventing the dissemination of pathogens and modulating immune responses (Han and Mallampalli, 2015; Autilio and Pérez-Gil, 2019). In this regard, most important are SP-A and SP-D, which are members of a family of innate immune proteins termed collectins involved in bacterial and viral clearance (Han and Mallampalli, 2015). These collagen-containing C-type lectins further have ability to opsonize pathogens and facilitate their phagocytosis by cells of the innate immune system, such as macrophages and monocytes (Han and Mallampalli, 2015). Most important, a paper published already 13 years ago demonstrated that SP-D could bind to the SARS-CoV carbohydrate moieties presented on the S-protein of the virus, thereby preventing activation of macrophages and potentially preventing pulmonary inflammation suggesting that SP-D might independent of surfactant itself act as a COVID-19-related factor at the alveolar spaces (Leth-Larsen et al., 2007). Although the exact domains in the SARS-CoV S-protein interacting with SP-D were not dissected in the mentioned study and natural carbohydrate moiety of SARS-CoV-2 might be rather different, the study supports the view that deficiencies in collectins acting as host lectins will have significant impact on innate immunity. In line, SP-A deficient mice exhibited impaired clearance against viruses (e.g., RSV) and showed greater pulmonary infiltration with polymorphonuclear leukocytes (LeVine et al., 1999). Similarly, SP-A inhibited influenza A virus infection of lung epithelial cells (Al-Qahtani et al., 2019), while a recombinant fragment of human SP-D was sufficient to act as an entry inhibitor of influenza A virus in vitro (Al-Ahdal et al., 2018). SP-A protein levels are increased in the serum, plasma and sputum of smokers (Kida et al., 1997; Nomori et al., 1998; Mazur et al., 2011), providing another rationale for the proposed beneficial effects of smoking or nicotine consumption in preventing COVID-19 (Farsalinos et al., 2020a). Furthermore, the composition of surfactant highly significant changes rapidly with exercise in a manner related to fitness and training (Doyle et al., 1994, 2000). In line, there is an inverse association between serum SP-D and body mass index (Zhao et al., 2007), and moreover inverse association with human obesity (Sorensen et al., 2006). Similarly, it was shown that SP-A levels negatively correlate with body mass index (Lugogo et al., 2018), possibly explaining why persons with high body mass index (BMI) having lower SP-A and SP-D levels are more susceptible to COVID-19. In regard to age, it was shown that the quantities of alveolar and total SP-A to body weight and in relationship to alveolar surface area decrease significantly during aging in rats (Ohashi et al., 1994). In humans, the total SP-A serum levels are not affected by age (Nomori et al., 1998). However, human SP-A consists of two functional genes (SP-A1, SP-A2) and a gradual decrease in the SP-A1/SP-A ratio was observed in healthy subjects with increased age (Tagaram et al., 2007). Moreover, the total phospholipid concentration in bronchoalveolar lavage fluid was found higher in children <8 years of age and shown to decrease with age (Ratjen et al., 1996). Historical experiments conducted in lambs and newborn piglets revealed that surfactant therapy results in a significant increase in pulmonary blood flow, decrease in pulmonary vascular resistance, reduction in right-to-left shunting, and decrease in mean arterial blood pressure (Moen et al., 1996; O'Toole et al., 1996). Conversely, it can be concluded that lowering surfactant compounds are causative involved in hypertension presenting a risk factor for developing severe and fatal COVID-19. Collectively, lowered concentrations or altered composition of pulmonary surfactant might be a critical risk factor for COVID-19. Furthermore, it is well-known that polymorphisms in surfactant proteins can predispose individuals to community acquired pneumonia and/or acute respiratory distress syndrome (Lin et al., 2000; Gong et al., 2004). This provides another argument why surfactant proteins or surfactant constituents are critical factors contributing to COVID-19 susceptibility and outcome. The potential connection of SARS-CoV-2 virus infection with a deficit in pulmonary surfactant or factors thereof and the administration of surfactant as a treatment modality for different phenotypes of COVID-19 are presently intensively discussed (Koumbourlis and Motoyama, 2020). Some authors speculate that the early administration of natural lung surfactant could improve the pulmonary function to restore pulmonary barrier function in patients with COVID-19 pneumonia, thereby reducing the duration of ventilation therapy and contributing to patients' recovery (Mirastschijski et al., 2020). Indeed, this could be easily done by adding the reconstituted lyophilizate powder into the trachea tube of the ventilated COVID-19 patient. In another hypothesis, it is argued that pulmonary or some chemical surfactants or stimulants of natural surfactant production may be effective not only for the treatment but also for the prophylactic protection for SARS-CoV-2 (Takano, 2020). In the respective theory, it is argued that the pulmonary surfactant not only is beneficial to reduce surface tension or to increase lung compliance, but also is a strong defender against the virus itself. However, none of the theories is actually supported with true experimental evidence. Even more, COVID-19 pathogenesis is rather complex consisting of three distinct phases classified on the site the respiratory epithelium infected (Mason, 2020). Consequently, the potential therapeutic outcome after surfactant treatment will strongly depend on the location (i.e., nose, conducting airways, alveoli) to which the virus has advanced. Presently, there are no studies available analyzing COVID-19 susceptibility and surfactant biology. However, such studies will be of fundamental importance. If surfactant protects against COVID-19, supplementation after early SARS-CoV-2 infection with purified or recombinant forms of surfactant compounds will offer novel therapeutic avenues in controlling pulmonary infection during COVID-19. It would be desirable if the biomarker “surfactant” would be included in as many COVID-19 studies as possible and to assess the fate of endogenous surfactant in bronchoalveolar lavage material of patients in ongoing and future investigations or trials. RW has drafted this contribution. Author's laboratory receives funds from the German Research Foundation (SFB/TRR57, projects P13 and Q3) and the Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (IZKF Aachen, project O3-1). None of the funding sources exerted influence on the content or decision to publish this Communication. 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Plasma surfactant protein D levels and the relation to body mass index in a chinese population. Scand. J. Immunol. 66, 71–76. doi: 10.1111/j.1365-3083.2007.01943.x PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: infection, surfactant, immunity, gender, body mass index, genetics, smoking, pandemic Citation: Weiskirchen R (2020) Severity of Coronavirus Disease 2019 (COVID-19): Does Surfactant Matter? Front. Microbiol. 11:1905. doi: 10.3389/fmicb.2020.01905 Received: 16 June 2020; Accepted: 21 July 2020; Published: 26 August 2020. Edited by: Reviewed by: Copyright © 2020 Weiskirchen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Ralf Weiskirchen, [email protected] ORCID: Ralf Weiskirchen orcid.org/0000-0003-3888-0931
, Louise Hiller, Anne-Laure Vallier, Shrushma Loi, Karen McAdam, Luke Hughes-Davies, Daniel Rea, Donna Howe, Kerry Raynes, Helen B Higgins, et al.
Health Technology Assessment, Volume 24, pp 1-190; https://doi.org/10.3310/hta24400

Abstract:
Background The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months’ trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority. Objectives To establish whether or not 6 months’ adjuvant trastuzumab is non-inferior to 12 months’ in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival. Design This was a Phase III randomised controlled non-inferiority trial. Setting The setting was 152 NHS hospitals. Participants A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part. Intervention Randomisation (1 : 1) to 6 months’ or 12 months’ trastuzumab treatment. Main outcomes The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months’ trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months’ trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model. Results Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months’ trastuzumab and 2043 were randomised to 6 months’ trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years’ median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiorityp = 0.01), demonstrating non-inferiority of 6 months’ trastuzumab. Congruent results were found for overall survival (non-inferiorityp = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiorityp = 0.03 (disease-free-survival) andp = 0.006 (overall survival)]. Six months’ trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients;p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients;p < 0.0001]. Health economic analysis showed that 6 months’ trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months’ trastuzumab, and thus there is a high probability that 6 months’ trastuzumab is cost-effective compared with 12 months’ trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently. Limitations The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered. Conclusions PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months’ adjuvant trastuzumab is non-inferior to 12 months’. Six months’ treatment resulted in significantly less cardiac toxicity and fewer severe adverse events. Future work Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned. Trial registration Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.
Ajam Uddin, Muhammad Rashedul Islam, Alamgir Kabir, Elias Al Mamun
Bangladesh Pharmaceutical Journal, Volume 23, pp 187-194; https://doi.org/10.3329/bpj.v23i2.48340

Abstract:
As one of the fundamental human rights, healthcare is usually sought during illness episode. A questionnaire-based survey was conducted on 221 residential university students to identify the existing disease patterns and treatment seeking behaviors. Among the students, 22.17% were devoid of normal body-weight and 45.7% of them exercise at least three days a week. Based on smoking habits they were non-smoker (60.18%), smoker (25.34%), and second-hand smoker (14.48%). Besides, 33.03% of them have an allergy (seasonal: 24.43%; perennial: 8.60%) and 75.11% of students’ family members have or had at least one of the eight specified diseases. In 2019, around 98% of the students had suffered from at least one illness like fever-all types (86.43%), common cold (52.94%), diarrhea (20.36%), cough (46.61%), nasal congestion (10.86%), pain/aches-all types (25.79%), gastric problems (49.32%), skin diseases (15.38%), dental diseases (1.36%), eye diseases (0.9%), and many other diseases (4.52%). To mitigate these illnesses majority took medications instead of self-recovery that was highest for dental and eye diseases (100%), and lowest for cough (58.25%) and nasal congestion (58.33%). Usually, 61.99% of the residents go to Government Hospital (DMCH: 45.70%, BSMMU: 9.95%) for seeking treatment followed by University Medical Center (41.63%), Private Medical Consultant (5.88%), Private Hospital (4.52%), and others (3.62%). Moreover, 67.42% of the students take prescribed medicines as stated in prescriptions. As there is a tendency among 83.26% of the students to take medicines without prescriptions, raising awareness on the detrimental impacts of self-treatment is needed to refrain them from self-medication practices. Bangladesh Pharmaceutical Journal 23(2): 187-194, 2020
, Matthew I. D’Entremont, J. Adam Law
Canadian Journal of Anesthesia/Journal canadien d'anesthésie, Volume 67, pp 1670-1672; https://doi.org/10.1007/s12630-020-01748-8

The publisher has not yet granted permission to display this abstract.
F. Fayed, E. Abdelkarim, M. Morsy
Published: 13 June 2020
by BMJ
Annals of the Rheumatic Diseases, Volume 79, pp 1896.3-1896; https://doi.org/10.1136/annrheumdis-2020-eular.4681

Abstract:
Background:Stress is a risk factor of various diseases including autoimmune diseases. Autoimmune diseases are one of the leading causes of morbidity in young adults.(1)Examination stress is a main concern nowadays due to the study style, lack of preparation, doctor- student relationship and family pressure.(2)The previous studies declared that stress may causes neuroendocrinal changes leading to immune dysregulations and cytokines production.(3)Objectives:The aim of study is to scope the light on the importance of stress as a predisposing factor in autoimmune disease flares particularly Examination stress.Methods:A three-year (2017-2019) cross-sectional prospective study conducted on 1365 students who presented to the Alexandria University rheumatology clinic during examinations. Clinical assessments, routine investigations, activity markers, activity indices, stress and anxiety questionnaires and perceived stress scale (PSS) were applied to all patients during consecutive visits.Results:Through 5800 visits in three years during examination sessions, patients age ranged from (17 -25) years with 76% females and 24% males. They grouped into SLE (31.35%), Rheumatoid arthritis (RA) (37.28%), Fibromyalgia (13.91%), FMF (2.63%), Ankylosing Spondylitis (1.75%), Psoriatic arthritis (0.73%), systemic sclerosis (0.58%), and undifferentiated connective tissue (11.73%). According to SLE patients, 43.92% were newly diagnosed whilst 54.16% of previously diagnosed SLE presented with Flare in particular lupus nephritis (56.33%), arthritis (43.22%), hematological (49.76%) and serositis (21.36%). Interestingly, RA patients who newly diagnosed were 35.16% of total RA patients while 42.42% of previously diagnosed RA patients presented with moderate and high DAS-28 due to incompliance with treatment in (64.37%) of patients, (11.53% on biological, 88.47% on conventional treatment). In addition, (49.36%) of FMF presented in recent attacks. It was also found that Arthralgia, bone aches and sleep deprivation are the main complaints. Concerning, A High perceived stress scale (PSS) was associated with High DAS28 and SLEDI-2K scores. (rs= 0.723, 0.865) (PConclusion:Examination stress is one of triggering factor for autoimmune disease flares. It is associated with high disease activities and ruthless outcomes.References:[1]Cooper, G. S., & Stroehla, B. C. The epidemiology of autoimmune diseases. Autoimmunity Reviews,2003:2(3);119–25.[2]Archana kumari, jagrati jain. Examination stress and anxiety: a study of college students. Global Journal of Multidisciplinary Studies 2014:4:ISSN 2348-0459Disclosure of Interests:None declared
Ruyuan Zhu, Beibei Chen, , Tianyi Miao, Li Rui, Hao Zhang, Bingke Xia, Yu Li, Sihua Gao, Xiang-Dong Wang, et al.
Published: 12 June 2020
Pharmacological Research, Volume 159; https://doi.org/10.1016/j.phrs.2020.104966

The publisher has not yet granted permission to display this abstract.
Nguyen Thi Thu Hoai, Nguyen Thuy Duong, Bui Thanh Tung, Dao Thi Vui, Dang Kim Thu
VNU Journal of Science: Medical and Pharmaceutical Sciences, Volume 36; https://doi.org/10.25073/2588-1132/vnumps.4214

Abstract:
Herbal extract, rich with natural compounds, has been used for medicinal purpose such as treating neurological disorders such as cognitive defection for a long period of time, often without significant adverse effects. We compared AChE and BuChE – inhibition effect of total extracts and fractions of Huperzia serrata (Thunb.) Trevis. with alcaloid-rich extract. Our samples were subjected under supersonic extraction with ethanol 50o as solvent and fractionally extracted with n-hexane, EtOAc and n-butanol, respectively; alcaloid-rich extract was collected simutaneously. Ellman’s method was used to assay AChE and BuChE inhibition activity. Results: Alcaloid-rich extraction proved to be the superior AChE inhibiting agent, its activity nearly 6 fold of the most active Huperzia serrata extraction with IC50 value of 7.93 (5.43-10.98) µg/ml. While the fractions as well as the total extract did not provide any BuChE inhibition activity, alcaloid-rich extract showed weak ability (IC50 at 76.67 (64.78 – 91.84) µg/ml). Overall, the superior enzyme inhibition effect of alcaloid-rich extract might open a new approach in preventing and treating neurological disorders such as alzheimer’s. Keywords Huperzia serrata (Thunb.) Trevis, alcaloid, Acetylcholinesrerase inhibitors (AChE); butyrylcholinesterase (BuChE), Alzheimer. References [1] Dos Santos Picanco, Leide C et al., Alzheimer's disease: A review from the pathophysiology to diagnosis, new perspectives for pharmacological treatment, Current medicinal chemistry 25(26) (2018) 3141 - 3159. https://doi.org/10.2174/0929867323666161213101126.[2] B.M. McGleenon, K.B. Dynan, A.P. Passmore, Acetylcholinesterase inhibitors in Alzheimer's disease, British journal of clinical pharmacology 48(4) (1999) 471-480. https://10.1046/j.1365-2125.1999.00026.x.[3] Agneta Nordberg, Clive Ballard, Roger Bullock, Taher Darreh-Shori, Monique Somogyi, A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer’s disease, The primary care companion for CNS disorders 15(2) (2013). https://10.4088/PCC.12r01412.[4] N.M. Ha, V.V. Dung et al., Report on the review of Vietnam’s wildlife trade policy, 2007.[5] D.H. Bich, et al., Medicinal plants and medicinal animals in Viet Nam. Science and Technics Publishing House 1 (2011) 896-897 (in Vietnamese).[6] Jia-Sen Liu, Yuan-Long Zhu, Chao-Mei Yu, You-Zuo Zhou, Yan-Yi Han, Feng-Wu Wu, Bao-Feng Qi, The structures of huperzine A and B, two new alkaloids exhibiting marked anticholinesterase activity. Canadian Journal of Chemistry 64(4) (1986) 837-839. https://doi.org/10.1139/v86-137.[7] Takuya Ohba, Yuta Yoshino et al., Japanese Huperzia serrata extract and the constituent, huperzine A, ameliorate the scopolamine-induced cognitive impairment in mice, Bioscience biotechnology and biochemistry 79(11) (2015) 1838-1844. https://doi.org/10.1080/09168451.2015.1052773.[8] Ju-Yeon Park, Hyuck Kim et al., Ethanol Extract of Lycopodium serratum Thunb. Attenuates Lipopolysaccharide-Induced C6 Glioma Cells Migration via Matrix Metalloproteinase-9 Expression, Chinese Journal of Integrative Medicine 24(11) (2018) 860-866. https://doi.org/10.1007/s11655-017-2923-9.[9] M. Maridass, G. Raju, Investigation of phytochemical and antimicrobial activity of Huperzia species, Pharmacologyonline 3 (2009) 688-692.[10] George.L.Ellman, K.Diane Courtney, et al., A new and rapid colorimetric determination of acetylcholinesterase activity, Biochemical Pharmacology 7(2) (1961) 88-95. https://doi.org/10.1016/0006-2952(61)90145-9.[11] Paul T Francis, et al., The cholinergic hypothesis of Alzheimer’s disease: a review of progress. Journal of Neurology, Neurosurgery & Psychiatry, 66(2) (1999) 137-147. http://dx.doi.org/10.1136/jnnp.66.2.137.[12] Prerna Upadhyaya, Vikas Seth, Mushtaq Ahmad, Therapy of Alzheimer’s disease: An update, African Journal of Pharmacy and Pharmacology 4(6) (2010) 408-421.[13] Hachiro Sugimoto, Hiroo Ogura, et al., Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor, The Japanese journal of pharmacology 89(1) (2002) 7-20.[14] N.T.K. Thu, et al., Acetylcholinesterase and butyrylcholinesterase inhibition effect of fractions extract of Huperzia serrata (Thunb.) Trevis. The journal of Pharmeceutical 56(11) 49-53 (in Vietnamese).[15] Xiaoqiang Ma, Changheng Tan, et al, Is there a better source of huperzine A than Huperzia serrata? Huperzine A content of Huperziaceae species in China. J Agric Food Chem, 53(5) (2005)1393-8. https://doi.org/10.1021/jf048193n.[16] Ya-Bing Yang, Xue-Qiong Yang, et al., A New Flavone Glycoside from Huperzia serrata. Chinese Journal of Natural Medicines 6(6) (2008) 408-410.[17] G.T. Ha, R.K. Wong, Y. Zhang, Huperzine a as potential treatment of Alzheimer's disease: an assessment on chemistry, pharmacology, and clinical studies, Chemistry & biodiversity 8(7) (2011) 1189-1204. https://doi.org/10.1002/cbdv.201000269.[18] H.Y. Zhang, X.C. Tang, Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease, Trends in pharmacological sciences 27(12) (2006) 619-625. https://doi.org/10.1016/j.tips.2006.10.004.[19] Y. Wang, X.C. Tang, H.Y. Zhang, Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice, Journal of neuroscience research 90(2) (2012) 508-517. https://doi.org/10.1002/jnr.22775.[20] C.Y. Wang, et al., Huperzine A activates Wnt/β-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model, Neuropsychopharmacology 36(5) (2011) 1073-1089. https://doi.org/10.1038/npp.2010.245.[21] R.K. Gordon, et al., The NMDA receptor ion channel: a site for binding of Huperzine A, Journal of applied toxicology 21(S1) (2001) S47-S51. https://doi.org/10.1002/jat.805.[22] M. Rafii, et al., A phase II trial of huperzine A in mild to moderate Alzheimer disease,...
Alex Belsey
Published: 29 February 2020
Abstract:
This chapter examines Keith Vaughan’s attempt to curate his own legacy with the publication of his self-edited Journal & Drawings (1966). At intervals throughout the 1950s he had been revisiting the wartime volumes of his journal and by the early 1960s his opinion of them had changed from scornful critique to aching nostalgia, so in 1965 he commenced (at the behest of Alan Ross) a long process of self-editing journal entries from 1939 to present to be published alongside previously unseen drawings and photographs. The first section of this chapter considers Vaughan’s practices of re-reading his journal and examines his typescripts as evidence of the extensive revisions made to the content and style of specific journal entries for publication. The second section reveals how Vaughan shaped the text of Journal & Drawings through processes of selecting, re-writing, and even devising entirely new material, resulting in a streamlined narrative at once confessional yet choreographed. The third section of this chapter surveys the placement of drawings and photographs in Journal & Drawings and how words and images work to communicate the interrelations between his journal-writing and visual practice – and to fix and control the image of ‘Keith Vaughan’.
, Nasreen Begum, Asm Anawrul Kabir, Khondoker Wasee Ahmed, Mahbuba Sharmin, Sumanta Kumar Saha, Bodroddoza Bayazid, Shahriar Hasan
Northern International Medical College Journal, Volume 10, pp 393-396; https://doi.org/10.3329/nimcj.v10i2.45475

Abstract:
Background: Vitamin D deficiency is one of the most neglected public health issues all over the world. Near about 1 billion people round the world suffer from vitamin D deficiency. Most of the countries in Asia having high prevalence of vitamin D deficiency. Objective: To find the vitamin D level among the patients attending in a private chamber in Dhaka city Methodology: A cross sectional observation study was carried out in a renowned diagnostic center of Dhaka city from July 2017 to June 2018. A sample of 1523 adult patients aged 18 years and above, presented with generalized body aches and pains selected conveniently for the study. Blood samples were taken and serum vitamin D levels were measured. In this study, vitamin D concentration below10 ng/ml was considered as vitamin D deficiency, 20–30 ng/ml as insufficiency, and 30–100 ng/ml as vitamin D sufficient. Data were analyzed by using SPSS version 22. Result: Out of 1523 patients 69.5% were women and 30.5% men. Urban and rural distribution was 63.16% and 36.84% respectively. Among the participants vitamin D deficiency was 54%, 35.8% vitamin D insufficient, and only 9.8% had normal level of vitamin D, regarding age specific deficiency highest 71.8% was in 71-80 years age group. Out of 1058 female 39.5% were vitamin D deficient, 45.6% had insufficient vitamin D level. Only 14.9% female were found normal level. Age specific deficiency found highest 63.8% in 61-70 year age group. On the other hand out of 465 male participants, 24% were vitamin D deficient, 34% were insufficient and 42% had normal level vitamin D. Highest deficiency 42.5% found in age group 61-70years. Conclusion: Considering the study result deficiency was higher among female than male. In female vitamin D deficiency increased after age of 31year. Vitamin D deficiency found highest in old age and middle age group. Over all age specific deficiency found significantly highest in 71 – 80 years. In both male and female Vitamin D deficiency was found highest above 61years of age. Northern International Medical College Journal Vol.10 (2) Jan 2019: 393-396
Atike Yilmaz, Hüseyin Kirimoğlu
Kastamonu Eğitim Dergisi; https://doi.org/10.24106/kefdergi.3564

Abstract:
Tr en Bu araştırma, Türkiye Bedensel Engelliler Spor Fede-rasyonu, Oturarak Voleybol oyuncularının özgüven düzey-lerini tespit etmek amacına odaklanmıştır. Katılımcıların öz güven düzeylerini belirlemek için araştırmacılar tarafından geliştirilen “Kişisel Bilgi Formu” ve Akın (2007) tarafından geliştirilen “Öz Güven Ölçeği” kullanılmıştır. Çalışmada genel tarama modeli kullanılmıştır. Araştırma grubu, Türki-ye Bedensel Engelliler Spor Federasyonu tarafında Alanya ilinde düzenlenen Bedensel Engelliler Oturarak Voleybol Müsabakalarına katılan genel toplamda 92 bedensel engelli sporcu içerisinden çalışmamıza gönüllü olarak katılmayı kabul eden, 52’si erkek, 6’sı kadın olmak üzere genel top-lamda 58 oturarak voleybol oyuncusundan oluşmuştur. Verilerin analizinde Mann-Whitney U ve Kruskal Wallis H testleri kullanılmıştır. Elde edilen verilere göre, kardeş sayısı, algılanan gelir düzeyi, lisans yaşı açılarından, oyun-cuların öz güven düzeylerinin istatistiksel açıdan anlamlı farklılık oluşturmadığı tespit edilirken, katılımcıların cinsi-yetleri ile iç özgüven düzeyleri ortalamaları arasında an-lamlı farklılık vardır. Yine katılımcıların, cinsiyetleri ile dış özgüven düzeyleri ortalamaları arasında anlamlı farklılık bulunmuştur. Katılımcıların farklı bir spor branşı ile uğraş-ma durumu açısından, faklı bir spor branşı ile uğraşanların iç öz güven düzeyleri, uğraşmayanlara oranla anlamlı düzeyde yüksek bulunmuştur. Bunun karşın farklı bir spor branşı ile uğraşma durumu açısından dış öz güven seviyele-rinde anlamlı farklılık tespit edilememiştir. Ancak genel öz güven puanları açısından, farklı bir spor branşı ile uğraşan katılımcıların, genel öz güven düzeyi, farklı bir spor branşı ile uğraşmayanlara oranla anlamlı düzeyde farklılık gös-termiştir (pThis research focuses on determining the level of self-confidence of Sitting Volleyball players of The Turkish Sports Federation for the Physically Disabled. The "Per-sonal Information Form" developed by the researchers and the "Self-Confidence Scale" developed by Akın (2007) were used in the study. The study group was consisted of 58 sitting volleyball players in total; 52 male, 6 female, who agreed to participate voluntarily from a total of 92 physical-ly challenged athletes who participated in Physically Disa-bled Sitting Volleyball Competitions organized by TSFPD in Alanya province. In the evaluation of the data analysis was used. Mann-Whitney U and Kruskal Wallis H tests. Accord-ing to the data, while it was determined that there was no statistically significant difference in the self-confidence levels in terms of the number of siblings, perceived income level and license age, there was a significant difference between participants' genders and levels of inner self-confidence. There was also a significant difference between the participants' genders and external self-confidence lev-els. In the external self-confidence, male participants re-ported higher levels of external self-confidence. Another finding from the study was that the inner self-confidence levels of participants, who deal with another sports branch, were significantly higher than those who doesn’t. However, no significant difference was found in the level of external self-confidence in terms of dealing with a different sports branch. Though, in terms of general self-confidence scores, the level of general self-confidence of the participants’ dealing with a different sports branch differed significantly (p Anahtar Kelimeler tr en Oturarak Voleybol, Öz Güven : Sitting Volleyball, Self-Confidence Kaynakça Akın, A. (2007). Özgüven Ölçeğinin Geliştirilmesi ve Psikometrik Özellikleri. Abant İzzet Baysal Üniversitesi Eğitim Fakültesi Dergisi, 2:165-175. Bandura, A. (1989). Sixtheories of child development. Annals of Child Development, 6,1-60. Bostancı, Ö., Karaduman, E., & Şebin, K. (2018). Dağcıların Özgüven Seviyelerinin Çeşitli Değişkenler Açısından İncelenmesi. Beden Eğitimi ve Spor Bilimleri Dergisi, 20(3), 144-153. Can, Y., & Kaçay, Z. (2016). Sporcu kimlik algısı ile cesaret ve özgüven duyguları arasındaki ilişkilerin incelenmesi. Journal of Human Sciences, 13(3), 6176-6184. doi:10.14687/jhs.v13i3.4353. Erdemir, İ., Tekin, H.A., Savucu, Y., & Tüfekçioğlu, E. (2009). Birinci ve İkinci Lig Tekerlekli Sandalye Basketbolcularında Performansı Etkileyen Faktörler. F.Ü.Sağ.Bil.Tıp Dergisi, 23 (2): 85 – 89. Ergun, N., & Bayramlar, K. K. (2011). Engelsiz Bir Yaşam İçin Egzersiz ve Spor. Ankara: Merdiven Tanıtım. Esatbeyoğlu, F. (2016). Yeti Yitimi Olan Gençler için Fiziksel Aktivitenin Önemi. Baran, A. G. ve Çakır, M. (Edt.) İnter-disipliner yaklaşımla gençliğin umudu toplumun beklentileri. Hacettepe Üniversitesi Yayınları. S. 261-282. Feltz, D. L. (1988). Self-confidence and sports performance. Exercise and Sport Sciences Reviews, 16(1), 423- 458. Feltz, D. T. & Lirgg, C. D. (2001). Self Efficacy Beliefs On Athletes, Teamandco Aches. (In R. N. Singer, H. A. Hausenblas, ve C. Janelle (Eds.). Handbook of sportpsychology(pp.340-361). New York: John Wiley&Sons Kabasakal, K. (2007). Zihinsel Engellilik, Zihinsel, Ruhsal, Duygusal Engellilik, Lokomotif Medya, Ünimat Ofset Matbaası, Konya. Kalbli, K. (2007). Comparative Study On The Serves Of Volleyball And Sitting Volleyball Games. Semmelweis University Facul-ty Of Physical Education And Sport Sciences, Hungary, 12th Annual Congress Of The Ecss, 11–14 July Jyvaskyla Finland. Karasar, N. (2005). Bilimsel Araştırma Yöntemleri, Nobel Yayınları. Ankara. Mutlu, T. O., Öntürk, Y., Karafil, A. Y., Zorba, E., Bingöl, E. & Kaya, K. ( 2016). Analysıs On The Self-Confıdence Per-ceptıons Of Unıversıty Students Playıng Tennıs In Sports. General Informatıon About Sstb Journal, 18, 17-28. Özbek, S., Yoncalık, M. T. & Alıncak, F. (2017). Sporcu ve Sedanter Lise Öğrencilerinin Özgüven Düzeylerinin Karşılaştırıl-ması (Kırşehir İli Örneği). Gaziantep Üniversitesi Spor Bilimleri Dergisi, 2(3), 46-56. Özyürek, M. (1982). Normal Öğrencilerle Birlikte ve Ayrı Eğitilen Ortopedik Arızalı Öğrencilerde Benlik Kavramı ve Denetleme Odağı. Ankara Üniversitesi Eğitim Fakültesi, Ankara, Yayınlanmamış Doçentlik Tezi. Pedro, L. F., Chatzisarantis N. & Pedro M.C.M.J. (2007). Precompetitive Anxiety and Self-Confidence in Athletes with Disabil-ity. Perceptual and Motor Skills, 105 (1). Schunk, D. H. (1985). Self-Efficacy and Classroom Learning. Psychology in the Schools, 22:208-223. Skučas, K. (2014). Athletıc identity and self-esteem of wheelchair basketball players. Baltic Journal Of Sport & Health Scienc-es,95(4). World Health Organization (2001). The International Classification of Functioning, Disability and Health (ICF). Gene-va:WHO. http://www.who.int/classifications/icf/en/ Zerger, M. (2008). A Study of Movement İn Sitting Volleyball. A Thesis Submitted To The Gradua The Faculty İn Partıal Fulfill-ment Of The Requirements For The Degree of Master of Science Kinesiology and Health Studies Unıversıty Of Central Oklohoma Edmond. Maggill, R. A. (1980). Motor Learning. 66-124, Wm. C. Brown Comp. Pub. USA. Martens, R. ( 1990). Seccessful Coaching. Second Edition, Leisure Press, Champaign, IIinois. Civan, A., Özdemir, İ., Taş, İ., & Çelik, A. (2012). Bedensel engelli ve engelli olmayan tenis sporcularının durumluk ve sürekli kaygı düzeylerinin karşılaştırılması. Selçuk Üniversitesi Beden Eğitimi ve Spor Bilim Dergisi, 14(1), 83-87. Ayrıntılar Birincil Dil tr Konular Eğitim, Bilimsel Disiplinler Yazarlar Yazar: Atike YILMAZ Kurum: MUŞ ALPARSLAN ÜNİVERSİTESİÜlke: Turkey Yazar: Hüseyin KIRIMOĞLU Kurum: MUŞ ALPARSLAN ÜNİVERSİTESİÜlke: Turkey Tarihler Yayımlanma Tarihi : 31 Ocak 2020 Kaynak Göster Bibtex @araştırma makalesi { kefdergi680052, journal = {Kastamonu Eğitim Dergisi}, issn = {}, eissn = {2147-9844}, address = {Aktekke Mah. Kastamonu eğitim Fakültesi Kastamonu}, publisher = {Kastamonu Üniversitesi}, year = {2020}, pages = { - }, doi = {10.24106/kefdergi.3564}, title = {Oturarak Voleybol Oyuncularının Öz Güven Düzeylerinin Tespiti}, key = {cite}, author = {YILMAZ, Atike and KIRIMOĞLU, Hüseyin} } APA YILMAZ, A , KIRIMOĞLU, H . (2020). Oturarak Voleybol Oyuncularının Öz Güven Düzeylerinin Tespiti. Kastamonu Eğitim Dergisi , , . DOI: 10.24106/kefdergi.3564 MLA YILMAZ, A , KIRIMOĞLU, H . "Oturarak Voleybol Oyuncularının Öz Güven Düzeylerinin Tespiti". Kastamonu Eğitim Dergisi (2020 ): Chicago YILMAZ, A , KIRIMOĞLU, H . "Oturarak Voleybol Oyuncularının Öz Güven Düzeylerinin Tespiti". Kastamonu Eğitim Dergisi (2020 ): RIS TY - JOUR T1 - Oturarak Voleybol Oyuncularının Öz Güven Düzeylerinin Tespiti AU - Atike YILMAZ , Hüseyin KIRIMOĞLU Y1 - 2020 PY - 2020 N1 - doi: 10.24106/kefdergi.3564 DO - 10.24106/kefdergi.3564 T2 - Kastamonu Eğitim Dergisi JF - Journal JO - JOR SP - EP - SN - -2147-9844 M3 - doi: 10.24106/kefdergi.3564 UR - https://doi.org/10.24106/kefdergi.3564 Y2 - 2019 ER - EndNote %0 Kastamonu Eğitim Dergisi Oturarak Voleybol Oyuncularının Öz Güven Düzeylerinin Tespiti %A Atike YILMAZ , Hüseyin KIRIMOĞLU %T Oturarak Voleybol Oyuncularının Öz Güven Düzeylerinin Tespiti %D 2020 %J Kastamonu Eğitim Dergisi %P -2147-9844 %R doi: 10.24106/kefdergi.3564 %U 10.24106/kefdergi.3564 ISNAD YILMAZ, Atike , KIRIMOĞLU, Hüseyin . "Oturarak Voleybol Oyuncularının Öz Güven Düzeylerinin Tespiti". Kastamonu Eğitim Dergisi (Ocak 2020): - . https://doi.org/10.24106/kefdergi.3564 AMA YILMAZ A , KIRIMOĞLU H . Oturarak Voleybol Oyuncularının Öz Güven Düzeylerinin Tespiti. Kastamonu Eğitim Dergisi. 2020; -. Vancouver YILMAZ A , KIRIMOĞLU H . Oturarak Voleybol Oyuncularının Öz Güven Düzeylerinin Tespiti. Kastamonu Eğitim Dergisi. 2020; -. Tam Metin ( )
, Shawn Hochman,
Published: 22 January 2020
Frontiers in Neural Circuits, Volume 13; https://doi.org/10.3389/fncir.2019.00084

Abstract:
Editorial on the Research TopicNeuromodulatory Control of Spinal Function in Health and Disease The classical ionotropic transmitters glutamate/ACh (acetylcholine) and glycine/GABA (gamma-amino butyric acid) are, respectively, responsible for the primary excitatory and inhibitory synaptic actions within spinal cord anatomical circuits, be they simple reflexes as the monosynaptic stretch reflex (and its reciprocal inhibition of antagonists), or more distributed and integrated networks along autonomic, sensory, and motor systems. The selection and complex spatiotemporal recruitment of intrinsic spinal circuits (e.g., locomotion) are profoundly sculpted by neuromodulation acting both at pre- and post-synaptic levels. Neuromodulation denotes to the ability of neurons to alter their electrical and synaptic properties in response to intracellular biochemical changes. Neuromodulation commonly occurs via activation of metabotropic (G protein-coupled) receptors that alter signal transduction pathways. Neuromodulators function to modulate rather than mediate activity and represent a broad class of neuroactive substances. By altering the cellular/synaptic properties of individual neurons embedded in networks, neuromodulators profoundly alter the operation of neural circuits and behavior. They provide flexibility in circuit selection and strength to allow the nervous system to adapt neural output according to the functional requirements and/or demands of the individual to achieve the desired behavioral state. At times, it appears that the neuromodulators have a more primary function in activating and controlling complex networks than the term “modulator” would tend to imply. Neuromodulatory transmitter systems undoubtedly affect all spinal cord functional systems including locomotion, respiration (via phrenic and other respiratory motoneurons), posture, balance, fine movements, autonomic functions (including control of bowel, bladder, blood pressure, and heart rate), reflexes, and sensory information processing (nociception, etc.). Since many neuromodulatory transmitter systems (e.g., such as those releasing monoamines) originate from neurons outside of the spinal cord, injuries to the spinal cord will necessarily damage their descending projections in addition to other non-neuromodulatory pathways controlling the anatomical network. Such injuries will therefore affect not only the initiation and control of spinal networks, but also the ability to adjust their output according to ongoing functional demands. The present Research Topic includes review and original research articles that seek to shed light on the neural processes underlying the neuromodulatory control of spinal cord function in health and disease. This Research Topic consists of 24 articles on various aspects of Spinal Cord research contributed by 105 authors. The assembled contributions are summarized below in three thematic categories: (i) locomotion, (ii) descending and segmental pathways, and (iii) disease/injury. The mesencephalic locomotor region (MLR) activates spinal locomotor generating neurons via pathways originating in the medial reticular formation and descending through the ventral funiculus. There is evidence that monoaminergic pathways are also activated both during MLR-evoked fictive locomotion and during spontaneous or voluntary locomotion. In the present original research, Noga et al. measured in real time, by fast-cyclic in vivo voltammetry, the release of the monoamines serotonin (5-HT) and norepinephrine (NE) in the decerebrate cat's lumbar spinal cord during MLR-evoked fictive locomotion. The time course, the spinal locations and the concentration of the release of these two monoamines were mapped. Monoamine release was observed in dorsal horn, intermediate zone/ventral horn. The results demonstrate that spinal monoamine release is modulated on a timescale of seconds, and that the concentrations are high enough to strongly activate various receptors subtypes and further suggest that monoamine action is, in part, mediated by extrasynaptic neurotransmission in the spinal cord. The review by Sharples et al. focuses on the role of dopamine in the spinal control of locomotion in vertebrates. It summarizes the biochemistry, pharmacology, anatomy, and function of dopamine (and to a lesser extent other monoamines) in the locomotor networks of various vertebrates including fish (lamprey and zebrafish), amphibians (larval xenopus), and mammalians (rodents). A brief discussion of the effects of dopamine on rhythmicity in invertebrates is also provided. Parallels are drawn with both noradrenergic and serotonergic systems. New experimental approaches (optogenetics, pharmacogenetics) together with more traditional approaches (intrathecal administration/cell transplantation) to the study of dopaminergic function and/or the treatment of gait disorders following SCI are discussed. Sensorimotor transformations are essential for control of goal-directed behavior and interaction with the outside world. The review by Daghfous et al. examines how the vertebrate CNS integrates sensory signals to generate locomotor behavior by examining the pathways and mechanisms involved in the transformation of cutaneous and olfactory inputs into motor output in the lamprey. The review also explores how serotonin modulates the system through actions on both sensory inputs and motor output. This timely review of mechanisms for sensory control of locomotion is also very thorough and helpful to the uninitiated in this area of lamprey pharmacology. Wienecke et al. studied the interaction between blood pressure, respiration, and locomotor activities in decerebrate cats. They observed periodic variation (Mayer waves) in blood pressure, which was synchronized with respiratory and locomotor drive potentials recorded in hindlimb motoneurons. The report demonstrates the intricate interrelations between respiratory networks and hindlimb locomotor networks. They conclude that the respiratory drive in hindlimb motoneurons is transmitted via elements of the locomotor central pattern generator. The rapid modulation related to Mayer waves suggests the existence of a more direct and specific descending modulatory control than has previously been demonstrated. The possibility that monoaminergic drive to the spinal cord may mediate the occurrence of Mayer waves is discussed. In addition to the classical monoamine neuromodulatory transmitters, another group of endogenous monoamines, the trace amines (TAs), may play a role in neuromodulatory actions within the nervous system. They share structural, metabolic, physiologic, and pharmacologic similarities to the classical monoamines and are synthesized from the same precursor amino acids. The paper by Gozal et al. provides evidence for the presence of trace amine synthetic enzymes, trace amine-associated receptors (TAARs), and TAs in the spinal cord. Furthermore, the authors demonstrate effects of TAs on spinal neuronal networks, effects that have a pharmacological profile distinct from that of more classical monoamine neurotransmitters. This data indicates that TAs may function as an intrinsic spinal monoaminergic modulatory system capable of promoting recruitment of locomotor circuits independent of the descending monoamines. These actions support their known sympathomimetic function. This study will likely stimulate further research in this area. How pattern generators are modulated in the absence of descending control from the brain is highly important for understanding the neural control of movement as well as for developing therapeutic approaches to improve mobility of SCI patients. The review by Cherniak et al. summarizes recent studies of sacral relay neurons with lumbar projections and evaluates their role in linking the sacral and thoracolumbar networks during different motor behaviors. They show that: (1) the activation of the locomotor central pattern generators through sacral sensory input is mediated by a heterogeneous group of dorsal, intermediate and ventral sacral-neurons with ventral and lateral ascending funicular projections, and (2) the rhythmic excitation of lumbar flexor motoneurons, produced by exposing the sacral segments to alpha-1 adrenoceptor agonists, is mediated exclusively by ventral clusters of sacral-neurons with lumbar projections through the ventral funiculus. The mechanisms and physiological implications of their findings are discussed. Given the recent increase in interest in combinatorial approaches to increasing function after spinal injury, this review of neural mechanisms contributing to the sacro-caudally activated lumbar motor rhythm is timely and should be of general interest to spinal cord rehabilitation, plasticity, and regeneration researchers. The monoamines serotonin (5-HT) noradrenaline (NA) and dopamine (DA) are known to reconfigure spinal circuits and facilitate expression of motor rhythms including locomotion. Beliez et al. explore the common and differential actions of these monoamines in coordinating rhythmic locomotor-related output along the thoracolumbar-sacral axis in the in vitro isolated neonatal rat spinal cord. The monoamines generated similar ventral root motor rhythms in terms of period/duration as well as left/right and flexor/extensor phase relations but differed in motor burst amplitude and other temporal characteristics including intersegmental phase relationships. Observed differences likely relate differences in descending behavioral drive linked to separate recruitment of these neuromodulators. C-boutons are important cholinergic modulatory loci for state-dependent alterations in motoneuron firing rate. Deardorff et al. present an elegant and systematic review of the state of knowledge of one of the major inputs to spinal motoneurons, the C terminals. The authors take the reader on a historical journey from the initial identification of the C-boutons and then introduce the unique molecular organization of the signaling ensemble surrounding the C-bouton synapse and its effect on the firing frequency of the spinal motoneuron via its effect on the post-spike after hyperpolarization. They then describe the C-bouton itself and its cell of origin, and its cholinergic identity and circuitry. Finally, they propose a possible mechanism by which the activity of C-bouton may play a role in enhancing firing rate during periods of increased excitatory drive, whilst also acknowledging alternative explanations. Bulbospinal systems may influence spinal neurons by classical synaptic and modulatory mechanisms and are involved in motor, sensory, and autonomic functions. Huma et al. report on the brainstem locations of cells of origin of bulbospinal pathways of the rat passing through the medial longitudinal fasciculus (MLF) and the caudal ventrolateral medulla (CVLM). Neurons were identified using anatomical tracing methods, their transmitter phenotypes identified, and their locations mapped onto brainstem diagrams. Cells that form pathways from the brainstem to the lumbar spinal cord passing through the MLF and CVLM for the most part, have overlapping spatial distributions. Although both populations contain crossing and uncrossing axons and similar proportions of excitatory and inhibitory axons, MLF and CVLM reticulospinal neurons have different spinal cord projections. Those in the MLF project more ventrally and are more likely to have direct motor functions than those in the CVLM. In contrast, CVLM projections are predominantly ipsilateral and concentrated within deep dorsal horn and intermediate gray but do not extend into motor nuclei or lamina VIII. CVLM pathway may function to coordinate activity of premotor networks. Johnson and Heckman provide a comprehensive review of the neuromodulatory control of the electrical properties of spinal motoneurons. Gain control of motoneuron output is important for generating the enormous range of forces required for the wide dynamic range of the normal movement repertoire. For diffuse neuromodulatory systems such as the monoaminergic projection to motoneurons, independent control of the gains of different motor pools is not feasible. In fact, the system is so diffuse that gain for all the motor pools in a limb likely increases in concert. Additionally, if there is a system that increases gain, probably a system to reduce gain is also needed. In this review, they summarize recent studies that show local inhibitory circuits within the spinal cord, especially reciprocal and recurrent inhibition, have the potential to solve both of these problems as well as constitute another source of gain modulation. In the manuscript by Becker and Parker, the lamprey model is used to compare cellular and synaptic properties of neurons above and below the lesion site in spinal cord injured (SCI) animals and in normal spinal cord of uninjured animals. They also examined the effects of lesioning on the modulatory effects of 5-HT. Based on their results, the authors suggest lesion specific changes occur in cellular and synaptic properties and in serotonin modulation. Therefore, pharmacological approaches to facilitate functional recovery should not be based on the effects reported in uninjured spinal cords. Although, the cellular and synaptic properties of motor neurons and spinal interneurons caudal to lesion site has been demonstrated previously by the same group, the strong differences between larval and adult stages justified the analysis in young adult lampreys. This is the first investigation on the effects of a spinal lesion on the modulatory effects of serotonin, and thus the study has the potential to make a strong contribution to the related literature. The original paper by Kou et al. describes the changes in the neural circuits in streptozotocin (STZ)-induced diabetic rats. Diabetic polyneuropathy (DPN) is one of the most common complications of diabetes mellitus but is not a single entity and encompasses several neuropathic syndromes, including sensory and motor defects. In this paper, the authors discuss both progressive mechanical allodynia and impaired locomotor activity. The alterations in myelinated nerve fibers, unmyelinated non-peptidergic nerve fibers, and peptidergic nerve fibers might be involved in the early stages of the development in DPN. The underlying mechanism of DPN might be addressed by the dysfunction of those subpopulations of afferents from the peripheral nervous system to the CNS. Both the allodynia and locomotor defects could be prevented and reversed by intrathecal insulin injection. The review by Fields and Mitchell addresses the well-known ability to exhibit plasticity of the neural system controlling breathing. The focus of the review is the less appreciated ability to exhibit metaplasticity, i.e., a change in the capacity to express plasticity (“plastic plasticity”). Key examples of metaplasticity in respiratory motor control, and our current understanding of mechanisms giving rise to spinal plasticity and metaplasticity in phrenic motor output is discussed. The metaplasticity is especially seen after pre-conditioning with intermittent hypoxia. This metaplasticity is not confined to the respiratory network but is also seen in motor networks involved in limb movements. The broad review by Ghosh and Pearse covers the promotion or facilitation of serotonergic signaling (including specific receptor systems) to enhance motoneuron excitability, stimulate CPG activity, and restore locomotor function following spinal cord lesions. These strategies have included pharmacological modulation of serotonergic receptors, through the administration of specific 5-HT receptor agonists, or by elevating the 5-HT precursor 5-hydroxytryptophan, which produces a global activation of all classes of 5-HT receptors. Another approach has been to employ cell therapeutics to replace the loss of descending serotonergic input to the CPG, either through transplanted fetal brainstem 5-HT neurons at the site of injury that can supply 5-HT to below the level of the lesion or by other cell types to provide a substrate at the injury site for encouraging serotonergic axon regrowth across the lesion to the caudal spinal cord for restoring locomotion. This approach is one direction at the forefront of research for generating putative interventional approaches for the treatment of SCI. Serotonergic systems are important for activation and modulation of locomotor circuits. However, locomotor circuits function differently following SCI that damages descending serotonergic (and other) pathways. The study by Strain et al. examines how the spinal cord adapts to sensory perturbations after injury when the serotonergic system is activated. They observed differences in the intralimb and interlimb coordination in SCI animals during serotonergic agonist-induced locomotor movements following sensory perturbation (range-of-motion restriction) in comparison to that seen in intact animals. Differences were observed for hindlimb and forelimb locomotor movements controlled by the distal and proximal (to spinal transection) areas of the spinal cord, respectively. The number of hindlimb steps observed following quipazine treatment was also significantly greater than intact controls, suggesting that the effects of quipazine treatment are related to “supersensitivity” of spinal segments distal to the site of injury. The results have implications for design of rehabilitation strategies to treat paralysis following SCI. The central molecular changes that might influence neurotrophic signaling pathways and modulate locomotor recovery and pain following SCI are investigated in the study by Strickland et al. Based on their previous work, they assess the expression of select miRNA species that might influence neurotrophic signaling pathways and functional recover following noxious peripheral electrical stimulation. The data show that uncontrollable nociception which activates sensorimotor circuits distal to the injury site, influences SCI-miRNAs and target mRNAs within the lesion site. SCI-sensitive miRNAs may well mediate adverse consequences of uncontrolled sensorimotor activation on functional recovery. However, their sensitivity to distal sensory input also implicates these miRNAs as candidate targets for the management of SCI and neuropathic pain. The long-term effectiveness of opiates for the treatment of pain is limited by the development of tolerance. This is thought to be the result of dysfunction of the μ-opioid receptor (MOR) and dopamine (D) receptor mediated second messenger pathways in the brain. Brewer et al. examine the role of the spinal cord in the development of tolerance since it plays a prominent role in the processing of nociceptive information and has both dopamine and MOR receptors in the dorsal horn. They reconfirm that D3 receptors are necessary for morphine analgesia in vivo and show for the first time that acute block of D3 receptors in the lumbar spinal cord prevents modulation of spinal reflex amplitude by morphine in vitro. Their data suggest that the D3 receptor modulates the MOR system in the spinal cord, and that a dysfunction of the D3 receptor can induce a morphine-resistant state. They propose that the D3KO mouse may serve as a model to study the onset of morphine resistance at the spinal cord level, the primary processing site of the nociceptive pathway. Involuntary movements and spasms may be the result of hyperactive motor networks. Regulation of such networks may be accomplished by intrinsic modulatory systems releasing transmitter such as purines. Such is the case for the ventral horn of the spinal cord. Carlsen and Perrier report on findings in the postnatal mouse that indicate that ventral horn astrocytes produce a tonic and a phasic inhibition of excitatory synaptic transmission in ventral horn neurons by releasing ATP. ATP is rapidly hydrolyzed to adenosine which then acts on presynaptic receptors and thereby decreases the probability of transmitter release. While a role of purinergic processes in synaptic modulation by astrocytes, at least in vitro, is established in diverse brain regions, this has been studied in less detail for (ventral) spinal neural circuits. Maturation of spinal motor circuits are influenced by the development and maintenance of descending serotonergic projections. The review article by Gackière and Vinay describes how 5-HT plays a role in the maturation of locomotor patterning and GABAergic synaptic transmission via actions on 5-HT2 and 5-HT7 receptors. They describe how postsynaptic inhibition is reduced after SCI and can be accounted for by a 5-HT2 receptor-mediated dysregulation of chloride transport in motoneurons. Evidence suggests that 5-HT enables restoration of locomotion after SCI via 5-HT receptors involved in the activation of signal transduction pathways that restore the chloride gradient needed for synaptic inhibition (5-HT2) and facilitate interneuronal activity (5-HT7). Sławinska et al. compare the effects of pharmacologic actions of 5-HT2 and 5-HT1A/7 receptor agonists, applied alone or in combination, on observed recovery of hindlimb treadmill locomotor function after low thoracic spinal transection in adult rats. Assessment of independent drug actions demonstrated that agonists act on complementary circuits: 5-HT2 receptors by facilitating motor excitability directly, and 5-HT1A/7 receptors by promoting locomotor circuit generating interlimb coordination. These findings add to earlier studies that support combined receptor targeting in locomotor recovery strategies while acknowledging limitations of potentially competing pharmacologic actions on afferent feedback and other intraspinal circuits. The neurotrophins nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) play an important role in neural circuit development and plasticity. Neurotrophins and their receptors are normally present in the spinal cord. Boyce and Mendell review how neurotrophic actions modify spinal sensory and motor circuit function including nociception, reflexes and stepping. Experimental interventions have targeted the introduction of exogenous neurotrophins to recapitulate their known trophic actions to improve function in disease states and after injury. This review focuses on more recent findings relevant to these translational issues. Grau et al. reviews the complex interplay of neuromodulatory factors that alter the capacity for activity-dependent adaptive reflex plasticity (spinal learning) and locomotor recovery after SCI. Adaptive or maladaptive behavioral outcomes are interpreted in relation to prior “priming” events that alter experimental outcome (meta-plasticity). Broadly, adaptive plasticity and motor recovery are tied to an up-regulation of BDNF signaling while maladaptive plasticity and motor deficits are associated with induction of a pro-inflammatory phenotype including expression of the cytokine tumor necrosis factor (TNF). An understanding of spinal cord neuromodulatory status after injury may provide a useful framework for training interventions in the clinical population. Previous experiments implicate cholinergic brainstem and spinal systems in the control of locomotion. Jordan et al. undertook a pharmacological exploration on the capacity of the spinal cholinergic system in modulating spinal locomotor networks with emphasis on capacity to facilitate recovery after SCI. Contrary to expectations, cholinergic (muscarinic) receptor activation disrupted locomotor recovery while receptor block (atropine) greatly facilitated expression of locomotion and recruitment of cutaneous reflexes. Their temporal correspondence supports the view that there is a tonic muscarinic inhibition of afferent feedback onto locomotor circuits thereby identifying a new opportunity for restoring locomotion after injury. Spinal motoneurons can exhibit differences in excitability early in development in amyotrophic lateral sclerosis (ALS). As serotonin, noradrenaline, and dopamine already modulate motor activity at early postnatal ages, Milan et al. used the SOD1G93A (SOD1) ALS mouse model to examine possible differences in their expression and function. In ventral horn, there were no differences in HPLC-detected content of these monoamines and metabolites between WT and SOD1 mice (P1 or P10). Similarly, no differences on the locomotor rhythm were observed in the SOD1 mouse when the monoamines were bath applied in the isolated spinal cord (P1–P3). However, NA generated a larger amplitude motor response in SOD1 mice, suggestive of adrenoceptor-based motor excitability increases at early postnatal ages. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. To the always helpful Frontiers team, whose organizational skills and understanding made possible this Research Topic. We would like to thank the authors and reviewers for their contributions to this Research Topic. Keywords: spinal cord, neuromodulation, monoamines, descending and segmental pathways, sensorimotor systems, locomotion, spinal cord injury, pain Citation: Noga BR, Hochman S and Hultborn H (2020) Editorial: Neuromodulatory Control of Spinal Function in Health and Disease. Front. Neural Circuits 13:84. doi: 10.3389/fncir.2019.00084 Received: 17 December 2019; Accepted: 30 December 2019; Published: 22 January 2020. Edited and reviewed by: Edward S. Ruthazer, McGill University, Canada Copyright © 2020 Noga, Hochman and Hultborn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Brian R. Noga, [email protected]
Published: 18 January 2020
Reactions Weekly, Volume 1787, pp 265-265; https://doi.org/10.1007/s40278-020-73903-y

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Alfred Maroyi
Journal of Pharmacy and Nutrition Sciences, Volume 10, pp 280-286; https://doi.org/10.29169/1927-5951.2020.10.05.14

Abstract:
Adenia gummifera (Harv.) Harms is a climber or liane widely used as traditional medicine throughout its distributional range in tropical Africa. Adenia gummifera occurs naturally in the Democratic Republic of Congo (DRC), Eswatini, Ethiopia, Kenya, Malawi, Mozambique, Seychelles, Somalia, South Africa, Tanzania, Uganda, Zambia and Zimbabwe. This study is aimed at providing a critical review of the medicinal uses, phytochemistry and biological activities of A. gummifera. Documented information on the medicinal uses, phytochemistry and biological activities of A. gummifera was collected from several online sources, which included Scopus, Google Scholar, PubMed and Science Direct. Additional information was gathered from pre-electronic sources such as book chapters, books, journal articles and scientific publications sourced from the university library. This study showed that the species is widely used as an emetic and a protective charm, and, as traditional medicine for infertility, sexually transmitted infections, gastro-intestinal infections, leprosy, respiratory infections, malaria and menstrual problems. Phytochemical compounds identified from the species include polyacetylenic diepoxide, alkaloids, flavonoids, flavonol, modeccin, proanthocyanidins, tetraphyllin, phenolics, polyphenol and tannins. Pharmacological research revealed that A. gummifera extracts and compounds isolated from the species have antibacterial, antifungal, acetylcholinesterase inhibitory (AChEI), anaesthetic, antioxidant, antiplasmodial and cytotoxicity activities. Future research on A. gummifera should focus on detailed phytochemical evaluations including toxicological, in vivo and clinical studies to corroborate the traditional medical applications of the species.
, Farhat Ullah, Abdul Sadiq, Myeong Ok Kim,
Published: 26 November 2019
Frontiers in Pharmacology, Volume 10; https://doi.org/10.3389/fphar.2019.01417

Abstract:
Editorial on the Research TopicNatural Products-Based Drugs: Potential Therapeutics Against Alzheimer’s Disease and Other Neurological Disorders Alzheimer’s disease (AD) and dementia are disorders of the aging population and becoming major health care burden worldwide due to unavailability of complete therapy. AD is the most frequent cause of dementia among 60% to 80% patients and has effected 45 million people globally which is estimated to triple by 2050 (Alzheimer’s, 2015). AD is a progressive, neurodegenerative disorder, characterized by behavioral turbulence, cognitive dysfunctions, imperfection in routine life activities, thus putting a huge socioeconomic burden on the health care system (Ahmad et al., 2015; Ali et al., 2017; Ayaz et al., 2017b). Among the pathophysiological hallmarks of the disease are the deficiency of vital neurotransmitter acetylcholine (ACh), deposition of amyloid plaques (Aβ), highly phosphorylated tau proteins, and imbalance in gluatamatergic system (Ayaz et al., 2017a; Khalil et al., 2018; Ovais et al., 2018a). Only five drugs are clinically approved for use, among which tacrine, galantamine, donepezil, and rivastigmine are cholinesterase inhibitors whereas the fifth one memantine is glutamatergic system modulator (Ayaz et al., 2015; Kamal et al., 2015). These drugs have limited efficacy and are associated with side effects like tacrine is hepatotoxic (Watkins et al., 1994). Currently, results from clinical trials performed in mild to moderate AD dementia have directed researchers to find more effective yet safe alternatives from natural sources (Yiannopoulou and Papageorgiou, 2013; Cummings et al., 2014; Ovais et al., 2018b). The plant kingdom consists of a huge number of species with tremendous diversity of bioactive metabolites with different chemical scaffold (Ramawat et al., 2009; Ahmad et al., 2016; Mir et al., 2019). According to reports, only 6% and 15% of medicinal plants have been systematically investigated for pharmacological and phytochemical potentials respectively (Choudhary, 2001). Since, natural products are synthesized by living organisms, they have naturally optimized properties for various biological functions including binding to specific bimolecules or target proteins. Comparison of the structural features of natural and compounds synthetic revealed that the major difference between the two sources originates from starting points which makes synthesis more easy. For instance, separation of chiral compounds is a big challenge, so usually molecules with less number of chiral centers is synthesized and favored (Jan et al., 2019; Hussain et al., 2019). Besides the less number of chiral centers, synthetic molecules have low molecular weight, high chain lengths, less number of Lipinski type H-bond receptors and donors, less oxygen, and more halogen, nitrogen and sulfer. Moreover, synthetic compounds have a high number of freely rotatable bonds, low number of rings, complex ring systems, high octanol-H2O2 partition coefficients (cLogP), and high degree of saturation. Consequently, due to less number of chiral centers and the abovementioned properties make the synthetic compounds less specific for biological targets. In contrast, natural compounds own selective biological properties due to affinity for specific proteins, have superior chemical diversity and biosynthetic complexity and more beneficial ADME/T properties (JI and ZHANG, 2008; Atanasov et al., 2015). Of particular interest regarding drug discovery is the use of ethnomedicinally important plants which are already proven to be safe and effective in human populations. This classical knowledge-based approach includes observation, description, and experimental investigations on bioactive metabolites. This approach is more effective, for instance, in the evaluation of 122 plant-derived compounds approved for clinical use as drugs, 80% originated from ethnomedicinal use of the same in local population for the same disease. Considering the “One-compound multiple-targets paradigm” for the development of more effective anti-AD drugs, natural compounds have got special interest. Despite partial success of the synthetic agents as potential multifunctional anti-AD drugs, the pharmacokinetics and safety issues are their major limiting factors (Fink et al., 1996). In contrast, natural compounds originated from medicinal plants or dietary sources have proven efficacy on multiple targets with broad safety profiles. For instance, curcumin has been reported to ameliorate cognitive dysfunction symptoms via modulation of inflammatory pathways in central nervous system, decline in free radicals load, chelate metals ions, inhibit Aβ aggregation, and thus is a potential multi-potent anti-AD candidate (Frautschy et al., 2001; Lim et al., 2001; Baum and Ng, 2004; Ono et al., 2004; Yang et al., 2005). Other flavonoids, including catechins, gossypetin, and myricetin, are also potential pleiotropic anti-AD agents, as they restrain Aβ aggregation, inhibit vital enzymes, and scavenge free radicals (Rice-Evans et al., 1996; Ayaz et al., 2019). Structure-activity relationship (SAR) studies on the flavonoids suggested that catechol moiety is a vital pharmacophore responsible for the anti-oxidant, anti-amyloid potentials of these compounds (Lashuel et al., 2002; Zhang, 2005). These findings suggest the development of catechol-based, multi-potent anti-AD drugs. Ethnopharmacology, a source of knowledge-driven drug discovery is playing a significant role in drug discovery from plants, animals, and fungi based on local or traditional knowledge of its pharmacological or toxicological properties in local population (Cordell and Colvard, 2005; Heinrich et al., 2009; Heinrich, 2010). Currently, about 119 drugs approved for clinical use are derived from medicinal plants. Among these, 74% were discovered from chemical identification of the constituents responsible for medicinal use by humans. These 119 drugs derived from plants are commercially produced from <90 species of plants. As there are more than 25000 species on the globe, their systematic analysis can lead to the development of more useful drugs against various diseases (Farnsworth, 1990). For the development of pharmaceuticals ranging from digitalis to vincristine, ethnopharmacological approach of drug discovery is proven extremely successful. The advent of high throughput, mechanisms-based bioassays coupled with plants candidates derived from painstaking ethnopharmacological research has lead to the discovery of novel pharmaceuticals almost in all major groups of drugs. The most important step in the drug discovery from natural sources is the selection of most suitable starting materials based on ethnobotanical, ethnomedicinal, and folkloric uses. Ethnopharmacological knowledge aid in drug discovery by providing three basic levels of information: 1. “As general indicator of non-specific bioactivity suitable for a panel of broad screens” 2. “As an indicator of specific bioactivity suitable for particular high-resolution bioassays” 3. “As an indicator of pharmacological activity for which mechanism-based bioassays have yet to be developed” (Cox, 1994). Galanthamine, a cholinesterase inhibitor is widely distributed alkaloid in several species of Amaryllidaceae family. The discovery and development of this modern drug for the management of AD is based on ethnopharmacological knowledge of its use in Europe (Heinrich and Teoh, 2004). The alkaloid was initially isolated from snowdrop (Galanthus spp., particulary Galanthus woronowii Losinsk.), and now obtained from several members of the same family including snowflake (Leucojum spp., particularly Leucojum aestivum L.), daffodil (Narcissus spp.) as well as from synthetic sources. The historical development of galanthamine till its approval for clinical use is comprised of several phases (Heinrich, 2010). According to some unconfirmed reports by a Bulgarian pharmacologist, people were applying common snowdrop on their foreheads to relieve nerve pain (Mashkovsky and Kruglikova-Lvova, 1951). Russian pharmacologists reported that in the early 1950s local villagers living at the foot of Ural mountains used wild Caucasian snowdrop for the treatment of disease in children they considered to be poliomyelitis (Shellard, 2000). In 1951, the first ever anti-cholinergic study on galanthamine was reported by Mashkovsky and Kruglikova-Lvova using rat smooth muscles (Heinrich, 2010). In 1952, Proskurnina and Yakovleva published the chemical structure of galanthamine isolated from G. woronowii (Paskov, 1986). In 1955, Mashkovsky published yet another cholinesterase inhibitory study on galanthamine but the source of galanthamine used was not reported. In 1956, Bulgarian pharmacologist D. Paskov reported the discovery of galanthamine from European daffodil and snowdrop, Galanthus nivalis. In 1960, an in-vivo cholinesterase inhibitory study was reported on galanthamine and in 1980s researchers working on AD started investigations of its therapeutic effects in detail. In 1990s, ganthamine was developed for clinical use and Sanochemia Pharmazeutika obtained the patency rights of galanthamine in 1996. In 2000, galanthamine was licensed for treatment of AD in UK, Iceland, Ireland, and Sweden. By now, it is used globally for the symptomatic relief of the AD. Unfortunately, galanthamine has limited efficacy and only delay the onset of severe symptoms but offer no complete eradication of the disease (Heinrich, 2010). Physostigmine also known as eserine is another alkaloid isolated from the calaabar bean Physostigma venenosum Balf. in 1864 (Mach et al., 2004). Physostigmine was used as anti-glaucoma drug for the first time in 1877 (Howes and Perry, 2011). And importantly, it was the first discovered AChE inhibitor which provided a foundation for the discovery and use in clinical conditions in 1980s. Owing to the presence of carbamate moiety it is a useful cholinesterase inhibitor and is used in glaucoma, AD, myasthenia gravis, and atropine-induced coma (Stilson et al., 2001). Despite of efficacy as AChE inhibitor, physostigmine has serious limitations including short half-life (30 min), narrow therapeutic index, gastrointestinal side effects it is not in clinical practice for the management of neurological disorders (Giacobini et al., 1987). However, the chemical structure of physostigmine provided a template for the development of more useful AChE inhibitors including rivastigmine (Orhan and Senol, 2013). Rivastigmine was licensed for clinical use in UK as a remedy in symptomatic relief of mild to moderate AD. Thus, these plant-derived alkaloids and AChE inhibitors are useful agents for the development drugs for the management neurological disorders (Griffith, 2008). This special topic was a platform for relevant experts in the field of ethnopharmacology and neuropharmacology to share cutting edge research and emerging literature-based reviews related to AD and other neurological disorders. The main objective of this research topic was to consider research and reviews related to the potential development of new drugs from natural sources against AD. A sufficient number of submissions focused on prevention to therapy of AD and other neurological disorders were considered. Gaiardo et al. reported the expression and possible role of dorsal hippocampus proteins in the memory enhancing properties of the standardized Ginkgo biloba extract in animal models. Authors used proteomic analysis to study the effect of G. biloba therapy on dorsal hippocampus proteins expression pattern which regulate CREB activity and synaptic plasticity implicated in long-term memory formation. G. biloba therapy at various doses was found to aid in retention of original memory, effect proteins involved in remodeling of cytoskeleton, size, shape, and stability of dendritic spines and formation of myelin sheath. Thus, G. biloba therapy modulates long-term memory via differential proteins expression which might act as important target in cognitive dysfunction disorders. G. biloba leaves extracts from different sources were also reported to rescued animals’ brain against Aβ42-induced neurotoxicity and electrophysiological alterations (Bader et al.). In a literature review, Javed et al. reported the inhibitory effects of phytochemicals on a pre-synaptic regulatory protein “α-Synuclein.” Literature clearly links the aggregation, oligomerization, and fibrillation of α-Synuclein with Parkinson’s disease, and inhibition of these processes is among the key strategies to counteract the disease. Plant extracts and isolated compounds were found to inhibit α-Synuclein fibril formation or aggregation and might be effective remedies against Parkinsonism related synucleinopathies . Owing to the significance of cholinesterase inhibitors therapy in AD, dos Santos et al. summarized the potential role of plant based cholinesterase inhibitors as lead anti-AD agents. Diverse group of extracts and phytochemicals including polyphenolics, alkaloids terpenes, and coumarins from 54 plant species and 29 families were evaluated. Alkaloids were found to be the most promising cholinesterase inhibitors, which required further studies including SAR analysis. Several authors employed scopolamine-induced AD model to check the neuroprotective effects of plants extracts and isolated compounds. Embelin an active constituent of Embelia ribes fruit and previously known cholinesterase inhibitor was tested by Bhuvanendran et al. for its anti-amnesic and nootropic effects in rat model at 0.3 to 1.2 mg/kg doses for 17 days. Cognitive defects were induced by 1 mg/kg of scopolamine for 9 days and the effects of embelin on cognition was assessed via elevated plus maze, novel object recognition paradigm. Moreover, gene expression for BDNF, CREB1, and mRNS levels of antioxidant enzymes (CAT, SOD1) were checked in hippocampus tissues of the animals. Sub-chronic treatment with embelin significantly improved recognition index and memory retention in behavioral models and increased inflection ratio in nootropic assay. Further, embelin increased the expression of BDNF, CREB1, CAT, SOD1 genes, and inhibited neurochemical and histological changes in scopolamine induced AD model. Using the same model, Zhou et al. studied the protective effect of seed extract from Moringa oleifera. Cognitive impairment was induced by 4 mg/kg i/p injection of scopolamine for six days in mice. Pretreatment with oral 250 to 500 mg/kg of M. oleifera significantly ameliorated scopolamine mediated cognitive dysfunction and improved cholinergic system reactivity and neurogenesis. Further, M. oleifera revived the proteins expressions for CREB, ERK1/2, Akt suppressed by scopolamine therapy, suggesting its beneficial effects are mediated via improvement of cholinergic neurotransmission and activation of vital signaling pathways. In another study by Mushtaq et al. the methanolic extract of Lavandula stoechas L considerably improved cognitive performance of rodents using elevated plus maze, light and dark, and hole board models. L. stoechas therapy improved the activity of antioxidant enzymes including CAT, SOD, GSH in the brain and reduced MDA, AChE activity in the brain tissues. Quercetin a widely distributed natural flavonoid was evaluated by Khan et al. for its protective effect against lipopolysaccharide (LPS) induced neuroinflammatory and neuro-protective potentials. Quercetin therapy at 30 mg/kg for 2 weeks considerably reduced activated gliosis, markers of inflammation, and neuroinflammatory process in cortex and hippocampus of mice brain. Further, it prevented mitochondrial apoptosis and neurodegeneration via regulation of Bax/Bcl2, declining cytochrome-c activation, caspase-3 activity, and breakdown of PARP-1 in cortex and hippocampus. Quercetin therapy significantly improved cognitive performance and upturned LPS-induced neuronal loss in animal brain. In a systematic review Ma et al. considered the neurocognitive potentials of traditionally important plant Rhodiola rosea L. Review included 36 studies and concluded that R. rosea improve cognitive performance in animals models via regulation of cholinergic neurotransmission, improving coronary blood flow, decline in neuro-inflammation, apoptosis, and free radicals load. Zhang et al. evaluated Da-Bu-Yin-Wan a Chinese herbal medicine for its ameliorative effects on DJ-1 protein-associated mitochondrial dysfunctions and Akt signaling in rat adrenal pheochromocytoma cells (PC-12). The PC-12 cells were transfected with plasmid pcDNA3-Flag-DJ-1 and were subsequently exposed to 1-methyl-4-phenyl pyridinium (Parkinsonism-related mitochondrial toxin) in the presence and absence of test sample. In Da-Bu-Yin-Wan-treated groups, the mitochondrial toxin-induced toxicity was significantly reduced, and DJ-1 expression was increased. Further, Akt phosphorylation was increased by DJ-1 expression. Thus, Da-Bu-Yin-Wan improved the ameliorative effects of DJ-1 on mitochondrial dysfunction via increasing Akt phosphorylation. In another study, gintonin, a ginseng-derived lysophosphatidic receptor ligand was reported for its neuroprotective effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced neurotoxicity model of Parkinson disease. Pre-treatment of animals with 100 mg/kg of gintonin considerably reduced motor dysfunctions, reduced loss of tyrosine hydroxylase-positive neurons, and inhibited activation of microglia and expression of inflammatory mediators following MPTP injection. Gintonin therapy also blocked MAPKs, NF-kB pathways, and activated Nrf2, LPARs pathways post MPTP injection (Choi et al., 2018). Taraxasterol isolated from Taraxacum officinale was reported by Liu et al. for its anti-neuroinflammatory potentials in LPS-stimulated BV2 micoglial cells. Taraxasterol considerably reduced LPS-mediated TNF-α, IL-1β generation, and activation of NF-kB. It has dislocated lipids rafts formation and prevented TLR4 translocation into lipids rafts. Moreover, taraxasterol has activated LXRα-ABCA1 signaling pathway which cause induction of cholesterol efflux from cells, concluding that it inhibits LPS-mediated neuroinflammatory process in microglia cells via activation of LXRα-ABCA1 signaling pathway. The role of phytochemicals as anti-neuroinflammatory agents in AD were summarized by Shal et al. in a comprehensive review. They concluded that plant derived secondary metabolites including flavonoids, phenolic derivatives, saponins, glycosides, alkaloids, and terpenoids mediate their neuroprotective effects via reduction of excessive microglial activation, expression of cytokines, NF-kβ, and ROS burden. Ullah and Khan evaluated the published literature on silymarin isolated from Silybum marianum in the context of its anti-Parkinson’s potentials. Silymarin was concluded to mediate its anti-Parkinson therapeutic effects via decline in oxidative stress, inflammatory cytokines, and alteration of cellular apoptosis, estrogen receptor machinery. Yet in another research study, fatty acids rich extract from Clerodendrum volubile was reported to restrain cell migration, decline oxidative stress, and regulates cell cycle progression in glioblastoma multiforme (U87MG) cells (Erukainure et al.). Owing to the role molecular simulation studies in drug discovery, Rasool et al. performed molecular docking studies on albiziasaponin-A, orientin, salvadorin against AChE, COX2, and MMP8 proteins. All compounds exhibited strong interactions with the target proteins with lowest binding energies comparable to already approved drugs. In-vivo studies suggested that these compounds considerably declined oxidative stress and inflammatory markers in serum of Sprague Dawley rate model of AD (Rasool et al., 2018). In an anti-depressant and anxiolytic study, two compounds isolated from ethyl acetate fraction of Quercus incana showed beneficial anxiolytic effects using Elevated Plus Maze and Light and Dark paradigms. In the presence of flumazenil (selective benzodiazepine receptor antagonist), the anxiolytic activity of the test compounds were reduced, suggesting that benzodiazepine binding site of GABA-A receptors might be involved in this activity. Further, both compounds exhibited significant anti-depressant potentials in force swimming and tail suspension tests (Sarwar et al.). In conclusion, medicinal plants are a major source of diverse bioactive constituents. Ethnopharmacology-directed studies will not only provide scientific base for the effective dose, potential toxicological effects to local community but can lead to the development of more effective multi-target drugs for the prevention and treatment of various diseases including neurological disorders. 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Curcumin inhibits formation of amyloid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem. 280 (7), 5892–5901. doi: 10.1074/jbc.M404751200 PubMed Abstract | CrossRef Full Text | Google Scholar Yiannopoulou, K. G., Papageorgiou, S. G. (2013). Current and future treatments for Alzheimer’s disease. Ther. Adv. In neurol Disord. 6 (1), 19–33. doi: 10.1177/1756285612461679 CrossRef Full Text | Google Scholar Zhang, H.-Y. (2005). Structure-activity relationships and rational design strategies for radical-scavenging antioxidants. Curr. Comput-Aided Drug Des 1 (3), 257–273. doi: 10.2174/1573409054367691 CrossRef Full Text | Google Scholar Keywords: Alzheimer’s disease, natural products, cognition, phytochemicals, β-amyloid Citation: Ayaz M, Ullah F, Sadiq A, Kim MO and Ali T (2019) Editorial: Natural Products-Based Drugs: Potential Therapeutics Against Alzheimer’s Disease and Other Neurological Disorders. Front. Pharmacol. 10:1417. doi: 10.3389/fphar.2019.01417 Received: 17 August 2019; Accepted: 07 November 2019; Published: 26 November 2019. Edited and reviewed by: Michael Heinrich, UCL School of Pharmacy, United Kingdom Copyright © 2019 Ayaz, Ullah, Sadiq, Kim and Ali. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Muhammad Ayaz, [email protected]
, Ayako Ito, Naoko Tanaka, Kiyoshi Ameno, Takanori Miki, Hiroshi Kinoshita
Bangladesh Journal of Medical Science, Volume 19, pp 83-89; https://doi.org/10.3329/bjms.v19i1.43876

Abstract:
Background: Ethanol (EtOH) and acetaldehyde (AcH) have long been associated with many adverse effects in the central nervous system. c-fos has been used as an indirect index of neural activity. Method: Here, we investigated the effects of systemic administration of EtOH and AcH on the expression of c-fos protein in the hippocampus of Aldh2-knockout (Aldh2-KO) mice. The animals received an intraperitoneal injection of saline (control), EtOH (1.0, 2.0 and 4.0 g/kg) or AcH (50, 100 and 200 mg/kg), and the expression of c-fos protein was measured by Western blotting. Result: We found that EtOH at doses of 2.0 and 4.0 g/kg decreased c-fos in wild-type (WT) mice, whereas EtOH at all three doses tested (1.0-4.0 g/kg) decreased c-fos in Aldh 2-KO mice. Likewise, AcH at doses of 100 and 200 mg/kg had a significant effect in lowering c-fos protein in both WT and Aldh2-KO mice. Conclusion: Our observations suggest that moderate to high EtOH and AcH can decrease the expression of c-fos protein in the mouse hippocampus. This effect may support, at least in part, the link between c-fos and spatial memory deficits following EtOH and AcH exposure as we have observed in our previous study. Bangladesh Journal of Medical Science Vol.19(1) 2020 p.83-89
Comment
Published: 25 October 2019
Frontiers in Pharmacology, Volume 10; https://doi.org/10.3389/fphar.2019.01289

Abstract:
A Commentary onMontelukast Prevents Mice Against Acetaminophen-Induced Liver Injuryby Pu S, Liu Q, Li Y, Li R, Wu T, Zhang Z, Huang C, Yang X and He J (2019) Front. Pharmacol. 10:1070. doi: 10.3389/fphar.2019.01070 Montelukast sodium (CAS-No.: 151767-02-1), marketed as Singulair, acts as a selective orally active leukotriene receptor antagonist inhibiting the cysteinyl leukotriene receptor 1 (CysLTR1). It is a medication for treatment of exercise-induced asthma, bronchospasm, allergic rhinitis, and was applied in some patients as a beneficial add-on remedy in the therapy of chronic idiopathic urticaria. Molecularly, this drug selectively antagonizes the activities of the cysteinyl leukotrienes LTC4, LTD4, and LTE4, thereby displaying important anti-oxidative and anti-inflammatory effects in various tissues and organs (Singh et al., 2013). Recent work conducted in fibroblast-like synoviocytes, which are the main contributors in rheumatoid arthritis, has shown that Montelukast attenuated IL-1β-induced phosphorylation and degradation of IκBα, nuclear translocation of p65 and NF-κB activity (Dong et al., 2018). These findings supports previous findings showing that Montelukast highly potently prevents the activation of NF-κB signaling, which is a central pathway controlling the inflammatory response (Maeba et al., 2005). In regard to liver, Montelukast treatment improved hepatic fibrosis in rats in a bile duct ligation model by modulating hepatic expression of TGF-β, NF-κB, changing the MMP-9/TIMP-1 ratio, and mediating other hepatoprotective effects (El-Swefy and Hassanen, 2009; Kuru et al., 2015). In humans, the drug is usually well-tolerated and reported adverse drug-reactions are mild and similar in type and frequency to side effects induced by a placebo. However, it is already known for long time that some patients under Montelukast therapy occasionally developed bleeding tendency, allergic reactions, hepatitis, and joint pain, muscle aches, and muscle cramps (Russmann et al., 2003; Duchemin et al., 2004; Goldstein et al., 2004). Pu et al. (2019) tested whether the pharmacological inhibition of CysLTR1 by Montelukast impacts acetaminophen (APAP)-induced acute liver failure in C57BL/6J mice. APAP-induced liver injury is a rather complex process in which intracellular and extracellular events are involved including mitochondrial and endoplasmic reticulum oxidative stress, sterile inflammation, microcirculatory dysfunction and liver regeneration (Yan et al., 2018). The authors found that Montelukast-induced CysLTR1 expression and significantly prevented drug-induced liver damage when given at 3 mg/kg body weight by gavage 1 h after APAP administration. In addition, the authors demonstrated that Montelukast upregulated hepatic GSH/GSSH level, provoked expression of Glutathione S-transferase A2 (GSTA2), and prevented liver inflammation, oxidative stress, as well as activation of the c-Jun-N-terminal kinase (JNK) (Figure 1). Moreover, Montelukast was in vitro effective in blocking cell death and inflammation induced by APAP treatment in mouse primary hepatocytes. Based on this data, the authors concluded that the inhibition of CysLTR1 by Montelukast may be a potential treatment strategy in APAP-induced hepatotoxicity. Figure 1 Montelukast prevents mice against APAP-induced liver damage. The observed beneficial effects of Montelukast in APAP-treated mice are depicted. The fact that targeting the CysLTR1 axis provokes a significant upregulation of hepatic GSH/GSSH level and GSTA2 expression shows that Montelukast increases the potential to scavenge ROS and genes relevant in the detoxification of toxins and products of oxidative stress. In line, the finding that JNK activation is blocked points to the therapeutic potential of Montelukast because the magnitude and duration of JNK activation is known to be a major determinant of acute injury from APAP (Win et al., 2018). The decrease of pro-inflammatory chemokines or cytokines including Mcp1, Tnfα, Il6, and Il18 by Montelukast in primary cultured hepatocytes treated with APAP, demonstrates that this drug prevents inflammatory signaling. Of course these findings are highly interesting and add Montelukast to the large list of drugs that evolve beneficial effects on liver health in classical rodent disease models (Weiskirchen, 2016). Commonly, these substances target intracellular reactive oxygen species (ROS) formation, prevent hepatic infiltration with circulating blood cells, or target pro-inflammatory and pro-fibrotic signaling pathways or mediators involved in generation or turnover of extracellular matrix (Weiskirchen, 2016). However, in most cases, it is highly questionable if the observed therapeutic promise of a drug candidate can be translated to the human situation. Although most of the mechanistic insight in the pathophysiology of APAP hepatoxicity has been gained from experiments with the murine system, the injury process progresses in mice is much faster than in humans (Jaeschke et al., 2014). There are also some limitations in experiments conducted in primary hepatocytes. In culture, these parenchymal cells lack the contact to non-parenchymal cells and are usually exposed to highly artificial media in which numerous alterations in regard to gene expression and oxidative stress will affect the sensitivity to drugs such as APAP (Jaeschke et al., 2014). Moreover, hepatic injury caused by acetaminophen is dependent upon conversion to a toxic and reactive metabolite (N-acetyl-p-benzoquinone imine, NAPQI) (McGill and Jaeschke, 2013), which depletes hepatic GSH, binds to proteins, and causes severe damage to the liver. Therefore, any intervention that blocks NAPQI formation will also prevent downstream effects, including inflammation. The data presented by the authors shows that Montelukast impacts NAPQI formation. Thus, the major and potentially more important mechanism of protection is inhibition of acetaminophen bioactivation, not inhibition of JNK signaling or inflammation. Therefore, the reduction in inflammation, for example, is likely a secondary effect of the protection. To sum up, because APAP-induced liver injury is one, if not the most frequently encountered drug hepatotoxicity, it is absolutely necessary to establish solid interventions or identify new therapeutic effective drugs impacting the outcome of APAP-induced liver injury. The study by Pu et al. (2019) adds a new candidate drug showing beneficial effects in ongoing APAP-induced liver injury. It will now be interesting to evaluate the curative effects of Montelukast in the respective rodent model in more detail and to test if the hepatoprotective effects can be reproduced in human volunteers. In addition, it will be essential to understand the cause of hepatotoxicity from Montelukast occurring with rare incidence (Sass et al., 2003; Russmann et al., 2003; Goldstein et al., 2004). RW has written this General Commentary. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author is grateful to Sabine Weiskirchen (Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen) for preparing the figure for this General Commentary. Dong, H., Liu, F., Ma, F., Xu, L., Pang, L., Li, X., et al. (2018). Montelukast inhibits inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes. Int Immunopharmacol. 61, 215–221. doi: 10.1016/j.intimp.2018.04.042 PubMed Abstract | CrossRef Full Text | Google Scholar Duchemin, J., Lion, F., Arnaud, B., Nicot, C., Blouch, M. T., Abgrall, J. F. (2004). Acquired thrombopathia related to montelukast therapy. Thromb. Haemost. 91, 1247–1248. doi: 10.1055/s-0037-1614262 PubMed Abstract | CrossRef Full Text | Google Scholar El-Swefy, S., Hassanen, S. I. (2009). Improvement of hepatic fibrosis by leukotriene inhibition in cholestatic rats. Ann. Hepatol. 8, 41–49. PMID: 19221533. Google Scholar Goldstein, M. F., Anoia, J., Black, M. (2004). 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R., Jaeschke, H. (2013). Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm. Res. 30, 2174–2187. doi: 10.1007/s11095-013-1007-6 PubMed Abstract | CrossRef Full Text | Google Scholar Pu, S., Liu, Q., Li, Y., Li, R., Wu, T., Zhang, Z., et al. (2019). Montelukast prevents mice against acetaminophen-induced liver injury. Front. Pharmacol. 10, 1070. doi: 10.3389/fphar.2019.01070 PubMed Abstract | CrossRef Full Text | Google Scholar Russmann, S., Iselin, H. U., Meier, D., Zimmermann, A., Simon, H. U., Caduff, P., et al. (2003). Acute hepatitis associated with montelukast. J. Hepatol. 38, 694–695. doi: 10.1016/S0168-8278(03)00085-0 PubMed Abstract | CrossRef Full Text | Google Scholar Sass, D. A., Chopra, K. B., Wu, T. (2003). A case of montelukast-induced hepatotoxicity. Am. J. Gastroenterol. 98, 704–705. doi: 10.1111/j.1572-0241.2003.07316.x PubMed Abstract | CrossRef Full Text | Google Scholar Singh, R. K., Tandon, R., Dastidar, S. G., Ray, A. (2013). A review on leukotrienes and their receptors with reference to asthma. J. Asthma. 50, 922–931. doi: 10.3109/02770903.2013.823447 PubMed Abstract | CrossRef Full Text | Google Scholar Weiskirchen, R. (2016). Hepatoprotective and anti-fibrotic agents: it’s time to take the next step. Front Pharmacol. 6, 303. doi: 10.3389/fphar.2015.00303 PubMed Abstract | CrossRef Full Text | Google Scholar Win, S., Than, T. A., Zhang, J., Oo, C., Min, R. W. M., Kaplowitz, N. (2018). New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases. Hepatology 67, 2013–2024. doi: 10.1002/hep.29689 PubMed Abstract | CrossRef Full Text | Google Scholar Yan, M., Huo, Y., Yin, S., Hu, H. (2018). Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol. 17, 274–283. doi: 10.1016/j.redox.2018.04.019 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: liver, animal model, Montelukast, acetaminophen, APAP, Singulair, GSH/GSSH, therapy Citation: Weiskirchen R (2019) Commentary: Montelukast Prevents Mice Against Acetaminophen-Induced Liver Injury. Front. Pharmacol. 10:1289. doi: 10.3389/fphar.2019.01289 Received: 18 September 2019; Accepted: 08 October 2019; Published: 25 October 2019. Edited by: Reviewed by: Copyright © 2019 Weiskirchen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Ralf Weiskirchen, [email protected]
, Eung-Soo Kim, Mattheos Koffas
Published: 9 October 2019
Frontiers in Microbiology, Volume 10; https://doi.org/10.3389/fmicb.2019.02307

Abstract:
Editorial on the Research TopicEngineering the Microbial Platform for the Production of Biologics and Small-Molecule Medicines Microorganisms are the prominent sources of valuable products ranging from large (e.g., proteins, carbohydrate polymers, nucleic acids, even cells) to small molecules (e.g., microbial metabolites, signaling molecules, growth factors, etc.). Most of these small molecules termed as “secondary metabolites (SM)s” are inessential to the producer for their growth and development. However, these SMs have significant applications in human and animal health (Demain, 2000; Bhan et al., 2013; Wang et al., 2016; Dhakal and Sohng, 2017). Besides, several biologics pharmaceutical ingredients extracted from animals, plants, and microorganisms such as antibodies, vaccines, receptor modulators or replacement/modulators of enzymes are applied for human welfare (Kinch, 2005; Lacana et al., 2007). The host microorganisms engineered for the production of such small molecular medicines or relatively complex biologics are termed as “microbial cell factories (MCF).” Recently, metabolic engineering approaches are developed for engineering of metabolism and biosynthetic pathways in these MCFs for better performance (Davy et al., 2017; Choi et al., 2018). The papers published in this Research Topic have attempted to explore the current state of the art of microbial engineering along with its diverse approaches. Pham et al. have summarized the biological activities and applications of a variety of small molecular medicines and biologics. The manuscript has reviewed the diverse microbial systems used for the production of these biomolecules along with the versatile engineering strategies of such microbial platforms. Generally, each of the microbial strains can produce multiple compounds, but it can produce only subsets of these compounds under specific growth conditions. Therefore, variations in cultivation parameters can elicit the production and discovery of new SMs. For example, by changing cultivation parameters such as temperature, salinity, aeration, and even by altering the shape of the flasks, the production profile from a microbial platform can be altered (Bode et al., 2002). Pan et al. have provided comprehensive information regarding the exploration of structural diversity of microbe secondary metabolites using one strain many compounds (OSMAC) approach. They have presented the role of variation in medium, cultivation conditions, use of epigenetic modifiers, and co-cultivation in the discovery of novel secondary metabolites from diverse microbial sources utilizing OSMAC approach (Pan et al.). Escherichia coli is reported as the most common cell factory for the production of both small molecules and biologics. The clear understanding of its physiological and genetic characteristics, fast-growth even in minimal salts medium, and availability of easy genetic manipulation techniques has established it as first-choice production host (Liu et al., 2015). Also, systems metabolic engineering approaches that combine knowledge of systems biology, synthetic biology, and evolutionary engineering into the traditional metabolic engineering, has facilitated the development of E. coli as a robust production host for heterologous expression of small molecules and complex biologics (Choi et al., 2019). So, different metabolic engineering approaches utilizing E. coli as microbial platform have been presented in this Research Topic. Wang et al. have reviewed different aspects of terpenoid production using E. coli including the metabolic engineering and genome engineering approaches. Li et al. utilized product resistance and targeted metabolic engineering for the production of equol in E. coli. Similarly, the combination of product tolerance, evolution engineering, and modular co-culture was utilized for the production of pinene (Niu et al.). The metabolic engineering approach utilizing gene over-expression cassette for enhanced production of nucleotide diphosphate (NDP)-sugars was utilized for generating the salicylate glucoside and other glycosylated variants (Qi et al.). Similarly, the gene-silencing approach was employed for enriching the titer of 3′-phosphoadenosine-5′-phosphosulfate (PAPS), which is donor substrate for sulfation of natural product (NP) precursors. Hence, by inhibiting the degradation of PAPS mediated by repression of PAPS reductase (cysH) and optimization of different sulfate donors significantly enhanced the production titer of naringenin-7-sulfate (Chu et al.). Ribosomally synthesized and post-translationally modified peptides (RiPPs) are special class of NPs with diverse structures and bioactivities, and thus possess a complex biosynthetic mechanism. Different aspects for heterologous expression of RiPPs in E. coli have been reviewed by Zhang et al. Due to the presence of endotoxins in products obtained from Gram negative bacteria as E. coli, some of the non-lethal Gram-positive bacteria including the native producer strains such as actinobacteria or heterologous hosts [generally recognized as safe (GRAS)] such as Bacillus and Corynebacterium are used as excellent cell factories in industries. Actinobacteria are characterized as the most prominent producers of thousands of bioactive molecules, particularly small molecular medicines such as commercially available antibiotics and anticancer-drugs (Dhakal et al., 2017; Rangseekaew and Pathom-aree, 2019). In some cases, NPs from these actinomycetes are cryptic or not produced in a significant amount. Thus, precise metabolic engineering can be employed in a native host or genetically tractable alternative heterologous hosts for significant production. Li et al. performed whole genome sequencing of the producer strain, analyzed the genome data by computational tools and isolated nocardamine utilizing genome mining of Streptomyces atratus SCSIOZH16. Peng et al. used S. lividans as platform organism and optimized the host for higher heterologous expression of foreign biosynthetic gene cluster (BCG) by modulation by a number of global positive and negative regulatory genes, and genes encoding drug efflux pumps. Further the optimized strain was used for production of NPs of diverse nature such as actinorhodin, murayaquinone, hybrubins, piericidin A1, dehydrorabelomycin, and actinomycin D. Generally, the production of SMs in Streptomyces is controlled by a complex regulatory network that involves pathway-specific, pleiotropic, and global regulators, which tune the expression level of biosynthetic genes in response to a variation in diverse physiological and environmental conditions (van Wezel and McDowall, 2011). Hence, the engineering of such regulation cascades by activators and repressors have significant role in determining the productivity of target molecules. Yu et al. identified AdpAch, as a bidirectional pleiotropic regulator of natamycin biosynthesis in S. chattanoogensis L10. Subsequently, the production titer of natamycin was enhanced by mutating the AdpAch-binding sites, that had an inhibitory effect. Recently, the application of precise genetic engineering based on clustered regularly interspaced short palindromic repeats (CRISPER) and its associated protein (Cas9) has enabled the multiplexed genome engineering of actinomycetes including Streptomyces. Tao et al. have reviewed the application of CRISPR/Cas9 based genome editing in Streptomyces for discovery, characterization, and production of NPs. The recent advances in heterologous expression of RiPPs in Streptomyces have been presented by Zhang et al. Bacillus species has an ability to adapt to varying environmental conditions and capacity for high production yield (Pham et al.), hence they are crucial industrial microorganisms. Further, the application of recent advances in metabolic engineering, enzyme/pathway engineering along with the synthetic biological tools have contributed to ameliorate the production titer from these microorganisms. Yang et al. utilized enzyme engineering of homogentisate dioxygenase for production of enhanced production of melanin. Similarly, a metabolic engineering approach was utilized for enhanced heterologous production of 2-deoxy-scyllo-inosose in Bacillus subtilis. Unlike E.coli and Bacillus, Corynebacterium has significant ability to utilize a variety of carbon sources (Heider and Wendisch, 2015). C. glutanicum is established as a major industrial producer of proteins, including biologics and enzymes as well as utilized in the production of diverse secondary metabolites as carotenoids, terpenes, and flavonoids. Lee and Kim have reviewed different crucial aspects of recombinant protein expression systems in C. glutanicum and its applications. Fungi is the second largest kingdom of microorganism after bacteria. They are established as a promising source of bioactive natural products containing unique chemical compounds against various diseases (Singh et al., 2019). Ever since Penicillium notatum was identified as a source of penicillin, there has been immense interest in the exploration of the potential of fungal species for their capacity to produce versatile NPs with biotechnological and pharmaceutical applications. Guzmán-Chávez et al. have summarized on the engineering aspects of the P. chrysogenum for establishing it as a sustainable cell factory for NPs. They have provided the comprehensive summary about the basic biosynthetic logic of such NPs and various rational strategies for activation of biosynthetic gene clusters by optimizing culture parameters or targeted genetic engineering Guzmán-Chávez et al. In addition to the bacteria and fungi, the yeast strain such as Saccharomyces cerevisiae is successfully employed for the production of both bulk and fine chemicals (Kavšček et al., 2015). The different aspects of biosynthesis and prospects of metabolic engineering for the production of terpenoids in S. cerevisiae are summarized by Wang et al. Taken together, all these papers illustrate the applicability of engineering of microbial platforms for the production of small molecular medicines to complex biologics. However, in case of all of these microbial cell factories (native, engineered, or heterologous) the industrial scale titer, yield, and productivity is generally difficult to achieve. The major constraint is unavailability of abundant information about their metabolic behavior, unavailability of appropriate genetic engineering tools, or complication in redesigning appropriate flux balance for diverting primary metabolites to target molecules (Bhan et al., 2013). Recently the application of large-scale genome sequencing, gene expression profiling, in silico metabolic modeling and simulation, and enzyme/pathway engineering has eased the rational approaches for metabolic engineering. Particularly, the traditional approach of single strain/pathway specific “try and test” approach is replaced by the application of systems metabolic engineering approach that utilizes integration of strain selection/development, pathway design/engineering, and enzyme selection/engineering for efficient production of target molecules. In addition, the application of tools for generating artificial genetic circuits/metabolic pathways incorporating efficient promoters, RBS, terminators, etc, or multiplexed genome engineering utilizing CRISPR/ Cas9 for gene knock-in/knock out, or activation/repression has advanced the engineering approaches of these MCFs to the next level. In future, it can be expected that it can be feasible to generate the super host with minimized genome and enriched metabolic pathway centered on particular class of molecules. Such super hosts can be engineered by introducing the synthetic genome to attain the designers' strain for specific target. The burgeoning development in both genetic studies as well as computational approaches such as artificial intelligence (AI) has great prospects for simulating the connection between the genomics and metabolomics to generate the intelligence in these super hosts, so that they can sense the environment condition, and respond rationally. DD wrote the manuscript. E-SK and MK revised and corrected the manuscript. The final draft of the manuscript was finalized and approved for publication by all the authors. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Editors would like to thank all authors that participated in this Research Topic in Engineering the Microbial Platform for the Production of Biologics and Small-Molecule Medicines. We are grateful all reviewers and editorial team members, who has contributed for success of this Research Topic. 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Microbiol. 10:2307. doi: 10.3389/fmicb.2019.02307 Received: 07 August 2019; Accepted: 20 September 2019; Published: 09 October 2019. Edited by: Reviewed by: Copyright © 2019 Dhakal, Kim and Koffas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Dipesh Dhakal, [email protected]; [email protected]; Eung-Soo Kim, [email protected]; Mattheos Koffas, [email protected]
, Bilal Çuğlan, Hasan Turhan, Ertan Yetkin
International Journal of Angiology, Volume 28, pp 272-273; https://doi.org/10.1055/s-0039-1695781

Abstract:
Author's Rebuttal Besides being a widespread health problem, chronic venous disease (CVD) of the lower extremities is also a cosmetic and growing economic problem. CVD or lower extremity varicose veins can be classified as a subgroup of dilating venous or vascular diseases.[1] [2] [3] Spider veins, varicose veins, edema, changed skin color, and ulcerations are the main clinical signs of the disease[4] and admission complaints of patients mostly include heavy legs, aching legs, swelling, night cramps, burning sensation, restless legs, throbbing, itching and tingling.[5] In addition to these symptoms, color changes including purpuric and ecchymotic lesions of the lower extremities have been described as a significant reason for admitting to phlebology clinics in this patient group.[6] [7] [8] [9] Until recently, the clinical severity of CVD was thought to be associated with the reflux in the large truncal veins of the lower extremities which is diagnosed by venous duplex ultrasonography.[10] For this reason, patients with reflux solely in the small superficial veins are usually neglected and may not be considered for treatment.[11] However, it is known from previous reports that that there may not be a significant difference in the symptoms of patients with and without duplex ultrasound confirmed functional venous disease.[12] In addition, a recently published study demonstrated that there is no significant association between truncal varicose vein diameter and patients clinical stage, symptoms, and quality-of-life measurements.[11] Therefore, the major question needs to be answered in this context is, which one really matters in CVD patients. Diameter of afflicted veins or symptoms? We believe that finding an appropriate answer to this question may help to understand the underlying etiology and pathogenesis of CVD. In the latest issue of the International Journal of Angiology, Radhakrishnan and colleagues published the results of their analysis about the relationship between the size of veins with blood reflux and clinical manifestations of CVD patients.[13] In their retrospective study design, including a relatively large population of CVD patients, they found throbbing sensation/pain and hyperpigmentation are the most common admission symptoms. In addition, the authors of the study analyzed the association between symptoms and the affected vein diameter. Briefly, they found that severity of the disease is significantly associated with blood reflux in veins with small diameter (< 4 mm) compared with the reflux in truncal veins. There was a strong relationship between the reflux in small veins and symptoms including edema, cellulitis, itching, ulceration, and hyperpigmentation. Only throbbing sensation/pain was associated with the reflux in great diameter veins.[13] We believe that there are important take home messages might be gathered from this study and these findings should be discussed in detail. Pathogenesis of CVD is not fully understood and therefore interpretation of symptoms in patients suffering from CVD may be difficult. In addition, symptoms may show a diverse spectrum due to the fact that this is a local manifestation of systemic vascular wall pathology named as “Dilating Vascular Diseases.”[1] [2] For example, in a recently published study by our group, we have shown that patients suffering from varicocele, which is a dilating venous disease of the pampiniform plexus, also suffer from varicose vein symptoms which are also present in the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms (VEINES-QoL/Sym) questionnaire.[14] In addition, similar to results published by Radhakrishnan et al,[13] there are several recently published papers in the literature describing skin lesions, such as ecchymosis, hyperpigmentation, and purpuric lesions, in CVD patients.[6] [7] [8] [9] The pathophysiological mechanism of these skin lesions is not clear, although the vascular wall abnormality, inflammation, oxidative stress, and subsequent rupture of small vessels are the suspected mechanisms. Accordingly, it is important to consider CVD or dilating venous disease more frequently in evaluating the signs and symptoms of lower extremities, especially of whom the underlying etiology is obscure. Given the findings of Radhakrishnan and colleagues, skin lesions really matter in differential diagnosis of CVD or varicose venous of lower extremities.
, Mario Ciccotti, Paola Aiello, Paola Minosi, Diego Munzi, Cosimo Buccolieri, , Maura Palmery, Florigio Lista
Published: 10 September 2019
Frontiers in Pharmacology, Volume 10; https://doi.org/10.3389/fphar.2019.00994

Abstract:
The presence of multiple chronic conditions (multi-morbidity) is common in veterans, in particular among the elderly (Golchin et al., 2015). Many of veterans’ injuries have been described as a poly-trauma clinical triad, which refers to the co-occurrence (Figure 1) of post-traumatic stress disorder (PTSD), chronic pain, and traumatic brain injury (TBI). While the concomitant injuries (Figure 1) accompanying TBI may be manifold, including fractures, amputations, burns, spinal cord injury, eye injury, and auditory trauma, the two most prevalent and functionally disabling conditions may be PTSD and chronic pain (Lew et al., 2009). Although it has been recently suggested that treatment with opioids is not superior to treatment with nonopioid medications, including acetaminophen, for improving pain-related function in patients with chronic pain (Krebs et al., 2018), paracetamol pharmacokinetic is affected by nutraceuticals and some plant foods (Figure 1) (Abdel-daim et al., 2018). Figure 1 Factors that account for the need of interprofessional approaches (including physical medicine and rehabilitation clinicians, pharmacologists, and nutritionists). PTSD, post-traumatic stress disorder; CAM, complementary and alternative medicine. Moreover, chronic pain symptoms are often comorbid with psychiatric conditions, such as depression (Runnals et al., 2013), substance use disorders (Figure 1) (Caldeiro et al., 2008), functional disability, and growing epidemic of prescription opioid abuse (Wilder et al., 2016). PTSD has been associated not only with cardiovascular diseases, such as hypertension (Abouzeid et al., 2012), but also with cancer (Boscarino, 2008), type 2 diabetes (Boyko et al., 2010), and poor health, including obesity (Figure 1) (Smith et al., 2015). As a consequence, the use of five or more medications (polypharmacy) (Figure 1) to control symptoms, in order to prevent both disease complications and the development of new medical conditions, is very common in veterans, so the accumulation of multiple medications represents a critical patient safety issue. In fact, the greater the number of total prescribed medications, the greater the likelihood of prescribing a potentially harmful drug. A suitable polypharmacy can extend life expectancy and maintain quality of life when medicines are prescribed according to the best evidence and their usage is optimized. However, it has been documented that too often polypharmacy can be a detriment in case of inappropriate prescriptions (Soerensen et al., 2016) and potential prescription omissions (Rongen et al., 2016). One possible solution is deprescribing, namely, the intentional, proactive, rational discontinuation of a medication that is no longer indicated or for which the potential risk outweighs the potential benefits. The issue becomes more complicated when certain medical guidelines [e.g., those for chronic heart failure (Yancy et al., 2017)] require treatment with multiple medications to achieve the optimal clinical effect. Furthermore, polypharmacy is sometimes associated with poor clinical outcomes, especially in older adults, including falls, frailty (Figure 1), impaired cognition, increased hospital admissions, and adverse drug reactions (Gnjidic et al., 2012). The most worrisome consequence of polypharmacy is the occurrence of therapeutic failures, adverse drug withdrawal events, and drug–drug interactions leading to hospitalization. All of these events are associated with similarly negative economic outcomes, such as increased drug cost and costs associated with more frequent usage of health services (Fried et al., 2014). On the other hand, the impact of some drugs on dietary habit and nutritional status is well documented (Lappin et al., 2018; Little, 2018). It is well known that polypharmacy, malnutrition, and sarcopenia are major causes of frailty (Figure 1) and that rehabilitation, nutrition, and interventions with mixed outcomes are important to improve disability (Singh et al., 2012; Little, 2018; Roberts et al., 2018; Wakabayashi, 2018). Despite nutritional supplements being taken into consideration in malnourishment in polypharmacy (Gaddey and Holder, 2014), another phenomenon that should not be underestimated is the trend to use vitamins and nutritional supplements instead of prescription medications. It can be assumed that costs, treatment beliefs, and/or health system distrust are the leading factors which have been influencing this trend. In the United States, especially among veterans, there is a penchant for the use of vitamins and supplements, which represent the most common form of complementary and alternative medicine (CAM) currently in use (Goldstein et al., 2014). According to a report on the website (US Food and Drug Administration, 2008), many patients use them in addition to or instead of (nearly one in five Americans) their prescription medications. At the same time, the use of CAM (Figure 1), including acupuncture, deep-breathing exercises, massage therapy, meditation, naturopathy, and yoga, is growing, specifically among patients with chronic conditions and those taking prescription drugs (Gardiner et al., 2006; Nahin et al., 2009). As regards veterans, a longing for a holistic approach to health care and the lack of trust in the health system are more common in those who use CAM (Kroesen et al., 2002). In particular, it has been shown that 75% of veterans, as well as the general population, used vitamins and supplements, whereas 18% substituted drugs (US Food and Drug Administration, 2008). Among the latter, 25% replaced hyperlipidemia medications, 17% the anxiolytics/antidepressants, 15% those for both arthritis/back pain and hot flashes, 10% the antidiabetic drugs, and 8% those for hypertension (Goldstein et al., 2014). Patti et al. (2017) suggested that the use of nutraceuticals containing omega-3, polyphenols, vitamins, and trace elements could be useful in contrasting metabolic syndromes. In addition to this, a recent meta-analysis has pointed out the improvement of moderate hypercholesterolemia determined by supplementation with red yeast rice (Fogacci et al., 2019). It has been reported that red yeast rice supplementation is safe and not associated with increased incidence of muscular adverse effects (Fogacci et al., 2019). Furthermore, bergamot, red yeast rice, soluble fiber, berberine, artichokes, plant sterols, and stanols have been suggested as an alternative or additional therapy to statins, alone or in combination with each other (e.g., with drugs, such as ezetimibe), in statin-intolerant patients (Cicero et al., 2017; Banach et al., 2018). On the contrary, Ward et al. (2018) reported that in their clinical practice experience, 1/18 patients with statin-associated muscle symptoms (SAMS) (5.5%) had side effects after nutraceutical treatment (muscle ache/stiffness and intolerance). On the other hand, the risk of statin-induced serious muscle injury, including rhabdomyolysis, is <0.1%, and the risk of serious hepatotoxicity is ≈0.001% (Newman et al., 2019), and in a meta-analysis, statins did not seem to modify rhabdomyolysis, myalgia, or rise in creatine kinase (Tramacere et al., 2019). It must be borne in mind that fermented red rice contains monacolin K, having the same formula of lovastatin (US National Library of Medicine1). In 2014, Italy was ranked first in Europe for consumption of nutraceuticals, and the presence of some problems related to their use has been reported by the Società Italiana per lo Studio dell’Aterosclerosi (SISA) (Averna and Pirro, 2017). The improper vigilance and the strong belief in the safety of natural products are cultural limits to be demolished through scientific information (Averna and Pirro, 2017). A significant percentage of people who consume nutraceuticals declared to have not purchased them as a result of medical advice (Averna and Pirro, 2017). In spite of the uncertainties about the efficacy of herbal preparations and dietary supplements, users who want to check their health personally often believe that herbal preparations and dietary supplements are natural and have fewer side effects (Wu et al., 2014). Actually, recent US data indicated that the use of a combination of dietary supplement products is most commonly associated with side effects (Austin et al., 2016; Knapik et al., 2016); furthermore, potential interactions can also occur between drugs and herbal/nutritional supplements (Figure 1) (Loya et al., 2009) with significant consequences, such as an increased risk of adverse drug reactions probably due to the induction or inhibition of cytochrome P450 isoenzymes (Henderson et al., 2002); for example, Hypericum perforatum, known for the antidepressant and sedative activity of its phytocomplex, has the ability to accelerate cytochrome P450, giving multiple interactions with different classes of drugs such as selective serotonin reuptake and monoamine oxidase inhibitor (Lantz et al., 1999), warfarin (Jiang et al., 2004), digoxin (Muller et al., 2004), statins (Sugimoto et al., 2001), and all cytochrome P450 metabolized agents (Markowitz et al., 2003). Moreover, coadministration of ephedra (Ephedra sinica), which can increase blood pressure and decrease platelet aggregation, and nonsteroidal anti-inflammatory drugs may potentiate the risk of cerebral hemorrhage and gastrointestinal ulcer bleeding (Meng and Liu, 2014). Possible interactions with drugs have also been suggested for mineral-fortified foods and fruit juices, which are able to influence the bioequivalence of levofloxacin and ciprofloxacin (Neuhofel et al., 2002; Amsden et al., 2003; Wallace et al., 2003). Accordingly, the Department of Veterans Affairs has dedicated a special section on its website to all the possible interactions between food and drugs, also indicating nutraceuticals (Figure 1) to be taken carefully if you are undergoing a polypharmacy (US Department of Veterans Affairs2). On one hand, drug–drug interactions are included in most pharmacovigilance systems owing to their widely recognized clinical relevance; on the other hand, nutrient–drug interactions are still underexplored, and their appraisal is not part of the clinical routine, despite being supported by a lot of data (Péter et al., 2017). Therefore, it would seem necessary to proceed with a systematic evaluation of such interactions by means of an appropriate analysis both of a possible influence of the nutritional status in the drug action and of the effect of adverse drug reactions on the nutritional status (Péter et al., 2017). This systematic analysis obviously has to provide for a nutritional appraisal throughout the phases of drug development and post-marketing surveillance. Adverse drug effects in clinical practice, in particular those related to nutrition, should be reported spontaneously, and a special attention should be paid to taking into account malnutrition, the global nutritional status, and the dietary supplements used (Péter et al., 2017). Particularly, regarding nutritional status, Becerra et al. (2016) have pointed out the extreme necessity to carry out health promotion measures among veterans in order to encourage a healthy diet in this population, especially those with limited access to healthy food options. In fact, negative dietary practices have come to light among veterans, which are associated with food insecurity. In this regard, the Department of Veteran Affairs provides guidance to veterans about how a healthy diet, rich in fruits and vegetables, accompanied by movement, can be useful in combating overweight and related diseases (Rutledge et al., 2017). Facilitating healthy diets, physical activity, and weight management in the veteran population is an important public health challenge (Figure 1). In fact, a cross-sectional analysis reported that approximately 37% and 33% of women and men veterans are obese, respectively (Das et al., 2005), while others demonstrated higher prevalence of overweight status (Koepsell et al., 2009) and greater waist circumference among veterans (Koepsell et al., 2012) as compared with the civilian population. Such a prevalence of overweight and obesity among veterans may be due to their dietary practices. In fact, recent studies have found that military service impacts soldiers’ food environment and food security, which then influences eating behavior and food choices both during military service and following discharge (Smith et al., 2009; Wang et al., 2015; Widome et al., 2015). During this time frame, veterans consume high-fat and high-carbohydrate foodstuffs, with a preference for specific food items (burgers and fries) (Smith et al., 2009), which is influenced by their low cost, an important aspect that could further be driving vulnerable populations away from healthier items, which usually are more expensive (Drewnowski and Darmon, 2005a; Drewnowski and Darmon, 2005b; Jetter and Cassady, 2006). A diet high in fruits and vegetables is associated with decreased risk for chronic diseases such as cardiovascular disease, hypertension, diabetes, and cancer (Adams and Standridge, 2006); therefore, it may play an important role in reducing veterans’ health risks. In our opinion, the Mediterranean Diet Pyramid could be the basis for integrative medicine for veterans with disabilities, but patient-centered and interprofessional approaches represent the real added value for the best health care management. A comprehensive approach should also include physical medicine and rehabilitation clinicians, pharmacists, and nutritionist in order to prevent malnutrition, self-prescription of CAM, and food–drug and/or nutraceutical–drug interactions according to a biopsychosocial model (Figure 1) (Ciccotti et al., 2018). Personalized health care for chronic noncommunicable diseases that impact quality of life should consider gut microbiota, genetic and epigenetic factors (Peluso et al., 2018a), and moods and hormones involved in stress response (Peluso et al., 2018b) rather than functional status. In particular, as previously suggested, in order to avoid potential food–drug interactions, plant foods should be chosen within those containing low phytochemicals and high micronutrients. If this aim is difficult to reach, vitamin and/or mineral supplementation can be recommended (top of the pyramid for veterans, Ciccotti et al., 2018). MC, PA, and PM developed the concept and wrote the paper. 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Tommaso Sciarra, [email protected]
Ladislav Senolt, Koopman Fa, Van Maanen Ma, Vervoordeldonk Mj, Tak Pp
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 282; https://doi.org/10.3410/f.727743157.793564292

Abstract:
Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune-mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so-called cholinergic anti-inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL-6 production and improved RA disease severity, even in some patients with therapy-resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.© 2017 The Association for the Publication of the Journal of Internal Medicine.
Takashi Ikawa, Yuko Watanabe, , Naohisa Goto, Nobutaka Okamura, Kyosuke Yamanishi, , Hiromichi Yamanishi, Haruki Okamura, Hideaki Higashino
Journal of Hypertension, Volume 37, pp 1644-1656; https://doi.org/10.1097/hjh.0000000000002083

Abstract:
Hypertension is one of the most prevalent diseases in humans who live a modern lifestyle. Alongside more effective care, clarification of the genetic background of hypertension is urgently required. Gene expression in mesenteric resistance arteries of spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and two types of renal hypertensive Wistar Kyoto rats (WKY), two kidneys and one clip renal hypertensive rat (2K1C) and one kidney and one clip renal hypertensive rat (1K1C), was compared using DNA microarrays. We used a simultaneous equation and comparative selection method to identify genes associated with hypertension using the Reactome analysis tool and GenBank database. The expression of 298 genes was altered between SHR and WKY (44 upregulated and 254 downregulated), while the expression of 290 genes was altered between SHRSP and WKY (83 upregulated and 207 downregulated). For SHRSP versus SHR, the expression of 60 genes was altered (36 upregulated and 24 downregulated). Several genes expressed in SHR and SHRSP were also expressed in the renovascular hypertensive 2K1C and 1K1C rats, indicative of the existence of hyper-renin and/or hypervolemic pathophysiological changes in SHR and SHRSP. The overexpression of Kcnq1, Crlf1, Alb and Xirp1 and the inhibition of Galr2, Kcnh1, Ache, Chrm2 and Slc5a7 expression may indicate that a relationship exists between these genes and the cause and/or worsening of hypertension in SHR and SHRSP. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0
Dang Kim Thu, Hoang Thu Thuy, Bui Thi Thanh Duyen, Luc Thi Thanh Hang, Nguyen Thi Trang, Bui Son Nhat, Tran Thi Quynh Hoa, Duong Thi Ky Duyen, Bui Thanh Tung
VNU Journal of Science: Medical and Pharmaceutical Sciences, Volume 35; https://doi.org/10.25073/2588-1132/vnumps.4169

Abstract:
Medicinal plants are a potential source of enzyme acetylcholinesrerase (AChE) inhibitors, a key target in the treatment of Alzheimer’s disease. This paper studies the AChE inhibitory activity and the antioxidant effect of Persea Americana Mill extract. The sample leave, seed, exocarp and mesocarp of avocado were extracted with 50% ethanol and subsequently fractionated with n-hexane, ethyl acetate (EtOA) and n-butanol (n-BuOH) solvents. The AChE inhibitory activity was evaluated by Ellman’s colorimetric method and the antioxidant activity by screening DPPH free radicals. The results show that the seed of Persea Americana extract had the strongest AChE inhibitory activity and antioxidant effect, followed by the leave extract, and the exocarp extract and mesocarp extract were the weakest. The Persea Americana seed extract inhibited AChE activity in a dose-dependent manner with an IC50 value of 47.43 ± 0.5 μg/mL and the antioxidant effect with an IC50 value of 68.7 ± 0.35 µg/mL. The results also show that n–BuOH fraction of Persea Americana seed extract had strong AChE inhibitory and antioxidant activities with an IC50 value of 15.24 ± 0.52 µg/ml and 15.73 ± 0.42 μg/mL, respectively. The study results suggest that the Persea Americana Mill is a promising ingredient in Alzheimer’s disease prevention and treatment. Keywords Persea Americana Mill, Acetylcholinesrerase inhibitors (AChE), Alzheimer, DPPH. References [1] M.M. Essa et al., Neuroprotective effect of natural products against Alzheimer's disease, Neurochem Res. 37(9) (2012) 1829.[2] B. McGleenon, K. Dynan, A. Passmore,. Acetylcholinesterase inhibitors in Alzheimer's disease, British journal of clinical pharmacology. 48 (1999) 471.[3] P. B. Watkins et al, Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease, In: Jama. pp. 992 (1994).[4] O. Adeyemi, S. Okpo, O. Ogunti,. Analgesic and anti-inflammatory effects of the aqueous extract of leaves of Persea americana Mill (Lauraceae). In: Fitoterapia. pp. 375 (2002).[5] P.D.D. Dzeufiet, et al, Antihypertensive potential of the aqueous extract which combine leaf of Persea americana Mill. (Lauraceae), stems and leaf of Cymbopogon citratus (DC) Stapf.(Poaceae), fruits of Citrus medical L.(Rutaceae) as well as honey in ethanol and sucrose experimental model. In: BMC complementary and alternative medicine. p. 507 (2014).[6] B.I. Brai, A. Odetola, P. Agomo,. Hypoglycemic and hypocholesterolemic potential of Persea americana leaf extracts, Journal of medicinal food. 10(2) (2007) 356.[7] Phạm Khuê. Bệnh Alzheimer. Nhà xuất bản Y học (2002).[8] Đàm Trung Bảo. Các gốc tự do, Tạp chí Dược học. 6 (2001) 29 [9] F.R. Mowsumi, A. Rahaman, N.C. Sarker, B.K. Choudhury, S. Hossain, In vitro relative free radical scavenging effects of Calocybe indica (milky oyster) and Pleurotus djamor (pink oyster), World J Pharm Pharm Sci. 4(07) (2015) 186.[10] Y. Bao, Y. Qu, J. Li, Y. Li, X. Ren, K....
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