Frontiers in Pharmacology最新文献

{"title":"Efficacy and safety of PD-1/PD-L1 inhibitors combined with tyrosine kinase inhibitors as first-line treatment for hepatocellular carcinoma: a meta-analysis and trial sequential analysis of randomized controlled trials.","authors":"Peng Tang, Fei Zhou","doi":"10.3389/fphar.2025.1535444","DOIUrl":"10.3389/fphar.2025.1535444","url":null,"abstract":"<p><strong>Background: </strong>The use of immune checkpoint inhibitors (ICIs) in treating hepatocellular carcinoma (HCC) has grown significantly. However, the therapeutic benefits of ICIs alone are notably modest. This meta-analysis assesses the efficacy and safety of using PD-1/PD-L1 inhibitors in conjunction with tyrosine kinase inhibitors (TKIs) for patients with advanced or unresectable HCC.</p><p><strong>Methods: </strong>An extensive search of the literature was performed using databases such as PubMed, Web of Science, Embase, and the Cochrane Library, capturing randomized controlled trials (RCTs) until 16 October 2024. Efficacy was measured by progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Safety was gauged through the occurrence of treatment-related adverse events (TRAEs). Hazard ratios (HRs) for PFS and OS, along with risk ratios (RRs) for ORR, DCR, and TRAEs, were calculated, each with 95% confidence intervals (CIs). Heterogeneity among studies was quantified using Cochran's Q test, I² statistics, and 95% prediction intervals (PIs).</p><p><strong>Results: </strong>This analysis incorporated 4 studies with a total of 2,174 patients. Treatment regimens combining PD-1/PD-L1 inhibitors with TKIs significantly improved PFS (HR = 0.694, 95% CI: 0.527-0.914; 95% PI: 0.228-2.114) and ORR (RR = 2.303, 95% CI: 1.360-3.902; 95% PI: 0.408-12.991) compared with first-line monotherapy or TKI monotherapy in the overall population. Subgroup analysis indicated that the improvements in PFS and OS were particularly significant among patients of Asian descent or those with hepatitis B virus (HBV) infection (all <i>p</i> < 0.05). While the occurrence of any grade TRAEs did not differ significantly between the two groups (RR = 1.016, 95% CI: 0.996-1.036; 95% PI: 0.941-1.097), the incidence of serious (RR = 2.068, 95% CI: 1.328-3.222; 95% PI: 0.487-8.776) and grade ≥3 TRAEs (RR = 1.287, 95% CI: 1.020-1.624; 95% PI: 0.574-2.883) increased in patients treated with the combination of PD-1/PD-L1 inhibitors and TKIs.</p><p><strong>Conclusion: </strong>This study revealed that combining PD-1/PD-L1 inhibitors with TKIs in the treatment of advanced or unresectable HCC leads to superior clinical outcomes compared to first-line monotherapy or TKIs alone, particularly in patients with HBV infection and those of Asian descent. Clinicians are advised to be vigilant regarding the potential for TRAEs in clinical settings.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1535444"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803006","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":"Indole-3-acetic acid and chenodeoxycholic acid attenuate TLR4/NF-κB signaling and endoplasmic reticulum stress in valproic acid-induced neurotoxicity.","authors":"Wedad S Sarawi, Ahlam M Alhusaini, Ghada S Barwaished, Myasah M Altamimi, Iman H Hasan, Amjad S Aljarboa, Norah K Algarzae, Saleh A Bakheet, Samiah A Alhabardi, Sheikh F Ahmad","doi":"10.3389/fphar.2025.1570125","DOIUrl":"10.3389/fphar.2025.1570125","url":null,"abstract":"<p><p>Valproic acid (VA) is a commonly prescribed medication for epilepsy and other neurological conditions. Although effective, VA use can lead to neurotoxicity, especially with chronic use. This study aimed to investigate the potential neuroprotective properties of indole-3-acetic acid (IAA) and chenodeoxycholic acid (CDCA) in an animal model of VA-induced brain injury. Rats received intraperitoneal injections of VA at a dose of 500 mg/kg/day for 3 weeks. Concurrently, they were orally treated with IAA (40 mg/kg/day) and/or CDCA (90 mg/kg/day). The results showed significantly increased oxidative stress and inflammation markers in the VA-exposed group indicated by the reduced levels of glutathione (GSH, P < 0.0001) and superoxide dismutase (SOD, P < 0.01) and the elevated inflammatory cytokines Interleukin-6 (IL-6, P < 0.0001) and tumor necrosis factor-alpha (TNFα, P < 0.01). VA also induced nuclear factor kappa B (NF-κB, P < 0.01), toll-like receptor 4 (TLR4, P < 0.05), and endoplasmic reticulum (ER) stress markers, as evidenced by increased immunoreactivity of GRP78 (glucose-regulated protein 78, P < 0.0001), transcription factor 6 (ATF-6, P < 0.05) and CHOP (C/EBP homologous protein, P < 0.0001). Treatment with IAA or CDCA attenuated VA-induced neurotoxicity, to a variable extent, by improving oxidative, inflammatory, and ER stress markers. This study demonstrates that IAA and CDCA exert protective effects against VA-induced neurotoxicity by mitigating oxidative stress, inflammation, and ER stress. Further investigations are recommended to validate these findings in other neurotoxicity models.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1570125"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803042","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 flavonoids from herbs and nutraceuticals as ferroptosis inhibitors in central nervous system diseases: current preclinical evidence and future perspectives.","authors":"Qiuhe Li, Xiaohang Yang, Tiegang Li","doi":"10.3389/fphar.2025.1570069","DOIUrl":"10.3389/fphar.2025.1570069","url":null,"abstract":"<p><p>Flavonoids are a class of important polyphenolic compounds, renowned for their antioxidant properties. However, recent studies have uncovered an additional function of these natural flavonoids: their ability to inhibit ferroptosis. Ferroptosis is a key mechanism driving cell death in central nervous system (CNS) diseases, including both acute injuries and chronic neurodegenerative disorders, characterized by iron overload-induced lipid peroxidation and dysfunction of the antioxidant defense system. This review discusses the therapeutic potential of natural flavonoids from herbs and nutraceuticals as ferroptosis inhibitors in CNS diseases, focusing on their molecular mechanisms, summarizing findings from preclinical animal models, and providing insights for clinical translation. We specifically highlight natural flavonoids such as Baicalin, Baicalein, Chrysin, Vitexin, Galangin, Quercetin, Isoquercetin, Eriodictyol, Proanthocyanidin, (-)-epigallocatechin-3-gallate, Dihydromyricetin, Soybean Isoflavones, Calycosin, Icariside II, and Safflower Yellow, which have shown promising results in animal models of acute CNS injuries, including ischemic stroke, cerebral ischemia-reperfusion injury, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury. Among these, Baicalin and its precursor Baicalein stand out due to extensive research and favorable outcomes in acute injury models. Mechanistically, these flavonoids not only regulate the Nrf2/ARE pathway and activate GPX4/GSH-related antioxidant pathways but also modulate iron metabolism proteins, thereby alleviating iron overload and inhibiting ferroptosis. While flavonoids show promise as ferroptosis inhibitors for CNS diseases, especially in acute injury settings, further studies are needed to evaluate their efficacy, safety, pharmacokinetics, and blood-brain barrier penetration for clinical application.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1570069"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803077","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":"Efficacy and cost-effectiveness analysis of 10-day versus 14-day eradication of <i>Helicobacter pylori</i> infection with vonoprazan amoxicillin: a prospective, multicenter, randomized controlled trial.","authors":"Yunfan Dong, Zhaotao Duan, Min Liu, Yanbing Ding, Guangxia Chen, Ruifang Wang, Xiaodan Xu, Lixia Ding, Qiang Zhan, Chengyu Pan, Hui Li, Faming Yang, Xiaorong Dai, Xiangsu Li, Xudong Wu, Peng Peng, Jianrong Wang, Kewei Hu, Duanmin Hu, Qiong Jie, Zhenyu Zhang","doi":"10.3389/fphar.2025.1543352","DOIUrl":"10.3389/fphar.2025.1543352","url":null,"abstract":"<p><strong>Objectives: </strong>To evaluate the efficacy and cost-effectiveness of 10-day vonoprazan-amoxicillin (VA) dual therapy compared to 14-day VA therapy.</p><p><strong>Methods: </strong>A non-inferiority trial was carried out at 10 clinical centers to recruit patients with H. pylori infection. Subjects were assigned at random to either the group for 10-day or 14-day, and where given vonoprazan 20 mg bid and amoxicillin 1 g tid. Comparisons were made in terms of eradication rates, adverse events, cost-effectiveness, and compliance.</p><p><strong>Results: </strong>914 participants were enrolled and randomly assigned to either the 10-day or 14-day VA groups. Using the intention-to-treat principle and multiple imputation for missing outcomes, the analysis showed an eradication rate of 88.79% in the 10-day group and 92.37% in the 14-day group (P = 0.064). The eradication rates were 89.14% and 93.35% by per-protocol analysis (P = 0.037). There were no significant differences in adverse events or compliance between the groups (P > 0.05). Logistic regression analysis indicated that smoking and prior failure of eradication were risk factors influencing the eradication rate (P < 0.05). For the economic evaluation, the cost-effectiveness ratio (CER) of the 10-day group was 426.30 yuan, the CER of the 14-day group was 485.27 yuan, and the incremental cost-effectiveness ratio was 1680.23 yuan. In probability sensitivity analysis, the cost-effectiveness acceptability curve showed that when the willingness-to-pay(WTP) threshold was below 1742 yuan, the 10-day group was more cost-effective. When the WTP threshold was above 1742 yuan, the 14-day group was more cost-effective.</p><p><strong>Conclusion: </strong>In this study, the 10-day VA was not found to be inferior to the 14-day VA. Compared with the 14-day group, the 10-day group is more cost-effective, but as the WTP threshold increases to 1742 yuan, the probability of the 14-day group being more cost-effective was greater than that of the 10-day group. Smoking and previous eradication attempts were associated with the eradication failure of VA therapy.</p><p><strong>Clinical trial registration: </strong>https://clinicaltrials.gov/, identifier NCT05469685.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1543352"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803005","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 use of an old drug: mechanism of oseltamivir phosphate inhibiting liver cancer through regulation of lipophagy via NEU1.","authors":"Yuyu Chen, Peiyu Han, Haixia Zhu, Wenchao Zhang, Xiaoyu Ma, Yiting He, Hetian Chen, Weiwei He, Yu Wu, Yuqiu Ge","doi":"10.3389/fphar.2025.1556661","DOIUrl":"10.3389/fphar.2025.1556661","url":null,"abstract":"<p><strong>Background: </strong>Neuraminidase-1 (NEU1) is an enzyme that breaks down sialic acids on glycoproteins and glycolipids. Aberrant expression of NEU1 has been linked to the progression of numerous malignancies, including liver cancer. Oseltamivir phosphate (OP) is a drug used to treat and prevent influenza, which specifically inhibits NEU1. However, the molecular mechanisms of NEU1 in liver cancer and the potential therapeutic effects of OP remain largely unclear.</p><p><strong>Methods: </strong>NEU1 expression in liver cancer was evaluated using public databases and validated in our samples. CRISPR/Cas9, CCK-8 assay, transwell assays, oil red O staining, RNA-sequencing, immunofluorescence and co-immunoprecipitation (Co-IP) and <i>in vivo</i> experiments were used to investigate the biological function of NEU1 and the therapeutic effect of OP in liver cancer.</p><p><strong>Results: </strong>We demonstrated that NEU1 expression was significantly elevated in liver cancer cells and tumor tissues. Patients with liver cancer exhibiting high levels of NEU1 expression tended to have a less favorable prognosis. NEU1 knockdown inhibited liver cancer cells proliferation, invasion and migration. Subsequent experiments demonstrated that NEU1 knockdown reduced lipid accumulation through promoting perilipin 2 (PLIN2)-mediated lipophagy. Notably, OP (NEU1 inhibitor), promoted lipophagy, thereby inhibiting liver cancer proliferation and tumorigenesis. Moreover, liver cancer cells were more sensitive to OP compared to other chemotherapeutics, like 5-fluorouracil and gemcitabine, with a reduced drug resistance.</p><p><strong>Conclusion: </strong>OP inhibits liver cancer progression by targeting NEU1 and inducing lipophagy through the suppression of PLIN2. Our findings provide new directions on the role of NEU1 in liver cancer and offer latent strategies to address the chemotherapy-induced drug resistance.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1556661"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803078","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":"<i>In vitro</i>, <i>in vivo</i>, and cellular mechanisms of <i>Astragalus onobrychis L.</i> extract against protoscoleces and hydatid cysts of <i>Echinococcus granulosus</i>.","authors":"Javad Ghasemian Yadegari, Amal Khudair Khalaf, Aram Oladi, Ali Shahbazi, Hossein Mahmoudvand","doi":"10.3389/fphar.2025.1531114","DOIUrl":"10.3389/fphar.2025.1531114","url":null,"abstract":"<p><strong>Introduction: </strong>In this study, we evaluated the <i>in vitro, ex vivo</i>, and <i>in vivo</i> effects of the chloroform extract of <i>Astragalus onobrychis</i> L. (Fabaceae family) (AOCE) on apoptosis induction and DNA damage in protoscoleces and hydatid cysts of <i>Echinococcus granulosus</i>.</p><p><strong>Methods: </strong>The protoscolicidal properties of AOCE were examined through both <i>in vitro</i> and <i>ex vivo</i> studies on hydatid cyst protoscoleces, utilizing the eosin exclusion assay. Additionally, we evaluated the effects of AOCE on apoptosis induction and DNA damage in the protoscoleces using a colorimetric protease assay and real-time PCR analysis, respectively. The <i>in vivo</i> efficacy was determined by measuring the quantity, dimensions, and mass of hydatid cysts in infected murine subjects.</p><p><strong>Results: </strong>The findings indicated that AOCE, particularly at a concentration of 45.0 mg/mL, effectively eliminated protoscoleces of hydatid cysts within a 30-min exposure period. Additionally, AOCE demonstrated prolonged anti-parasitic effects in <i>ex vivo</i> conditions, in contrast to the immediate lethal effects observed <i>in vitro</i> (<i>p</i> < <i>0.001</i>). AOCE significantly (<i>p</i> < <i>0.01</i>) induced caspase-3 activation in protoscoleces obtained from hydatid cysts relative to the control normal saline group. Furthermore, the results from Real-time PCR analysis indicated a significant (<i>p</i> < <i>0.001</i>) upregulation in the expression levels of the <i>EgATM</i> and <i>EgP53</i> genes following treatment with AOCE. By <i>in vivo</i>, we found that treatment with AOCE mainly at 200 mg/kg significantly (<i>p</i> < <i>0.001</i>) reduced the number, size, and weight of hydatid cyst relative to the control group treated with normal saline group. Biochemical analysis also demonstrated that administration of AOCE to infected mice, led to a marked improvement and a reduction in serum levels of liver function factors.</p><p><strong>Conclusion: </strong>The results indicated that AOCE exhibits considerable <i>in vitro</i> and <i>ex vivo</i> scolicidal properties against hydatid cyst protoscoleces. Furthermore, the results highlighted AOCE's capacity to eradicate protoscoleces through the induction of apoptosis and the infliction of DNA damage. Additionally, AOCE demonstrated significant therapeutic efficacy in managing hydatid cysts in murine models. However, further studies are required to clarify the specific mechanisms underlying its action and to assess its efficacy in clinical trials, which may facilitate the application of AOCE in the context of hydatid cyst surgical procedures.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1531114"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802976","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":"Diffusion constraints in neuroprotection: implications for clinical trials.","authors":"Daniil P Aksenov, Evan D Doubovikov","doi":"10.3389/fphar.2025.1542431","DOIUrl":"10.3389/fphar.2025.1542431","url":null,"abstract":"","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1542431"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802989","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":"Structural characterization of a polysaccharide from Qi-Gui herb pair and its anti-tumor activity in colon cancer cells.","authors":"Wen-Juan Liu, Ye-Zi Ma, Jia-Xin Li, Bei-Sheng Fan, Xiao-Qiang Li, Wei Cao, Yu-Ping Tang","doi":"10.3389/fphar.2025.1557151","DOIUrl":"10.3389/fphar.2025.1557151","url":null,"abstract":"<p><p><i>Astragalus membranaceus</i> (Fisch.) Bunge and <i>Angelica sinensis</i> (Oliv.) Diels forms a classic herb pair (Qi-Gui her pair) in Chinese medicine, which was commonly used for treating menstrual anemia and microvascular ischemic diseases. While polysaccharides are known to be key bioactive components of the Qi-Gui herb pair, their structural characteristics and pharmacological activities remain underexplored. In this research, a homogeneous polysaccharide with a molecular weight of 18.1 kDa was isolated, and its structure was analyzed via high pressure size exclusion chromatography, high performance liquid chromatography, gas chromatography mass spectrometry, and nuclear magnetic resonance spectroscopy. The structural analysis revealed that AAPS-1a was composed of α-T-Glc<i>p</i> (5.9%), β-1,3-Gal<i>p</i> (3.9%), α-1,4-Man<i>p</i> (3.6%), α-1,4-Gal<i>p</i> (2.1%), α-1,4-Glc<i>p</i> (2.8%), and α-1,6-Glc<i>p</i> (81.7%). Furthermore, NMR analysis revealed that AAPS-1a consists of a repeat unit: α-T-Glc<i>p</i>-(1→4)-α-Gal<i>p</i>-(1→4)-α-Man<i>p</i>-(1→4)-α-Glc<i>p</i>-(1→[6)-α-Glc<i>p</i>-(1]_n→3)-β-Gal<i>p</i>-(1→. <i>In vitro</i> studies showed that AAPS-1a could significantly inhibit the proliferation of HCT116 cells, and induces G1 arrest and G2/M arrest, as well as apoptosis of HCT116 cells. This study presents the inaugural report establishing a connection between the structural characteristics of Qi-Gui herbal polysaccharides and their anti-colon cancer activity, demonstrating that AAPS-1a holds promise as a therapeutic agent for the treatment of colon cancer.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1557151"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802776","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":"Yiqi Qingre Gao alleviates renal fibrosis in UUO mice via PI3K/AKT pathway.","authors":"Qi Jin, Qian Li, Liping Yang, Fang Ma, Huimin Mao, Yuyang Wang, Tongtong Liu, Liang Peng, Ping Li, Yongli Zhan","doi":"10.3389/fphar.2025.1538061","DOIUrl":"10.3389/fphar.2025.1538061","url":null,"abstract":"<p><p><b>Introduction:</b> Renal fibrosis is an endpoint event of various progressive chronic kidney diseases (CKD), but there are no effective antifibrotic treatments. Yiqi Qingre Gao (YQQRG) has shown potential in alleviating CKD, although its exact mechanism of action remains uncertain. This study aims to evaluate the impact of YQQRG on renal fibrosis and to explore the molecular pathways involved. <b>Methods:</b> The study employed a unilateral ureteral obstruction (UUO) mouse model, followed by a 2-week course of YQQRG treatment. Renal function was assessed through measurements of serum creatinine (SCr) and blood urea nitrogen (BUN). Kidneys were collected for histological and molecular biology analysis. To identify the detailed mechanisms, network pharmacology, RNA sequencing (RNA-Seq), transforming growth factor-beta1 (TGF-β1)-stimulated human renal proximal tubular epithelial (HK-2) cells, and molecular docking were used. <b>Results:</b> YQQRG treatment significantly improved renal function, pathological damage, and renal fibrosis in UUO mice. Ten blood-entering components and 403 potential targets of YQQRG were identified by liquid chromatography-mass spectrometry (LC-MS) and network pharmacology. 20,107 targets of renal fibrosis were revealed by RNA-Seq of kidneys from the control and UUO groups. The results of the KEGG pathway enrichment analysis of YQQRG and renal fibrosis were combined, which showed that YQQRG's renoprotective effects were strongly associated with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Experimental validation further confirmed that YQQRG suppressed the PI3K/AKT pathway in the renal tissues of UUO mice; the addition of the PI3K/AKT agonist reversed the antifibrotic effects of YQQRG in TGF-β1-stimulated HK-2 cells. Furthermore, molecular docking indicated that YQQRG's primary active components exhibited a strong binding affinity to critical targets. <b>Discussion:</b> This study initially demonstrated that YQQRG improved renal function and kidney injury in UUO mice by revealing its antifibrotic mechanism, and it operates through the inhibition of the PI3K/AKT pathway, which highlights YQQRG as a potential therapeutic option for treating CKD.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1538061"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802810","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":"Potential bidirectional regulatory effects of botanical drug metabolites on tumors and cardiovascular diseases based on the PI3K/Akt/mTOR pathway.","authors":"Su-Ya Ma, Yong-Mei Liu, Jie Wang","doi":"10.3389/fphar.2025.1467894","DOIUrl":"10.3389/fphar.2025.1467894","url":null,"abstract":"<p><p>Pharmacological interventions targeting the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway are predominantly employed as anticancer therapies, yet they are frequently associated with significant cardiac toxicity. Additionally, the PI3K/Akt/mTOR pathway plays a crucial role in the treatment of cardiovascular diseases, highlighting its dual significance in both oncology and cardiology. Therefore, the PI3K/Akt/mTOR pathway has become an ideal signaling pathway for studying cardioprotection, anticancer effects, and their associated cardiac toxicity. Botanical drugs have emerged as a significant source for developing therapeutic agents with anticancer and cardioprotective effects, often exhibiting bidirectional protective properties. Consequently, this study investigates the bidirectional regulatory influence of botanical drug metabolites in oncology and cardiology via the PI3K/Akt/mTOR pathway. The research indicated that the PI3K/Akt/mTOR signaling pathway plays a critical regulatory role in the pathogenesis of both tumors and cardiovascular diseases. The botanical drug metabolites Ruscogenin, Sulforaphane, Naringenin, Kaempferol, Poncirin, and Puerarin can improve cancer by inhibiting the phosphorylation levels within the PI3K/Akt/mTOR signaling cascade. Moreover, they also provide cardioprotective effects in cardiac injury conditions by activating the phosphorylation levels of the PI3K/Akt/mTOR pathway. Therefore, the phosphorylation dynamics of key components in the PI3K/Akt/mTOR pathway, particularly the phosphorylation of Akt, along with the functional implications of different phosphorylation sites, may offer new therapeutic strategies and insights for cancer treatment and the mitigation of cardiotoxicity associated with cancer therapies.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1467894"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803045","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}