Frontiers in Medicine

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ISSN / EISSN : 2296-858X / 2296-858X
Current Publisher: Frontiers Media SA (10.3389)
Total articles ≅ 2,699
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Jessica Y. Morales, Cassandra M. Young-Stubbs, Caroline G. Shimoura, William R. Kem, Victor V. Uteshev,
Published: 13 April 2021
Frontiers in Medicine, Volume 8; doi:10.3389/fmed.2021.642960

Abstract:
There is a critical need for safe treatment options to control inflammation in patients with systemic lupus erythematosus (SLE) since the inflammation contributes to morbidity and mortality in advanced disease. Endogenous neuroimmune mechanisms like the cholinergic anti-inflammatory pathway can be targeted to modulate inflammation, but the ability to manipulate such pathways and reduce inflammation and end organ damage has not been fully explored in SLE. Positive allosteric modulators (PAM) are pharmacological agents that inhibit desensitization of the nicotinic acetylcholine receptor (α7-nAChR), the main anti-inflammatory feature within the cholinergic anti-inflammatory pathway, and may augment α7-dependent cholinergic tone to generate therapeutic benefits in SLE. In the current study, we hypothesize that activating the cholinergic anti-inflammatory pathway at the level of the α7-nAChR with systemic administration of a partial agonist, GTS-21, and a PAM, PNU-120596, would reduce inflammation, eliminating the associated end organ damage in a mouse model of SLE with advanced disease. Further, we hypothesize that systemic α7 ligands will have central effects and improve behavioral deficits in SLE mice. Female control (NZW) and SLE mice (NZBWF1) were administered GTS-21 or PNU-120596 subcutaneously via minipumps for 2 weeks. We found that the increased plasma dsDNA autoantibodies, splenic and renal inflammation, renal injury and hypertension usually observed in SLE mice with advanced disease at 35 weeks of age were not altered by GTS-21 or PNU-120596. The anxiety-like behavior presented in SLE mice was also not improved by GTS-21 or PNU-120596. Although no significant beneficial effects of α7 ligands were observed in SLE mice at this advanced stage, we predict that targeting this receptor earlier in the pathogenesis of the disease may prove to be efficacious and should be addressed in future studies.
, Verlaine Timms, Eby Sim, Rebecca Rockett, Nathan Bachmann, Matthew O'Sullivan, Ben Marais
Published: 13 April 2021
Frontiers in Medicine, Volume 8; doi:10.3389/fmed.2021.641260

Abstract:
Virulence arresting drugs (VAD) are an expanding class of antimicrobial treatment that act to “disarm” rather than kill bacteria. Despite an increasing number of VAD being registered for clinical use, uptake is hampered by the lack of methods that can identify patients who are most likely to benefit from these new agents. The application of pathogen genomics can facilitate the rational utilization of advanced therapeutics for infectious diseases. The development of genomic assessment of VAD targets is essential to support the early stages of VAD diffusion into infectious disease management. Genomic identification and characterization of VAD targets in clinical isolates can augment antimicrobial stewardship and pharmacovigilance. Personalized genomics guided use of VAD will provide crucial policy guidance to regulating agencies, assist hospitals to optimize the use of these expensive medicines and create market opportunities for biotech companies and diagnostic laboratories.
Zheyuan Li, Bo Liu, Hongli Si, Kangzhi Li, Bo Shen, Xiang Li, Xia Ling,
Published: 13 April 2021
Frontiers in Medicine, Volume 8; doi:10.3389/fmed.2021.589969

Abstract:
Objective: To investigate the clinical characteristics of patients with dizziness/vertigo accompanied by loss of the posterior canal(s) (LPC). Methods: Clinical data of 23 patients with LPC were collected. We determined video-head-impulse test (vHIT) gains of all six semicircular canals and correlated vHIT findings with other vestibulo-cochlear tests, including caloric test, ocular and cervical vestibular-evoked myogenic potentials (oVEMP, cVEMP), pure tone audiometry (PTA), and analyzed the differences in clinical manifestations of patients with LPC with different etiologies. Results: LPC was identified in 23 patients. At the time of disease onset, most patients presented with dizziness (47.8%) and vertigo (30.4%) only, and some patients (21.7%) complained of unsteadiness. Among these 23 patients with LPC, there were 14 (60.9%) patients of isolated LPC (ILPC), 21 (91.3%) patients of unilateral LPC (ULPC), and 2 (8.7%) patients of bilateral LPC (BLPC). (1) Among 14 patients with ILPC, 13 (92.9%) patients had unilateral ILPC, the rate of ipsilesional impairment on caloric test, or oVEMP/cVEMP test or PTA ipsilesionally was 53.8% (7/13) in patients with unilateral ILPC. The causes of unilateral ILPC were vertigo/dizziness of unclear origin (38.5%), labyrinthine infarction (15.4%), vestibular migraine (15.4%), and other diseases (30.8%); (2) among 21 patients with ULPC, 7 patients (33.3%) were accompanied with horizontal semicircular canal hypofunction ipsilesionally, the abnormal rate of caloric test, or oVEMP/cVEMP tests or PTA ipsilesionally was 57.1%. The causes of ULPC were vertigo/dizziness of unclear origin (33.3%), autoimmune inner ear disease (14.3%), labyrinthine infarction (14.3%), vestibular neuritis (9.5%), vestibular migraine (9.5%), and other diseases (19.0%); (3) among two patients with BLPC, one patient presented with unsteadiness, the causes of BLPC were vestibular paroxysmia and autoimmune inner ear disease. Conclusion: vHIT is a fast and effective method for assessing LPC, which can be used to detect isolated PC dysfunction. The causes of ILPC were peripheral origin or central origin. Patients with ILPC and ULPC mostly presented with dizziness/vertigo, and ULPC was often accompanied by ipsilateral vestibulo-cochlear impairment.
Jia Yang, Jiaojiao Zhou, Xin Wang, Ling Ji, Siwen Wang, Xuelian Chen, Lichuan Yang
Published: 13 April 2021
Frontiers in Medicine, Volume 8; doi:10.3389/fmed.2021.634882

Abstract:
The aim of the present study was to investigate the effect of erythropoietin (EPO) on contrast-induced nephrology (CIN) in vivo and in vitro. Male C57BL/6J mice were divided into four groups: control, CIN (iohexol 6.0 g/kg), EPO (3,000 IU/kg), and CIN+EPO. Hematoxylin and eosin (H&E) staining and biochemical index analyses were performed to evaluate renal injury. The cellular proliferation rate was detected using the Cell Counting Kit-8 (CCK-8) assay. In addition, a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and flow cytometric assay were used to assess the apoptosis of tissue and cells, respectively. Renal protein expression associated with apoptosis, pyroptosis, and signaling pathways was determined by Western blot (WB) assays for tissues and cells. The results showed that EPO significantly decreased serum creatinine, blood urea nitrogen, and cystatin C levels and alleviated renal histological changes in vivo. The protein levels of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway components were overexpressed in the EPO treatment group. Furthermore, EPO suppressed the cell apoptosis and pyroptosis; decreased the protein levels of cleaved caspase-3, Bax, gasdermin D (GSDMD), and caspase-1; and enhanced the expression of Bcl-2. In summary, EPO could exert renoprotective effect by activating the JAK2/STAT3 signaling pathway, which may be a novel potential therapy for the treatment of CIN in the clinic.
Yanjiao Ou, Yong Deng, Hong Wang, Qingyi Zhang, Huan Luo, Peng Hu
Published: 13 April 2021
Frontiers in Medicine, Volume 8; doi:10.3389/fmed.2021.649279

Abstract:
Objective: Increasing evidence highlights antisense long non-coding RNAs (lncRNAs) as promising therapeutic targets for cancers. Herein, this study focused on the clinical implications and functions of a novel antisense lncRNA PRKAG2-AS1 in hepatocellular carcinoma (HCC). Methods: PRKAG2-AS1 expression was examined in a cohort of 138 HCC patients by RT-qPCR. Overall survival (OS) and disease-free survival (DFS) analyses were presented based on PRKAG2-AS1 expression, followed by ROCs. After silencing PRKAG2-AS1, cell proliferation was assessed via CCK-8, colony formation and EdU staining assays. Migrated and invasive capacities were assessed by wound healing and transwell assays. The relationships between PRKAG2-AS1, miR-502-3p and BICD2 were validated by luciferase reporter, RIP and RNA pull-down assays. The expression and prognostic value of BICD2 were analyzed in TCGA database. Results: PRKAG2-AS1 was up-regulated in HCC than normal tissue specimens. High PRKAG2-AS1 expression was indicative of poorer OS and DFS time. Area under the curves (AUCs) for OS and DFS were 0.8653 and 0.7891, suggesting the well predictive efficacy of PRKAG2-AS1 expression. Targeting PRKAG2-AS1 distinctly inhibited proliferation, migration, and invasion in HCC cells. PRKAG2-AS1 was mainly expressed in cytoplasm of HCC cells. PRKAG2-AS1 may directly bind to the sites of miR-502-3p. Up-regulation of BICD2 was found in HCC tissues and associated with unfavorable prognosis. BICD2 was confirmed to be a downstream target of miR-502-3p. PRKAG2-AS1 could regulate miR-502-3p/BICD2 axis. Conclusion: Our findings identified a novel lncRNA PRKAG2-AS1 that was associated with clinical implications and malignant behaviors. Thus, PRKAG2-AS1 could become a promising therapeutic target.
Peng Hu, Bingxia Ming, Xuefen Wu, Shaozhe Cai, Jungen Tang, Yuanji Dong, Tianshu Zhou, Zheng Tan, Jixin Zhong, Fang Zheng, et al.
Published: 13 April 2021
Frontiers in Medicine, Volume 8; doi:10.3389/fmed.2021.645816

Abstract:
Evidences have suggested that Sjogren's syndrome (SS) is associated with viral infection. The aim of this study was to investigate the involvement of respiratory viral poly(I:C) in the pathogenesis of SS and potential mechanisms using a SS-like NOD/ShiLtJ (NOD) mouse model. 5-week female NOD mice were intratracheally administered poly(I:C) every other day for 5 times to mimic viral infection. Pilocarpine induced saliva secretion was determined every 8 days. Submandibular glands (SMG) and lungs were harvested for the detection of pathological changes. We found that intratracheal administration of poly(I:C) significantly advanced and enhanced the reduction of saliva flow rate in NOD mice. Furthermore, poly(I:C) treatment aggravated the histopathological lesions and inflammatory cells infiltration in SMG. Accompanied by elevated expression of IFN cytokines and IL-33, Th1 activation was enhanced in SMG of poly(I:C)-treated NOD mice, but Th17 cells activation was unchanged among the groups. In addition, intratracheal poly(I:C) exposure promoted the expression of IL-33 and increased T cells proportion in the lung, which were consistent with the change in SMG. Therefore, intratracheal poly(I:C) exposure aggravated the immunological and function disorder of SMG in NOD mice.
Roy Koomullil, Behnam Tehrani, Kayla Goliwas, Yong Wang, Selvarangan Ponnazhagan, Joel Berry,
Published: 13 April 2021
Frontiers in Medicine, Volume 8; doi:10.3389/fmed.2021.643793

Abstract:
Cellular exosome-mediated crosstalk in tumor microenvironment (TME) is a critical component of anti-tumor immune responses. In addition to particle size, exosome transport and uptake by target cells is influenced by physical and physiological factors, including interstitial fluid pressure, and exosome concentration. These variables differ under both normal and pathological conditions, including cancer. The transport of exosomes in TME is governed by interstitial flow and diffusion. Based on these determinants, mathematical models were adapted to simulate the transport of exosomes in the TME with specified exosome release rates from the tumor cells. In this study, the significance of spatial relationship in exosome-mediated intercellular communication was established by treating their movement in the TME as a continuum using a transport equation, with advection due to interstitial flow and diffusion due to concentration gradients. To quantify the rate of release of exosomes by biomechanical forces acting on the tumor cells, we used a transwell platform with confluent triple negative breast cancer cells 4T1.2 seeded in BioFlex plates exposed to an oscillatory force. Exosome release rates were quantified from 4T1.2 cells seeded at the bottom of the well following the application of either no force or an oscillatory force, and these rates were used to model exosome transport in the transwell. The simulations predicted that a larger number of exosomes reached the membrane of the transwell for 4T1.2 cells exposed to the oscillatory force when compared to controls. Additionally, we simulated the interstitial fluid flow and exosome transport in a 2-dimensional TME with macrophages, T cells, and mixtures of these two populations at two different stages of a tumor growth. Computational simulations were carried out using the commercial computational simulation package, ANSYS/Fluent. The results of this study indicated higher exosome concentrations and larger interstitial fluid pressure at the later stages of the tumor growth. Quantifying the release of exosomes by cancer cells, their transport through the TME, and their concentration in TME will afford a deeper understanding of the mechanisms of these interactions and aid in deriving predictive models for therapeutic intervention.
, Ander Vergara, Sheila Bermejo, María A. Azancot, Joana Sellarés,
Published: 13 April 2021
Frontiers in Medicine, Volume 8; doi:10.3389/fmed.2021.655871

Abstract:
Obesity is one of the epidemics of our era. Its prevalence is higher than 30% in the U.S. and it is estimated to increase by 50% in 2030. Obesity is associated with a higher risk of all-cause mortality and it is known to be a cause of chronic kidney disease (CKD). Typically, obesity-related glomerulopathy (ORG) is ascribed to renal hemodynamic changes that lead to hyperfiltration, albuminuria and, finally, impairment in glomerular filtration rate due to glomerulosclerosis. Though not only hemodynamics are responsible for ORG: adipokines could cause local effects on mesangial and tubular cells and podocytes promoting maladaptive responses to hyperfiltration. Furthermore, hypertension and type 2 diabetes mellitus, two conditions generally associated with obesity, are both amplifiers of obesity injury in the renal parenchyma, as well as complications of overweight. As in the native kidney, obesity is also related to worse outcomes in kidney transplantation. Despite its impact in CKD and cardiovascular morbility and mortality, therapeutic strategies to fight against obesity-related CKD were limited for decades to renin-angiotensin blockade and bariatric surgery for patients who accomplished very restrictive criteria. Last years, different drugs have been approved or are under study for the treatment of obesity. Glucagon-like peptide-1 receptor agonists are promising in obesity-related CKD since they have shown benefits in terms of losing weight in obese patients, as well as preventing the onset of macroalbuminuria and slowing the decline of eGFR in type 2 diabetes. These new families of glucose-lowering drugs are a new frontier to be crossed by nephrologists to stop obesity-related CKD progression.
Laura Hernández-Hernández, Catalina Sanz, Elena Marcos-Vadillo, Asunción García-Sánchez, Esther Moreno, Félix Lorente, David González-De-Olano, Ignacio Dávila, María Isidoro-García
Published: 13 April 2021
Frontiers in Medicine, Volume 8; doi:10.3389/fmed.2021.577081

Abstract:
Background: Some recent familial studies have described a pattern of autosomal dominant inheritance for increased basal serum tryptase (BST), but no correlation with mRNA expression and gene dose have been reported. Objective: We analyzed TPSAB1 mRNA expression and gene dose in a four-member family with high BST and in two control subjects. Methods: Blood samples were collected from the family and control subjects. Complete morphologic, immunophenotypical, and molecular bone marrow mast cell (MC) studies were performed. mRNA gene expression and gene dose were performed in a LightCycler 480 instrument. Genotype and CNV were performed by quantitative real-time digital PCR (qdPCR). Results: CNV analysis revealed a hereditary copy number gain genotype (3β2α) present in all the family members studied. The elevated total BST in the family members correlated with a significant increase in tryptase gene expression and dose. Conclusions and Clinical Relevance: We present a family with hereditary α-tryptasemia and elevated BST which correlated with a high expression of tryptase genes and an increased gene dose. The family members presented with atypical MC-mediator release symptoms or were even asymptomatic. Clinicians should be aware that elevated BST does not always mean an MC disorder.
, Afshin Ostovar, Saba Maleki Birjandi, Iraj Nabipour, Bagher Larijani,
Published: 13 April 2021
Frontiers in Medicine, Volume 8; doi:10.3389/fmed.2021.655759

Abstract:
Background: Sarcopenia is defined by the loss of muscle mass and function with a considerable prevalence which increases morbidity and mortality. We aimed to develop and validate a simple tool for screening of sarcopenia in Iranian older population. Methods: In this study, we included 2,211 adults aged 60 years or older that participated in the stage II of Bushehr Elderly Health (BEH) program, a population-based prospective cohort study. We defined sarcopenia as reduced skeletal muscle strength plus low muscle mass. The study sample was divided into two parts; development set which were allocated to the development of the model (n = 1,499) and validation set (n = 712) were allocated to validation of the model. Results: There were 22.9% of men and 23.2% women classified as having sarcopenia based on EWGSOP-2.After selection of variables, the final models named SarSA-Mod (Sarcopenia Scoring Assessment Models) were developed with area to under curves (AUC) of 0.82 (0.79–0.86) and 0.87 (0.84–0.90) in men and women, respectively. The final model included “age,” “weight,” and “calf circumference” in both sexes. The sensitivity and specificity and positive and negative predictive values for sarcopenia were 84.3, 76.0, 49.8, and 94.5% for women, 85.4, 64.8, 40.2, and 94.2% for men, respectively. The model performance was tested in the validation set with accuracy 91 and 84% among women and men, respectively. Conclusions: Sarcopenia could be detected using SarSA-Mod, as a simple screening test with high accuracy among both sexes. Also, this screening test is valid, feasible, reliable and cost-effective compared to other tools.
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