Biochemical pharmacology最新文献

{"title":"Exenatide administration time-dependently affects the hepatic circadian clock through glucagon-like peptide-1 receptors in the central nervous system","authors":"Pingping Xu ,&nbsp;Jun-ichi Morishige ,&nbsp;Zheng Jing ,&nbsp;Naoto Nagata ,&nbsp;Yifan Shi ,&nbsp;Tomohiro Iba ,&nbsp;Takiko Daikoku ,&nbsp;Masanori Ono ,&nbsp;Yoshiko Maida ,&nbsp;Tomoko Fujiwara ,&nbsp;Hiroshi Fujiwara ,&nbsp;Hitoshi Ando","doi":"10.1016/j.bcp.2024.116567","DOIUrl":"10.1016/j.bcp.2024.116567","url":null,"abstract":"<div><div>Accumulating evidence indicates that disruption of the circadian clock contributes to the development of lifestyle-related diseases. We have previously shown that exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, can strongly affect the molecular clocks in the peripheral tissues. This study aimed to investigate the effects of its dosing time and the central nervous system-specific GLP-1 receptor knockdown (GLP1RKD) on the hepatic clock in mice treated with exenatide. Male C57BL/6J and GLP1RKD mice were housed under a 12-h/12-h light/dark cycle, and feeding was restricted to either the light period (L-TRF) or the first 4 h in the dark period (D-TRF). In parallel, exenatide was administered 4–5 times, once daily either at the beginning of the dark (ZT 12) or light period (ZT 0), and we assessed the mRNA expression rhythms of clock genes in the liver thereafter. Exenatide administration at ZT 12 counteracted the phase shift effect of the L-TRF on the hepatic clock of wild-type mice, whereas the dosing at ZT 0 enhanced its effect. However, exenatide did not influence the phase of the hepatic clock under D-TRF regardless of the dosing time. The effect of exenatide in wild-type mice weakened in GLP1RKD mice. These results showed that exenatide dosing time-dependently affects the hepatic circadian clock through the central GLP-1 system. Exenatide administration at the beginning of the active period (i.e., in the morning for humans) might prevent disruption of the peripheral clocks caused by irregular eating habits.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116567"},"PeriodicalIF":5.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carnitine traffic and human fertility","authors":"Tiziano Mazza ,&nbsp;Mariafrancesca Scalise ,&nbsp;Lara Console ,&nbsp;Michele Galluccio ,&nbsp;Nicola Giangregorio ,&nbsp;Annamaria Tonazzi ,&nbsp;Lorena Pochini ,&nbsp;Cesare Indiveri","doi":"10.1016/j.bcp.2024.116565","DOIUrl":"10.1016/j.bcp.2024.116565","url":null,"abstract":"<div><div>Carnitine is a vital molecule in human metabolism, prominently involved in fatty acid β-oxidation within mitochondria. Predominantly sourced from dietary intake, carnitine also derives from endogenous synthesis. This review delves into the complex network of carnitine transport and distribution, emphasizing its pivotal role in human fertility. Together with its role in fatty acid oxidation, carnitine modulates the acety-CoA/CoA ratio, influencing carbohydrate metabolism, lipid biosynthesis, and gene expression. The intricate regulation of carnitine homeostasis involves a network of membrane transporters, notably OCTN2, which is central in its absorption, reabsorption, and distribution. OCTN2 dysfunction, results in Primary Carnitine Deficiency (PCD), characterized by systemic carnitine depletion and severe clinical manifestations, including fertility issues. In the male reproductive system, carnitine is crucial for sperm maturation and motility. In the female reproductive system, carnitine supports mitochondrial function necessary for oocyte quality, folliculogenesis, and embryonic development. Indeed, deficiencies in carnitine or its transporters have been linked to asthenozoospermia, reduced sperm quality, and suboptimal fertility outcomes in couples. Moreover, the antioxidant properties of carnitine protect spermatozoa from oxidative stress and help in managing conditions like polycystic ovary syndrome (PCOS) and endometriosis, enhancing sperm viability and fertilization potential of oocytes. This review summarizes the key role of membrane transporters in guaranteeing carnitine homeostasis with a special focus on the implications in fertility and possible treatments of infertility and other related disorders.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116565"},"PeriodicalIF":5.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Construction of cytochrome P450 3A and P-glycoprotein knockout rats with application in rivaroxaban-verapamil interactions","authors":"Shengbo Huang ,&nbsp;Bingyi Yao ,&nbsp;Yuanqing Guo ,&nbsp;Xi Chen,&nbsp;Yuan Xu,&nbsp;Junze Huang,&nbsp;Jie Liu,&nbsp;Chenmeizi Liang,&nbsp;Yuanjin Zhang,&nbsp;Xin Wang","doi":"10.1016/j.bcp.2024.116566","DOIUrl":"10.1016/j.bcp.2024.116566","url":null,"abstract":"<div><div>Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), as important metabolic enzymes and transporters, participate in the biological transformation and transport of many substances in the body. CYP3A and P-gp are closely related, with very high substrate overlap and regulation similarity, making it particularly difficult to investigate the function of one or the other individually <em>in vivo</em>. Rivaroxaban and verapamil are commonly used together to treat nonvalvular atrial fibrillation in clinical practice. However, this combination therapy can increase systemic exposure to rivaroxaban and the risk of major bleeding and intracranial hemorrhage. In this study, <em>Cyp3a1/2</em> and <em>Mdr1a/b</em> quadruple gene knockout (qKO) rat model was generated and characterized for the first time. CYP3A1/2 and P-gp are completely absent in this novel rat model. Then, the qKO rat model was applied for the evaluation of the drug-drug interactions (DDI) between rivaroxaban and verapamil. The results demonstrated that CYP3A and P-gp were jointly and selectively involved in the pharmacokinetic interactions between rivaroxaban and verapamil. This study may provide useful information for understanding the role of CYP3A and P-gp in rivaroxaban-verapamil therapy and predicting the potential interaction between CYP3A and P-gp.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116566"},"PeriodicalIF":5.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378979","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}

{"title":"Sex differences in the metabolic activation of and platelet response to vicagrel in mice: Androgen as a key player","authors":"Li-Ping Jiang ,&nbsp;Min Fu ,&nbsp;Na Yin ,&nbsp;Yu-Meng Jia ,&nbsp;Fu-Yang Duan ,&nbsp;Lei Feng ,&nbsp;Li Yang ,&nbsp;Hao-Ru Han ,&nbsp;Jin Wang ,&nbsp;Ting Zhu ,&nbsp;Jin-Zi Ji ,&nbsp;Ting Tai ,&nbsp;Xue-Mei Li ,&nbsp;Zhao-Dong Zheng ,&nbsp;Pei-Jie Ding ,&nbsp;Ya-Lan Sun ,&nbsp;Qiong-Yu Mi ,&nbsp;Hong-Guang Xie","doi":"10.1016/j.bcp.2024.116564","DOIUrl":"10.1016/j.bcp.2024.116564","url":null,"abstract":"<div><div>As a biological variable, sex influences the metabolism of and/or response to certain drugs. Vicagrel is being developed as an investigational new drug in China; however, it is unknown whether sex could affect its metabolic activation and platelet responsiveness. This study aimed to determine whether such differences could exist, and to elucidate the mechanisms involved. Orchiectomized (ORX) or ovariectomized (OVX) mouse models were used to investigate the effects of androgens or estrogens on the metabolic activation of and platelet response to vicagrel. Plasma vicagrel active metabolite H4 concentrations, platelet inhibition of vicagrel, and protein levels of intestinal hydrolases Aadac and Ces2 were measured, respectively. Further, p38-MAPK signaling pathway was enriched, whose role was determined using SB202190. Results showed that female mice exhibited significantly elevated systemic exposure of H4 and enhanced platelet responses to vicagrel than males, and that protein expression levels of Aadac and Ces2 differed by sex. OVX mice exhibited less changes than sham mice. ORX mice exhibited increases in protein levels of intestinal hydrolases, systemic exposure of H4, and platelet inhibition of vicagrel, but dihydrotestosterone (DHT) reversed these changes in ORX mice and suppressed these changes in OVX mice. Phosphorylated p38 levels were reduced in female or ORX mice but increased in ORX mice by DHT. SB202190 reversed DHT-induced changes observed in ORX mice. We concluded that sex differences exist in metabolic activation of and platelet response to vicagrel in mice through elevation of p38 phosphorylation by androgens, suggesting sex-based vicagrel dosage adjustments for patient care.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116564"},"PeriodicalIF":5.3,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375014","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}

{"title":"PCSK9 inhibitor attenuates cardiac fibrosis in reperfusion injury rat by suppressing inflammatory response and TGF-β1/Smad3 pathway","authors":"Qing Huang ,&nbsp;Zhina Zhou ,&nbsp;Lei Xu ,&nbsp;Peng Zhan ,&nbsp;Guangwei Huang","doi":"10.1016/j.bcp.2024.116563","DOIUrl":"10.1016/j.bcp.2024.116563","url":null,"abstract":"<div><div>Progressive cardiac fibrosis, a hallmark of heart failure, remains poorly understood regarding Proprotein convertase subtilisin/kexin type 9 (PCSK9) ’s role. This study aims to elucidate PCSK9′s involvement in cardiac fibrosis. After ischemia/reperfusion (I/R) injury surgery in rats, PCSK9 inhibitors were used to examine their effects on the transforming growth factor-β1 (TGF-β1)/small mother against decapentaplegic 3 (Smad3) pathway and inflammation. Elevated PCSK9, TGF-β1, and Smad3 levels were observed in cardiac tissues post-I/R injury, indicating fibrosis. PCSK9 inhibition reduced pro-fibrotic protein expression, protecting the heart and mitigating I/R-induced damage and fibrosis. Additionally, it ameliorated cardiac inflammation and reduced post-myocardial infarction (MI) size, improving cardiac function and slowing heart failure progression. PCSK9 inhibitors significantly attenuate myocardial fibrosis induced by I/R via the TGF-β1/Smad3 pathway.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116563"},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370888","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}

{"title":"Corrigendum to “Autophagy contributes to dasatinib-induced myeloid differentiation of human acute myeloid leukemia cells” [Biochem. Pharmacol. 89/1 (2014) 74–85]","authors":"Nan Xie ,&nbsp;Like Zhong ,&nbsp;Lu Liu,&nbsp;Yanfeng Fang,&nbsp;Xiaotian Qi,&nbsp;Ji Cao,&nbsp;Bo Yang,&nbsp;Qiaojun He,&nbsp;Meidan Ying","doi":"10.1016/j.bcp.2024.116553","DOIUrl":"10.1016/j.bcp.2024.116553","url":null,"abstract":"","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116553"},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364221","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}

{"title":"The thienopyridine A-769662 and benzimidazole 991 inhibit human TASK-3 potassium channels in an AMPK-independent manner","authors":"Esraa A. Said ,&nbsp;Ryan W. Lewis ,&nbsp;Mark L. Dallas ,&nbsp;Chris Peers ,&nbsp;Fiona A. Ross ,&nbsp;Asier Unciti-Broceta ,&nbsp;D. Grahame Hardie ,&nbsp;A. Mark Evans","doi":"10.1016/j.bcp.2024.116562","DOIUrl":"10.1016/j.bcp.2024.116562","url":null,"abstract":"<div><div>Heteromeric <u>T</u>andem pore domain <u>A</u>cid <u>S</u>ensitive (TASK)-1/3 channels are critical to oxygen-sensing by carotid body type 1 cells, where hypoxia-induced inhibition of TASK-3 and/or TASK-1/3 potassium currents leads to voltage-gated calcium entry, exocytotic transmitter release and increases in carotid body afferent input responses that initiate corrective changes in breathing patterns. It was proposed that, in response to hypoxia, the AMP–activated protein kinase (AMPK) might directly phosphorylate and inhibit TASK channels, in particular TASK–3, but studies on rat type I cells questioned this view. However, sequence alignment identified a putative AMPK recognition motif in human (h) TASK-3, but not hTASK–1, with Ser⁵⁵ representing a potential phosphorylation site. We therefore studied the effects of five different AMPK activators on recombinant hTASK–3 potassium channels expressed in human embryonic kidney (HEK)–293 cells. Two structurally unrelated AMPK activators, the thienopyridine A–769662 (100–500 µM) and the benzimidazole 991 (3–30 µM) inhibited hTASK–3 currents in a concentration–dependent manner, while the 4-azabenzimidazole MK–8722 (3–30 µM) partially inhibited hTASK–3 at concentrations above those required for maximal AMPK activation. By contrast, the 4-azabenzimidazole, BI-9774 (10–100 µM; a closely related analogue of MK8722) and the pro-drug AICA-riboside (1 mM; metabolised to ZMP, an AMP-mimetic) had no significant effect on hTASK–3 currents at concentrations sufficient to maximally activate AMPK. Importantly, A–769662 (300 µM) also inhibited hTASK–3 channel currents in HEK–293 cells that stably over-expressed an AMPK–β1 subunit mutant (S108A) that renders AMPK insensitive to activators that bind to the Allosteric Drug and Metabolite site, such as A–769662. We therefore identify A–769662 and 991 as novel hTASK–3 channel inhibitors and provide conclusive evidence that AMPK does not regulate hTASK–3 channel currents.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116562"},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370889","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}

{"title":"Isovalerylspiramycin I suppresses small cell lung cancer proliferation via ATR/CHK1 mediated DNA damage response and PERK/eIF2α/ATF4/CHOP mediated ER stress","authors":"Yongle Xu ,&nbsp;Xiaohua Gu ,&nbsp;Shan Shan ,&nbsp;Zeyu Liu ,&nbsp;Shaoyang Wang ,&nbsp;Jingyuan Zhang ,&nbsp;Yuqiong Lei ,&nbsp;Cheng Zhong ,&nbsp;Qi Zheng ,&nbsp;Tao Ren ,&nbsp;Zhanxia Li","doi":"10.1016/j.bcp.2024.116557","DOIUrl":"10.1016/j.bcp.2024.116557","url":null,"abstract":"<div><div>Small cell lung cancer (SCLC) urgently needs new therapeutic approaches. We found that the antibiotic-derived compound Isovalerylspiramycin I (ISP-I) has potent anti-tumor activity against SCLC cell lines H1048 and DMS53 both in vitro and in vivo. ISP-I induced apoptosis, G2/M phase cell cycle arrest, and mitochondrial respiratory chain dysfunction in both cell lines. Comprehensive RNA sequencing revealed that the anti-SCLC effects of ISP-I were primarily attributed to ATR/CHK1-mediated DNA damage response and PERK/eIF2α/ATF4/CHOP-mediated ER stress. Importantly, the induction of DNA damage, ER stress, and apoptosis by ISP-I was mitigated by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC), underscoring the critical role of ROS in the anti-SCLC mechanism of ISP-I. Moreover, ISP-I treatment induced immunogenic cell death (ICD) in SCLC cells, as evidenced by increased adenosine triphosphate (ATP) secretion, elevated release of high-mobility group box 1 (HMGB1), and enhanced exposure of calreticulin (CRT) on the cell surface. Additionally, network pharmacology analysis, combined with cellular thermal shift assay (CETSA) and cycloheximide (CHX) chase experiments, demonstrated that ISP-I acted as a ligand for apurinic/apyrimidinic endonuclease 1 (APEX1) and promoted its degradation, leading to the accumulation of ROS. In conclusion, our findings elucidate the multifaceted mechanisms underlying the anti-cancer effects of ISP-I, highlighting its potential as a promising therapeutic candidate for SCLC treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116557"},"PeriodicalIF":5.3,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aspirin increases estrogen levels in the placenta to prevent preeclampsia by regulating placental metabolism and transport function","authors":"Shengbo Huang ,&nbsp;Yuan Xu ,&nbsp;Yuanqing Guo ,&nbsp;Yuanjin Zhang,&nbsp;Yu Tang,&nbsp;Chenmeizi Liang,&nbsp;Liangcai Gao,&nbsp;Bingyi Yao,&nbsp;Xin Wang","doi":"10.1016/j.bcp.2024.116561","DOIUrl":"10.1016/j.bcp.2024.116561","url":null,"abstract":"<div><div>Preeclampsia is a unique multisystem progressive disease during pregnancy, which seriously endangers the health of pregnant women and fetuses. In clinical practice, aspirin is recommended for the prevention of preeclampsia, but the mechanism by which aspirin prevents preeclampsia has not yet been revealed. This report comprehensively evaluates the effects of aspirin on the expression and activity of placental metabolic enzymes and transporters. We found that after aspirin administration, only the expression of organic anion transporter 4 (OAT4) in the placenta showed a significant increase at both mRNA and protein levels, consistent with the results in JAR cells. Meanwhile, studies on the metabolic enzyme activity in the placenta showed a high upregulation of CYP19A1 activity. Subsequently, significant increases in endogenous substrates of OAT4 and CYP19A1 (dehydroepiandrosterone sulfate (DHEAS) and androstenedione) as well as estrone were detected in placental tissue. In summary, aspirin enhances the transport of DHEAS through OAT4 and promotes the metabolism of androstenedione through CYP19A1, thereby increasing estrogen levels in the placenta. This may be the mechanism by which aspirin prevents preeclampsia and maintains pregnancy by regulating the metabolism and transport function of the placenta.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116561"},"PeriodicalIF":5.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340411","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}

{"title":"Curcumol effectively improves obesity through GDF15 induction via activation of endoplasmic reticulum stress response","authors":"Lin Wang ,&nbsp;Jia-jia Huang ,&nbsp;Wei-jia Zhu ,&nbsp;Zhao-kun Zhai ,&nbsp;Chan Lin ,&nbsp;Xiao Guan ,&nbsp;Hai-ping Liu ,&nbsp;Tong Dou ,&nbsp;Yi-zhun Zhu ,&nbsp;Xu Chen","doi":"10.1016/j.bcp.2024.116560","DOIUrl":"10.1016/j.bcp.2024.116560","url":null,"abstract":"<div><div>The escalating prevalence of obesity presents a formidable global health challenge, underscoring the imperative for efficacious pharmacotherapeutic interventions. However, current anti-obesity medications often exhibit limited efficacy and adverse effects, necessitating the exploration of alternative therapeutic approaches. Growth differentiation factor 15 (GDF15) has emerged as a promising target for obesity management, given its crucial role in appetite control and metabolic regulation. In this study, we aimed to investigate the efficacy of curcumol, a sesquiterpene compound derived from plants of the <em>Zingiberaceae</em> family, in obesity treatment. Our findings demonstrate that curcumol effectively induces the expression of GDF15 through the activation of the endoplasmic reticulum stress pathway. To confirm the role of GDF15 as a critical target for curcumol’s function, we compared the effects of curcumol in wild-type mice and <em>Gdf15</em>-knockout mice. Using a high-fat diet-induced obese murine model, we observed that curcumol led to reduced appetite and altered dietary preferences mediated by GDF15. Furthermore, chronic curcumol intervention resulted in promising anti-obesity effects. Additionally, curcumol administration improved glucose tolerance and lipid metabolism in the obese mice. These findings highlight the potential of curcumol as a GDF15 inducer and suggest innovative strategies for managing obesity and its associated metabolic disorders. In conclusion, our study provides evidence for the efficacy of curcumol in obesity treatment by inducing GDF15 expression. The identified effects of curcumol on appetite regulation, dietary preferences, glucose tolerance, and lipid metabolism emphasize its potential as a therapeutic agent for combating obesity and related metabolic disorders.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116560"},"PeriodicalIF":5.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340412","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}