Pharmacological research最新文献

{"title":"AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease","authors":"Lulu Zhang ,&nbsp;Yi Zheng ,&nbsp;Mingyan Shao ,&nbsp;Aiping Chen ,&nbsp;Meiyi Liu ,&nbsp;Wenlong Sun ,&nbsp;Tianxing Li ,&nbsp;Yini Fang ,&nbsp;Yang Dong ,&nbsp;Shipeng Zhao ,&nbsp;Hui Luo ,&nbsp;Juan Feng ,&nbsp;Qi Wang ,&nbsp;Lingru Li ,&nbsp;Yanfei Zheng","doi":"10.1016/j.phrs.2025.107617","DOIUrl":"10.1016/j.phrs.2025.107617","url":null,"abstract":"<div><div>Metabolic-associated fatty liver disease (MAFLD) is a chronic, progressive disorder characterized by hepatic steatosis and excessive lipid accumulation. Its high global adult prevalence (approximately 50.7 %) is a significant concern worldwide. However, FDA-approved therapeutic drugs remains lacking. Qigui Jiangzhi Formula (QGJZF) shows promise in treating MAFLD by effectively decreasing lipid levels and improving hepatic steatosis, however its mechanisms remain unclear. This study investigated QGJZF’s effects in high-fat diet-induced zebrafish and golden hamsters, and in palmitate (PA) and oleic acid (OA) - induced HepG2 cells, using the SymMap database to identify potential targets and pathways of QGJZF in MAFLD and AlphaFold algorithms to predict protein structures. <em>In vivo,</em> QGJZF significantly alleviated hepatic lipid deposition. Intriguingly, QGJZF decreased lipid droplets and its levels are negative correlated with the numbers of autolysosomes, indicating that QGJZF’s mechanism of ameliorating liver lipid deposition may be related to the regulation of autophagy. QGJZF upregulated the expressions of phosphorylated -Adenosine 5‘-monophosphate (AMP) - activated protein kinase (p-AMPK), Sirtuin deacetylase 1 (SIRT1) and Transcription factor EB (TFEB), accompanied by the changes in autophagy-related proteins. <em>In vitro</em>, QGJZF inhibited the lipid deposition in PA/OA-stimulated HepG2 cells, and its effect was blocked by an autophagy inhibitor Baf-A1, which was mediated through upregulation of TFEB and its mediated autophagy-lysosomal pathway. Moreover, cotreatment with AMPK inhibitor Compound C, the regulation of QGJZF on TFEB, SIRT1, autophagy-related protein levels, and lipid deposition were reversed. Network pharmacology identified the PRKAA2 (AMPK) and SIRT1 as key hub targets. Futher analysis of their structures using AlphaFold3 algorithms, yielded high-ranking scores of 0.97 and 0.93, respectively. Liquid chromatography-mass spectrometry combined with molecular docking expounded its five compounds in QGJZF binding to AMPK protein. These findings suggest that QGJZF as a therapeutic agent in augmenting autophagy-facilitated lipid clearance for the management of MAFLD via AMPK/SIRT1-TFEB axis.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107617"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009735","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":"Ginseng polysaccharides circumvent acquired resistance to anti-PD-1 immunotherapy in patients with non-small cell lung cancer","authors":"Jumin Huang ,&nbsp;Ziming Wang ,&nbsp;Feng Li ,&nbsp;Huiting Wang,&nbsp;Yang Xiang,&nbsp;Runze Li,&nbsp;Chun Xie,&nbsp;Yuwei Wang,&nbsp;Zhihong Jiang,&nbsp;Yabing Cao,&nbsp;Wenhua Liang,&nbsp;Elaine Lai-Han Leung","doi":"10.1016/j.phrs.2025.107611","DOIUrl":"10.1016/j.phrs.2025.107611","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107611"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009341","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":"Sailing south from regulations to strategies: Macau as a promising gateway for the export of proprietary Chinese medicines to ASEAN countries","authors":"Dong-mei Xue,&nbsp;Dan-ni Wang,&nbsp;Jia Yuan,&nbsp;Lan Yao,&nbsp;Ying Bian","doi":"10.1016/j.phrs.2025.107600","DOIUrl":"10.1016/j.phrs.2025.107600","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107600"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009472","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":"Exploring the benefits and prescribing informations of combining East Asian herbal medicine with conventional medicine in the treatment of rheumatoid arthritis: A systematic review and multifaceted analysis of 415 randomized controlled trials","authors":"Hee-Geun Jo ,&nbsp;Jihye Seo ,&nbsp;Eunhye Baek ,&nbsp;Donghun Lee","doi":"10.1016/j.phrs.2025.107616","DOIUrl":"10.1016/j.phrs.2025.107616","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Notwithstanding progress in conventional medicine (CM), the management of rheumatoid arthritis (RA) continues to be problematic due to factors such as limited patient response to treatment and restricted medication access. This study aimed to evaluate the extent to which East Asian herbal medicine with CM combination therapy (EACM) provides additional benefits in effectiveness and safety.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We conducted a comprehensive search across 11 databases in English, Chinese, Korean, and Japanese for randomized controlled trials. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using the American College of Rheumatology (ACR) 20/50/70 Response Criteria and the incidence of adverse events (AEI) as primary outcomes. This meta-analysis was performed using a random-effects model. The quality of each study was assessed according to the RoB 2. Of the 1036 full-text articles screened, 415 were included in the review.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;This review included data from 37,839 participants. EACM was associated with higher ACR responses: ACR 20 (RR: 1.2332; 95 % CI: 1.1852–1.2831, p &lt; 0.0001), ACR 50 (RR: 1.3782; 95 % CI: 1.2936–1.4684, p &lt; 0.0001), and ACR 70 (RR: 1.7084; 95 % CI: 1.5555–1.8762, p &lt; 0.0001), as well as a favorable AEI (OR: 0.3977; 95 % CI: 0.3476–0.4551, p &lt; 0.0001), indicating both better efficacy and safety compared to CM alone. These patterns were consistent across eight secondary outcomes measuring pain, inflammation, and disease activity in RA. Subgroup analyses showed that EACM's effects were independent of the control CM type. Through a comprehensive analysis of a polyherbal prescription dataset, we identified 18 key herbs and 16 significant combination rules, further supported by relevant preclinical evidence. These herbs and synergistic herbal combinations were anticipated to be the most pharmacologically influential in contributing to the meta-analysis outcomes, as substantiated by analytical metrics including network topology and intricate association pattern evaluations.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;The findings suggest that EACM may serve as a valuable complementary strategy for RA patients insufficiently managed by CM alone. In particular, given that the ACR index integrates multiple aspects of RA patients, the results are expected to provide valuable complementary decision support for the management of RA patients who do not respond well to CM therapy, both for medical and economic reasons. Additionally, the key herbs derived through the multifaceted analysis, which actively reflect clinicians' implicit preferences for prescribing EACMs, may serve as important hypotheses for further research and clinical application. However, additional qualitative and quantitative improvements in research are needed for more definitive conclusions. Further analysis of the herbal prescriptions p","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107616"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040819","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":"Therapeutics of bitter plants from Northeast region of India and their pharmacological and phytochemical perspectives","authors":"Bhaskar Das ,&nbsp;Bharat Gopalrao Somkuwar ,&nbsp;Sushil Kumar Chaudhary ,&nbsp;Evanylla Kharlyngdoh ,&nbsp;Careen Liza Pakyntein ,&nbsp;Kishor Basor ,&nbsp;Jitendra Kumar Shukla ,&nbsp;Pardeep Kumar Bhardwaj ,&nbsp;Pulok Kumar Mukherjee","doi":"10.1016/j.phrs.2025.107626","DOIUrl":"10.1016/j.phrs.2025.107626","url":null,"abstract":"<div><div>Natural resources have been used for food and medicine since the beginning of human civilization, and they have always been a low-cost, easily accessible source for individuals. Northeast region of India (NER) represents a significant portion of India's flora and fauna. Marginality, fragility, inaccessibility, ethnicity, and cultural diversity thrived in the region, resulting in the richest reservoir of genetic variation of bioresources. Several bitter plants are used by the locals as both food and medicine to treat a variety of diseases. These medicinal plants are an excellent source of chemically diverse biologically active phytometabolites. There have been few efforts to raise awareness about health benefits of bitter plant resources abound in this region that may provides opportunities for their sustainable utilization. Understanding the structural features of plant derived bitterants in relationship with specific bitter receptor will provide research prospects to identify biomolecules with health benefits. In this context the present review is intended to deliver phyto-pharmacological aspects of bitter plant resources of NER together with detailed understanding of possible association between plant derived phytometabolites as bitter agonists with extraoral bitter receptors.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107626"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059334","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":"Protein kinase inhibitors as targeted therapy for glioblastoma: a meta-analysis of randomized controlled clinical trials","authors":"José Pinto-Fraga ,&nbsp;Celia García-Chico ,&nbsp;Simone Lista ,&nbsp;Pedro Miguel Lacal ,&nbsp;Giuseppe Carpenzano ,&nbsp;Maurizio Salvati ,&nbsp;Alejandro Santos-Lozano ,&nbsp;Grazia Graziani ,&nbsp;Claudia Ceci","doi":"10.1016/j.phrs.2024.107528","DOIUrl":"10.1016/j.phrs.2024.107528","url":null,"abstract":"<div><div>Glioblastoma (GBM) is the most common and lethal primary brain tumor. The standard treatment for newly diagnosed GBM includes surgical resection, when feasible, followed by radiotherapy and temozolomide-based chemotherapy. Upon disease progression, the anti-vascular endothelial growth factor-A (VEGF-A) monoclonal antibody bevacizumab, can be considered.</div><div>Given the limited efficacy of pharmacological treatments, particularly for the recurrent disease, several molecularly targeted interventions have been explored, such as small-molecule protein kinase inhibitors (PKIs), inhibiting tyrosine kinase growth factor receptors and downstream signaling pathways involved in GBM angiogenesis and infiltrative behavior.</div><div>This meta-analysis, based on searches in PubMed and Web Of Science, evaluated 12 randomized controlled trials (RCTs) examining PKIs in patients with newly diagnosed or recurrent GBM. Pooled analysis of shared clinical outcomes - progression-free survival (PFS) and overall survival (OS) - revealed a lack of significant improvements with the use of PKIs. In newly diagnosed GBM, no significant differences were observed in median [-1.02 months, 95 % confidence interval (CI), −2.37–0.32, <em>p = 0.14</em>] and pooled [hazard ratio (HR) = 1.13, 95 % CI, 0.95–1.35, <em>p = 0.17</em>) OS, or in median (0.34 months, 95 % CI, −0.9–1.58, <em>p = 0.60</em>) and pooled (HR = 0.98, 95 % CI, 0.76–1.27, <em>p = 0.89</em>) PFS, when comparing PKI addition to standard chemo-radiotherapy <em>versus</em> chemo-radiotherapy alone. In recurrent GBM, three different analyses were conducted: PKI <em>versus</em> other treatments, PKI combined with other treatments <em>versus</em> those treatments alone, PKI <em>versus</em> PKI combined with other treatments. Also, across these analyses, no significant clinical benefits were found. For instance, when comparing PKI treatment with other treatments, median OS and PFS showed no significant difference (-0.78 months, 95 % CI, −2.12–0.55, <em>p = 0.25;</em> −0.23 months, 95 % CI, −0.79–0.34, <em>p = 0.43,</em> respectively), and similar non-significant results were observed in the pooled analyses (OS: HR = 0.89, 95 % CI, 0.59–1.32, <em>p = 0.55</em>; PFS: HR = 0.83, 95 % CI, 0.63–1.11, <em>p = 0.21</em>).</div><div>Despite these overall negative findings, some data indicate improved clinical outcomes in a subset of GBM patients treated with certain PKIs (i.e., regorafenib) and encourage further research to identify PKIs with better blood-brain barrier penetration and lower risk for resistance development.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107528"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786403","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":"New insights into anti-depression effects of bioactive phytochemicals","authors":"Ruohan Zhao ,&nbsp;Jingwen Wang ,&nbsp;Sookja Kim Chung ,&nbsp;Baojun Xu","doi":"10.1016/j.phrs.2024.107566","DOIUrl":"10.1016/j.phrs.2024.107566","url":null,"abstract":"<div><div>Depression is one of the most common psychological disorders, and due to its high prevalence and mortality rates, it imposes a significant disease burden. Contemporary treatments for depression involve various synthetic drugs, which have limitations such as side effects, single targets, and slow onset of action. Unlike synthetic medications, phytochemicals offer the benefits of a multi-target and multi-pathway mode of treatment for depression. In this literature review, we describe the pharmacological actions, experimental models, and clinical trials of the antidepressant effects of various phytochemicals. Additionally, we summarize the potential mechanisms by which these phytochemicals prevent depression, including regulating neurotransmitters and their receptors, the HPA axis, inflammatory responses, managing oxidative stress, neuroplasticity, and the gut microbiome. Phytochemicals exert therapeutic effects through multiple pathways and targets, making traditional Chinese medicine (TCM) a promising adjunctive antidepressant for the prevention, alleviation, and treatment of depression. Therefore, this review aims to provide robust evidence for subsequent research into developing phytochemical resources as effective antidepressant agents.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107566"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922480","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":"Deciphering consciousness: The role of corticothalamocortical interactions in general anesthesia","authors":"Yuxi Zhou ,&nbsp;Shiqian Huang ,&nbsp;Tianhao Zhang ,&nbsp;Daling Deng ,&nbsp;Li Huang ,&nbsp;Xiangdong Chen","doi":"10.1016/j.phrs.2025.107593","DOIUrl":"10.1016/j.phrs.2025.107593","url":null,"abstract":"<div><div>General anesthesia is administered to millions of individuals each year, however, the precise mechanism by which it induces unconsciousness remains unclear. While some theories suggest that anesthesia shares similarities with natural sleep, targeting sleep-promoting areas and inhibiting arousal nuclei, recent research indicates a more complex process. Emerging evidence highlights the critical role of corticothalamocortical circuits, which are involved in higher cognitive functions, in controlling arousal states and modulating transitions between different conscious states during anesthesia. The administration of general anesthetics disrupts connectivity within these circuits, resulting in a reversible state of unconsciousness. This review elucidates how anesthetics impair corticothalamocortical interactions, thereby affecting the flow of information across various cortical layers and disrupting higher-order cognitive functions while preserving basic sensory processing. Additionally, the role of the prefrontal cortex in regulating arousal through both top-down and bottom-up pathways was examined. These findings highlight the intricate interplay between the cortical and subcortical networks in maintaining and restoring consciousness under anesthesia, offering potential therapeutic targets for enhancing anesthesia management.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107593"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952901","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":"Neoadjuvant chemoimmunotherapy for locally advanced squamous cell carcinoma of the head and neck: Systematic review and meta-analysis","authors":"Xiayi Zhu,&nbsp;Jie Qiu,&nbsp;Ya Zhang,&nbsp;Chunni Lin,&nbsp;Xiaohui Wang,&nbsp;Xiwei Shi,&nbsp;Siya Yang,&nbsp;Qiaoyan Wu,&nbsp;Li Cong","doi":"10.1016/j.phrs.2025.107598","DOIUrl":"10.1016/j.phrs.2025.107598","url":null,"abstract":"<div><h3>Background</h3><div>Neoadjuvant chemoimmunotherapy emerged as a promising treatment for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, a comparison of clinical outcomes with neoadjuvant chemotherapy was lacking.</div></div><div><h3>Objective</h3><div>To provide evidence supporting clinical decision-making for neoadjuvant chemoimmunotherapy in LA-SCCHN treatment.</div></div><div><h3>Methods</h3><div>Literature was retrieved from PubMed, Web of Science, Embase, and the Cochrane Library for studies on the efficacy and safety of neoadjuvant chemoimmunotherapy and chemotherapy in LA-SCCHN published before August 10, 2024. The study was registered in the PROSPERO (CRD42024573816).</div></div><div><h3>Results</h3><div>A total of 28 clinical trials with 2021 patients were included. The neoadjuvant chemoimmunotherapy group had significantly higher pathologic complete response (pCR) (33 % vs. 18 %, <em>P</em> = 0.04) and partial response (PR) (65 % vs. 38 %, <em>P</em> &lt; 0.01). No significant differences were found in overall survival (OS) (hazard ratio: 0.85, 95 % CI: 0.77–0.93) and progression-free survival (PFS) (hazard ratio: 0.72, 95 % CI: 0.61–0.86). Regarding safety outcomes, in the single-arm trials, grade 3–4 treatment-related adverse events (TRAEs) occurred in 14 % of the chemoimmunotherapy group and 13 % of the chemotherapy group, with grade 5 TRAEs at 0 % and 4 %, respectively, showing no significant difference (<em>P</em> = 0.80; <em>P</em> = 0.08). In both RCTs and non-RCT, chemoimmunotherapy had a higher Risk Ratio (RR) for grade 3–4 TRAEs (RR: 1.42, 95 % CI: 0.87–2.31).</div></div><div><h3>Conclusion</h3><div>Neoadjuvant chemoimmunotherapy has shown promising efficacy and safety for LA-SCCHN, but further randomized trials are needed to confirm long-term survival benefits.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107598"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979402","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":"Wogonin effects on the efflux transporters BCRP and MRP2, explain its effectiveness in ulcerative colitis: Implications for metabolic and transport interactions","authors":"Yuanyuan Liu ,&nbsp;Zerong Zhang ,&nbsp;Xiaoyan Li ,&nbsp;Qinghong Hu ,&nbsp;Zhangyu Jiang ,&nbsp;Jia Lv ,&nbsp;Jiayi Xue ,&nbsp;Dongyu Wang ,&nbsp;Jianxiong Cao ,&nbsp;Lingyu Li ,&nbsp;Xiaowen Ou ,&nbsp;Lijun Zhu ,&nbsp;Zhongqiu Liu ,&nbsp;Tao Su","doi":"10.1016/j.phrs.2024.107570","DOIUrl":"10.1016/j.phrs.2024.107570","url":null,"abstract":"<div><div>Wogonin is a flavonoid with efficacy in ulcerative colitis (UC), while the mechanism of its action remains to be fully elucidated. Previous research has indicated that the triple recycling significantly enhances the bioavailability of flavonoids. The efflux transporters, breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 2 (MRP2) are critical regulatory molecules within the enterohepatic triple recycling pathways. Therefore, we investigated the regulatory impact of wogonin on BCRP and MRP2, as well as the roles of these transporters in wogonin's therapeutic efficacy in UC. Using dextran sulfate sodium (DSS)-induced UC model, we found that the anti-UC efficacy of wogonin was diminished in <em>Bcrp</em>^<em>-/-</em><em>-Mrp2</em>^<em>-/-</em> mice compared to wild-type (WT) mice. In these knockout mice, the content of wogonin was increased in the plasma but decreased in the colon tissues, suggesting that deficiencies in BCRP and MRP2 hinder the efflux of wogonin, resulting in elevated content in the plasma. Moreover, <em>in vitro</em> results showed that after knockout of BCRP and MRP2, the concentration of wogonin increased, and its UGT metabolite wogonoside decreased in both cells and mitochondria. These indicate that inhibiting efflux transporters suppresses cellular and mitochondrial glucuronidation metabolism. Interestingly, proteomic sequencing of mitochondrial subcellular organelles revealed that wogonin exhibited anti-UC effects by inhibiting afamin (AFM), with these effects modulated by BCRP and MRP2. These findings not only suggest a new mechanism for the anti-UC effects of wogonin, but also provide a pharmacological foundation for the clinical use of wogonin in treating UC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107570"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922495","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}