The autophagy-lysosome pathway plays an essential role in promoting lipid catabolism and preventing hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). Transcription factor EB (TFEB) enhances the autophagy-lysosome pathway by regulating the expression of genes related to autophagy and lysosome biogenesis. Therefore, targeting TFEB provides a novel strategy for the treatment of lipid metabolic diseases. In this study, the antiallergic drug desloratadine was screened and identified as a novel TFEB agonist. Desloratadine effectively induced translocation of TFEB to the nucleus and promoted autophagy and lysosome biogenesis. Desloratadine-induced TFEB activation was dependent on AMPK rather than mTORC1. Moreover, desloratadine treatment enhanced clearance of lipid droplets in cells induced by fatty acids oleate and palmitate. Furthermore, high-fat diet (HFD) induced obesity mouse model experiments indicated treatment with desloratadine markedly reduced the body weight of HFD-fed mice, as well as the levels of hepatic triglycerides and total cholesterol, serum glutamic pyruvic transaminase and glutamic-oxaloacetic transaminase. Oil red O staining showed the liver fat was significantly reduced after desloratadine treatment, and H&E staining analysis demonstrated hepatocellular ballooning was improved. In addition, autophagy and lysosomal biogenesis was stimulated in the liver of desloratadine treated mice. Altogether, these findings demonstrate desloratadine ameliorates hepatic steatosis through activating the TFEB-mediated autophagy-lysosome pathway, thus desloratadine has an exciting potential to be used to treat fatty liver disease.
{"title":"The novel TFEB agonist desloratadine ameliorates hepatic steatosis by activating the autophagy-lysosome pathway","authors":"Jieru Lin, Chunhuan Huang, Jingye Zhao, Lu Li, Zhenwei Wu, Tingyu Zhang, Yuyin Li, Wei Li, Baoqiang Guo, Zhenxing Liu, Aipo Diao","doi":"10.3389/fphar.2024.1449178","DOIUrl":"https://doi.org/10.3389/fphar.2024.1449178","url":null,"abstract":"The autophagy-lysosome pathway plays an essential role in promoting lipid catabolism and preventing hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). Transcription factor EB (TFEB) enhances the autophagy-lysosome pathway by regulating the expression of genes related to autophagy and lysosome biogenesis. Therefore, targeting TFEB provides a novel strategy for the treatment of lipid metabolic diseases. In this study, the antiallergic drug desloratadine was screened and identified as a novel TFEB agonist. Desloratadine effectively induced translocation of TFEB to the nucleus and promoted autophagy and lysosome biogenesis. Desloratadine-induced TFEB activation was dependent on AMPK rather than mTORC1. Moreover, desloratadine treatment enhanced clearance of lipid droplets in cells induced by fatty acids oleate and palmitate. Furthermore, high-fat diet (HFD) induced obesity mouse model experiments indicated treatment with desloratadine markedly reduced the body weight of HFD-fed mice, as well as the levels of hepatic triglycerides and total cholesterol, serum glutamic pyruvic transaminase and glutamic-oxaloacetic transaminase. Oil red O staining showed the liver fat was significantly reduced after desloratadine treatment, and H&E staining analysis demonstrated hepatocellular ballooning was improved. In addition, autophagy and lysosomal biogenesis was stimulated in the liver of desloratadine treated mice. Altogether, these findings demonstrate desloratadine ameliorates hepatic steatosis through activating the TFEB-mediated autophagy-lysosome pathway, thus desloratadine has an exciting potential to be used to treat fatty liver disease.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.3389/fphar.2024.1443475
Qiang Li, Yubin Liu, Boyuan Ren, Jiayan Jin, Lin Zhang, ChuTse Wu, JiDe Jin
Thrombosis, a prevalent condition, can provoke severe health issues like acute coronary syndrome (ACS), deep vein thrombosis (DVT), and pulmonary embolism (PE). The rising incidence of these diseases annually significantly impacts patient wellbeing and poses a substantial burden on healthcare systems. Recombinant neorudin is a developing anticoagulant drug for thrombotic diseases whose phase I clinical trials has been completed. The distribution pattern of it and its active metabolite, hirudin, in thrombi, blood surrounding the thrombus and peripheral blood remains uncertain. This study explored their distribution using a rat arteriovenous bypass thrombosis model, revealing higher neorudin levels in blood surrounding the thrombus and elevated hirudin concentrations in thrombus. Recombinant neorudin significantly increased Thrombin Time (TT) in both plasma surrounding the thrombus and peripheral blood, and reduced the wet weight of the thrombus. The results above demonstrated the anticoagulant and antithrombotic efficacy of recombinant neorudin in vivo. Give the distribution pattern of neorudin and hirudin, we hypothesized that neorudin was cleaved at the site of thrombus formation to produce hirudin, leading to the rapid accumulation of hirudin within local thrombi and resulting in a higher concentration inside the thrombus. This insight was crucial for understanding the action mechanisms of anticoagulants in thrombosis management and provided a valuable guidance for therapeutic strategies in treating thrombotic diseases.
血栓是一种常见病，可引发严重的健康问题，如急性冠状动脉综合征（ACS）、深静脉血栓（DVT）和肺栓塞（PE）。这些疾病的发病率逐年上升，严重影响了患者的健康，并给医疗保健系统带来沉重负担。重组 neorudin 是一种治疗血栓性疾病的抗凝药物，其 I 期临床试验已经完成。它及其活性代谢产物水蛭素在血栓、血栓周围血液和外周血中的分布模式仍不确定。本研究利用大鼠动静脉旁路血栓形成模型探讨了它们的分布情况，结果显示血栓周围血液中的新芦丁水平较高，而血栓中的水蛭素浓度较高。重组新芦丁能显著延长血栓周围血浆和外周血中的凝血酶时间（TT），并降低血栓的湿重。上述结果证明了重组新芦丁在体内的抗凝和抗血栓功效。根据新芦丁和水蛭素的分布模式，我们推测新芦丁在血栓形成部位被裂解生成水蛭素，导致水蛭素在局部血栓内迅速积累，从而在血栓内形成较高浓度。这一发现对理解抗凝剂在血栓治疗中的作用机制至关重要，并为血栓性疾病的治疗策略提供了宝贵的指导。
{"title":"Recombinant neorudin and its active metabolite hirudin: the fate in vivo of a novel anticoagulant drug","authors":"Qiang Li, Yubin Liu, Boyuan Ren, Jiayan Jin, Lin Zhang, ChuTse Wu, JiDe Jin","doi":"10.3389/fphar.2024.1443475","DOIUrl":"https://doi.org/10.3389/fphar.2024.1443475","url":null,"abstract":"Thrombosis, a prevalent condition, can provoke severe health issues like acute coronary syndrome (ACS), deep vein thrombosis (DVT), and pulmonary embolism (PE). The rising incidence of these diseases annually significantly impacts patient wellbeing and poses a substantial burden on healthcare systems. Recombinant neorudin is a developing anticoagulant drug for thrombotic diseases whose phase I clinical trials has been completed. The distribution pattern of it and its active metabolite, hirudin, in thrombi, blood surrounding the thrombus and peripheral blood remains uncertain. This study explored their distribution using a rat arteriovenous bypass thrombosis model, revealing higher neorudin levels in blood surrounding the thrombus and elevated hirudin concentrations in thrombus. Recombinant neorudin significantly increased Thrombin Time (TT) in both plasma surrounding the thrombus and peripheral blood, and reduced the wet weight of the thrombus. The results above demonstrated the anticoagulant and antithrombotic efficacy of recombinant neorudin <jats:italic>in vivo</jats:italic>. Give the distribution pattern of neorudin and hirudin, we hypothesized that neorudin was cleaved at the site of thrombus formation to produce hirudin, leading to the rapid accumulation of hirudin within local thrombi and resulting in a higher concentration inside the thrombus. This insight was crucial for understanding the action mechanisms of anticoagulants in thrombosis management and provided a valuable guidance for therapeutic strategies in treating thrombotic diseases.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.3389/fphar.2024.1424400
Zhen-peng Huang, Hu Qiu
BackgroundHypercholesterolemia induces cholelithiasis and dysfunction of gallbladder motility. Interstitial cells of Cajal (ICCs) contribute to gallbladder motility. Emodin modulates the contractility of the gallbladder muscle; however, the underlying mechanism is unknown.AimThis study aimed to explore the effects of emodin on gallbladder ICCs with cholelithiasis in a guinea pig model.MethodsAnimals were randomly divided into a healthy control group and three study groups. All study groups received a high-cholesterol diet (HCD) for 8 weeks. Subsequently, they were randomly assigned to either the HCD group or one of the emodin treatment groups lasting 4 or 8 weeks. Total cholesterol (TC) and triglycerides (TG) were measured to determine changes in serum lipid levels. Immunohistochemistry was performed to detect the morphology and number of ICCs. TUNEL assays were performed to detect ICC apoptosis. Transmission electron microscopy was employed to observe ICC structure. Western blotting and real-time polymerase chain reaction were used to detect changes in stem cell factor (SCF)/c-kit pathway expression.ResultsSerum TC and TG were higher in all study groups. In cases of cholelithiasis, the SCF/c-kit pathway was downregulated, the number of gallbladder ICCs decreased, apoptosis increased, and the ICC network structure was damaged. After emodin treatment, the SCF/c-kit pathway was upregulated, the number of gallbladder ICCs increased, apoptosis decreased, and the ICC network structure recovered.ConclusionCholelithiasis downregulates the SCF/c-kit pathway and damages gallbladder ICCs. Emodin upregulates the SCF/c-kit pathway and increases gallbladder ICCs, contributing to recovery from gallbladder motility disorders.
{"title":"Emodin repairs interstitial cells of Cajal damaged by cholelithiasis in the gallbladder","authors":"Zhen-peng Huang, Hu Qiu","doi":"10.3389/fphar.2024.1424400","DOIUrl":"https://doi.org/10.3389/fphar.2024.1424400","url":null,"abstract":"BackgroundHypercholesterolemia induces cholelithiasis and dysfunction of gallbladder motility. Interstitial cells of Cajal (ICCs) contribute to gallbladder motility. Emodin modulates the contractility of the gallbladder muscle; however, the underlying mechanism is unknown.AimThis study aimed to explore the effects of emodin on gallbladder ICCs with cholelithiasis in a guinea pig model.MethodsAnimals were randomly divided into a healthy control group and three study groups. All study groups received a high-cholesterol diet (HCD) for 8 weeks. Subsequently, they were randomly assigned to either the HCD group or one of the emodin treatment groups lasting 4 or 8 weeks. Total cholesterol (TC) and triglycerides (TG) were measured to determine changes in serum lipid levels. Immunohistochemistry was performed to detect the morphology and number of ICCs. TUNEL assays were performed to detect ICC apoptosis. Transmission electron microscopy was employed to observe ICC structure. Western blotting and real-time polymerase chain reaction were used to detect changes in stem cell factor (SCF)/c-kit pathway expression.ResultsSerum TC and TG were higher in all study groups. In cases of cholelithiasis, the SCF/c-kit pathway was downregulated, the number of gallbladder ICCs decreased, apoptosis increased, and the ICC network structure was damaged. After emodin treatment, the SCF/c-kit pathway was upregulated, the number of gallbladder ICCs increased, apoptosis decreased, and the ICC network structure recovered.ConclusionCholelithiasis downregulates the SCF/c-kit pathway and damages gallbladder ICCs. Emodin upregulates the SCF/c-kit pathway and increases gallbladder ICCs, contributing to recovery from gallbladder motility disorders.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.3389/fphar.2024.1462368
Yufu Liu, Hongwei Zhang, Tianyan Chen, Chang Xu, Xingfu Bao
As a novel class of smart biomaterials with promising potentials, metal-organic frameworks (MOFs) are widely utilized in the field of biomedicine. Current researches indicate that the therapeutic strategies for osteoarthritis (OA) are highly limited to achieving symptom improvement and reducing both pain and inflammation. Together, the introduction of MOFs into the treatment of OA holds the potential to offer significant benefits. This is because MOFs not only have intrinsic biological activities, but also act as carriers to facilitate controlled drug delivery and prolong the duration in the management of OA. This paper presents a review of the recent studies that have explored the potential usage of MOFs as drugs or carriers in the treatment of OA, which also examines the progress of MOFs in tissue engineering for the treatment of OA. These studies are anticipated to not only enhance the comprehension of MOFs but also provide strong evidence in favor of their utilization in the treatment of OA.
金属有机框架（MOFs）是一类新型智能生物材料，具有广阔的应用前景，在生物医学领域得到广泛应用。目前的研究表明，骨关节炎（OA）的治疗策略主要局限于改善症状、减轻疼痛和炎症。因此，将 MOFs 引入 OA 的治疗有望带来显著的益处。这是因为 MOFs 不仅具有固有的生物活性，还可作为载体促进药物的可控递送，延长治疗 OA 的持续时间。本文综述了近期探索将 MOFs 作为药物或载体用于治疗 OA 的潜在用途的研究，同时还探讨了 MOFs 在组织工程学治疗 OA 方面的进展。预计这些研究不仅能加深人们对 MOFs 的理解，还能为利用 MOFs 治疗 OA 提供有力证据。
{"title":"Metal-organic frameworks (MOFs) and their derivatives as emerging biomaterials for the treatment of osteoarthritis","authors":"Yufu Liu, Hongwei Zhang, Tianyan Chen, Chang Xu, Xingfu Bao","doi":"10.3389/fphar.2024.1462368","DOIUrl":"https://doi.org/10.3389/fphar.2024.1462368","url":null,"abstract":"As a novel class of smart biomaterials with promising potentials, metal-organic frameworks (MOFs) are widely utilized in the field of biomedicine. Current researches indicate that the therapeutic strategies for osteoarthritis (OA) are highly limited to achieving symptom improvement and reducing both pain and inflammation. Together, the introduction of MOFs into the treatment of OA holds the potential to offer significant benefits. This is because MOFs not only have intrinsic biological activities, but also act as carriers to facilitate controlled drug delivery and prolong the duration in the management of OA. This paper presents a review of the recent studies that have explored the potential usage of MOFs as drugs or carriers in the treatment of OA, which also examines the progress of MOFs in tissue engineering for the treatment of OA. These studies are anticipated to not only enhance the comprehension of MOFs but also provide strong evidence in favor of their utilization in the treatment of OA.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.3389/fphar.2024.1443235
Wei Li, Zechen Zhang, Yuyi Li, Zhenyu Wu, Chengjie Wang, Zhen Huang, Baisheng Ye, Xin Jiang, Xiaolong Yang, Xiaolin Shi
BackgroundEvidence shows that the total flavonoids of Rhizoma Drynariae (TFRD) can improve bone mineral density (BMD). However, there is no evidence to summarize the improvement of biochemical indicators of bone metabolism (BIBM).MethodsThe PubMed, Web of Science, Cochrane Library, Embase, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, Chongqing VIP Information Database (VIP) and SinoMed were searched from inception to 6 May 2024. The final included studies performed meta-analyses using RevMan 5.3.ResultsNine randomized controlled trials (RCTs) were ultimately included. The TFRD group had higher bone gla protein (BGP) and type I procollagen-N-propeptide (PINP) compared to the Other therapies (WMD: 5.11; 95% CI: 3.37, 6.84; p < 0.00001; WMD: 13.89; 95% CI: 11.81, 15.97; p < 0.00001). The tartrate-resistant acid phosphatase (TRACP) decreased significantly (WMD: −1.34; 95% CI: −1.62, −1.06; p < 0.00001). The alkaline phosphatase (ALP) increased significantly (WMD: 7.47; 95% CI: 6.29, 8.66; p < 0.00001). There were no significant differences in serum calcium (SC) or serum phosphorus (SP) levels between the TFRD and control groups (WMD: 0.08; 95% CI: −0.04, 0.20; p = 0.17; WMD: 0.02; 95% CI: −0.02, 0.05; p = 0.36).ConclusionTFRD can stimulate bone formation and prevent bone resorption in osteoporosis (OP) patients, but it has no effect on SC and SP.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/.
{"title":"Effects of total flavonoids of Rhizoma Drynariae on biochemical indicators of bone metabolism: a systematic review and meta-analysis","authors":"Wei Li, Zechen Zhang, Yuyi Li, Zhenyu Wu, Chengjie Wang, Zhen Huang, Baisheng Ye, Xin Jiang, Xiaolong Yang, Xiaolin Shi","doi":"10.3389/fphar.2024.1443235","DOIUrl":"https://doi.org/10.3389/fphar.2024.1443235","url":null,"abstract":"BackgroundEvidence shows that the total flavonoids of Rhizoma Drynariae (TFRD) can improve bone mineral density (BMD). However, there is no evidence to summarize the improvement of biochemical indicators of bone metabolism (BIBM).MethodsThe PubMed, Web of Science, Cochrane Library, Embase, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, Chongqing VIP Information Database (VIP) and SinoMed were searched from inception to 6 May 2024. The final included studies performed meta-analyses using RevMan 5.3.ResultsNine randomized controlled trials (RCTs) were ultimately included. The TFRD group had higher bone gla protein (BGP) and type I procollagen-N-propeptide (PINP) compared to the Other therapies (WMD: 5.11; 95% CI: 3.37, 6.84; <jats:italic>p</jats:italic> &lt; 0.00001; WMD: 13.89; 95% CI: 11.81, 15.97; <jats:italic>p</jats:italic> &lt; 0.00001). The tartrate-resistant acid phosphatase (TRACP) decreased significantly (WMD: −1.34; 95% CI: −1.62, −1.06; <jats:italic>p</jats:italic> &lt; 0.00001). The alkaline phosphatase (ALP) increased significantly (WMD: 7.47; 95% CI: 6.29, 8.66; <jats:italic>p</jats:italic> &lt; 0.00001). There were no significant differences in serum calcium (SC) or serum phosphorus (SP) levels between the TFRD and control groups (WMD: 0.08; 95% CI: −0.04, 0.20; <jats:italic>p</jats:italic> = 0.17; WMD: 0.02; 95% CI: −0.02, 0.05; <jats:italic>p</jats:italic> = 0.36).ConclusionTFRD can stimulate bone formation and prevent bone resorption in osteoporosis (OP) patients, but it has no effect on SC and SP.Systematic Review Registration<jats:ext-link>https://www.crd.york.ac.uk/PROSPERO/</jats:ext-link>.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundAlzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function, which significantly increases pain and social burden. However, few therapeutic interventions are effective in preventing or mitigating the progression of AD. An increasing number of recent studies support the hypothesis that the gut microbiome and its metabolites may be associated with upstream regulators of AD pathology.MethodsIn this review, we comprehensively explore the potential mechanisms and currently available interventions targeting the microbiome for the improvement of AD. Our discussion is structured around modern research advancements in AD, the bidirectional communication between the gut and brain, the multi-target regulatory effects of microbial metabolites on AD, and therapeutic strategies aimed at modulating gut microbiota to manage AD.ResultsThe gut microbiota plays a crucial role in the pathogenesis of AD through continuous bidirectional communication via the microbiota-gut-brain axis. Among these, microbial metabolites such as lipids, amino acids, bile acids and neurotransmitters, especially sphingolipids and phospholipids, may serve as central components of the gut-brain axis, regulating AD-related pathogenic mechanisms including β-amyloid metabolism, Tau protein phosphorylation, and neuroinflammation. Additionally, interventions such as probiotic administration, fecal microbiota transplantation, and antibiotic use have also provided evidence supporting the association between gut microbiota and AD. At the same time, we propose an innovative strategy for treating AD: a healthy lifestyle combined with targeted probiotics and other potential therapeutic interventions, aiming to restore intestinal ecology and microbiota balance.ConclusionDespite previous efforts, the molecular mechanisms by which gut microbes act on AD have yet to be fully described. However, intestinal microorganisms may become an essential target for connecting the gut-brain axis and improving the symptoms of AD. At the same time, it requires joint exploration by multiple centers and multiple disciplines.
背景阿尔茨海默病（AD）是一种神经退行性疾病，其特点是认知功能进行性下降，大大增加了患者的痛苦和社会负担。然而，很少有治疗干预措施能有效预防或缓解阿尔茨海默病的进展。最近越来越多的研究支持这样的假设，即肠道微生物组及其代谢物可能与 AD 病理学的上游调节因素有关。方法在这篇综述中，我们全面探讨了针对微生物组改善 AD 的潜在机制和目前可用的干预措施。我们的讨论围绕着 AD 的现代研究进展、肠道与大脑之间的双向交流、微生物代谢物对 AD 的多靶点调控作用以及旨在调节肠道微生物群以控制 AD 的治疗策略展开。其中，微生物代谢产物，如脂类、氨基酸、胆汁酸和神经递质，尤其是鞘磷脂和磷脂，可作为肠脑轴的核心成分，调节与AD相关的致病机制，包括β-淀粉样蛋白代谢、Tau蛋白磷酸化和神经炎症。此外，益生菌施用、粪便微生物群移植和抗生素使用等干预措施也提供了支持肠道微生物群与 AD 之间关联的证据。同时，我们提出了一种治疗 AD 的创新策略：将健康的生活方式与有针对性的益生菌和其他潜在的治疗干预措施相结合，旨在恢复肠道生态和微生物群平衡。然而，肠道微生物可能成为连接肠道-大脑轴和改善 AD 症状的重要靶点。同时，这也需要多中心、多学科的共同探索。
{"title":"Gut microbiota metabolites: potential therapeutic targets for Alzheimer’s disease?","authors":"Shanshan Zhang, Jing Lu, Ziqi Jin, Hanying Xu, Dongmei Zhang, Jianan Chen, Jian Wang","doi":"10.3389/fphar.2024.1459655","DOIUrl":"https://doi.org/10.3389/fphar.2024.1459655","url":null,"abstract":"BackgroundAlzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function, which significantly increases pain and social burden. However, few therapeutic interventions are effective in preventing or mitigating the progression of AD. An increasing number of recent studies support the hypothesis that the gut microbiome and its metabolites may be associated with upstream regulators of AD pathology.MethodsIn this review, we comprehensively explore the potential mechanisms and currently available interventions targeting the microbiome for the improvement of AD. Our discussion is structured around modern research advancements in AD, the bidirectional communication between the gut and brain, the multi-target regulatory effects of microbial metabolites on AD, and therapeutic strategies aimed at modulating gut microbiota to manage AD.ResultsThe gut microbiota plays a crucial role in the pathogenesis of AD through continuous bidirectional communication via the microbiota-gut-brain axis. Among these, microbial metabolites such as lipids, amino acids, bile acids and neurotransmitters, especially sphingolipids and phospholipids, may serve as central components of the gut-brain axis, regulating AD-related pathogenic mechanisms including β-amyloid metabolism, Tau protein phosphorylation, and neuroinflammation. Additionally, interventions such as probiotic administration, fecal microbiota transplantation, and antibiotic use have also provided evidence supporting the association between gut microbiota and AD. At the same time, we propose an innovative strategy for treating AD: a healthy lifestyle combined with targeted probiotics and other potential therapeutic interventions, aiming to restore intestinal ecology and microbiota balance.ConclusionDespite previous efforts, the molecular mechanisms by which gut microbes act on AD have yet to be fully described. However, intestinal microorganisms may become an essential target for connecting the gut-brain axis and improving the symptoms of AD. At the same time, it requires joint exploration by multiple centers and multiple disciplines.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.3389/fphar.2024.1470377
Qingqing Li, Xiaohai Chen, Siping Zhang, Wanshu Li, Hangjuan Lin
Riociguat, an orally soluble guanylate cyclase (sGC)-promoting drug, is mainly used in the clinical treatment of pulmonary hypertension (PH). In this study, a novel ultra-performance liquid chromatography-tandem mass spectrometry method was developed to quantify the concentrations of riociguat and its metabolite (M1) in plasma. The precision, stability, accuracy, matrix effect, and recovery of the methodology were satisfactory. Quercetin, a well-recognized compound, functions as a novel anticancer agent with the potential to alleviate symptoms of PH. Therefore, the potential interaction between quercetin and riociguat was investigated in this study. The levels of riociguat and M1 in rat plasma were measured using the method developed in this study to evaluate the interactions between riociguat and quercetin in rats. The results revealed that quercetin significantly inhibited riociguat and M1 metabolism with increased systemic exposure.
{"title":"Analysis of riociguat and desmethyl riociguat by UPLC-MS/MS and its interaction with quercetin","authors":"Qingqing Li, Xiaohai Chen, Siping Zhang, Wanshu Li, Hangjuan Lin","doi":"10.3389/fphar.2024.1470377","DOIUrl":"https://doi.org/10.3389/fphar.2024.1470377","url":null,"abstract":"Riociguat, an orally soluble guanylate cyclase (sGC)-promoting drug, is mainly used in the clinical treatment of pulmonary hypertension (PH). In this study, a novel ultra-performance liquid chromatography-tandem mass spectrometry method was developed to quantify the concentrations of riociguat and its metabolite (M1) in plasma. The precision, stability, accuracy, matrix effect, and recovery of the methodology were satisfactory. Quercetin, a well-recognized compound, functions as a novel anticancer agent with the potential to alleviate symptoms of PH. Therefore, the potential interaction between quercetin and riociguat was investigated in this study. The levels of riociguat and M1 in rat plasma were measured using the method developed in this study to evaluate the interactions between riociguat and quercetin in rats. The results revealed that quercetin significantly inhibited riociguat and M1 metabolism with increased systemic exposure.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.3389/fphar.2024.1450733
Hongtuo Kuang, Lingping Kong, Ajiao Hou, Anni Yang, Hai Jiang
Polygalae radix (PR) is the dried root of Polygala tenuifolia Willd. and Polygala sibirica L. and enjoys the reputation as the “key medicine for nourishing life.” In this study, information about “Polygala tenuifolia Willd.,” “Polygala sibirica L.,” and “Yuanzhi” was retrieved from scientific databases, including Google Scholar, Baidu Scholar, Web of Science, PubMed, CNKI, and Wan Fang Data. Information from Chinese herbal medicine classics, Yaozhi Data, and the Gaide Chemical Network was also collected. Information related to botany, phytochemistry, pharmacology, toxicity, industrial applications, and processing is summarized in this paper to tap its potentialities and promote its further development and clinical application. More than 320 metabolites have been isolated from PR; saponins, xanthones, and oligosaccharide esters are the main functional metabolites. Pharmacological research shows that its pharmacological action mainly focuses on resisting nervous system diseases, and it also has the functions of anti-oxidation, anti-inflammation, anti-tumor, anti-pathogenic microorganisms and others. The gastrointestinal irritation of its saponins impeded its application, but this irritation can be reduced by controlling the dosage, compatibility with other herbs, or processing. The future progress of PR faces opportunities and challenges. More attention should be paid to the traditional application and processing methods of PR recorded in ancient books. The lack of safety and clinical studies has limited its application and transformation of achievements. Moreover, it is one-sided to take the content of only a few metabolites as the index of processing optimization and quality control, which cannot reflect the full pharmacological and toxicological activities of PR.
{"title":"A review of the botany, metabolites, pharmacology, toxicity, industrial applications, and processing of Polygalae Radix: the “key medicine for nourishing life”","authors":"Hongtuo Kuang, Lingping Kong, Ajiao Hou, Anni Yang, Hai Jiang","doi":"10.3389/fphar.2024.1450733","DOIUrl":"https://doi.org/10.3389/fphar.2024.1450733","url":null,"abstract":"<jats:italic>Polygalae radix</jats:italic> (PR) is the dried root of <jats:italic>Polygala tenuifolia</jats:italic> Willd. and <jats:italic>Polygala sibirica</jats:italic> L. and enjoys the reputation as the “key medicine for nourishing life.” In this study, information about “<jats:italic>Polygala tenuifolia</jats:italic> Willd.,” “<jats:italic>Polygala sibirica</jats:italic> L.,” and “Yuanzhi” was retrieved from scientific databases, including Google Scholar, Baidu Scholar, Web of Science, PubMed, CNKI, and Wan Fang Data. Information from Chinese herbal medicine classics, Yaozhi Data, and the Gaide Chemical Network was also collected. Information related to botany, phytochemistry, pharmacology, toxicity, industrial applications, and processing is summarized in this paper to tap its potentialities and promote its further development and clinical application. More than 320 metabolites have been isolated from PR; saponins, xanthones, and oligosaccharide esters are the main functional metabolites. Pharmacological research shows that its pharmacological action mainly focuses on resisting nervous system diseases, and it also has the functions of anti-oxidation, anti-inflammation, anti-tumor, anti-pathogenic microorganisms and others. The gastrointestinal irritation of its saponins impeded its application, but this irritation can be reduced by controlling the dosage, compatibility with other herbs, or processing. The future progress of PR faces opportunities and challenges. More attention should be paid to the traditional application and processing methods of PR recorded in ancient books. The lack of safety and clinical studies has limited its application and transformation of achievements. Moreover, it is one-sided to take the content of only a few metabolites as the index of processing optimization and quality control, which cannot reflect the full pharmacological and toxicological activities of PR.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.3389/fphar.2024.1464145
Qingliu He, Qingfu Su, Chengcheng Wei, Pu Zhang, Weihui Liu, Junyi Chen, Xiaoping Su, Wei Zhuang
BackgroundThe role of focal amplifications and extrachromosomal circular DNA (eccDNA) is still uncertain in prostate adenocarcinoma (PRAD). Here, we first mapped the global characterizations of eccDNA and then investigate the characterization of eccDNA-amplified key differentially expressed encoded genes (eKDEGs) in the progression, immune response and immunotherapy of PRAD.MethodsCircular_seq was used in conjunction with the TCGA-PRAD transcriptome dataset to sequence, annotate, and filter for eccDNA-amplified differentially expressed coding genes (eDEGs) in PRAD and para-cancerous normal prostate tissues. Afterwards, risk models were created and eKDEGs linked to the PRAD prognosis were identified using Cox and Lasso regression analysis. The immune microenvironment of the risk model was quantified using a variety of immunological algorithms, which also identified its characteristics with regard to immunotherapy, immune response, and immune infiltration.ResultsIn this research, there was no significant difference in the size, type, and chromosomal distribution of eccDNA in PRAD and para-cancerous normal prostate tissues. However, 4,290 differentially expressed eccDNAs were identified and 1,981 coding genes were amplified. Following that, 499 eDEGs were tested in conjunction with the transcriptome dataset from TCGA-PRAD. By using Cox and Lasso regression techniques, ZNF330 and PITPNM3 were identified as eKDEGs of PRAD, and a new PRAD risk model was conducted based on this. Survival analysis showed that the high-risk group of this model was associated with poor prognosis and validated in external data. Immune infiltration analysis showed that the model risks affected immune cell infiltration in PRAD, not only mediating changes in immune cell function, but also correlating with immunophenotyping. Furthermore, the high-risk group was negatively associated with anti-CTLA-4/anti-PD-1 response and mutational burden. In addition, Tumor Immune Dysfunction and Exclusion analyses showed that high-risk group was more prone to immune escape. Drug sensitivity analyses identified 10 drugs, which were instructive for PRAD treatment.ConclusionZNF330 and PITPNM are the eKDEGs for PRAD, which can be used as potential new prognostic markers. The two-factor combined risk model can effectively assess the survival and prognosis of PRAD patients, but also can predict the different responses of immunotherapy to PRAD patients, which may provide new ideas for PRAD immunotherapy.
{"title":"Extrachromosomal circular DNAs in prostate adenocarcinoma: global characterizations and a novel prediction model","authors":"Qingliu He, Qingfu Su, Chengcheng Wei, Pu Zhang, Weihui Liu, Junyi Chen, Xiaoping Su, Wei Zhuang","doi":"10.3389/fphar.2024.1464145","DOIUrl":"https://doi.org/10.3389/fphar.2024.1464145","url":null,"abstract":"BackgroundThe role of focal amplifications and extrachromosomal circular DNA (eccDNA) is still uncertain in prostate adenocarcinoma (PRAD). Here, we first mapped the global characterizations of eccDNA and then investigate the characterization of eccDNA-amplified key differentially expressed encoded genes (eKDEGs) in the progression, immune response and immunotherapy of PRAD.MethodsCircular_seq was used in conjunction with the TCGA-PRAD transcriptome dataset to sequence, annotate, and filter for eccDNA-amplified differentially expressed coding genes (eDEGs) in PRAD and para-cancerous normal prostate tissues. Afterwards, risk models were created and eKDEGs linked to the PRAD prognosis were identified using Cox and Lasso regression analysis. The immune microenvironment of the risk model was quantified using a variety of immunological algorithms, which also identified its characteristics with regard to immunotherapy, immune response, and immune infiltration.ResultsIn this research, there was no significant difference in the size, type, and chromosomal distribution of eccDNA in PRAD and para-cancerous normal prostate tissues. However, 4,290 differentially expressed eccDNAs were identified and 1,981 coding genes were amplified. Following that, 499 eDEGs were tested in conjunction with the transcriptome dataset from TCGA-PRAD. By using Cox and Lasso regression techniques, ZNF330 and PITPNM3 were identified as eKDEGs of PRAD, and a new PRAD risk model was conducted based on this. Survival analysis showed that the high-risk group of this model was associated with poor prognosis and validated in external data. Immune infiltration analysis showed that the model risks affected immune cell infiltration in PRAD, not only mediating changes in immune cell function, but also correlating with immunophenotyping. Furthermore, the high-risk group was negatively associated with anti-<jats:italic>CTLA-4</jats:italic>/anti-<jats:italic>PD-1</jats:italic> response and mutational burden. In addition, Tumor Immune Dysfunction and Exclusion analyses showed that high-risk group was more prone to immune escape. Drug sensitivity analyses identified 10 drugs, which were instructive for PRAD treatment.Conclusion<jats:italic>ZNF330</jats:italic> and <jats:italic>PITPNM</jats:italic> are the eKDEGs for PRAD, which can be used as potential new prognostic markers. The two-factor combined risk model can effectively assess the survival and prognosis of PRAD patients, but also can predict the different responses of immunotherapy to PRAD patients, which may provide new ideas for PRAD immunotherapy.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18eCollection Date: 2024-01-01DOI: 10.3389/fphar.2024.1473279
Polina Savosina, Dmitry Druzhilovskiy, Dmitry Filimonov, Vladimir Poroikov
{"title":"WWAD: the most comprehensive small molecule World Wide Approved Drug database of therapeutics.","authors":"Polina Savosina, Dmitry Druzhilovskiy, Dmitry Filimonov, Vladimir Poroikov","doi":"10.3389/fphar.2024.1473279","DOIUrl":"10.3389/fphar.2024.1473279","url":null,"abstract":"","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365001","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}
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