Acta Pharmacologica Sinica最新文献

{"title":"Cannabinoid-2 receptor depletion promotes non-alcoholic fatty liver disease in mice via disturbing gut microbiota and tryptophan metabolism.","authors":"Wei-Ting Cheng, Si-Ya Pei, Jie Wu, Yan-Jie Wang, Yong-Wen Yang, Mei-Fang Xiao, Jun Chen, Yuan-Yuan Wang, Li Wu, Ze-Bing Huang","doi":"10.1038/s41401-025-01495-w","DOIUrl":"10.1038/s41401-025-01495-w","url":null,"abstract":"<p><p>Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a spectrum of liver damage starting with liver steatosis and lipid disorders presented as the hallmark. Cannabinoid-2 receptor (CB2R) is the receptor of endocannabinoids mainly expressed in immune cells. Our preliminary study revealed the preventative role of CB2R in liver injury related to lipid metabolism. In this study, we aimed to explore the role of CB2R in NAFLD and the underlying mechanism related to microbial community. High-fat diet-induced NAFLD model was established in mice. We found that hepatic CB2R expression was significantly reduced in NAFLD mice and CB2R^-/- mice fed with normal chow. Interestingly, cohousing with or transplanted with microbiota from WT mice, or treatment with an antibiotic cocktail ameliorated the NAFLD phenotype of CB2R^-/- mice. The gut dysbiosis in CB2R^-/- mice including increased Actinobacteriota and decreased Bacteroidota was similar to that of NAFLD patients and NAFLD mice. Microbial functional analysis and metabolomics profiling revealed obviously disturbed tryptophan metabolism in NAFLD patients and NAFLD mice, which were also seen in CB2R^-/- mice. Correlation network showed that the disordered tryptophan metabolites such as indolelactic acid (ILA) and xanthurenic acid in CB2R^-/- mice were mediated by gut dysbiosis and related to NAFLD severity indicators. In vitro and in vivo validation experiments showed that the enriched tryptophan metabolites ILA aggravated NAFLD phenotypes. These results demonstrate the involvement of CB2R in NAFLD, which is related to gut microbiota-mediated tryptophan metabolites. Our findings highlight CB2R and the associated microbes and tryptophan metabolites as promising targets for the treatment of NAFLD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1676-1691"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466623","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":"SEC62-dependent ER-phagy contributes to apelin-13/APJ-induced monocyte-vascular endothelial cell adhesion in atherosclerosis pathogenesis.","authors":"Zhe Chen, Jun Cheng, Qun Zhou, Le-le Wu, Jia-Wei Chen, Xiang-Ning Duan, Jia-Long Yan, Jian-Gang Cao, Xiao-Dan Xia, Lan-Fang Li, Lin-Xi Chen","doi":"10.1038/s41401-024-01471-w","DOIUrl":"10.1038/s41401-024-01471-w","url":null,"abstract":"<p><p>The monocyte adhesion to vascular endothelial cells constitutes a key step in atherosclerosis pathogenesis. We previously found that ROS-autophagy pathway participated in the monocyte-endothelial cell adhesion induced by angiotensin domain type 1 receptor-associated proteins (APJ) and its endogenous ligand apelin-13. In this study, we investigated what specific type of autophagy apelin-13 regulated in this process. By conducting full-scale transcriptomic analysis in apelin-13-treated human umbilical vein endothelial cells (HUVECs), we found that the transcription levels of ER-phagy receptor protein SEC62 were significantly elevated. Importantly, SEC62 was also upregulated in human atherosclerotic lesions. Thus, we investigated the effects of SEC62-dependent ER-phagy on apelin-13-induced monocyte-endothelial cell adhesion and atherosclerosis pathogenesis. We demonstrated that Apelin-13 (0.001-1 μM) dose-dependently upregulated SEC62 expression thereby inducing ER-phagy in HUVECs. This effect was reversed by autophagy inhibitor 3MA (10 mM) and endoplasmic reticulum stress inhibitor salubrinal (10 μM). The siRNA-Sec62, 3MA (10 mM), and salubrinal (10 μM) all inhibited apelin-13-induced monocyte-endothelial cells adhesion, whereas vascular endothelial cells specific SEC62 deletion alleviated atherosclerotic plaques area, intercellular adhesion molecules expression and lesional macrophages in apelin-13-treated APOE^-/- mice with high-fat and high-cholesterol diet. Moreover, we demonstrated that ubiquitin-like modification of ALDH1L1 was involved in SEC62-dependent ER-phagy in apelin-13-treated HUVECs: apelin-13 upregulated small ubiquitin-like protein UBL4A, which mediated the ubiquitination-like modification of ALDH1L1 at 812-lysine site. This, in turn, promoted insertion of ALDH1L1 into ER membrane and led to SEC62-dependent ER-phagy. We showed that siRNA-UBL4A, siRNA-ALDH1L1, siRNA-ASNA1, and the mutant of 812 lysine site of ALDH1L1 all decreased apelin-13-induced monocyte-endothelial cell adhesion. We conclude that apelin-13 induces SEC62-dependent ER-phagy to promote monocyte-endothelial cell adhesion and atherosclerosis. This study reveals new mechanisms underlying atherosclerosis and identifies a potential therapeutic target.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1652-1663"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389835","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":"CXCR2 modulates chronic pain comorbid depression in mice by regulating adult neurogenesis in the ventral dentate gyrus.","authors":"Xiao-Jie Li, Shuo Wu, Zi-Han Liu, An-An Liu, Hui-Sheng Peng, Yu-Jun Wang, Ye-Xiang Chen, Jing-Gen Liu, Chi Xu","doi":"10.1038/s41401-025-01496-9","DOIUrl":"10.1038/s41401-025-01496-9","url":null,"abstract":"<p><p>Research shows that chronic pain may induce depression-like behaviors through impairing adult hippocampal neurogenesis (AHN) in the ventral dentate gyrus (DG), whereas restoration of AHN may effectively alleviate depression. The C-X-C motif chemokine receptor 2 (CXCR2) is a chemokine receptor involved in various neural activities of the hippocampus including AHN. In this study we investigated the role of CXCR2 of neural stem cells (NSCs) in the ventral DG in regulating both AHN and depression-like behaviors of mice with chronic neuropathic pain. Chronic neuropathic pain was induced in mice by the spared nerve injury (SNI) surgery; mechanical allodynia and depression-like behaviors were monitored, then mouse DG was collected for analysis. We observed that chronic neuropathic pain significantly decreased the number of immature neurons in the ventral DG by inhibiting the neuronal differentiation of NSCs; specific overexpression of CXCR2 in NSCs by injecting the adeno-associated virus (AAV) into the DG restored adult neurogenesis accompanied by alleviated depression-like behaviors in SNI mice. In contrast, the knockdown of CXCR2 in hippocampal NSCs of naive mice was sufficient to inhibit adult neurogenesis, inducing depression-like behaviors. Moreover, we found that the Wnt3a/β-catenin pathway was downregulated in the ventral DG of SNI mice, which was restored after CXCR2 overexpression or infusing a CXCR2 agonist CXCL1 into the ventral DG. We conclude that CXCR2 expressed in hippocampal NSCs is crucial for regulating adult neurogenesis and chronic pain-induced depression-like behavior, thus representing a new target for the treatment of chronic pain comorbid depression.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1567-1579"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456574","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":"Gastrodin promotes CNS myelinogenesis and alleviates demyelinating injury by activating the PI3K/AKT/mTOR signaling.","authors":"Xiao-Yu Shi, Yi-Xi He, Man-Yue Ge, Peng Liu, Ping Zheng, Zheng-Hao Li","doi":"10.1038/s41401-025-01492-z","DOIUrl":"10.1038/s41401-025-01492-z","url":null,"abstract":"<p><p>Demyelination is a common feature of numerous neurological disorders including multiple sclerosis and leukodystrophies. Although myelin can be regenerated spontaneously following injury, this process is often inadequate, potentially resulting in neurodegeneration and exacerbating neurological dysfunction. Several drugs aimed at promoting the differentiation of oligodendrocyte precursor cells (OPCs) have yielded unsatisfactory clinical effects. A recent study has shifted the strategy of pro-OPC differentiation towards enhancing myelinogenesis. In this study we identified the pro-myelinating drug using a zebrafish model. Five traditional Chinese medicine monomers including gastrodin, paeoniflorin, puerarin, salidroside and scutellarin were assessed by bath-application in Tg (MBP:eGFP-CAAX) transgenic line at 1-5 dpf. Among the 5 monomers, only gastrodin exhibited significant pro-myelination activity. We showed that gastrodin (10 µM) enhanced myelin sheath formation and oligodendrocyte (OL) maturation without affecting the number of OLs. Gastrodin markedly increased the phosphorylation levels of PI3K, AKT, and mTOR in primary cultured OLs via direct interaction with PI3K. Co-treatment with the PI3K inhibitor LY294002 (5 µM) mitigated gastrodin-induced OL maturation. Furthermore, injection of gastrodin (100 mg·kg^-1·d^-1, i.p.) effectively facilitated remyelination in a lysophosphatidylcholine-induced demyelinating mouse model and alleviated demyelination in the experimental autoimmune encephalomyelitis mice. These results identify gastrodin as a promising therapeutic agent for demyelinating diseases and highlight the potential of the zebrafish model for screening pro-myelinogenic pharmacotherapy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1610-1623"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514330","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":"Exploring immunotherapeutic strategies for neurodegenerative diseases: a focus on Huntington's disease and Prion diseases.","authors":"Abhiyanta Mukherjee, Soumojit Biswas, Ipsita Roy","doi":"10.1038/s41401-024-01455-w","DOIUrl":"10.1038/s41401-024-01455-w","url":null,"abstract":"<p><p>Immunotherapy has emerged as a promising therapeutic approach for the treatment of neurodegenerative disorders, which are characterized by the progressive loss of neurons and impaired cognitive functions. In this review, active and passive immunotherapeutic strategies that help address the underlying pathophysiology of Huntington's disease (HD) and prion diseases by modulating the immune system are discussed. The current landscape of immunotherapeutic strategies, including monoclonal antibodies and vaccine-based approaches, to treat these diseases is highlighted, along with their potential benefits and mechanisms of action. Immunotherapy generally works by targeting disease-specific proteins, which serve as the pathological hallmarks of these diseases. Additionally, the review addresses the challenges and limitations associated with immunotherapy. For HD, immunotherapeutic approaches focus on neutralizing the toxic effects of mutant huntingtin and tau proteins, thereby reducing neurotoxicity. Immunotherapeutic approaches targeting flanking sequences, rather than the polyglutamine tract in the mutant huntingtin protein, have yielded promising outcomes for patients with HD. In prion diseases, therapies attempt to prevent or eliminate misfolded proteins that cause neurodegeneration. The major challenge in prion diseases is immune tolerance. Approaches to overcome the highly tolerogenic nature of the prion protein have been discussed. A common hurdle in delivering antibodies is the blood‒brain barrier, and strategies that can breach this barrier are being investigated. As protein aggregation and neurotoxicity are related, immunotherapeutic strategies being developed for other neurodegenerative diseases could be repurposed to target protein aggregation in HD and prion diseases. While significant advances in this field have been achieved, continued research and development are necessary to overcome the existing limitations, which will help in shaping the future of immunotherapy as a strategy for managing neurological disorders.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1511-1538"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073264","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":"Cardiorenal syndrome: clinical diagnosis, molecular mechanisms and therapeutic strategies.","authors":"Bo-Rui Zhao, Xin-Rong Hu, Wei-Dong Wang, Yi Zhou","doi":"10.1038/s41401-025-01476-z","DOIUrl":"10.1038/s41401-025-01476-z","url":null,"abstract":"<p><p>As the heart and kidneys are closely connected by the circulatory system, primary dysfunction of either organ usually leads to secondary dysfunction or damage to the other organ. These interactions play a major role in the pathogenesis of a clinical entity named cardiorenal syndrome (CRS). The pathophysiology of CRS is complicated and involves multiple body systems. In early studies, CRS was classified into five subtypes according to the organs associated with the vicious cycle and the acuteness and chronicity of CRS. Increasing evidence shows that CRS is associated with a variety of pathological mechanisms, such as haemodynamics, neurohormonal changes, hypervolemia, hypertension, hyperuraemia and hyperuricaemia. In this review, we summarize the classification and currently available diagnostic biomarkers of CRS. We highlight the recently revealed molecular pathogenesis of CRS, such as oxidative stress and inflammation, hyperactive renin‒angiotensin‒aldosterone system, maladaptive Wnt/β-catenin signalling pathway and profibrotic TGF‒β1/Smad signalling pathway, as well as other pathogeneses, such as dysbiosis of the gut microbiota and dysregulation of noncoding RNAs. Targeting these CRS-associated signalling pathways has new therapeutic potential for treating CRS. In addition, various chemical drugs, natural products, complementary therapies, blockers, and agonists that protect against CRS are summarized. Since the molecular mechanisms of CRS remain to be elucidated, no single intervention has been shown to be effective in treating CRS. Pharmacologic therapies designed to block CRS are urgently needed. This review presents a critical therapeutic avenue for targeting CRS and concurrently illuminates challenges and opportunities for discovering novel treatment strategies for CRS.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1539-1555"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254140","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":"Neddylation of RhoA impairs its protein degradation and promotes renal interstitial fibrosis progression in diabetic nephropathy.","authors":"Xue-Qi Li, Bo Jin, Si-Xiu Liu, Yan Zhu, Nan Li, Qing-Yan Zhang, Cheng Wan, Yuan Feng, Yue-Xian Xing, Kun-Ling Ma, Jing Liu, Chun-Ming Jiang, Jian Lu","doi":"10.1038/s41401-024-01460-z","DOIUrl":"10.1038/s41401-024-01460-z","url":null,"abstract":"<p><p>Diabetic nephropathy (DN) is a common and serious complication of diabetes, characterized by chronic fibro-inflammatory processes with an unclear pathogenesis. Renal fibrosis plays a significant role in the development and progression of DN. While recent research suggests that the neddylation pathway may influence fibrotic processes, its specific dysregulation in DN and the underlying mechanisms remain largely unexplored. This study identified the neddylation of RhoA as a novel post-translational modification that regulates its expression and promotes renal fibrosis in DN. We here demonstrated that two key components of the neddylation pathway-NEDD8-activating enzyme E1 subunit 1 (NAE1) and NEDD8-are significantly upregulated in human chronic kidney disease (CKD) specimens compared to healthy kidneys, implicating neddylation in CKD-associated fibrosis. Our findings further revealed that both pharmacological inhibition of neddylation using MLN4924 and genetic knockdown of NAE1 mitigate renal fibrosis in mouse models of streptozotocin-induced diabetes and unilateral ureteral obstruction (UUO). Immunoprecipitation-mass spectrometry (IP-MS) and subsequent function assays demonstrated a direct interaction between RhoA and NEDD8. Importantly, neddylation inhibition reduced RhoA protein expression, highlighting a potential therapeutic target. Additionally, a positive correlation was noted between elevated NEDD8 mRNA levels and RhoA mRNA expression in human CKD specimens. RhoA overexpression counteracted the antifibrotic effects of neddylation inhibition, underscoring its critical role in fibrosis progression. Mechanistically, we unveiled that neddylation enhances RhoA protein stability by inhibiting its ubiquitination-mediated degradation, which subsequently activates the ERK1/2 pathway. Collectively, this study provides novel insights into NAE1-dependent RhoA neddylation as a key contributor to renal fibrosis in DN. The NAE1 protein mediates RhoA protein hyper-neddylation and subsequent stabilization of the RhoA protein, which, in turn, contributes to the development of renal fibrosis and inflammation through an ERK1/2-dependent mechanism. Consequently, targeting neddylation inhibition represents a viable therapeutic approach for the treatment of renal fibrosis in DN.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1692-1705"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121772","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":"Madecassoside mitigates acute myocardial infarction injury by activating the PKCB/SPARC signaling pathway.","authors":"Peng Wang, Ji-Qin Yang, Dan-Dan Xu, Si-Jia Zhang, Shan Lu, Yong Ji","doi":"10.1038/s41401-024-01442-1","DOIUrl":"10.1038/s41401-024-01442-1","url":null,"abstract":"<p><p>The current treatments and drugs of myocardial infarction (MI) remain insufficient. In recent years, natural products have garnered significant attention for their potential in treating cardiovascular diseases due to their availability and lower toxicity. Saponins, in particular, showed promising effects for cardiac protection. In this study, we investigated the therapeutic effects of the saponin compound madecassoside in the treatment of MI, and underlying molecular mechanisms. The acute MI model was established in male mice by ligation of the left anterior descending coronary artery. The mice were treated with madecassoside (20 mg· kg^-1 ·d^-1, i.g.) for 14 days. After sacrificing the mice, hearts were harvested for analysis. We showed that madecassoside administration significantly mitigated cardiac function decline in MI mice by promoting angiogenesis and inhibiting myocardial cell apoptosis and fibrosis. By conducting systems pharmacology and RNA sequencing, we demonstrated that madecassoside upregulated SPARC gene expression by activating protein kinase C-β (PKCB) that had a strong promoting effect on endothelial cell angiogenesis, thus playing a crucial protective role against MI. We showed that inhibition of SPARC gene significantly reduced madecassoside-stimulated migration and tube formation of endothelial cells in vitro; co-administration of the PKCB-specific inhibitor ruboxistaurin (10 mg· kg^-1 ·d^-1, i.g.) abolished the cardioprotective effect of madecassoside in MI mice, validating the critical role of the PKCB/SPARC signaling pathway. This study demonstrates that madecassoside regulates the PKCB/SPARC pathway, promotes the proliferation and regeneration of vascular endothelial cells, and effectively alleviates the symptoms of MI.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1624-1638"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942407","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":"Natural compound PEITC inhibits gain of function of p53 mutants in cancer cells by switching YAP-binding partners between p53 and p73.","authors":"Yi-Xuan Wang, Li-Wei Wang, Ying Huang, Lin Zhou, Guo-Yu Li, Jia-Wen Yang, Xue-Feng Wu, Jing-Cai Cheng, Qiang Xu, Yan Shen","doi":"10.1038/s41401-025-01474-1","DOIUrl":"10.1038/s41401-025-01474-1","url":null,"abstract":"<p><p>Phenethyl isothiocyanate (PEITC) derived from cruciferous vegetables has shown anticancer activities by modulating apoptosis, cell cycle arrest, drug-metabolizing enzymes and even preferentially restoring a 'WT-like' conformation to p53^R175H. But its molecular anti-cancer mechanisms are not well understood. Evidence shows that switching YAP-binding partners from pro-tumorigenic to pro-apoptotic proteins might hold great potential for the treatment of human cancers harboring mtp53. In this study we investigated the impact of PEITC on mtp53-YAP-p73 interaction in cancers harboring a variety of p53 mutants, but not limited to structural mutations. We showed that breast cancer, colorectal and lung cancer cells harboring mtp53 (p53^R280K, p53^R273H) were more sensitive to PEITC than those cells harboring wtp53. We demonstrated that PEITC bound to YAP at its WW binding domain, and induced a conformational change, facilitated the dissociation of YAP-mtp53 complex and inhibited their pro-proliferative transcriptional activity in different cancer cells harboring mtp53. Concomitantly, PEITC acted as a molecular glue to enhance the association of YAP-p73 complex and induced apoptosis. These results provide insights into the anticancer activity of PEITC against a wide spectrum of cancers and highlight a unique mode of action for PEITC-based cancer therapy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1722-1732"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389832","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":"Semaglutide ameliorates metabolic disorders in offspring via regulation of oocyte ROS of pre-pregnancy obesity mice.","authors":"Jun-Kai Zhang, Xiao-Ping Li, Yang Tang, Li-Ping Zeng, Xuan Liu, Jian-Li Zhang, Cai-Yu Chen, Shuo Zheng, Zhi-Zhao Liu, Xue Gong, Pedro A Jose, Li Guo, Chun-Yu Zeng","doi":"10.1038/s41401-025-01501-1","DOIUrl":"10.1038/s41401-025-01501-1","url":null,"abstract":"<p><p>Pre-pregnancy obesity (PPO) seriously threatens the health of both mother and offspring. Pre-pregnancy weight management is particularly important for the prevention of metabolic diseases in offspring. Semaglutide is one of the most effective glucagon-like peptide-1 agonizts for the management of obesity and metabolic diseases, but little is known about its effect on the long-term health of offspring. In this study we investigated the effects of semaglutide administered before pregnancy on the offspring health from PPO mice. PPO mice model was established by feeding with high-fat diet for 16 weeks, and then injected with semaglutide (30 nmol/kg^-1·d^-1, sc.) for 22 days before pregnancy. After the treatment, the mice were mated with normal males or underwent in vitro fertilization (IVF) for offspring reproduction. We showed that the semaglutide treatment not only improved the lipid and glucose metabolic disorders and fertility of PPO mice, but also significantly reversed the overweight, impaired energy balance, adipose inflammatory state, lipid and glucose metabolic disorders and insulin resistance of their IVF offspring. By conducting RNA-seq analysis, SOD activity and malondialdehyde assays in ovaries, as well as ROS staining in oocytes, we revealed that the semaglutide treatment reduced the elevated oxidative stress in ovaries and high ROS levels in oocytes from PPO mice, possibly through activating the PI3K/AKT pathway and improving the state of SOD. Interestingly, incubation of oocytes from semaglutide-treated dams with H₂O₂ (100 μM) in vitro during IVF blocked the protective effects of semaglultide against the metabolic disorders in the offspring. In conclusion, semaglutide treatment before pregnancy effectively alleviates obesity-related metabolic disorders in offspring. The regulation of ROS in oocytes plays a crucial role in the protective effects of semaglutide.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1664-1675"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472156","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}