Frontiers in Pharmacology

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EISSN: 16639812
Published by: Frontiers Media SA
Total articles ≅ 18,752

Latest articles in this journal

, Johan Fritzell, Bo Burström, Kristina Johnell, Johan Fastbom
Published: 8 February 2023
Frontiers in Pharmacology, Volume 14; https://doi.org/10.3389/fphar.2023.1030849

Abstract:
Introduction: Potentially inappropriate drug use (PID) is common among older adults. Cross-sectional data suggest that there are marked regional variations in PID in Sweden. There is, however, a lack of knowledge about how the regional variations have changed over time.Objectives: This study aimed to investigate the regional differences in the prevalence of PID in Sweden, 2006–2020.Methods: In this repeated cross-sectional study, we included all older adults (≥75 years) registered in Sweden, yearly from 2006 to 2020. We used nationwide data from the Swedish Prescribed Drug Register linked at the individual level to the Swedish Total Population Register. We selected three indicators of PID according to the Swedish national “Quality indicators for good drug therapy in the elderly”: 1) Excessive polypharmacy (use of ≥10 drugs); 2) Concurrent use of three or more psychotropic drugs; 3) Use of “drugs that should be avoided in older adults unless specific reasons exist.” The prevalence of these indicators was calculated for each of Sweden’s 21 regions, yearly from 2006 to 2020. The annual coefficient of variation (CV) was calculated for each indicator by dividing the standard deviation of the regions by the national average, to measure relative variability.Results: In the population of about 800,000 older adults per year, the national prevalence of “drugs that should be avoided in older adults,” was reduced by 59% from 2006 to 2020. There was a slight decline in the use of three or more psychotropics, while the prevalence of excessive polypharmacy increased. The CV for excessive polypharmacy was 14% in 2006 and 9% in 2020 compared to 18% and 14% for “use of three or more psychotropics”, and stable at around 10% for ‘drugs that should be avoided in older adults.’Conclusions: The regional variation in potentially inappropriate drug use decreased or were stable from 2006 to 2020. The regional differences were largest for the use of three or more psychotropics. We found a general tendency that regions with a good performance at the start of the period performed well across the entire period. Future studies should investigate the reasons for regional variation and explore strategies to reduce unwarranted differences.
Azraul Mumtazah Razak, Siti Nor Asyikin Zakaria, Nur Fathiah Abdul Sani, Nazirah Ab Rani, Nur Haleeda Hakimi, Mazlina Mohd Said, Jen Kit Tan, Han Kwang Gan, Mariam Firdhaus Mad Nordin,
Published: 8 February 2023
Frontiers in Pharmacology, Volume 14; https://doi.org/10.3389/fphar.2023.1006265

Abstract:
Introduction: Ginger (Zingiber officinale Roscoe) can scavenge free radicals, which cause oxidative damage and inflamm-ageing. This study aimed to evaluate the antioxidant and anti-inflammatory effects of soil ginger's sub-critical water extracts (SWE) on different ages of Sprague Dawley (SD) rats. The antioxidant properties and yield of SWE of soil- and soilless-grown ginger (soil ginger and soilless ginger will be used throughout the passage) were compared and evaluated.Methods: Three (young), nine (adult), and twenty-one (old) months old SD rats were subjected to oral gavage treatments with either distilled water or the SWE of soil ginger at a concentration of 200 mg/kg body weight (BW) for three months.Results: Soil ginger was found to yield 46% more extract than soilless ginger. While [6]-shogaol was more prevalent in soilless ginger, and [6]-gingerol concentration was higher in soil ginger (p < 0.05). Interestingly, soil ginger exhibited higher antioxidant activities than soilless ginger by using 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assay. With ginger treatment, a reduced levels of tumour necrosis factor-α (TNF-α) and C-reactive protein (CRP) but not interleukin-6 (IL-6) were observed in young rats. In all ages of SD rats, ginger treatment boosted catalase activity while lowering malondialdehyde (MDA). Reduction of urine 15-isoprostane F2t in young rats, creatine kinase-MM (CK-MM) in adult and old rats and lipid peroxidation (LPO) in young and adult rats were also observed.Discussion: The findings confirmed that the SWE of both soil and soilless grown ginger possessed antioxidant activities. Soil ginger produced a higher yield of extracts with a more prominent antioxidant activity. The SWE of soil ginger treatment on the different ages of SD rats ameliorates oxidative stress and inflammation responses. This could serve as the basis for developing a nutraceutical that can be used as a therapeutic intervention for ageing-related diseases.
Yunfang Su, Ningning Liu, Ruiqin Sun, Jinlian Ma, Zhonghua Li, Pan Wang, Huifen Ma, Yiran Sun, Junying Song, Zhenqiang Zhang
Published: 8 February 2023
Frontiers in Pharmacology, Volume 14; https://doi.org/10.3389/fphar.2023.1115387

Abstract:
Radix Rehmanniae Praeparata (RRP, Shu Dihuang in Cinese) is widely used as primal medicine in Chinese herbal formula for the treatment of Alzheimer’s disease (AD). However, the underlying mechanism of RRP for AD remains unclear. The aim of this study was to investigate the therapeutic effect of RRP on intracerebroventricular injection of streptozotocin (ICV-STZ)-induced AD model mice and its potential mechanism. ICV-STZ mice were continuously gavaged with RRP for 21 days. The pharmacological effects of RRP were evaluated by behavioral tests, brain tissue H&E staining and hippocampal tau protein phosphorylation levels. The expression levels of insulin receptor (INSR), IRS-1, pSer473-AKT/AKT and pSer9-GSK-3β/GSK-3β proteins in hippocampal and cortical tissues were detected by Western-blot method. The 16S rRNA gene sequencing was used to analyze the changes of intestinal microbiota in mice. The compounds in RRP were analyzed by mass spectrometry and their binding ability to INSR proteins was detected by molecular docking. The results showed that RRP ameliorated cognitive dysfunction and neuronal pathological changes of brain tissue in ICV-STZ mice, reduced tau protein hyperphosphorylation, INSR, IRS-1, pSer473-AKT/AKT, and pSer9-GSK-3β/GSK-3β levels in hippocampal and cortical tissues. Meanwhile, RRP reversed ICV-STZ-induced dysregulation of intestinal microbiota in AD mice. Mass spectrometry analysis showed that the RRP consisted mainly of seven compounds, namely Acteoside (Verbascoside), 5-Hydroxymethyl-2-furaldehyde (5-HMF), Apigenin7-O-glucuronide, Icariin, Gallic acid, Quercetin-3β-D-glucoside, and Geniposide. Molecular docking results further indicated that the compounds in RRP have binding ability to INSR protein and potential multiple synergistic effects. RRP ameliorates cognitive dysfunction and brain histopathological changes in AD mice. The mechanism of RRP ameliorating AD may be related to the regulation of INSR/IRS-1/AKT/GSK-3β signaling pathway and intestinal microbiota. This study supports the potential anti-AD efficacy of RRP and initially reveals the pharmacological mechanism of RRP, providing a theoretical basis for further clinical application of RRP.
Haibo Hu, Fengchan Wang, Ping Han, Peng Li, Kun Wang, Huan Song, Guojing Zhao, Yue Li, Xuechao Lu, Weihong Tao, et al.
Published: 8 February 2023
Frontiers in Pharmacology, Volume 14; https://doi.org/10.3389/fphar.2023.1084617

Abstract:
Introduction: Bu-Fei-Huo-Xue capsule (BFHX) has been used to treat pulmonary fibrosis (PF) in clinic. However, the mechanism of Bu-Fei-Huo-Xue capsule on pulmonary fibrosis remains unclear. Recent studies have shown that the changes in gut microbiota were closely related to the progression of pulmonary fibrosis. Modulating gut microbiota provides new thoughts in the treatment of pulmonary fibrosis.Methods: In this study,a mouse model of pulmonary fibrosis was induced using bleomycin (BLM) and treated with Bu-Fei-Huo-Xue capsule. We firstly evaluated the therapeutic effects of Bu-Fei-Huo-Xue capsule on pulmonary fibrosis model mice. Besides,the anti-inflammatory and anti- oxidative effects of Bu-Fei-Huo-Xue capsule were evaluated. Furthermore, 16S rRNA sequencing was used to observe the changes in gut microbiota in pulmonary fibrosis model mice after Bu-Fei-Huo-Xue capsule treatment.Results: Our results showed that Bu-Fei-Huo-Xue capsule significantly reduced the collagen deposition in pulmonary fibrosis model mice. Bu-Fei-Huo-Xue capsule treatment also reduced the levels and mRNA expression of pro-inflammatory cytokines and inhibited the oxidative stress in lung. 16S rRNA sequencing showed that Bu-Fei-Huo-Xue capsule affected the diversity of gut microbiota and the relative abundances of gut microbiota such as Lactobacillus, Lachnospiraceae_NK4A136_group, and Romboutsia.Conclusion: Our study demonstrated the therapeutic effects of Bu-Fei-Huo-Xue capsule on pulmonary fibrosis. The mechanisms of Bu-Fei-Huo-Xue capsule on pulmonary fibrosis may be associated with regulating gut microbiota.
Thi-Phuong Tao, Ilka Maschmeyer, Edward L. LeCluyse, Eda Rogers, Katrin Brandmair, Silke Gerlach, Julia Przibilla, Fredy Kern, Camille Genies, Carine Jacques, et al.
Published: 8 February 2023
Frontiers in Pharmacology, Volume 14; https://doi.org/10.3389/fphar.2023.1076254

Abstract:
All cosmetic ingredients registered in Europe must be evaluated for their safety using non-animal methods. Microphysiological systems (MPS) offer a more complex higher tier model to evaluate chemicals. Having established a skin and liver HUMIMIC Chip2 model demonstrating how dosing scenarios impact the kinetics of chemicals, we investigated whether thyroid follicles could be incorporated to evaluate the potential of topically applied chemicals to cause endocrine disruption. This combination of models in the HUMIMIC Chip3 is new; therefore, we describe here how it was optimized using two chemicals known to inhibit thyroid production, daidzein and genistein. The MPS was comprised of Phenion® Full Thickness skin, liver spheroids and thyroid follicles co-cultured in the TissUse HUMIMIC Chip3. Endocrine disruption effects were determined according to changes in thyroid hormones, thyroxine (T4) and 3,3’,5-triiodothyronine (T3). A main part of the Chip3 model optimization was the replacement of freshly isolated thyroid follicles with thyrocyte-derived follicles. These were used in static incubations to demonstrate the inhibition of T4 and T3 production by genistein and daidzein over 4 days. Daidzein exhibited a lower inhibitory activity than genistein and both inhibitory activities were decreased after a 24 h preincubation with liver spheroids, indicating metabolism was via detoxification pathways. The skin-liver-thyroid Chip3 model was used to determine a consumer-relevant exposure to daidzein present in a body lotion based on thyroid effects. A “safe dose” of 0.235 μg/cm2 i.e., 0.047% applied in 0.5 mg/cm2 of body lotion was the highest concentration of daidzein which does not result in changes in T3 and T4 levels. This concentration correlated well with the value considered safe by regulators. In conclusion, the Chip3 model enabled the incorporation of the relevant exposure route (dermal), metabolism in the skin and liver, and the bioactivity endpoint (assessment of hormonal balance i.e., thyroid effects) into a single model. These conditions are closer to those in vivo than 2D cell/tissue assays lacking metabolic function. Importantly, it also allowed the assessment of repeated doses of chemical and a direct comparison of systemic and tissue concentrations with toxicodynamic effects over time, which is more realistic and relevant for safety assessment.
Wanxu Guo, Xiaoxiao Yao, Ranji Cui, Wei Yang, Lei Wang
Published: 8 February 2023
Frontiers in Pharmacology, Volume 13; https://doi.org/10.3389/fphar.2022.934199

Abstract:
Paeoniflorin (PF) has been widely used for the treatment of depression in mice models, some Chinese herbal compound containing PF on treating depression, such as Xiaoyao San, Chaihu-Shugan-San, Danggui Shaoyao San etc. Many experiments are also verifying whether PF in these powders can be used as an effective component in the treatment of depression. Therefore, in this review the antidepressant effect of PF and its mechanism of action are outlined with particular focus on the following aspects: increasing the levels of monoamine neurotransmitters, inhibiting the HPA axis, promoting neuroprotection, enhancing neurogenesis in the hippocampus, and elevating levels of brain-derived neurotrophic factor (BDNF). This review may be helpful for the application of PF in the treatment of depression.
Ming Wu, Hui Ding, Xiao Tang, Jiayi Chen, Meng Zhang, Ziqiong Yang, , Jun Wang
Published: 8 February 2023
Frontiers in Pharmacology, Volume 14; https://doi.org/10.3389/fphar.2023.1111267

Abstract:
Objective: The aim of this study was to develop a thermosensitive in situ gel (TISG) as an effective rectal delivery platform for delivering Periplaneta americana extracts (PA) to alleviate ulcerative colitis (UC) and explore the underlying molecular mechanism.Materials and methods: Thermosensitive (poloxamer 407) and adhesive polymers (chondroitin sulfate modified carboxymethyl chitosan, CCMTS) were used to construct the in situ gel. CCMTS and aldehyde poloxamer 407 (P407-CHO) were synthesized and chemically cross-linked by Schiff base reaction to formulate thermosensitive in situ gel, which carried Periplaneta americana extracts (PA/CCMTS-P). The cytotoxicity and cellular uptake of CCMTS-P were investigated in lipopolysaccharide (LPS) -induced macrophages by CCK-8 assay. The anti-inflammatory effects of PA/CCMTS-P were studied in lipopolysaccharide-induced RAW264.7 cells and dextran sulfate sodium (DSS)-induced ulcerative colitis mouse models. In addition, the ability of PA/CCMTS-P to restore the intestinal mucosal barrier after rectal administration was evaluated by immunohistochemical analysis (IHC).Results: PA/CCMTS-P was prepared and characterized as gel with a phase-transition temperature of 32.9°C. The results of the in vitro experiments indicated that the hydrogels promoted the cellular uptake of Periplaneta americana extracts without causing any toxicity as compared to the free gel. PA/CCMTS-P showed superior anti-inflammatory activity both in vitro and in vivo, which restored the damaged intestinal mucosal barrier associated by inhibiting necroptosis in dextran sulfate sodium-induced ulcerative colitis models.Conclusion: The findings from our study show that the rectal administration of PA/CCMTS-P holds a promising potential for the treatment of ulcerative colitis.
Fahad S. Alshehri, Nasser M. Alorfi
Published: 7 February 2023
Frontiers in Pharmacology, Volume 14; https://doi.org/10.3389/fphar.2023.1130670

Abstract:
Background: Vancomycin is a glycopeptide antibiotic with a high risk of acute liver injury. Resveratrol is believed to protect the liver against toxicity.Aim: To investigate the ability of resveratrol to attenuate vancomycin-induced liver toxicity in rats injected with vancomycin.Method: Twenty-four adult male Wistar rats were distributed into three groups. The control group received only a vehicle, while the treated group received either vancomycin 200 (mg/kg, i. p.) only or vancomycin (200 mg/kg, i. p.) with resveratrol (20 mg/kg, oral gavage). All groups received their dose once daily for 7 days. Hepatic damage was assessed by measuring biochemical parameter levels in serum, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH). Also, antioxidants and inflammation biomarkers such as Interleukin-6 (IL-6), malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) were measured. Furthermore, the vancomycin-induced pathological changes in the liver were evaluated by histopathological studies.Results: In the vancomycin-treated group, hepatic serum biomarkers such as AST, ALT, ALP, IL-6, and MDA were elevated, while NO and GSH were depleted. However, resveratrol co-treatment with vancomycin prevented the elevation of AST, ALT, ALP, IL-6, and MDA and it protected the liver from NO and GSH depletion. Also, regarding vancomycin-induced degeneration of hepatocytes, resveratrol co-treatment with vancomycin prevented such degeneration and improved mononuclear cells in the liver.Conclusion: The results showed that oral administration of resveratrol has a significant hepatoprotective effect against vancomycin-induced hepatotoxicity.
Sanaya Rehman, , Peter John
Published: 7 February 2023
Frontiers in Pharmacology, Volume 14; https://doi.org/10.3389/fphar.2023.1127201

Abstract:
Objective: This study aimed to assess the anti-rheumatic potential of Dodonaea viscosa and to evaluate its bioactive small molecules for their beneficial effects in the management of rheumatoid arthritis.Methods:In vitro bioactivity assays were performed to assess the healing potential of D. viscosa and statistical analysis was performed by using the linear regression technique. In silico analysis was performed to identify the key inhibitors of the disease to target TNF-α. The plant extract was prepared using ethanol solvent via the Soxhlet method. Phytochemical and bioactivity testing was performed. Gas chromatography–mass spectrometry (GC-MS) analysis was conducted for bioactive plant compounds. Disease-specific target was shortlisted by HUB gene analysis. Molecular docking and molecular dynamic simulations were run for validation of the results.Results: Phytochemical studies verified the presence of phenols, flavonoids, steroids, sterols, saponins, coumarins, tannins, and terpenoids. The significant antioxidant potential of plant extract was evaluated by the DPPH and Ferric Reducing Antioxidant Power (FRAP) assays, while the anti-inflammatory potential was evaluated by the protein denaturation and Human Red Blood Cell (HRBC) membrane stabilization assays. In silico studies revealed that nine of the 480 compounds found in D. viscosa (ethanol extract) had drug-like properties. Tumor necrosis factor alpha (TNF-α) was selected as a key disease gene through HUB gene analysis. Results of molecular docking and MD simulation analysis demonstrated that 4-(1-hydroxy-3-oxo-1H-isoindol-2-yl) benzoic acid (PubChemID 18873897), had the best binding affinity with TNF-α amongst all nine compounds.Conclusion: 4-(1-hydroxy-3-oxo-1H-isoindol-2-yl) benzoic acid (PubChemID 18873897), have the potential to be a good small molecule inhibitor of TNF-α against rheumatoid arthritis.
Wei Zhuang, Tao He, Bei-Bei Jia, Zhi-Zhou Wang, Lan Zhang, Xian-Zhe Dong,
Published: 7 February 2023
Frontiers in Pharmacology, Volume 14; https://doi.org/10.3389/fphar.2023.1040778

Abstract:
Background: Digoxin is one of the most widely and commonly used cardiac drug, which plays an irreplaceable role in treating heart failure and arrhythmia. The 2010 Edition of Pharmacopoeia of the People’s Republic of China stipulates that the effective range of digoxin plasma concentration is 0.5–2.0 ng/mL and it is toxic at plasma concentration >2 ng/mL. Its effective plasma drug concentration is close to the toxic concentration, and large individual differences in the effects of the drug have been observed. It is often used in combination with other drugs, but drug interactions have a great impact on the plasma concentration of digoxin and lead to adverse reactions (ADRs), such as poisoning. Most of the reported drug interactions are with Western drugs. However, there are many combinations of traditional Chinese medicine (TCM) and Western drugs, TCM interacting with digoxin comprises monomer components, single medicines, and Chinese patent medicines.Aim of the study: We aimed i) to provide an overview of the TCM formulations affecting the pharmacology of digoxin and their mechanisms of action and ii) to provide a theoretical reference for the safe and rational use of digoxin in combination with TCM in clinical practice and to avoid ADRs.Methods: A literature search of electronic databases, including PubMed, MEDLINE, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and WANFANG Data, was performed to search for articles published between 1 January 1960, and 1 August 2022. Search terms used included “digoxin,” “traditional Chinese medicine,” “Chinese patent medicine,” and “adverse reactions” and their combinations.Results: A total of 49 articles were obtained, including clinical reports, pharmacological experiments and in vitro experiments. The mechanisms of action affecting the pharmacology of digoxin are complex. TCM formulations may affect the pharmacology of digoxin in vivo by influencing gastrointestinal motility or gastric juice pH, regulating P-glycoprotein levels, exerting cumulative pharmacological effects, and enhancing the sensitivity of the heart to digoxin. Although studies have shown that some TCM formulations interact with digoxin, they may be influenced by the complexity of the composition and the pharmacological effects of the TCM, the sensitivity of digoxin concentration determination methods, etc. The results of existing studies are controversial and further in-depth studies are required.Conclusion: Combinations of digoxin and TCM formulations are commonly used. This article serves as a reference to understand the interactions between TCM formulations and digoxin to avoid the occurrence of ADRs and improve the efficacy and safety of digoxin.
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