Frontiers in Pharmacology最新文献

The rise of β-Lactamase mediated antibiotic resistance is a major concern for public health; hence, there is an urgent need to find new treatment approaches. Structure-guided drug repurposing offers a promising approach to swiftly deliver essential therapeutics in the fight against escalating antibiotic resistance. Here, a structure-guided virtual screening approach was used involving drug profiling, molecular docking, and molecular dynamics (MD) simulation to identify existing drugs against β-Lactamase-associated drug resistance. We exploited a large panel of FDA-approved drugs to an extensive in silico analysis to ascertain their ability to inhibit β-Lactamase. First, molecular docking investigations were performed to assess the binding affinities and interactions of screened molecules with the active site of β-Lactamase enzymes. Out of all the screened candidates, Aristospan was identified to possess promising characteristics, which include appropriate drug profiles, high binding specificity, and efficiency towards the binding pocket of β-Lactamase. Further analysis showed that Aristospan possesses several desirable biological characteristics and tends to bind to the β-Lactamase binding site. To explore the interactions further, the best docking pose of Aristospan was selected for MD simulations to assess the thermodynamic stability of the drug-enzyme complex and its conformational changes over 500 ns. The MD simulations in independent replica runs demonstrated that the β-Lactamase-Aristospan complex was stable in the 500 ns trajectory. These enlightening results suggest that Aristospan may harbor the potential for further evolution into a possible β-Lactamase inhibitor, with potential applications in overcoming antibiotic resistance in both Gram-positive and Gram-negative bacteria.

Introduction: Septic cardiomyopathy (SCM) arises as a consequence of sepsis-associated cardiovascular dysfunction, for which there is currently no specific targeted therapy available. Previous studies have demonstrated the beneficial therapeutic effect of berberine (BBR) on SCM; however, the underlying mechanisms of action remain unclear. The objective of this is to elucidate how BBR alleviates SCM.

Methods: Septic cardiomyopathy rat model was established by performing cecal ligation and puncture (CLP), while a cardiomyocyte injury model was provoked in H9C2 cells using lipopolysaccharide (LPS). Cardiac function was assessed through echocardiography, and myocardial histopathology was examined with hematoxylin-eosin (HE) staining. Cardiomyocyte viability was determined through Cell Counting Kit-8 (CCK8) assay, and measurement of ATP levels was done with an ATP assay kit. Mitochondrial ultrastructure was observed using transmission electron microscopy. Real-time polymerase chain reaction (RT-PCR) and Western blotting were employed to analyze the expression of Notch1 signaling pathway components and downstream molecules in myocardial tissues and cells.

Result: In vivo, BBR markedly improved symptoms and cardiac function in SCM rats, leading to enhanced ATP content, and ameliorated mitochondrial structure. Additionally, BBR increased Notch1 protein expression in myocardial tissue of the rats. In vitro, BBR elevated the survival rates of H9C2 cell, improved mitochondrial morphology, and raised ATP levels. The mRNA expression of Notch1, Hes1, and Hes2, and Notch1 protein expression was upregulated by BBR. While these effects were reversed upon inhibiting the Notch1 signaling pathway.

Conclusion: BBR improves septic cardiomyopathy by modulating Notch1 signaling to protect myocardial mitochondria.

As of December 2020, around 200 vaccine candidates for Coronavirus Disease 2019 (COVID-19) are being developed. COVID-19 vaccines have been created on a number of platforms and are still being developed. Nucleic acid (DNA, RNA) vaccines, viral vector vaccines, inactivated vaccines, protein subunit vaccines, and live attenuated vaccines are among the COVID-19 vaccine modalities. At this time, at least 52 candidate vaccines are being studied. Spike protein is the primary protein that COVID-19 vaccines are targeting. Therefore, it is critical to determine whether immunizations provide complete or fractional protection, whether this varies with age, whether vaccinated people are protected from reoccurring diseases, and whether they need booster shots if they've already been inoculated. Despite the enormous achievement of bringing several vaccine candidates to market in less than a year, acquiring herd immunity at the national level and much more so at the global level remains a major challenge. Therefore, we gathered information on the mechanism of action of presently available COVID-19 vaccines in this review and essential data on the vaccines' advantages and downsides and their future possibilities.

Background and objective: In recent years, the consumption of fish products has led to a worrying trend where approximately two-thirds of the total amount of fish is discarded as waste. At the same time, scientific interest in exploring natural collagen sources for cosmetics and dietary supplements has increased. This study explores the potential of valorizing sardine scales (Sardina pilchardus), a by-product of the canning industry, through the extraction of collagen for potential use in dermocosmetic formulations and food supplements.

Methods: Collagen from sardine scales was obtained though acid and enzymatic extraction. The collagen extracts were characterized by UV-Vis, FTIR spectroscopy, SDS-PAGE, powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The collagen was hydrolysed with papain to small peptides. Subsequently, the biological activities of acid-soluble collagen as well as the collagen peptides in terms of antioxidant and antimicrobial activity were evaluated. Furthermore, the capacity of collagen peptides to permeate the intestinal barrier, simulated with caco-2 cells, was evaluated.

Results: Purified collagen extracts were obtained from sardine scales, with enzymatic extraction method having a yield three times higher than the acid method. The SDS-PAGE analysis confirmed the extraction of type I collagen as well as its hydrolysis into small fragments (25-12 kDa). In terms of biological activities, collagen and collagen peptides have not demonstrated antimicrobial activity. However, regarding antioxidant activity, collagen peptides showed three times more capacity compared to non-hydrolyzed collagen. Meanwhile, in 6 h, about 6.37% of collagen peptides could permeate the intestinal barrier.

Conclusion: This work represents a continuous effort to advance our understanding and utilization of Portuguese marine waste resources, with focus on the valorization of sardine co-products for the development of food supplement or cosmetic formulations, contributing to the sustainable evolution of the circular blue economy.

Background: Gastrodiae rhizoma (GR) refers to the dried tuber of Gastrodia elata Bl. and has been used for many centuries to treat brain diseases, such as Alzheimer's disease, major depressive disorder, and cerebral ischemia. However, the processing of GR is complex and varied, resulting in unstable clinical treatment effects. The processing protocols significantly affect the active ingredients and curative effects of GR. We can optimize the processing of GR by identifying quality markers to treat brain diseases.

Methods: Fresh tubers of G. elata Bl. were processed under eight different protocols, and their resulting contents of potentially bioactive compounds were compared using liquid chromatography mass spectrometry to screen the potential quality markers of GR through stoichiometric analysis. The potential quality markers of GR targeting Alzheimer's disease, major depressive disorder, and cerebral ischemia were identified by network pharmacology, and the potentially neuroprotective effects of these components were validated through simulated docking to likely protein targets. Finally, a fit degree analysis was carried out using different composition ratios and proportions of the disease component degree value, and the therapeutic effects of different processing methods on Alzheimer's disease, major depressive disorder, and cerebral ischemia were outlined clearly.

Results: We identified 32 potential therapeutic components and screened 13 quality markers in GR, of which five quality markers (galactinol, glucosyringic acid, parishins C and E, and S-(4-hydroxybenzyl)-glutathione) showed efficacy against all three brain diseases. Furthermore, steaming and microwave-drying during processing can optimize the components of these quality markers for treating the three diseases.

Conclusion: Processing protocols significantly affect the therapeutic components of GR and may also impact its effectiveness in treating brain diseases. Accordingly, optimizing the processing methods of GR to correspond to different therapeutic purposes may improve its efficacy against brain diseases.

Fibrosis is significantly associated with a wide variety of diseases and is involved in their progression. Fibrosis activated under the influence of different combinations of factors is considered a double-edged sword. Although there has been much research on organ fibrosis in recent years, a variety of organ fibrosis diseases and cancers are not well controlled in terms of prevention, treatment, and prognosis. Clinical studies still lack exploration and discovery of effective targets for the pathogenesis of organ fibrosis. Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) is a protein kinase and the synthesis and secretion of collagen are related to the sustained activation of P4HA1. As further studies are being conducted, the potential role of P4HA1 in the development of fibrosis-associated diseases and cancer is becoming clear. Consequently, we conducted a systematic review and discussion on the role of P4HA1 in the pathogenesis of various fibrosis-related diseases and cancers. We reviewed the possible strategies of P4HA1 in the diagnosis and treatment of fibrosis-related diseases and cancers, and analyzed its potential relevance as a biomarker in the diagnosis and treatment of fibrosis-related diseases and cancer.

Background: The success of mass drug administration (MDA) for lymphatic filariasis (LF) elimination relies on achieving a participation rate of at least 65% within the endemic community. However, participation of sub-population in the community varies and a significant treatment gap among the elderly population, remains to be addressed. The present study explores the factors influencing the elderly participation in MDA and propose possible solutions to bridge the gap.

Methods: A cross-sectional study of individuals aged 60 years and above was conducted from August to December 2023 in Yadgiri district of Karnataka, which is endemic for LF. The participants were interviewed using a structured questionnaire, focusing on the perception about LF and MDA and drug consumption behaviours. STATA 14 software was used to analyse the data. We used a logistic regression model to determine the factors influencing drug consumption.

Results: The study included 315 elderly individuals with a mean age (SD) of 67.4 (6.2) years. Although, 58.4% of them received the drugs during the last round of MDA in 2023, only 40.6% consumed it. The drug refusal rate was 19.4%. Fear of side effects (22.9%) was cited as the primary reason for not accepting the drugs. Weak perception of LF transmission risk (25.7%) and mistrust of drug safety (42.5%) were reported as reasons for non-compliance. Logistic regression identified significant associations, including residence (peri-urban: OR = 6.80), chronic disease (diabetes: OR = 2.89), trust on drug safety (OR = 16.27), and opinion of neighbours (OR = 5.35).

Conclusion: Participation of elderly population in MDA was suboptimal (40.6%). Tailored interventions to improve consumption such as addressing misconceptions, building trust in MDA and effective monitoring and management of adverse events are vital to enhance their participation. The National Programme should have specific guidelines and strategies to address this issue to improve their participation in MDA for elimination of LF.

Background: This study aimed to explore the mechanism of action of DiWuYangGan (DWYG) capsule in improving Immunological non-responder (INR) by analyzing the active ingredients of DWYG.

Methods: The study employed a randomized, controlled, double-blind, single-simulation method. Patients were randomly divided into control and trial groups and treated with the primal highly effective antiretroviral therapy. To demonstrate the effect of DWYG on INR, patients in the control group were administered simulated DWYG, whereas patients in the trial group were administered DWYG capsules (ChiCTR1900024673). The chemical composition of DWYG was analyzed using ultra-performance liquid chromatography-high-resolution mass spectrometry. Potential targets of DWYG in the treatment of INR were identified and predicted using network pharmacology and molecular docking. The molecular mechanisms underlying the effects of DWYG were validated using a peripheral blood monocyte model.

Results: The CD4:CD8 ratio in the trial group was significantly higher than that in the control group (p < 0.01). A total of 210 DWYG compounds were identified and network pharmacology revealed 182 potential therapeutic targets for DWYG and INR. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the toll-like receptor signaling pathway is one of the key pathways. This study demonstrated that DWYG reduced the expression level of TLR4 and the levels of IL-2, IL-10, and TNF-α, which are important cytokines involved in the immune response.

Conclusion: The efficacy of DWYG in the treatment of INR confirmed the potential practical components of DWYG. Moreover, the results of network pharmacology and experimental validation showed that DWYG could restore the immune function of acquired immune deficiency syndrome patients by inhibiting the expression of TLR4 and related signaling pathways and the overactivation of immune function.

Clinical trial registration: https://www.chictr.org.cn/index.html, identifier ChiCTR1900024673.

Objective: Tirzepatide, a novel GIP and GLP1 agonist, has been extensively examined in clinical trials. However, specific data on its adverse drug events (ADEs) remain limited. This study aims to comprehensively assess real-world ADEs associated with tirzepatide by mining data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Methods: ADE reports from the FAERS database were retrieved for the second quarter of 2022 through the first quarter of 2024. Significant associations between ADEs and tirzepatide were evaluated using proportional disproportionality analyses, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinkage (MGPS).

Results: A total of 37,827 ADE reports associated with tirzepatide were identified, with 100 significantly disproportionate preferred terms (PTs) recognized by all four algorithms. The top five PTs with the highest reporting rates were incorrect dose administered, injection site pain, off-label use, nausea, and injection site hemorrhage. Additionally, unexpected signals such as starvation ketoacidosis were identified. The median time to onset for all ADEs was 23 days. Furthermore, sex-specific high-intensity signals were found, with males primarily experiencing gastrointestinal disorders and females experiencing general disorders and administration site conditions.

Conclusion: This study provides valuable insights into the occurrence of ADEs following tirzepatide administration, potentially supporting clinical monitoring and risk identification efforts.

Background: Despite growing use, questions remain surrounding the utility, acceptability and feasibility of chemical adherence testing (CAT) as part of hypertension management in clinical practice.

Objectives: This scoping review aimed to (i) identify and summarise studies using CAT in hypertension management, and (ii) describe and critically evaluate how CAT is currently being used in the clinical management of hypertension.

Eligibility criteria: Peer-reviewed and published studies in English, reporting original research in any setting, with any study design, were included. Search concepts included hypertension, medication adherence, CAT, and their synonyms.

Sources of evidence: Searches were carried out using Ovid Medline, EMBASE, and PsycInfo (EBSCO), alongside manual searching of reference lists. Using Covidence software, we screened titles and abstracts, followed by full-text articles. Data from the included articles were tabulated and summarised.

Results: Of the 618 studies identified, 48 were included. The studies cover diverse clinical settings, and were mostly observational in design. 7 studies reporting adherence analyses within clinical trials for hypertension therapies. The use of theoretical frameworks to guide reporting was rare, and there was considerable variation in key terminology and definitions, most notably in the definition of adherence.

Conclusion: The current body of evidence demonstrates considerable variability in the approach to implementing CAT for hypertension management in clinical practice, and a paucity of randomised controlled trials to evaluate its impact. Future research could (i) adopt a cohesive theoretical framework including clear operational definitions to standardise the approach to this important topic; (ii) further explore the impact of CAT on clinical outcomes using RCTs.