Acta Pharmacologica Sinica最新文献

{"title":"YY1/HIF-1α/mROS positive-feedback loop exacerbates glomerular mesangial cell proliferation in mouse early diabetic kidney disease.","authors":"Ting-Ting Yang, Yu-Ting Shao, Qian Cheng, Yu-Tian He, Zhen Qiu, Dan-Dan Pan, Huan-Ming Zhang, Zhen-Zhou Jiang, Meng Yan, Chang-Jiang Ying, Bao-Jing Li, Jun-Jie Liu, Si-Tong Qian, Tao Wang, Xiao-Xing Yin, Qian Lu","doi":"10.1038/s41401-025-01498-7","DOIUrl":"https://doi.org/10.1038/s41401-025-01498-7","url":null,"abstract":"<p><p>Mesangial cells (MCs) are the most active intrinsic cells in the glomerulus. MCs excessively proliferate at the early stage of diabetic kidney disease (DKD), eventually causing glomerular sclerosis and even renal failure; inhibiting glomerular MC proliferation in early DKD is a promising prevention and treatment strategy for early DKD. Our previous study shows that Yin Yang 1 (YY1), a zinc finger protein, is a novel regulator of DKD-induced renal fibrosis. In this study we investigated the role of YY1 in glomerular MC proliferation in DKD in vivo and in vitro. We first showed that YY1 expression levels were significantly increased in the glomerular MCs of DKD patients and db/db mice and in high glucose (HG)-treated SV40-MES13 cells. By using YY1 expression/knockdown plasmids, we confirmed that YY1 contributed to glomerular MC proliferation in vitro. We demonstrated that YY1 upregulated hypoxia-inducible factor-1 alpha (HIF-1α) expression and activity in HG-treated SV40-MES13 cells, leading to overproduction of mROS. Moreover, mROS contributed to positive feedback regulation of YY1/HIF-1α signaling, and the YY1/HIF-1α/mROS positive feedback loop exacerbated glomerular MC proliferation in HG-treated SV40-MES13 cells. In addition, renal-specific YY1 overexpression promoted glomerular MC proliferation in normal mice, whereas renal-specific YY1 knockdown mitigated MC proliferation in early diabetic mice by inactivating HIF-1α/ROS signaling. In conclusion, the YY1/HIF-1α/mROS positive feedback loop might be an attractive therapeutic target for overcoming glomerulosclerosis in early DKD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intracerebellar upregulation of Rheb(S16H) ameliorates motor dysfunction in mice with SCA2.","authors":"Sehwan Kim, Junwoo Park, Hyemi Eo, Gi Beom Lee, Se Min Park, Minsang Shin, Seung Eun Lee, Youngpyo Nam, Sang Ryong Kim","doi":"10.1038/s41401-025-01504-y","DOIUrl":"https://doi.org/10.1038/s41401-025-01504-y","url":null,"abstract":"<p><p>Cerebellar ataxia (CA) is characterized by impaired balance and coordination due to the loss of cerebellar neurons caused by various factors, and effective treatments are currently lacking. Recently, we observed reduced expression of signaling molecules in the mammalian target of rapamycin complex 1 (mTORC1) pathway in the cerebellum of mice with spinocerebellar ataxia type 2 (SCA2) compared with wild-type mice. To investigate the effects of mTORC1 upregulation on motor dysfunction in mice with SCA2, we administered an intracerebellar injection of adeno-associated virus serotype 1 carrying a constitutively active form of Ras homolog enriched in brain [Rheb(S16H)], which is an upstream activator of mTORC1. This treatment led to increased Rheb(S16H) expression in calbindin-D28K-positive Purkinje cells and increased levels of neurotrophic factors. Additionally, Rheb(S16H) upregulation reduced abnormal behaviors and protected Purkinje cells in mice with SCA2. Our findings suggest that upregulating Rheb(S16H) in the cerebellum may be a promising therapeutic strategy for hereditary CA.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy.","authors":"Lei Wang, Xue-Qing Tang, Yang Shi, Hui-Min Li, Zi-Yu Meng, Hui Chen, Xiao-Han Li, Yong-Chao Chen, Heng Liu, Yang Hong, Heng-Hui Xu, Ling Liu, Limin Zhao, Wei-Na Han, Xin Liu, Yong Zhang","doi":"10.1038/s41401-025-01503-z","DOIUrl":"https://doi.org/10.1038/s41401-025-01503-z","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-driven antibody design with generative diffusion models: current insights and future directions.","authors":"Xin-Heng He, Jun-Rui Li, James Xu, Hong Shan, Shi-Yi Shen, Si-Han Gao, H Eric Xu","doi":"10.1038/s41401-024-01380-y","DOIUrl":"10.1038/s41401-024-01380-y","url":null,"abstract":"<p><p>Therapeutic antibodies are at the forefront of biotherapeutics, valued for their high target specificity and binding affinity. Despite their potential, optimizing antibodies for superior efficacy presents significant challenges in both monetary and time costs. Recent strides in computational and artificial intelligence (AI), especially generative diffusion models, have begun to address these challenges, offering novel approaches for antibody design. This review delves into specific diffusion-based generative methodologies tailored for antibody design tasks, de novo antibody design, and optimization of complementarity-determining region (CDR) loops, along with their evaluation metrics. We aim to provide an exhaustive overview of this burgeoning field, making it an essential resource for leveraging diffusion-based generative models in antibody design endeavors.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"565-574"},"PeriodicalIF":6.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of chikusetsusaponin IVa as a novel lysine-specific demethylase 1 inhibitor that ameliorates high fat diet-induced MASLD in mice.","authors":"Yu-Wen Liu, Ru-Yue Luo, An-Qi Liu, Jia-Wei Wang, Na-Ping Hu, Wang-Ting Li, Jian-Kang Li, Jing-Wen Wang, Jia-Lin Duan","doi":"10.1038/s41401-024-01412-7","DOIUrl":"10.1038/s41401-024-01412-7","url":null,"abstract":"<p><p>Diet-induced metabolic dysfunction steatotic liver disease (MASLD) is also called as non-alcoholic fatty liver disease (NAFLD) with limited effective strategies available. We previously have shown that chikusetsusaponin IVa (CHS), a dietary saponin from herbs in South American known for their metabolic benefits, mitigates diet-induced diabetes. In this study we investigated the beneficial effects of CHS on MASLD and the underlying mechanisms. MAFLD mouse model was established by the high-fat diet (HFD) for 6 weeks and then were treated with CHS (50 mg·kg^-1·d^-1, i.g.) for another 8 weeks. By conducting transcriptomic analysis in palmitic acid-treated HepG2 cells and primary hepatocytes as well as lipidomic analysis in liver tissues, we demonstrated that HFD activated the intestinal farnesoid X receptor (FXR) pathway, leading to the release of FGF15/19, which in turn promoted hepatic FXR-SHP binding with cAMP-responsive element-binding protein H (CREBH), thereby inhibiting CREBH-mediated fatty acid oxidation (FAO) and ketogenesis. Intriguingly, we found that CHS improved lipid metabolism in HFD mice by suppressing the enterohepatic crosstalk of FXR-SHP to enhance CREBH transactivation. Among these, lysine-specific demethylase 1 (LSD1)-mediated histone demethylation played a crucial role in lipid metabolic reprogramming. Moreover, we identified LSD1 as a critical cellular target of CHS, directly binding to Lys661 and Tyr761 of LSD1 to inhibit its histone demethylation activity. Our results suggest that targeting intestinal LSD1 with CHS could be a promising strategy for MAFLD treatment, offering new insights into the bioavailability and efficacy of natural products.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"632-652"},"PeriodicalIF":6.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A recombinant fragment antigen-binding (Fab) of trastuzumab displays low cytotoxic profile in adult human cardiomyocytes: first evidence and the key implication of FcγRIIA receptor.","authors":"Anna De Bartolo, Naomi Romeo, Alessandro Marrone, Vittoria Rago, Maria Concetta Granieri, Maria Luigia Vommaro, Arianna Cupelli, Maria Carmela Cerra, Cesare Indiveri, Raffaele Ronca, Maria Cantile, Riccardo Sanna, Carmine Rocca, Tommaso Angelone","doi":"10.1038/s41401-024-01397-3","DOIUrl":"10.1038/s41401-024-01397-3","url":null,"abstract":"<p><p>Fragment crystallizable gamma receptors (FcγRs) mediate various cellular responses with significant cardiovascular implications. They contribute to the anticancer activity of trastuzumab (TRZ), a recombinant humanized monoclonal antibody that interferes with human epidermal growth factor receptor 2 (HER2), thereby blocking its physiological function in cardiac cells. This is responsible for cardiac complications that hamper TRZ clinical application. In this study we investigated the involvement of FcγRs in the TRZ cardiotoxicity. We used a recombinant antigen-binding fragment (Fab) of TRZ (rFab-HER2) to examine whether the absence of the Fc region resulted in fewer cardiomyocyte toxicity while preserving TRZ's ability to inhibit HER2. When exposed to rFab-HER2, AC16 human adult ventricular cardiomyocytes were less vulnerable to damage and death, than to TRZ. Specifically, TRZ exhibited cytotoxicity at a lower concentration (150 µg/mL, corresponding to ~1 µM) compared to rFab-HER2 (250 µg/mL, corresponding to ~5 µM). Like TRZ, rFab-HER2 negatively modulated HER2 levels in cardiomyocyte (without inducing cytotoxic activity in BJ human fibroblast cells that either did not express or express very low levels of HER2) and inhibited the downstream ERK/AKT cascades. But rFab-HER2 did not alter cardiomyocyte mitochondrial dynamic balance, and affect apoptosis and inflammation, while it limited cytosolic and mitochondrial ROS indicators. On contrary, the Fc region (50-250 μg/mL) exerted direct cytotoxic action on cardiomyocytes (but not on human fibroblasts that lacked Fc receptors). TRZ (150 μg/mL) markedly upregulated the expression level of FcγRIIA (a FcγRs strongly involved in TRZ-induced antibody-dependent cellular toxicity) in cardiomyocytes, whereas the Fab fragment (150 μg/mL) had no effect. Our results demonstrate that Fc region plays an important pathogenic role in TRZ-induced cardiomyocyte toxicity. In addition, targeting FcγRIIA might contribute to the off-target effects of TRZ therapy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"618-631"},"PeriodicalIF":6.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intestinal human carboxylesterase 2 (CES2) expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice.","authors":"Yao-Geng Wang, Chang-Pei Gan, Joke Beukers-Korver, Hilde Rosing, Wen-Long Li, Els Wagenaar, Maria C Lebre, Ji-Ying Song, Colin Pritchard, Rahmen Bin Ali, Ivo Huijbers, Jos H Beijnen, Alfred H Schinkel","doi":"10.1038/s41401-024-01407-4","DOIUrl":"10.1038/s41401-024-01407-4","url":null,"abstract":"<p><p>Carboxylesterase 2 (CES2) is expressed mainly in liver and intestine, but most abundantly in intestine. It hydrolyzes carboxylester, thioester, and amide bonds in many exogenous and endogenous compounds, including lipids. CES2 therefore not only plays an important role in the metabolism of many (pro-)drugs, toxins and pesticides, directly influencing pharmacology and toxicology in humans, but it is also involved in energy homeostasis, affecting lipid and glucose metabolism. In this study we investigated the pharmacological and physiological functions of CES2. We constructed Ces2 cluster knockout mice lacking all eight Ces2 genes (Ces2^-/- strain) as well as humanized hepatic or intestinal CES2 transgenic strains in this Ces2^-/- background. We showed that oral availability and tissue disposition of capecitabine were drastically increased in Ces2^-/- mice, and tissue-specifically decreased by intestinal and hepatic human CES2 (hCES2) activity. The metabolism of the chemotherapeutic agent vinorelbine was strongly reduced in Ces2^-/- mice, but only marginally rescued by hCES2 expression. On the other hand, Ces2^-/- mice exhibited fatty liver, adipositis, hypercholesterolemia and diminished glucose tolerance and insulin sensitivity, but without body mass changes. Paradoxically, hepatic hCES2 expression rescued these metabolic phenotypes but increased liver size, adipose tissue mass and overall body weight, suggesting a \"healthy\" obesity phenotype. In contrast, intestinal hCES2 expression efficiently rescued all phenotypes, and even improved some parameters, including body weight, relative to the wild-type baseline values. Our results suggest that the induction of intestinal hCES2 may combat most, if not all, of the adverse effects of metabolic syndrome. These CES2 mouse models will provide powerful preclinical tools to enhance drug development, increase physiological insights, and explore potential solutions for metabolic syndrome-associated disorders.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"777-793"},"PeriodicalIF":6.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dependence of NPPS creates a targetable vulnerability in RAS-mutant cancers.","authors":"Rui-Xue Xia, Pei-Chen Zou, Jun-Ting Xie, Ya-Bin Tang, Miao-Miao Gong, Fu Fan, Ayinazhaer Aihemaiti, Yu-Qing Liu, Ying Shen, Bin-Bing S Zhou, Liang Zhu, Hui-Min Lei","doi":"10.1038/s41401-024-01409-2","DOIUrl":"10.1038/s41401-024-01409-2","url":null,"abstract":"<p><p>RAS is the most frequently mutated oncoprotein for cancer driving. Understanding of RAS biology and discovery of druggable lynchpins in RAS pathway is a prerequisite for targeted therapy of RAS-mutant cancers. The recent identification of KRAS^G12C inhibitor breaks the \"undruggable\" curse on RAS and has changed the therapy paradigm of KRAS-mutant cancers. However, KRAS mutations, let alone KRAS^G12C mutation, account for only part of RAS-mutated cancers. Targeted therapies for cancers harboring other RAS mutations remain the urgent need. In this study we explored the pivotal regulatory molecules that allow for broad inhibition of RAS mutants. By comparing the expression levels of nucleotide pyrophosphatase (NPPS) in a panel of cell lines and the functional consequence of increased NPPS expression in RAS-mutant cells, we demonstrated that cancer cells with various kinds of RAS mutations depended on NPPS for growth and survival, and that this dependence conferred a vulnerability of RAS-mutant cancer to treatment of NPPS inhibition. RAS-mutant cells, compared with RAS-wildtype cells, bored and required an upregulation of NPPS. Transcriptomics and metabolomics analyses revealed a NPPS-dependent hyperglycolysis in RAS-mutant cells. We demonstrated that NPPS promoted glucose-derived glycolytic intermediates in RAS-mutant cells by enhancing its interaction with hexokinase 1 (HK1), the enzyme catalyzing the first committed step of glycolysis. Pharmacological inhibition of NPPS-HK1 axis using NPPS inhibitor Enpp-1-IN-1 or HK1 inhibitor 2-deoxyglucose (2-DG), or genetic interfere with NPPS suppressed RAS-mutant cancers in vitro and in vivo. In conclusion, this study reveals an unrecognized mechanism and druggable lynchpin for modulation of pan-mutant-RAS pathway, proposing a new potential therapeutic approach for treating RAS-mutant cancers.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"728-739"},"PeriodicalIF":6.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clozapine impaired glucose-stimulated insulin secretion partly by increasing plasma 5-HT levels due to the inhibition of OCT1-mediated hepatic 5-HT uptake in mice.","authors":"Wen-Han Wu, Hao Zhi, Wen-Ke Feng, Ling Jiang, Lu Yang, Li-Qiang Qian, Rui-Xi Zhao, Yong-Mei Tan, Han-Yu Yang, Xiao-Dong Liu, Li Liu","doi":"10.1038/s41401-024-01401-w","DOIUrl":"10.1038/s41401-024-01401-w","url":null,"abstract":"<p><p>Patients taking atypical antipsychotics (AAPs), especially clozapine, are often associated with hyperglycaemia. Here, clozapine served as a representative agent for investigating how AAPs induce hyperglycaemia. In normal mice and mice fed a high fat diet (HFD), clozapine impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS) following intraperitoneal glucose administration and increased plasma 5-HT levels. Intraperitoneal 5-HT administration also impaired glucose tolerance and GSIS in mice. In INS-1 cells, high 5-HT levels impaired GSIS, which was attenuated by the 5-HTR₃ antagonist tropisetron or by silencing 5-HTR_3a. The 5-HTR_2a agonist TCB2 attenuated clozapine-induced GSIS impairment. Silencing 5-HTR_2a or the 5-HTR_2a antagonist ketanserin impaired GSIS. In mice, 5-HT administration impaired GSIS, which was attenuated by tropisetron but aggravated by clozapine. Clozapine increased plasma [²H]5-HT exposure following intravenous administration to mice. In HEK293-OCT1 cells, clozapine inhibited [²H]5-HT and MPP⁺ uptake. Clozapine or OCT1 silencing impaired 5-HT metabolism in mouse primary hepatocytes, demonstrating that clozapine increased plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Liver-specific silencing of OCT1 increased plasma [²H]5-HT exposure and 5-HT levels and impaired GSIS and glucose tolerance in mice. In conclusion, clozapine impaired GSIS and glucose tolerance by increasing plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Increased 5-HT impaired GSIS by activating islet 5-HTR_3a. The antagonistic effect of clozapine on islet 5-HTR_2a also contributed to GSIS impairment. The finding that clozapine-induced GSIS impairment was attributed to increased 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake may partly explain hyperglycaemia caused by other AAPs.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"687-701"},"PeriodicalIF":6.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luteolin ameliorates chronic stress-induced depressive-like behaviors in mice by promoting the Arginase-1⁺ microglial phenotype via a PPARγ-dependent mechanism.","authors":"Nai-Jun Yuan, Wen-Jun Zhu, Qing-Yu Ma, Min-Yi Huang, Rou-Rou Huo, Kai-Jie She, Jun-Ping Pan, Ji-Gang Wang, Jia-Xu Chen","doi":"10.1038/s41401-024-01402-9","DOIUrl":"10.1038/s41401-024-01402-9","url":null,"abstract":"<p><p>Accumulating evidence shows that neuroinflammation substantially contributes to the pathology of depression, a severe psychiatric disease with an increasing prevalence worldwide. Although modulating microglial phenotypes is recognized as a promising therapeutic strategy, effective treatments are still lacking. Previous studies have shown that luteolin (LUT) has anti-inflammatory effects and confers benefits on chronic stress-induced depression. In this study, we investigated the molecular mechanisms by which LUT regulates the functional phenotypes of microglia in mice with depressive-like behaviors. Mice were exposed to chronic restraint stress (CRS) for 7 weeks, and were administered LUT (10, 30, 40 mg· kg^-1 ·day^-1, i.g.) in the last 4 weeks. We showed that LUT administration significantly ameliorated depressive-like behaviors and decreased hippocampal inflammation. LUT administration induced pro-inflammatory microglia to undergo anti-inflammatory arginase (Arg)-1⁺ phenotypic polarization, which was associated with its antidepressant effects. Furthermore, we showed that LUT concentration-dependently increased the expression of PPARγ in LPS + ATP-treated microglia and the hippocampus of CRS-exposed mice, promoting the subsequent inhibition of the NLRP3 inflammasome. Molecular dynamics (MD) simulation and microscale thermophoresis (MST) analysis confirmed a direct interaction between LUT and peroxisome proliferator-activated receptor gamma (PPARγ). By using the PPARγ antagonist GW9662, we demonstrated that LUT-driven protection, both in vivo and in vitro, resulted from targeting PPARγ. First, LUT-induced Arg-1⁺ microglia were no longer detected when PPARγ was blocked. Next, LUT-mediated inhibition of the NLRP3 inflammasome and downregulation of pro-inflammatory cytokine production were reversed by the inhibition of PPARγ. Finally, the protective effects of LUT, which attenuated the microglial engulfment of synapses and prevented apparent synapse loss in the hippocampus of CRS-exposed mice, were eliminated by blocking PPARγ. In conclusion, this study showed that LUT ameliorates CRS-induced depressive-like behaviors by promoting the Arg-1⁺ microglial phenotype through a PPARγ-dependent mechanism, thereby alleviating microglial pro-inflammatory responses and reversing microglial phagocytosis-mediated synapse loss.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"575-591"},"PeriodicalIF":6.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}