Biochemical pharmacology最新文献

{"title":"Evaluation of UCP1162, a potent propargyl-linked inhibitor of dihydrofolate reductase with potential application to cancer and autoimmune disease","authors":"Didem Ozcan Tezgin ,&nbsp;Shan Kurkcu ,&nbsp;Debjani Si ,&nbsp;Jolanta Krucinska ,&nbsp;Adriane Mosley ,&nbsp;Pratik Mehta ,&nbsp;Ivan Babic ,&nbsp;Elmar Nurmemmedov ,&nbsp;Alan Kuo ,&nbsp;Wu He ,&nbsp;Craig E Nelson ,&nbsp;Lee Wright ,&nbsp;Dennis L. Wright ,&nbsp;Charles Giardina","doi":"10.1016/j.bcp.2024.116617","DOIUrl":"10.1016/j.bcp.2024.116617","url":null,"abstract":"<div><div>Cellular resistance can limit the effectiveness of antifolate drugs for the treatment of cancer and autoimmune diseases. We examined the biochemical and cellular effects of a propargyl linked, non-classical antifolate UCP1162 that shows exceptional potency and resilience in the background of methotrexate resistance. UCP1162 inhibited the human DHFR enzyme with affinity and kinetics comparable to methotrexate (MTX). UCP1162 also inhibited cancer cell proliferation and bound cellular DHFR at low nanomolar concentrations. Leucovorin suppressed the cellular effects of UCP1162, consistent with UCP1162 working as an antifolate. Like other antifolates, UCP1162 reduced acute inflammation in mice and inhibited FLS cell growth and motility. Single cell RNA-seq showed that MTX and UCP1162 generated overlapping gene expression changes after a 48-hour exposure. However, while leukemia cells (CCRF-CEM) resistant to MTX could be readily selected, UCP1162-resistant cells could not be obtained. Long-term exposure to UCP1162 resulted in static culture expressing stem cell genes (CD34, ABCG2, ABCB1), adaptive genes (TCN2, CDKN1A), and genes that might serve as therapeutic targets (TPBG/5T4, TNFRSF10A, ACE). These findings suggest that UCP1162 is a unique tool for studying cellular responses to long-term antifolate treatment and holds promise as a lead compound capable of overcoming some forms of antifolate resistance.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116617"},"PeriodicalIF":5.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613945","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":"Detailed functional characterization of four nanobodies as positive allosteric modulators of the human Calcium-Sensing receptor.","authors":"Wei Du, Sabrina N Rahman, Eleanor Barker, Hans Bräuner-Osborne, Jesper M Mathiesen, Donald T Ward, Anders A Jensen","doi":"10.1016/j.bcp.2024.116619","DOIUrl":"https://doi.org/10.1016/j.bcp.2024.116619","url":null,"abstract":"<p><p>The calcium-sensing receptor (CaSR) plays a key role in calcium homeostasis, and small-molecule and peptide positive allosteric modulators (PAMs) of CaSR, so-called calcimimetics, are used in the treatment of hyperparathyroidism and hypocalcemic disorders. In this study, four monovalent nanobodies - representing four distinct nanobody families with CaSR PAM activity - were subjected to elaborate pharmacological profiling at the receptor. While Nb5 displayed negligible PAM activity at CaSR in all assays, Nb4, Nb10 and Nb45 all potently potentiated Ca²⁺-evoked signalling through a myc epitope-tagged CaSR expressed in HEK293 or HEK293T cells in Gα_q and Gα_i1 protein activation assays and in a Ca²⁺/Fluo-4 assay. Nb4 and Nb10 also displayed comparable PAM properties at a stable CaSR-HEK293 cell line in a Ca²⁺/Fura-2 imaging assay, but surprisingly Nb45 was completely inactive at this cell line in both the Ca²⁺/Fura-2 and Ca²⁺/Fluo-4 assays. Investigations into this binary difference in Nb45 activity revealed that the nanobody only possesses modulatory activity at CaSRs tagged N-terminally with various epitopes (myc, HA, Flag-SNAP), whereas it is inactive at the untagged wild-type receptor. In conclusion, overall each of the nanobodies exhibit similar CaSR PAM properties in a range of assays, and thus none of them display pathway bias as modulators. However, of the four nanobodies Nb4 and Nb10 would be applicable as pharmacological tools for the wild-type CaSR, and the complete inactivity of Nb45 at the untagged CaSR serves as an reminder that epitope-tagging of a receptor, even if deemed functionally silent, can have profound implications for ligand discovery efforts.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116619"},"PeriodicalIF":5.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613942","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":"Heat shock protein 27 downregulation attenuates isoprenaline-induced myocardial fibrosis and diastolic dysfunction by modulating the endothelial-mesenchymal transition","authors":"Yifei Zou,&nbsp;Henghe Shi,&nbsp;Yinghao Li,&nbsp;Tianyi Li,&nbsp;Ning Liu ,&nbsp;Bin Liu","doi":"10.1016/j.bcp.2024.116612","DOIUrl":"10.1016/j.bcp.2024.116612","url":null,"abstract":"<div><div>Heart failure (HF), an end-stage clinical syndrome secondary to cardiac impairment, significantly affects patients’ quality of life and long-term prognosis. Myocardial fibrosis leads to systolic and diastolic dysfunction, and promotes the progression of HF. Several studies involving the modulation of myocardial fibrosis have been conducted in an effort to improve cardiac function. Heat shock protein 27 (HSP27) is a small chaperone protein that is overexpressed in cellular stress states. HSP27 modulates epithelial-mesenchymal transition, playing a crucial role in the pathology of several fibrotic diseases. However, its association with myocardial fibrosis regulation is unknown. This study aimed to investigate the mechanisms by which HSP27 regulates myocardial fibrosis. We created cardiac-specific HSP25 (the murine ortholog of human HSP27) knockout mice and found that HSP25 knockdown inhibited endothelial-mesenchymal transition (EndMT), attenuated myocardial fibrosis, and ameliorated diastolic dysfunction in isoproterenol-induced HF mice via echocardiography, histology, and western bloting. <em>In vitro</em>, HSP27 knockdown attenuated transforming growth factor beta-induced EndMT, whereas HSP27 overexpression promoted EndMT. Furthermore, the SMAD3/SNAIL1 pathway was found to be crucial for HSP27-mediated EndMT regulation. As an essential molecule in EndMT regulation and myocardial fibrosis modulation, HSP27 may hold promise as a therapeutic target for patients with HF.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116612"},"PeriodicalIF":5.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614002","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":"Yohimbine treatment improves pulmonary fibrosis by attenuating the inflammation and oxidative stress via modulating the MAPK pathway","authors":"Vaishnavi Kambhampati ,&nbsp;Abhisheik Eedara ,&nbsp;Sai Balaji Andugulapati","doi":"10.1016/j.bcp.2024.116613","DOIUrl":"10.1016/j.bcp.2024.116613","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disorder characterized by the accumulation of extracellular matrix and collagen, resulting in significant parenchymal scarring and respiratory failure that leads to mortality. Yohimbine (YBH) is an α-2 adrenergic receptor antagonist with anti-oxidant and anti-inflammatory properties. In the current study, we aimed to investigate the anti-inflammatory, anti-oxidant and anti-fibrotic activity of YBH against LPS/TGF-β-induced differentiation in BEAS-2B/LL29 cells and bleomycin (BLMN) induced pulmonary fibrosis model in rats. Network pharmacology, gene expression, Western-blot analysis, immune-cytochemistry/immunohistochemistry, lung functional analysis, and histology techniques were used to assess the fibrotic marker expression/levels in cells or rat lung tissues. YBH treatment significantly attenuated the LPS-induced pro-inflammatory (identified through a network-pharmacology approach) and oxidative stress markers expression in lung epithelial cells. TGF-β stimulation significantly elevated the fibrotic cascade of markers and treatment with YBH attenuated these markers’ expression/levels. Intra-tracheal administration of BLMN caused a significant elevation of various inflammatory/oxidative stress and fibrotic markers expression in lung tissues and treatment with YBH significantly mitigated the same. Ashcroft score analysis revealed that BLMN exhibited severe distortion of the lungs, elevation of thickness of the alveolar walls and accumulation of collagen in tissues, further treatment with YBH significantly suppressed these events and improved the lung architecture. Lung functional parameters demonstrated that BLMN-induced stiffness and resistance were reduced considerably upon YBH treatment and restored lung function dose-dependently. Overall, this study reveals that YBH treatment significantly attenuated the BLMN-induced fibrosis by regulating the MAPK pathway and provided insightful information for progressing towards translational outcomes.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116613"},"PeriodicalIF":5.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614022","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":"Activated microglia secretome and proinflammatory cytokines increase neuronal mu-opioid receptor signalling and expression.","authors":"Javier Cuitavi, Pere Duart-Abadia, Julie Sanchez, Christian M Sánchez-López, Jesús D Lorente, Antonio Marcilla, Isabel Fariñas, Meritxell Canals, Lucía Hipólito","doi":"10.1016/j.bcp.2024.116608","DOIUrl":"10.1016/j.bcp.2024.116608","url":null,"abstract":"<p><p>Due to its potential role in processes which rely on mu-opioid receptor function, investigating the relationship between Mu-Opioid receptors (MORs), neuroinflammation, and glial cells has gained momentum. Traditionally, MOR activation has been associated with immunosuppression, but recent findings suggest a more nuanced, bidirectional relationship with the immune system. To further investigate this relationship, herein, we investigated the role of the activated microglia secretome and proinflammatory cytokines in neuronal MOR expression and signalling. Our results show that both microglial secretome and specific cytokines increase neuronal MOR expression and enhance the [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO)-induced MOR activation. We also show that DAMGO-induced neuroinflammation increases neuronal MOR expression, activation, and regulation. Our findings suggest a feedback loop between microglial activation, cytokine release, and neuronal MOR dynamics. Future research should delve into the temporal dynamics and functional implications of this relationship, particularly concerning clinically relevant opioids like morphine and fentanyl and pain management.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116608"},"PeriodicalIF":5.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613796","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":"Niclosamide attenuates calcification in human heart valvular interstitial cells through inhibition of the AMPK/mTOR signaling pathway","authors":"Minh Hung Vu ,&nbsp;Saugat Shiwakoti ,&nbsp;Ju-Young Ko ,&nbsp;Geul Bang ,&nbsp;Eunmi Lee ,&nbsp;Eunmin Kim ,&nbsp;Sin-Hee Park ,&nbsp;Eun-Hye Park ,&nbsp;Chan Woo Kim ,&nbsp;Jin Young Kim ,&nbsp;Hwan-Hee Sim ,&nbsp;Kiyuk Chang ,&nbsp;Min-Sik Kim ,&nbsp;Min-Ho Oak","doi":"10.1016/j.bcp.2024.116614","DOIUrl":"10.1016/j.bcp.2024.116614","url":null,"abstract":"<div><div>Calcific aortic valve disease (CAVD) is a considerable health burden with a lack of effective therapeutic options. There is an urgent need to develop interventions that inhibit the osteogenic transformation of valvular interstitial cells (VICs) and delay the calcification process. Niclosamide, an FDA-approved anti-helminthic drug, has emerged as a promising candidate that demonstrates a negative regulatory effect on porcine VICs calcification. However, its molecular mechanism in human VICs (hVICs) remains to be investigated. In this study, high-resolution mass spectrometry-based proteomics and phosphoproteomics were employed, and 8373 proteins and 3697 phosphosites were identified in hVICs treated with a pro-calcifying medium and niclosamide. The quantitative proteomic and phosphoproteomic analysis resulted in the identification of calcification markers and osteogenesis-associated proteins. Bioinformatic analysis of the protein–protein interaction network and affected kinase prediction revealed that the AMPK/mTOR/p70S6K signaling cascade was altered upon calcific induction and niclosamide treatment. Further validation indicated that niclosamide inhibited the calcification of hVICs by targeting the mammalian target of the rapamycin (mTOR) signaling pathway. This study provides the first evidence that niclosamide could prevent osteoblastic differentiation in hVICs partially through the inhibition of the AMPK/mTOR/p70S6k signaling pathway, thereby mitigating hVICs calcification. These findings present a foundation for potential therapeutic strategies to impede the progression of CAVD and provide valuable insights into the pharmacological effects of niclosamide on human VICs.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116614"},"PeriodicalIF":5.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614008","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":"Chemical proteomics accelerates the target discovery of natural products","authors":"Shu-Jie He ,&nbsp;Jun Li ,&nbsp;Jie-Chun Zhou ,&nbsp;Zhi-You Yang ,&nbsp;Xi Liu ,&nbsp;Yue-Wei Ge","doi":"10.1016/j.bcp.2024.116609","DOIUrl":"10.1016/j.bcp.2024.116609","url":null,"abstract":"<div><div>More than half of the global novel drugs are directly or indirectly derived from natural products (NPs) because of their better selectivity towards proteins. Traditional medicines perform multiple bioactivities through various NPs binding to drug targets, which highlights the opportunities of target discovery for drug development. However, detecting the binding relationship between NPs and targets remains challenging. Chemical proteomics, an interdisciplinary field of chemistry, proteomics, biology, and bioinformatics, has emerged as a potential approach for uncovering drug-target interactions. This review summarizes the principles and characteristics of the current widely applied chemical proteomic technologies, while delving into their latest applications in the target discovery of natural medicine. These endeavours demonstrate the potential of chemical proteomics for target discovery to supply dependable methodologies for the target elucidation of NPs.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116609"},"PeriodicalIF":5.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603086","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":"Pharmacological characterization of prostaglandin E2 EP2 and EP4 receptors in male rat locus coeruleus neurons ex vivo","authors":"Amaia Nazabal,&nbsp;Aitziber Mendiguren,&nbsp;Joseba Pineda","doi":"10.1016/j.bcp.2024.116602","DOIUrl":"10.1016/j.bcp.2024.116602","url":null,"abstract":"<div><div>The inflammatory mediator prostaglandin E₂ (PGE₂) binds to G_s-coupled EP2 and EP4 receptors. These receptors are located in the locus coeruleus (LC), the principal noradrenergic nucleus in the brain, but their functional role remains unknown. In this study, the PGE₂ EP2 and EP4 receptors in LC cells from male rat brain slices were pharmacologically characterized by single-unit extracellular electrophysiology. The EP2 receptor agonists butaprost (0.01–10 μM) and treprostinil (0.03–10 µM) and the EP4 receptor agonists rivenprost (0.01 nM–1 µM) and TCS2510 (0.20 nM–2 µM) increased the firing rate of LC neurons in a concentration-dependent manner. The EP2 receptor antagonist PF-04418948 (10 nM) hindered the excitatory effect of butaprost and treprostinil while the EP4 receptor antagonist L-161,982 (30 and 300 nM) blocked the excitatory effect caused by rivenprost and TCS2510. The effects of butaprost and rivenprost were prevented by extracellular sodium replacement but were not modified by the protein kinase A (PKA) activator 8-Br-cAMP (1 mM) or the inhibitor H-89 (10 μM). However, the G_βγ subunit blocker gallein (20 μM) hindered the stimulatory effect of butaprost while the G_αs subunit inhibitor NF449 (10 µM) prevented that of rivenprost. Finally, rivenprost-induced stimulation (30 nM) was not occluded by butaprost (1 µM).</div><div>In conclusion, activation of EP2 and EP4 receptors excites LC noradrenergic neurons through sodium-dependent currents via different G protein subunits in male rat brain slices. EP2 and EP4 in the LC may constitute pharmacological targets for the treatment of pain, fever, drug addiction, anxiety and neuroinflammatory diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116602"},"PeriodicalIF":5.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603065","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":"Regulatory roles of histamine receptor in astrocytic glutamate clearance under conditions of increased glucose variability","authors":"Yu Zhou ,&nbsp;Wenhuo Xie ,&nbsp;Chenghua Kong ,&nbsp;Wei Luo ,&nbsp;Hong Wei ,&nbsp;Jiaping Zheng","doi":"10.1016/j.bcp.2024.116611","DOIUrl":"10.1016/j.bcp.2024.116611","url":null,"abstract":"<div><div>In diabetic patients, repeated episodes of hypoglycemia can increase glucose variability (GV), which may lead to glutamate neurotoxicity in the brain and consequently affect cognitive functions. Astrocytes play a crucial role in regulating the balance of glutamate within the brain, and their function is influenced by the histamine receptor (HR) signaling pathway. However, the specific role of this mechanism under conditions of high GV is not yet clear. The results showed that increased GV resulted in decreased expression of HRs in mice hippocampus and astrocytes cultured in vitro. Additionally, a decrease in the expression of proteins related to glutamate metabolic clearance was observed, accompanied by a reduction in glutamate reuptake capacity. Notably, the intervention with histidine/histamine was able to reverse the above changes. Further mechanistic studies showed that inhibition of HRs that increased GV led to significant disturbances in astrocytic mitochondrial function. These abnormalities encompassed increased fragmentation morphology and the accumulation of reactive oxygen species, accompanied by decreased mitochondrial respiratory capacity and dysregulation of dynamics. Distinct HR subtypes exhibited variations in the modulation of mitochondrial function, with H₃R demonstrating the most pronounced impact. The overexpression of H₃R could enhance glutamate metabolic by reversing disturbances in mitochondrial dynamics. Therefore, this study suggests that H₃R is able to maintain glutamate metabolic clearance capacity and exert neuroprotective effects in astrocytes that increased GV by regulating mitochondrial dynamic balance. This provides an important basis for potential therapeutic targets for diabetes-related cognitive dysfunction.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116611"},"PeriodicalIF":5.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603100","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":"Daphnetin ameliorates hepatic steatosis by suppressing peroxisome proliferator-activated receptor gamma (PPARG) in ob/ob mice","authors":"Zhen Wang ,&nbsp;Peipei Gao ,&nbsp;Jing Gao ,&nbsp;Bing Liang ,&nbsp;Qingqing Ma ,&nbsp;Qiong Sun ,&nbsp;Yachong Hu ,&nbsp;Yan Wang ,&nbsp;Yunhua Peng ,&nbsp;Huadong Liu ,&nbsp;Yuan Wu ,&nbsp;Tao Yi ,&nbsp;Jiankang Liu ,&nbsp;Li-na Qu ,&nbsp;Hui Guo ,&nbsp;Le Shi ,&nbsp;Jiangang Long","doi":"10.1016/j.bcp.2024.116610","DOIUrl":"10.1016/j.bcp.2024.116610","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) is the predominant metabolic liver disorder and currently lacks effective and safe pharmaceutical interventions. Daphnetin (DA), a natural coumarin derivative with anti-inflammatory and antioxidant activities, is a promising agent for NAFLD treatment. In this study, we evaluated the effects and mechanisms of DA on hepatic lipid metabolism in ob/ob mice. Our results showed that DA effectively ameliorates glucose metabolism and hepatic lipid accumulation in ob/ob mice. Metabolomics and RNA sequencing (RNA-seq), combined with GEO data analysis, suggest that DA primarily modulates the peroxisome proliferator-activated receptor gamma (PPARG) pathway, as validated <em>in vivo</em> in ob/ob mice. Mechanistically, DA selectively targets PPARG in hepatic cells by inhibiting <em>PPARG</em> promoter activity and downregulating its expression, resulting in decreased transcription of downstream lipid metabolism-related genes, including fatty acid binding protein 4 (<em>Fabp4</em>), cluster of differentiation 36 (<em>Cd36</em>), and fatty acid synthase <em>(Fasn).</em> This effect was abolished in <em>PPARG</em>-deficient HepG2 cells subjected to palmitic acid (PA) insult. Our findings provide evidence that DA acts as a selective suppressor of hepatic PPARG, suggesting an attractive strategy by targeting PPARG for the prevention of hepatic steatosis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116610"},"PeriodicalIF":5.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603095","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}