Frontiers in Pharmacology最新文献

{"title":"β-blockers and metabolic modulation: unraveling the complex interplay with glucose metabolism, inflammation and oxidative stress.","authors":"Szymon Drygała, Michał Radzikowski, Mateusz Maciejczyk","doi":"10.3389/fphar.2024.1489657","DOIUrl":"https://doi.org/10.3389/fphar.2024.1489657","url":null,"abstract":"<p><p>The growing burden of metabolic disorders manifested by hypertension, type 2 diabetes mellitus, hyperlipidemia, obesity and non-alcoholic fatty liver disease presents a significant global health challenge by contributing to cardiovascular diseases and high mortality rates. Β-blockers are among the most widely used drugs in the treatment of hypertension and acute cardiovascular events. In addition to blocking the receptor sites for catecholamines, third-generation β-blockers with associated vasodilating properties, such as carvedilol and nebivolol, provide a broad spectrum of metabolic effects, including anti-inflammatory and antioxidant properties and a favorable impact on glucose and lipid metabolism. This review aims to report the impact of β-blockers on metabolic modulation based on available literature data. We present an overview of β-blockers and their pleiotropic properties, discuss mechanisms by which these drugs affect cellular metabolism and outline the future perspectives. The influence of β-blockers on glucose metabolism, insulin sensitivity, inflammation and oxidative stress is complex and varies depending on the specific β-blocker used, patient population and underlying health conditions. Recent evidence particularly highlights the potential role of vasodilatory and nitric oxide-mediated properties of nebivolol and carvedilol in improving glycemic control, insulin sensitivity, and lipid metabolism and mitigating oxidative stress and inflammation. It suggests that these drugs may be potential therapeutic options for patients with metabolic disorders, extending beyond their primary role in cardiovascular management.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1489657"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of icariin on ovarian cancer: a combined network pharmacology and meta-analysis of <i>in vitro</i> studies approach.","authors":"Shang-Mei Cao, Bo-Lin Chen, Zhen-Zhen Zou, Shao-Zhe Yang, Xiu-Hong Fu","doi":"10.3389/fphar.2024.1418111","DOIUrl":"https://doi.org/10.3389/fphar.2024.1418111","url":null,"abstract":"<p><strong>Introduction: </strong>An abundance of experimental evidence indicates that icariin (ICA) could potentially exert an anti-tumor effect on ovarian cancer (OC). Nevertheless, the reliability of this evidence remains ambiguous. This study aimed to explore the impact of ICA on OC and the underlying mechanisms.</p><p><strong>Methods: </strong>Bioinformatics analysis was employed to pinpoint ICA-targeted genes and signaling pathways implicated in OC, utilizing network pharmacology. Subsequently, PubMed, EMBASE, and Web of Science databases were systematically searched from 2001 through June 2023 for <i>in vitro</i> trials evaluating the anti-tumor efficacy of conventional ICA versus placebo in OC. The pathways and genes identified in the literature were recorded, and the therapeutic targets were statistically analyzed and compared with the predicted targets from network pharmacology to confirm the precision of the targets.</p><p><strong>Results and discussion: </strong>Fourteen target genes were validated with success. The pathways corresponding to the remaining genes-excluding these 14-were analyzed and found to be primarily associated with cell apoptosis, anti-tumor, and other related pathways. Out of the 76 studies retrieved, eight fulfilled the inclusion criteria. The subsequent meta-analysis suggested that ICA treatment was significantly correlated with reduced cell growth and induced apoptosis. This study demonstrated a certain efficacy of ICA compared to placebo in enhancing anti-tumor outcomes, characterized by increased abilities in reducing cell growth and inducing apoptosis. The pathways involved in the therapeutic effect may be linked to cell apoptosis and anti-tumor mechanisms.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1418111"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-effectiveness analysis of first-line combination chemotherapy regimens for metastatic pancreatic cancer and evidence-based pricing strategy of liposomal irinotecan in China.","authors":"Zuojuan Xiang, Ling Ma, Zhengxiong Li, Yingzhou Fu, Yong Pan","doi":"10.3389/fphar.2024.1488645","DOIUrl":"https://doi.org/10.3389/fphar.2024.1488645","url":null,"abstract":"<p><strong>Background: </strong>The phase III NAPOLI-3 trial, which upgraded FOLFIRINOX (leucovorin, fluorouracil, irinotecan and oxaliplatin) to NALIRIFOX (liposomal irinotecan, oxaliplatin, leucovorin, and fluorouracil), demonstrated the superiority of NALIRIFOX over GEMNABP (gemcitabine and nab-paclitaxel) as the first-line treatment for metastatic pancreatic ductal adenocarcinoma. The purpose of this study was to assess the cost-effectiveness of NALIRIFOX, FOLFIRINOX, and GEMNABP, and to simulate the price of liposomal irinotecan at which NALIRIFOX could achieve cost-effectiveness.</p><p><strong>Methods: </strong>A partitioned survival model was performed to evaluate the cost-effectiveness of NALIRIFOX, FOLFIRINOX and GEMNABP from the perspective of the Chinese healthcare system. Survival data was obtained from a recently published network meta-analysis (NMA). Drug prices were collected from the database of the Hunan Province Drug and Medical Consumables Procurement Management Subsystem. Other cost and utility values were sourced from established literature. Cumulative costs, LYs (life-years), quality-adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs), net monetary benefits (NMBs) and incremental net monetary benefits (INMBs) were the main outputs. Furthermore, the variations in ICER were analyzed as the price of liposomal irinotecan gradually decreased when comparing NALIRIFOX with FOLFIRINOX or GEMNABP. The robustness of the model was assessed by sensitivity analysis and scenario analysis.</p><p><strong>Results: </strong>At the willingness-to-pay (WTP) threshold of $38,223.34, GEMNABP was the favored treatment. NALIRIFOX was associated with the highest LYs, QALYs, and cost. The cost-effectiveness of NALIRIFOX would be obtained if the price of liposomal irinotecan was less than $3.36/mg and $2.08/mg compared to FOLFIRINOX and GEMNABP, respectively, without considering the patient assistance program (PAP). Sensitivity analysis and scenario analysis revealed that the results of the model were stable.</p><p><strong>Conclusion: </strong>From an economic standpoint, GEMNABP represents the favored choice in the prevailing market conditions among these three first-line combination chemotherapy regimens. The price simulation of liposomal irinotecan conducted in this study could provide valuable evidence for healthcare decision-making. Further evidence regarding the budget impact is still needed.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1488645"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacogenomics for neurodegenerative disorders - a focused review.","authors":"S Rehan Ahmad, Md Zeyaullah, Mohammad Suhail Khan, Abdullah M AlShahrani, Abdelrhman A Galaleldin Altijani, Haroon Ali, Adam Dawria, Ali Mohieldin, Mohammad Shane Alam, Awad Osman Abdalla Mohamed","doi":"10.3389/fphar.2024.1478964","DOIUrl":"https://doi.org/10.3389/fphar.2024.1478964","url":null,"abstract":"<p><p>Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by the progressive degeneration of neuronal structure and function, leading to severe cognitive and motor impairments. These conditions present significant challenges to healthcare systems, and traditional treatments often fail to account for genetic variability among patients, resulting in inconsistent therapeutic outcomes. Pharmacogenomics aims to tailor medical treatments based on an individual's genetic profile, thereby improving therapeutic efficacy and reducing adverse effects. This focused review explores the genetic factors influencing drug responses in neurodegenerative diseases and the potential of pharmacogenomics to revolutionize their treatment. Key genetic markers, such as the APOE ε4 allele in AD and the CYP2D6 polymorphisms in PD, are highlighted for their roles in modulating drug efficacy. Additionally, advancements in pharmacogenomic tools, including genome-wide association studies (GWAS), next-generation sequencing (NGS), and CRISPR-Cas9, are discussed for their contributions to personalized medicine. The application of pharmacogenomics in clinical practice and its prospects, including ethical and data integration challenges, are also examined.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1478964"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The novel pleuromutilin derivative 22-((4-((4-nitrophenyl)acetamido)phenyl)thio)deoxy pleuromutilin possesses robust anti-mycoplasma activity both <i>in vitro</i> and <i>in vivo</i>.","authors":"Xirui Xia, Xuan Ji, Yaxi Li, Yubo Wang, Yue Zhao, Wenxiang Wang, Huanzhong Ding","doi":"10.3389/fphar.2024.1491223","DOIUrl":"https://doi.org/10.3389/fphar.2024.1491223","url":null,"abstract":"<p><strong>Objective: </strong>Mycoplasmas are structurally simple pathogenic microorganisms that can cause a wide range of diseases in humans and animals and conventional antibiotic therapies of fluoroquinolones and tetracyclines are toxic to young children and young animals and macrolide resistance is increasing. In this context, new anti-mycoplasma antimicrobial agents need to be developed. 22-((4-((4-nitrophenyl)acetamido)phenyl)thio)deoxypleuromutilin (compound 16C) is a novel acetamine phenyl pleuromutilin derivative. This study aimed to evaluate its acute toxicity in mice and generate pharmacokinetic and anti-mycoplasma profiles.</p><p><strong>Methods: </strong>The safety of compound 16C was preliminarily evaluated by oral and intramuscular acute toxicity tests and single intravenous and intramuscular pharmacokinetic experiments were performed to obtain its pharmacokinetic profile. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and time-killing curves reflected the <i>in vitro</i> effects of the compounds against <i>Mycoplasma pneumoniae.</i> Five groups consisted of three treatments for compound 16C (20, 40, and 80 mg/kg), and two treatments for tiamulin (oral and intramuscular 40 mg/kg) were continued for 4 d. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected at the end of treatment (96 h) and 4 days later (192 h) to assess the <i>in vivo</i> anti-mycoplasma and anti-pneumonia effects. ELISA assays were performed to detect IFN-γ, TNF-α, and IL-8 (CXCL1) in BALF. Lung tissues were fixed with 4% paraformaldehyde and sectioned for histopathological assessment.</p><p><strong>Results: </strong>The results show that compound 16C has low toxicity (LD₅₀ > 5,000 mg/kg). Its pharmacokinetic profile is characterized by a short time to maximum concentration (Tmax = 0.24 h), high bioavailability (F = 71.29%), and short elimination half-life (T_1/2kel) (intramuscular and intravenous administration was 2.20 and 1.89 h, respectively). Treatment with compound 16C and intramuscular tiamulin reduced the <i>mycoplasma</i> load in mice. Intramuscular compound 16C and tiamulin also inhibited the release of IFN-γ, TNF-α, and CXCL1, decreasing the accumulation of inflammatory cells in the lungs, thereby mitigating lung damage.</p><p><strong>Conclusion: </strong>This study proved that compound 16C has a strong antimicrobial effect against <i>M. pneumoniae</i>, can be rapidly absorbed and has therapeutic efficacy that provides a basis for developing new anti-mycoplasma drugs.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1491223"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of pharmacogenetic data in epic genomic module drives clinical decision support alerts.","authors":"Kimberly J Newsom, Bradley Hall, Katherine A Martinez, Scott Nelson, Petr Starostik, Khoa Nguyen","doi":"10.3389/fphar.2024.1458095","DOIUrl":"https://doi.org/10.3389/fphar.2024.1458095","url":null,"abstract":"<p><strong>Introduction: </strong>The Precision Medicine Program (PMP) at the University of Florida (UF) focuses on advancing pharmacogenomics (PGx) to improve patient care.</p><p><strong>Methods: </strong>The UF PMP, in collaboration with the UF Health Pathology Laboratory (UFHPL), utilized Health Level Seven (HL7) standards to integrate PGx data into Epic's Genomic Module to enhance the management and utilization of PGx data in clinical practice.</p><p><strong>Results: </strong>A key feature of the Genomic Module is the introduction of genomic indicators-innovative tools that flag actionable genetic information directly within the electronic health record (EHR). These indicators enable the effective presentation of phenotypic information and, when leveraged with existing clinical decision support (CDS) alerts, help provide timely and informed therapeutic decisions based on genomic data.</p><p><strong>Discussion: </strong>This advancement represents a significant shift in the utilization of genetic data, moving beyond traditional PDF reports to provide a comprehensive understanding of PGx data. Ultimately, this integration empowers healthcare providers with genomics-guided recommendations, enhancing precision and personalization in patient care, contributing significantly to the advancement of personalized medicine.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1458095"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The endocannabinoid anandamide prevents TH17 programming of activated T lymphocytes while preserving TH1 responses.","authors":"Anastasiia Kiprina, Tom Teichmann, Virna Margarita Martín Giménez, Wenqing Xu, Fiona Sailer, Maike Windbergs, Walter Manucha, Andreas Weigert, Ralf P Brandes","doi":"10.3389/fphar.2024.1528759","DOIUrl":"https://doi.org/10.3389/fphar.2024.1528759","url":null,"abstract":"<p><strong>Introduction: </strong>Anandamide (AEA) is an endocannabinoid that has recently been recognized as a regulator of various inflammatory diseases as well as cancer. While AEA was thought to predominantly engage cannabinoid (CB) receptors, recent findings suggest that, given its protective anti-inflammatory role in pathological conditions, anandamide may engage not only CB receptors.</p><p><strong>Methods: </strong>In this study, we studied the role of exogenous AEA in a mouse AirPouch model of acute inflammation by examining immune cell infiltrates by flow cytometry. Human primary immune cells were used to validate findings towards immune cell activation and migration by flow cytometry and bead-based ELISA.</p><p><strong>Results: </strong>We found that AEA decreases the acute infiltration of myeloid cells including granulocytes and monocytes into the inflamed area, but unexpectedly increases the number of T cells at the site of inflammation. This was related to AEA signaling through nuclear receptor subfamily 4A (NR4A) transcription factors rather than CB receptors. Exploring regulatory mechanisms in the human system, we found that AEA broadly inhibits the migratory capacity of immune cells, arguing for blocked emigration of T cells from the inflamed tissue. Taking a closer look at the impact of AEA on T cells revealed that AEA profoundly alters the activation and exhaustion status of CD4⁺ T and CD8⁺ T cells, thereby strongly inhibiting TH17 responses, while not altering TH1 differentiation.</p><p><strong>Discussion: </strong>These data suggest that AEA has the potential to block chronic inflammation without influencing crucial anti-viral and anti-microbial immune defense mechanisms, and may therefore be an attractive molecule to interfere with the establishment of chronic inflammation.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1528759"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of immunostimulatory activities and active compounds from sequentially extracted fractions of rhizosphere fungal fermentation broth of <i>Atractylodes macrocephala</i> Koidz. rhizomes.","authors":"Yuxin Xie, Na Lin, Pingping Song, Xiangyan Ni, Yakun Wang, Peng Huang, Zhili Han, Dianlei Wang, Nianxia Sun","doi":"10.3389/fphar.2024.1460614","DOIUrl":"https://doi.org/10.3389/fphar.2024.1460614","url":null,"abstract":"<p><strong>Introduction: </strong>Pharmacological studies have shown that the rhizome of Atractylodes macrocephala Koidz. (Compositae), commonly known as atractylodes macrocephala rhizome (AMR), can modulate immunity. Nevertheless, its resources have been largely depleted, and the pharmacological activity of artificial AMR is relatively modest. We hypothesized that the fermented crude extracts of the rhizosphere fungi of AMR would have similar immunomodulatory effects since the metabolites generated by these fungi are similar to those of the host plant given their long-term synergistic evolution.</p><p><strong>Methods: </strong>Rhizosphere fungi were isolated from the rhizosphere soil of AMR and cultured to produce the secondary metabolites. These metabolites were then sequentially extracted with four solvents of increasing polarities (petroleum ether, ethyl acetate, n-butanol, and water). The in vitro immunomodulatory activities of the metabolite extracts were evaluated by cell proliferation capacity, cell phagocytosis activity, NO secretion capacity, cell morphology changes, and cytokine (TNF-α, IL-1β and IL-6) secretion capacity in RAW264.7 macrophage cells. The biologically active secondary metabolites produced by the rhizosphere fungi were identified using ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS).</p><p><strong>Results: </strong>Three rhizosphere fungi, namely Penicillium (MK-1), Penicillium glaucoroseum (MN-1), and Purpureocillium lilalium (MG-1), were isolated from the rhizosphere soil of AMR. The assays for cell proliferation capacity, cell phagocytosis activity, and NO secretion capacity showed that all metabolite extracts exhibited in vitro immunomodulatory activities. The crude extracts of MG-1 exhibited the highest levels of in vitro immunomodulatory activities compared to the other extracts. Furthermore, it was demonstrated that the fermented extracts of MG-1 could facilitate immunological enhancement in vitro by altering the cellular morphology in the resting state and increasing the secretions of TNF-α, IL-1β, and IL-6. Meanwhile, there was no observable endotoxin contamination. The metabolite profiling of MG-1 by UHPLC-Q-TOFMS revealed the presence of several compounds with established immunoreactive activities, including L-arginine, prostaglandin I2, deoxyguanosine, bestatin, and osthole.</p><p><strong>Discussion: </strong>The present study demonstrated that the metabolite extracts of the rhizosphere fungi isolated from the rhizosphere soil of AMR exhibited in vitro immunoreactive activities and that these rhizosphere fungi could produce several bioactive metabolites. The crude extracts of the rhizosphere fungi may hence extend the medicinal utility of AMR and provide a basis for further development of natural plant-based immunomodulators.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1460614"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural ingredients in the regulation of abnormal lipid peroxidation: a potential therapy for pulmonary diseases.","authors":"Yundou Liu, Chunyi Wang, Mengru Li, Yi Zhu, Ke Liu, Yufei Liu, Maocai Luo, Chuantao Zhang","doi":"10.3389/fphar.2024.1507194","DOIUrl":"https://doi.org/10.3389/fphar.2024.1507194","url":null,"abstract":"<p><p>Pulmonary diseases are a major category of diseases that pose a threat to human health. The most common drugs currently used to treat lung diseases are still chemical drugs, but this may lead to drug resistance and damage to healthy organs in the body. Therefore, developing new drugs is an urgent task. Lipid peroxidation is caused by the disruption of redox homeostasis, accumulation of reactive oxygen species (ROS), depletion of glutathione (GSH), and inactivation of glutathione peroxidase 4 (GPX4). Lipid peroxidation is closely related to the occurrence and progression of respiratory diseases, including acute lung injury, asthma, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease, and lung cancer. Natural ingredients have high safety, high availability, and low cost, and can regulate lipid peroxidation through multiple pathways and targets, making them valuable new drugs. This article aims to summarize the pharmacology and mechanism of natural ingredients targeting lipid peroxidation in the treatment of lung diseases. The reviewed data indicate that natural ingredients are a promising anti-lipid peroxidation drug, mainly alleviating lipid peroxidation through the cystine/glutamate antiporter (System X_c ^-)/GSH/GPX4 axis, Nrf2 pathway, and ROS pathway. In the future, it will still be necessary to further study the mechanisms of natural products in treating pulmonary diseases through lipid peroxidation and conduct multi-center, large-sample clinical trials to promote the development of new drugs.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1507194"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tenecteplase: biochemical and clot lysis activity comparisons.","authors":"Jan Bechmann, Ira Schmid, Simone Brand, Felix Miller, Chengzhi Zhang","doi":"10.3389/fphar.2024.1498116","DOIUrl":"https://doi.org/10.3389/fphar.2024.1498116","url":null,"abstract":"<p><strong>Introduction: </strong>In the last decades, the recombinant tissue plasminogen activator alteplase has been the standard fibrinolytic treatment of acute myocardial infarction, pulmonary embolism, and acute ischemic stroke. An optimized version of alteplase, tenecteplase, has been developed by exchanging six amino acids to increase half-life, achieve higher fibrin selectivity and increase resistance to plasminogen activator inhibitor-1. Meanwhile, several products containing tenecteplase exist. The aim of this study was to compare the fibrinolytic activity and overall product quality of the 25 mg/vial presentation of tenecteplase originator Metalyse^® (Boehringer Ingelheim Pharma GmbH and Co., KG, Ingelheim, Germany) to the 16 mg/vial formulation of the tenecteplase copy Mingfule^® (CSPC Recomgen Pharmaceutical, Guangzhou, Co., Ltd.).</p><p><strong>Methods: </strong>We have systematically analyzed and evaluated the biochemical and fibrinolytic differences between Metalyse^® and Mingfule^® using a wide range of routine quality testing assays, supplemented by mass spectrometry analysis and surface plasmon resonance assays. Additional host cell protein quantification and clot lysis testing following plasmin incubation over time were performed.</p><p><strong>Results: </strong>Several key differences in biochemical composition and clot lysis activity were observed between the two tenecteplase variants. Versus Metalyse^®, Mingfule^® exhibited lower clot lysis activity and contained less of the two-chain form of tenecteplase. In addition, there were differences in sialic acid content, galactosylation, and fucosylation patterns, with Mingfule^® exhibiting more bi- and less tri- and tetra-antennary glycosylation, leading to a different charge and size heterogeneity profile. Furthermore, Mingfule^® displayed highly dissimilar binding to the three clearance receptors (LRP-1, ASGR, and mannose receptor) compared with Metalyse^®. Purity analysis showed that Mingfule^® contained a lower monomer content and, in contrast to Metalyse^®, substantial amounts of host cell protein.</p><p><strong>Discussion: </strong>Taken together, these data demonstrate that the tenecteplase copy Mingfule^® has several meaningful fibrinolytic and biochemical differences compared with Metalyse^®. This raises the question of whether data from clinical studies with one of the products can be generalized for all tenecteplase variants.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1498116"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}