Pharmacology Research & Perspectives最新文献_第8页

The epsilon toxin from Clostridium perfringens stimulates calcium-activated chloride channels, generating extracellular vesicles in Xenopus oocytes. 产气荚膜梭菌的epsilon毒素刺激钙激活的氯离子通道，在爪蟾卵母细胞中产生细胞外囊泡。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70005

Mercè Cases, Jonatan Dorca-Arévalo, Marta Blanch, Sergi Rodil, Beatrice Terni, Mireia Martín-Satué, Artur Llobet, Juan Blasi, Carles Solsona

{"title":"The epsilon toxin from Clostridium perfringens stimulates calcium-activated chloride channels, generating extracellular vesicles in Xenopus oocytes.","authors":"Mercè Cases, Jonatan Dorca-Arévalo, Marta Blanch, Sergi Rodil, Beatrice Terni, Mireia Martín-Satué, Artur Llobet, Juan Blasi, Carles Solsona","doi":"10.1002/prp2.70005","DOIUrl":"https://doi.org/10.1002/prp2.70005","url":null,"abstract":"The epsilon toxin (Etx) from Clostridium perfringens has been identified as a potential trigger of multiple sclerosis, functioning as a pore-forming toxin that selectively targets cells expressing the plasma membrane (PM) myelin and lymphocyte protein (MAL). Previously, we observed that Etx induces the release of intracellular ATP in sensitive cell lines. Here, we aimed to re-examine the mechanism of action of the toxin and investigate the connection between pore formation and ATP release. We examined the impact of Etx on Xenopus laevis oocytes expressing human MAL. Extracellular ATP was assessed using the luciferin-luciferase reaction. Activation of calcium-activated chloride channels (CaCCs) and a decrease in the PM surface were recorded using the two-electrode voltage-clamp technique. To evaluate intracellular Ca2+ levels and scramblase activity, fluorescent dyes were employed. Extracellular vesicles were imaged using light and electron microscopy, while toxin oligomers were identified through western blots. Etx triggered intracellular Ca2+ mobilization in the Xenopus oocytes expressing hMAL, leading to the activation of CaCCs, ATP release, and a reduction in PM capacitance. The toxin induced the activation of scramblase and, thus, translocated phospholipids from the inner to the outer leaflet of the PM, exposing phosphatidylserine outside in Xenopus oocytes and in an Etx-sensitive cell line. Moreover, Etx caused the formation of extracellular vesicles, not derived from apoptotic bodies, through PM fission. These vesicles carried toxin heptamers and doughnut-like structures in the nanometer size range. In conclusion, ATP release was not directly attributed to the formation of pores in the PM, but to scramblase activity and the formation of extracellular vesicles.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70005"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The gut-brain axis in appetite, satiety, food intake, and eating behavior: Insights from animal models and human studies. 食欲、饱腹感、食物摄入量和进食行为中的肠脑轴：动物模型和人体研究的启示

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70027

Georgia S Clarke, Amanda J Page, Sally Eldeghaidy

{"title":"The gut-brain axis in appetite, satiety, food intake, and eating behavior: Insights from animal models and human studies.","authors":"Georgia S Clarke, Amanda J Page, Sally Eldeghaidy","doi":"10.1002/prp2.70027","DOIUrl":"https://doi.org/10.1002/prp2.70027","url":null,"abstract":"The gut-brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut-brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70027"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11483575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of cyclosporin A on respiratory viral replication in fully differentiated ex vivo human airway epithelia. 环孢素 A 对完全分化的体外人体气道上皮细胞呼吸道病毒复制的影响

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.1242

Louise Bondeelle, Song Huang, Samuel Constant, Sophie Clément, Maud Salmona, Jérôme Le Goff, Anne Bergeron, Caroline Tapparel

{"title":"Effect of cyclosporin A on respiratory viral replication in fully differentiated ex vivo human airway epithelia.","authors":"Louise Bondeelle, Song Huang, Samuel Constant, Sophie Clément, Maud Salmona, Jérôme Le Goff, Anne Bergeron, Caroline Tapparel","doi":"10.1002/prp2.1242","DOIUrl":"10.1002/prp2.1242","url":null,"abstract":"Cyclosporin A (CsA), an immunosuppressive drug used in transplant recipients, inhibits graft rejection by binding to cyclophilins and competitively inhibiting calcineurin. While concerns about respiratory infections in immunosuppressed patients exist, contradictory data emerged during the COVID-19 pandemic, prompting investigations into CsA's impact on viral infections. This study explores CsA's antiviral effects on SARS-CoV-2 Omicron BA.1, Delta variants, and human parainfluenza virus 3 (HPIV3) using an ex vivo model of human airway epithelium (HAE). CsA exhibited a dose-dependent antiviral effect against the SARS-CoV-2 Delta variant, reducing viral load over 10 days. However, no significant impact was observed against SARS-CoV-2 Omicron or HPIV3, indicating a virus-specific effect. At high concentrations, CsA was associated with an increase of IL-8 and a decrease of IFNλ expression in infected and noninfected HAE. This study highlights the complexity of CsA's antiviral mechanisms, more likely involving intricate inflammatory pathways and interactions with specific viral proteins. The research provides novel insights into CsA's effects on respiratory viruses, emphasizing the need for understanding drug-virus interactions in optimizing therapeutic approaches for transplant recipients and advancing knowledge on immunosuppressive treatments' implications on respiratory viral infections. Limitations include the model's inability to assess T lymphocyte activation, suggesting the necessity for further comprehensive studies to decipher the intricate dynamics of immunosuppressive treatments on respiratory viral infections.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e1242"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The endocannabinoid system in appetite regulation and treatment of obesity. 内源性大麻素系统在食欲调节和肥胖症治疗中的作用。

IF 2.6 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70009

Marija Kurtov,Igor Rubinić,Robert Likić

引用次数: 0

Cromolyn sodium and masitinib combination inhibits fibroblast-myofibroblast transition and exerts additive cell-protective and antioxidant effects on a bleomycin-induced in vitro fibrosis model. 色甘酸钠和马西替尼复方制剂可抑制成纤维细胞-肌成纤维细胞转化，并对博莱霉素诱导的体外纤维化模型产生细胞保护和抗氧化作用。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70018

Azize Yasemin Göksu, Hulya Dirol, Fatma Gonca Kocanci

{"title":"Cromolyn sodium and masitinib combination inhibits fibroblast-myofibroblast transition and exerts additive cell-protective and antioxidant effects on a bleomycin-induced in vitro fibrosis model.","authors":"Azize Yasemin Göksu, Hulya Dirol, Fatma Gonca Kocanci","doi":"10.1002/prp2.70018","DOIUrl":"10.1002/prp2.70018","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an in vitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA-approved mast cell stabilizer. This study aims to investigate the anti-fibrotic and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple-immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl-2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2-induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti-fibrotic, cell-protective, and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70018"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A dose-adjusted, open-label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. 一项关于脓毒症重症患者使用 STC3141 的安全性、耐受性和药代动力学的剂量调整、开放标签试验研究。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70015

Rinaldo Bellomo, John Patava, Ruth Van Lancker, Nathalie Layios, Marijke Peetermans, Mark Plummer, Rachid Attou, Robert McNamara, Andrew Udy, Bradley Wibrow, Adam Deane, Edward Litton, Marcel Tanudji, Fuhong Su, Zhang Zhong, Linda Shi, Li Ning

{"title":"A dose-adjusted, open-label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis.","authors":"Rinaldo Bellomo, John Patava, Ruth Van Lancker, Nathalie Layios, Marijke Peetermans, Mark Plummer, Rachid Attou, Robert McNamara, Andrew Udy, Bradley Wibrow, Adam Deane, Edward Litton, Marcel Tanudji, Fuhong Su, Zhang Zhong, Linda Shi, Li Ning","doi":"10.1002/prp2.70015","DOIUrl":"https://doi.org/10.1002/prp2.70015","url":null,"abstract":"Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre-clinical studies showed benefit with a histone-neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose-adjusted, open-label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady-state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug-related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half-life values ranged from 5 to 7 h. The mean (±SD) terminal half-life for non-RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70015"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disposition of orally administered atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor in healthy participants. 口服新型 5-脂氧合酶激活蛋白抑制剂 Atuliflapon 在健康参与者体内的分布情况。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70029

Xue-Qing Li, Bo Lindmark, Carl Amilon, Kristin Samuelsson, Lars Weidolf, Karin Nelander, Jane Knöchel, Maria Heijer, Ryan A Bragg, Malin Gränfors, Eva-Lotte Lindstedt, Sharan Sidhu, Pavlo Garkaviy, Hans Ericsson

{"title":"Disposition of orally administered atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor in healthy participants.","authors":"Xue-Qing Li, Bo Lindmark, Carl Amilon, Kristin Samuelsson, Lars Weidolf, Karin Nelander, Jane Knöchel, Maria Heijer, Ryan A Bragg, Malin Gränfors, Eva-Lotte Lindstedt, Sharan Sidhu, Pavlo Garkaviy, Hans Ericsson","doi":"10.1002/prp2.70029","DOIUrl":"https://doi.org/10.1002/prp2.70029","url":null,"abstract":"In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [14C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half-life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug-related exposure (DRE), while a direct N-glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of the recovered dose in excreta, while metabolites resulting from phase 1 oxidative pathways accounted for more than 30% of the excreted dose. Overall, a single oral dose of 200 mg [14C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70029"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Study on the mechanism of echinacoside in preventing and treating hypoxic pulmonary hypertension based on proteomic analyses. 基于蛋白质组分析的紫锥菊苷防治缺氧性肺动脉高压的机制研究

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70025

Xiangyun Gai, Qingqing Xia, Hongmai Wang, Hongtao Bi, Jinyu Wang, Yuefu Zhao

{"title":"Study on the mechanism of echinacoside in preventing and treating hypoxic pulmonary hypertension based on proteomic analyses.","authors":"Xiangyun Gai, Qingqing Xia, Hongmai Wang, Hongtao Bi, Jinyu Wang, Yuefu Zhao","doi":"10.1002/prp2.70025","DOIUrl":"https://doi.org/10.1002/prp2.70025","url":null,"abstract":"Hypoxic pulmonary hypertension (HPH), a chronic condition affecting the cardiopulmonary system, has high mortality. Echinacoside (ECH) is a phenylethanoid glycoside, which is used to ameliorate pulmonary vascular remodeling and pulmonary vasoconstriction in rats. Accordingly, we aimed to explore the mechanism of ECH in preventing and treating HPH. Sprague Dawley rats were housed in a hypobaric hypoxia chamber for 28 days to obtain the HPH model. The experimental rats were randomly allocated into the following several groups: normoxia group, chronic hypoxia group, and ECH group. The therapeutic results of ECH (10, 20, and 40 mg/kg) showed that ECH reduced mPAP, Hb, Hct, and RVHI in HPH rats. Then this work employed label-free quantitative proteomic analysis, western blotting, and RT-PCR to investigate the mechanism by which ECH prevents HPH. The results found that in the chronic hypoxia group, the levels of ACSL1, COL6A1, COL4A2, COL1A1, and PC increased compared to the normoxia group. However, the opposite effect was observed in the chronic hypoxia group treated with ECH. The study indicates that the administration of ECH may slow the pathological progression of HPH by suppressing the inflammatory response, inhibiting smooth muscle cell proliferation, and minimizing the deposition of extracellular matrix.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70025"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Plasma and urinary CP I and CP III concentrations in chimeric mice with human hepatocytes after rifampicin administration. 人肝细胞嵌合小鼠服用利福平后血浆和尿液中的 CP I 和 CP III 浓度。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70017

Yurina Shishido, Tomohiro Yoshida, Keiyu Oshida, Masashi Uchida

{"title":"Plasma and urinary CP I and CP III concentrations in chimeric mice with human hepatocytes after rifampicin administration.","authors":"Yurina Shishido, Tomohiro Yoshida, Keiyu Oshida, Masashi Uchida","doi":"10.1002/prp2.70017","DOIUrl":"10.1002/prp2.70017","url":null,"abstract":"The interest in transporter-mediated drug interactions has been increasing in the field of drug development. In this study, we measured the plasma and urinary concentrations of coproporphyrin (CP) I and CP III as endogenous substrates for organic anion-transporting polypeptide (OATP) using chimeric mice with human hepatocytes (PXB mice) and examined the influence of an OATP inhibitor, rifampicin (RIF). CP I and CP III were actively taken up intracellularly, and RIF inhibited the uptake in a concentration-dependent manner for both CP I and CP III in human hepatocytes (PXB-cells). Single doses of RIF at 10 and 30 mg/kg were orally or intravenously administered to PXB mice and wild-type ICR mice. Plasma concentrations (AUC0-8h) of CP I increased in both mice. However, a marked increase in CP III was only observed in ICR mice, after intravenous administration of RIF at 30 mg/kg. The IC50 values of RIF for intracellular CP I/III uptake and the unbound plasma concentrations of RIF suggested that the increase in plasma CP I is associated with the exposure of RIF to OATPs. The 24-h cumulative urinary excretions of CP I and CP III increased in both mice, but more markedly in PXB mice. Thus, RIF increased the plasma and urinary concentrations of CP I and CP III in the mice, as reported in humans, and CP I may be a more sensitive biomarker of OATP-mediated drug interactions in PXB mice.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70017"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interaction of myricetin, ampelopsin (dihydromyricetin), and their sulfate metabolites with serum albumin, cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes, and organic anion-transporting polypeptides (OATP1B1 and OATP2B1). 杨梅素、安瓿素（二氢杨梅素）及其硫酸盐代谢物与血清白蛋白、细胞色素 P450（CYP2C9、2C19 和 3A4）酶和有机阴离子转运多肽（OATP1B1 和 OATP2B1）的相互作用。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70021

Ágnes Dombi, Hana Kaci, Kateřina Valentová, Éva Bakos, Csilla Özvegy-Laczka, Miklós Poór

{"title":"Interaction of myricetin, ampelopsin (dihydromyricetin), and their sulfate metabolites with serum albumin, cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes, and organic anion-transporting polypeptides (OATP1B1 and OATP2B1).","authors":"Ágnes Dombi, Hana Kaci, Kateřina Valentová, Éva Bakos, Csilla Özvegy-Laczka, Miklós Poór","doi":"10.1002/prp2.70021","DOIUrl":"10.1002/prp2.70021","url":null,"abstract":"Myricetin (MYR) and ampelopsin (AMP, or dihydromyricetin) are flavonoid aglycones found in certain plants and dietary supplements. During the presystemic biotransformation of flavonoids, mainly sulfate and glucuronide derivatives are produced, which are the dominant metabolites in the circulation. In this study, we tested the interactions of MYR, myricetin-3'-O-sulfate (M3'S), AMP, and ampelopsin-4'-O-sulfate (A4'S) with human serum albumin (HSA), cytochrome P450 enzymes (CYPs), and organic anion-transporting polypeptides (OATPs) using in vitro models, including the recently developed method for measuring flavonoid levels in living cells. M3'S and MYR bound to albumin with high affinity, and they showed moderate displacing effects versus the Site I marker warfarin. MYR, M3'S, AMP, and A4'S exerted no or only minor inhibitory effects on CYP2C9, CYP2C19, and CYP3A4 enzymes. M3'S and MYR caused considerable inhibitory actions on OATP1B1 at low micromolar concentrations (IC50 = 1.7 and 6.4 μM, respectively), while even their nanomolar levels resulted in strong inhibitory effects on OATP2B1 (IC50 = 0.3 and 0.4 μM, respectively). In addition, M3'S proved to be a substrate of OATP1B1 and OATP2B1. These results suggest that MYR-containing dietary supplements may affect the OATP-mediated transport of certain drugs, and OATPs are involved in the tissue uptake of M3'S.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70021"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11440035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0