Biochemical pharmacology最新文献

{"title":"Development of a long-acting unbiased GIP receptor agonist for studies of GIP’s role in bone metabolism","authors":"Esther Karen Tordrup ,&nbsp;Sarina Gadgaard ,&nbsp;Johanne Windeløv ,&nbsp;Jens Juul Holst ,&nbsp;Lærke Smidt Gasbjerg ,&nbsp;Bolette Hartmann ,&nbsp;Mette Marie Rosenkilde","doi":"10.1016/j.bcp.2025.116893","DOIUrl":"10.1016/j.bcp.2025.116893","url":null,"abstract":"<div><div>The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates bone remodeling postprandially. Species variations complicate the development of long-acting agonists with similar effects on rodent and human GIP receptors (GIPR). We created a series of long-acting molecules suitable for rat studies based on human GIP, stabilized with Aib insertion in position 2, lipidations in the middle region (compounds <strong>1</strong>–<strong>4:</strong> positions 14/16/17/20) or the C-terminus (compound <strong>5:</strong> position 40), and elongation with an exendin-4 tail in the C-terminus (Cex). The compounds were tested in vitro on the human and rat GIPR for cAMP accumulation, beta-arrestin recruitment and internalization. Pharmacokinetic profiling in rats was completed for two compounds, and one was selected for bone remodeling studies in rats (measurements of C-terminal telopeptide (CTX) and procollagen type 1 N-propeptide). All five compounds retained the potency and efficacy of native (human and rat) GIP in cAMP accumulation and arrestin recruitment on human and rat GIPR with no differences in relative activities from native GIP. Only compound <strong>3</strong> induced internalization like species-matched GIP on respective receptors and was chosen for in vivo assessments in rats. Mean T_1/2 was 9.1 h, and it decreased plasma levels of CTX compared to vehicle treatment following 1000 µg·kg⁻¹ injections. In conclusion, the long-acting, unbiased compound <strong>3</strong> (hGIP(1–30-Cex)/Aib2/C16-diacid moiety in position 17), with retained activity for the human and rat GIPR, is suitable for bone remodeling studies in rats; hence, a useful tool compound for future research of GIP’s therapeutic potential in bone-related diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116893"},"PeriodicalIF":5.3,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708334","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":"Decoding YOD1: Insights into tumour regulation and translational opportunities","authors":"Chong Zhi-Xiong","doi":"10.1016/j.bcp.2025.116889","DOIUrl":"10.1016/j.bcp.2025.116889","url":null,"abstract":"<div><div>YOD1 deubiquitinase is a 38 kDa protein that belongs to the ovarian tumour protease (OTU) family, and its dysregulation can precipitate cancer development. Still, an up-to-date review article that can summarize its detailed tumour-regulatory function and translational potentials in different cancer types is lacking. To fill this literature gap, this review aims to discuss the tumour-modulatory role of YOD1 based on findings from different pre-clinical and clinical studies, followed by exploring the potential translational values of YOD1 as a tumour biomarker or therapeutic target. Overall, YOD1 could control the development of at least 15 tumour types by deubiquitinating or targeting different cellular proteins to modulate the activities of the cell cycle, p53, β-catenin, extracellular-regulated signal kinase (ERK), and YES-associated pathway (YAP) activities. Additionally, four long non-coding RNAs (lncRNAs), 12 microRNAs (miRNAs), and a few compounds can also directly or indirectly alter the expression and activity of YOD1, mediating tumourigenesis across different cancer types. Cellular expression data showed that YOD1 expression is dysregulated in eight cancer types, giving YOD1 the potential to be used as a diagnostic biomarker. Besides, YOD1 dysregulation can affect the clinical outcomes of various cancers. Hence, targeting YOD1 could potentially help slow tumourigenesis. The major drawback of considering YOD1 as a biomarker or therapeutic target is that its tumour-regulatory role is mainly based on the findings from single-center studies with relatively small sample sizes. Hence, future large-scale and in-depth clinical trials should be conducted to further verify the translational values of YOD1 as a biomarker or therapeutic target.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116889"},"PeriodicalIF":5.3,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697932","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":"SUMOylation of RAD51 upregulates GOLPH3 expression and promotes cisplatin resistance in colon cancer cells by Sp1 transcriptional activity","authors":"Yuze Wu ,&nbsp;Bingchen Lin ,&nbsp;Zhiyong Xie ,&nbsp;Jingshan Huang ,&nbsp;Yi Qiu ,&nbsp;Xiaojing Chen ,&nbsp;Zhongshi Hong ,&nbsp;Chengzhi Qiu","doi":"10.1016/j.bcp.2025.116888","DOIUrl":"10.1016/j.bcp.2025.116888","url":null,"abstract":"<div><div>Platinum-based chemotherapy is a first-line treatment for colon cancer. Previous studies have shown that Golgi phosphoprotein 3 (GOLPH3) overexpression drives platinum resistance in colon cancer and is associated with DNA damage repair (DDR). However, the mechanism by which DDR induces GOLPH3 expression remains unclear. This study investigates how RAD51 recombinase (RAD51) SUMOylation upregulates GOLPH3 expression and promotes platinum resistance in colon cancer. In DDP-resistant colon adenocarcinoma (COAD) cells, Specificity protein 1 (Sp1) and GOLPH3 were overexpressed, while N-myc downstream regulated 1 (NDRG1) was downregulated. Knockdown of Sp1 or GOLPH3 increased NDRG1 expression, inhibited COAD cell proliferation, promoted cell apoptosis, and enhanced cell sensitivity to cisplatin (DDP). Immunohistochemistry (IHC) and bioinformatics analyses of COAD tissues revealed a positive correlation between RAD51, SUMO1 and Sp1 expression. Sp1 was found to increase DDP resistance by transcriptionally activating GOLPH3 expression. RAD51 was SUMOylated by SUMO1 at the K57 site, and this modification decreased COAD cell sensitivity to DDP by enhancing Sp1 transcriptional activity. Furthermore, RAD51 overexpression led to upregulation of GOLPH3 and downregulation of NDRG1, promoting cell proliferation, inhibiting apoptosis, and increasing resistance to DDP. Conversely, the RAD51 mutant did not affect GOLPH3 expression or platinum resistance in vivo and in vitro. In conclusion, RAD51 SUMOylation at the K57 site enhances Sp1 transcriptional activity, thereby reducing colon cancer cell sensitivity to DDP by regulating GOLPH3 and NDRG1 expression. This discovery elucidates the molecular mechanism of DDR-induced GOLPH3 upregulation, offering a new perspective for overcoming DDP resistance in colon cancer.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116888"},"PeriodicalIF":5.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697881","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 Notch1 promotes macrophage polarization and exacerbates sepsis-induced acute lung injury via β-catenin/NF-κB signaling","authors":"Zhi Liu ,&nbsp;Yuxi Lei ,&nbsp;Jing Zuo ,&nbsp;Ruiyu Zhang ,&nbsp;Hui Du ,&nbsp;Huizhi Hu ,&nbsp;Junwen Zheng ,&nbsp;Pu Yang ,&nbsp;Dongchi Zhao","doi":"10.1016/j.bcp.2025.116892","DOIUrl":"10.1016/j.bcp.2025.116892","url":null,"abstract":"<div><div>Sepsis-induced acute lung injury (ALI) is a critical condition characterized by excessive inflammation, with macrophage polarization playing a pivotal role in its pathogenesis. In this study, we constructed myeloid-specific Notch1 knockout mice, overexpressed the Notch intracellular domain (NICD), and inhibited β-catenin using XAV939 to investigate the impact and mechanisms of Notch1 regulation in macrophage polarization and inflammatory responses in cecal ligation and puncture (CLP)-induced septic mice. The results demonstrated that Notch1 knockout significantly reduced M1 macrophage polarization, alleviated systemic inflammation, mitigated lung injury, and improved survival in septic mice. In sepsis, Notch1 enhances β-catenin expression, which synergizes with the NF-κB pathway to promote M1 polarization and pro-inflammatory cytokine production. Specifically, NICD interacts with β-catenin in macrophages, amplifying NF-κB activation and its nuclear translocation. These results demonstrate that the Notch1 signaling pathway plays a pivotal role in regulating macrophage phenotypic switching, highlighting its potential as a therapeutic target for attenuating sepsis-associated ALI through immune homeostasis restoration.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116892"},"PeriodicalIF":5.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699659","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":"Natural small molecule thymoquinone increases the chemosensitivity of glioblastoma to temozolomide through inhibiting Wnt/β-catenin signaling pathway to downregulate MGMT expression: In vitro and in vivo validation","authors":"Peiying Bai ,&nbsp;Peng Wang ,&nbsp;Ting Ren ,&nbsp;Qing Tang ,&nbsp;Ziao Lin ,&nbsp;Na Zhang ,&nbsp;Lijiao Zhao ,&nbsp;Rugang Zhong ,&nbsp;Guohui Sun","doi":"10.1016/j.bcp.2025.116886","DOIUrl":"10.1016/j.bcp.2025.116886","url":null,"abstract":"<div><div>Temozolomide (TMZ) is the only one oral first-line chemotherapeutic drug for glioblastoma treatment. However, O⁶-methylguanine-DNA methyltransferase (MGMT) can repair the lethal O⁶-methylguaine (O⁶-MeG) lesion produced by TMZ, thus imparting resistance to TMZ. Currently, the clinical utility of small molecule covalent MGMT inhibitors is limited by the occurrence of severe hematological toxicity. Therefore, developing new strategies for overcoming MGMT-mediated resistance is highly urgent. Here, we explored the feasibility that modulating Wnt/β-catenin signaling pathway in glioblastoma to inhibit MGMT expression to overcome TMZ resistance. From eight natural products or approved drugs with inhibitory effects on Wnt/β-catenin pathway, we found thymoquinone (TQ) completely suppressed MGMT expression in glioblastoma SF763 and SF767 cell lines within 24 h. As expected, TQ exhibited synergistic killing effects with TMZ in SF763 and SF767 cells, while in MGMT-negative SF126 cells only additive effect observed. Moreover, TQ remarkably enhanced the inhibition of TMZ on cell proliferation, clone formation, invasion and migration, and promoted cell apoptosis. In resistant SF763 mice tumor xenograft model, TQ significantly increased the suppression of TMZ on tumor growth, meanwhile maintaining good biosafety. Western blotting analysis indicated that TQ significantly inhibited the nuclear translocation of β-catenin and the expression of downstream proteins Cyclin D1 and MGMT. The addition of Wnt activator LiCl reversed the nuclear translocation of β-catenin and the expression of Cyclin D1 and MGMT induced by TQ. For the first time, our findings indicate that TQ can considerably increase the sensitivity of glioblastoma to TMZ by interfering Wnt/β-catenin pathway to downregulate MGMT expression.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116886"},"PeriodicalIF":5.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697933","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":"Macrophage-derived CCL1 targets CCR8 receptor in hepatic stellate cells to promote liver fibrosis through JAk/STAT pathway","authors":"Shaoxi Diao ,&nbsp;Liangyun Li ,&nbsp;Jintong Zhang ,&nbsp;Minglu Ji ,&nbsp;Lijiao Sun ,&nbsp;Wenwen Shen ,&nbsp;Shuai Wu ,&nbsp;Zixiang Chen ,&nbsp;Cheng Huang ,&nbsp;Jun Li","doi":"10.1016/j.bcp.2025.116884","DOIUrl":"10.1016/j.bcp.2025.116884","url":null,"abstract":"<div><div>Liver fibrosis is caused by liver injury resulting from the wound healing response. According to recent research, the primary factor responsible for liver fibrosis is the activation of hepatic stellate cells (HSCs). C-C motif chemokine ligand 1 (CCL1) is one of several chemokine genes clustered on chromosome 17, which is involved in immune regulation and inflammatory processes. However, the role of CCL1 in liver fibrosis has not been reported. We found that CCL1 secreted by macrophages can target and activate the receptor protein C-C motif chemokine receptor 8 (CCR8) of HSCs, accelerating liver fibrosis progression by activating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway. This suggested that the CCL1-mediated regulation of CCR8 is an important event in liver fibrosis progression. In conclusion, this study identified a novel signalling axis, the CCL1/CCR8/JAK/STAT pathway, which regulates the activation and apoptosis of HSCs, thus providing a novel therapeutic strategy for liver fibrosis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116884"},"PeriodicalIF":5.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690497","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":"E3 ubiquitin ligases and their therapeutic potential in disease Management","authors":"Geet Madhukar ,&nbsp;Md Azizul Haque ,&nbsp;Shawez Khan ,&nbsp;Jong-Joo Kim ,&nbsp;Danishuddin","doi":"10.1016/j.bcp.2025.116875","DOIUrl":"10.1016/j.bcp.2025.116875","url":null,"abstract":"<div><div>Ubiquitination is a vital post-translational modification that regulates protein stability and various cellular processes through the addition of ubiquitin molecules. Central to this process are E3 ubiquitin ligases, which determine the specificity of ubiquitination by coordinating the attachment of ubiquitin to target proteins, influencing their degradation, localization, and activity. E3 ubiquitin ligases are involved in numerous cellular pathways, including DNA repair, cell proliferation, and immune responses. Dysregulation of E3 ubiquitin ligases is often associated with cancer, contributing to tumor progression and resistance to therapies. The development of targeted protein degraders, such as proteolysis-targeting chimeras (PROTACs), represents a significant advancement in drug discovery, leveraging the specificity of E3 ubiquitin ligases to selectively eliminate pathogenic proteins. However, challenges remain in translating this knowledge into effective therapies, including issues related to tissue-specific targeting and off-target effects. The limitations also include a limited understanding of ligase-substrate interactions that includes both the identification of novel E3 ligases and their substrates, as well as understanding the dynamic, context-dependent nature of these interactions, which can vary across tissue types or disease states This review emphasizes the therapeutic potential of E3 ubiquitin ligases, exploring their diverse roles in disease, their contribution to targeted degradation strategies while highlighting the need for further research to overcome current limitations and enhance therapeutic efficacy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116875"},"PeriodicalIF":5.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690423","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":"7′-Hydroxyl substituted xanthones from Gentianella acuta revert hepatic steatosis in obese diabetic mice through preserving mitochondrial homeostasis","authors":"Jian Li ,&nbsp;Jiaqi Wu ,&nbsp;Qian Chen ,&nbsp;Haiyang Yu ,&nbsp;Mengyang Liu ,&nbsp;Yadong Wang ,&nbsp;Yi Zhang ,&nbsp;Tao Wang","doi":"10.1016/j.bcp.2025.116878","DOIUrl":"10.1016/j.bcp.2025.116878","url":null,"abstract":"<div><div>Mitochondrial dysfunction is a key contributor to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Xanthones, bioactive flavonoids derived from various herbal medicines, are renowned for their anti-inflammatory, antioxidant, and anti-tumor properties. This study aimed to investigate the effects of xanthones isolated from <em>Gentianella acuta</em> on hepatic steatosis and the underlying mechanisms regulating mitochondrial function. We report that a xanthone fraction (400 mg/kg/day) effectively prevented obesity and hepatic steatosis in obese diabetic <em>db/db</em> mice <em>in vivo</em>. <em>In vitro</em>, xanthones inhibited lipid accumulation and mitochondrial dysfunction induced by high glucose (20 mM) and high palmitic acid (200 µM) in HepG2 cells. Mechanistically, norathyriol (NTR), a major <em>in vivo</em> metabolite of <em>Gentianella acuta</em>, inhibited the activity of dynamin-related protein 1 (Drp1), a protein associated with mitochondrial fission, and prevented its translocation from the cytoplasm to the mitochondria by inhibiting the orphan nuclear receptor (Nur77). Additionally, NTR increased the expression of the mitochondrial outer membrane protein FUN14 domain containing 1 (FUNDC1), which stimulated mitophagy to clear damaged or dysfunctional mitochondria under overnutrition conditions. We also discovered that reactive oxygen species (ROS) targeted FUNDC1, leading to mitochondrial damage, but this effect could be reversed by 7′-hydroxyl substituted xanthones. Collectively, 7′-hydroxyl substituted xanthones inhibited mitochondrial fission while promoting mitophagy, ultimately improving mitochondrial and liver function in diabetic hepatic steatosis. The modulation of mitochondrial function by 7′-hydroxyl substituted xanthones presents a novel approach for treating hepatic steatosis, particularly in diabetic conditions.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116878"},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672955","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":"Ginsenosides from Panax ginseng modulate lipid mediator profiles in human leukocytes by interference with cellular 5-lipoxygenase activity","authors":"Vera Bruggink ,&nbsp;Clemens Gutjahr ,&nbsp;Angelika Decker ,&nbsp;Hannes Engelbrecht ,&nbsp;Uwe Beekmann ,&nbsp;Dana Kralisch ,&nbsp;Markus Werner ,&nbsp;Patrick Schädel ,&nbsp;Paul M. Jordan ,&nbsp;Oliver Werz ,&nbsp;Robert K. Hofstetter","doi":"10.1016/j.bcp.2025.116882","DOIUrl":"10.1016/j.bcp.2025.116882","url":null,"abstract":"<div><div>Lipid mediators are a superfamily of bioactive molecules that are crucially involved in immune responses, regulating all stages of inflammation. <em>Panax (P.) ginseng</em> has pleiotropic pharmacological effects, including anti-cancer, anti-diabetic, and anti-inflammatory properties. Ginsenosides, unique triterpenoid glycosides from the plant’s root, are proposed as active ingredients responsible for the immunomodulating potential of <em>P.<!--> <!-->ginseng</em>. Here, we comprehensively screened 23 ginsenosides for manipulating the lipid mediator network in various primary human innate immune cells. Several ginsenosides selectively inhibited 5-lipoxygenase (5-LOX)-mediated formation of pro-inflammatory leukotriene B₄, but not of prostaglandins, in monocyte-derived macrophages and polymorphonuclear leukocytes by a unique irreversible mechanism. Structure-activity relationships revealed (i) higher anti-5-LOX activity of PPD-type ginsenosides, (ii) correlation with lipophilicity (<em>R</em>² = 0.91), and (iii) eudysmic ratios favoring the 20<em>S</em>-epimers. Our findings highlight ginsenosides as immunomodulatory principles of <em>P. ginseng</em> and reveal abrogation of leukotriene formation rather than interference with prostaglandins as immediate anti-inflammatory mechanism.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116882"},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672870","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":"Allo-lithocholic acid, a microbiome derived secondary bile acid, attenuates liver fibrosis","authors":"Silvia Marchianò ,&nbsp;Michele Biagioli ,&nbsp;Cristina Di Giorgio ,&nbsp;Carmen Massa ,&nbsp;Rachele Bellini ,&nbsp;Martina Bordoni ,&nbsp;Ginevra Urbani ,&nbsp;Ginevra Lachi ,&nbsp;Valentina Sepe ,&nbsp;Elva Morretta ,&nbsp;Eleonora Distrutti ,&nbsp;Angela Zampella ,&nbsp;Maria Chiara Monti ,&nbsp;Stefano Fiorucci","doi":"10.1016/j.bcp.2025.116883","DOIUrl":"10.1016/j.bcp.2025.116883","url":null,"abstract":"<div><div>Secondary bile acids, lithocholic acid and deoxycholic acid (LCA and DCA), are dehydroxylated derivatives of primary bile acids. However, in addition to LCA and DCA the intestinal microbiota produced a variety of poorly characterized metabolites. Allo-LCA, a LCA metabolite, acts as a dual GPBAR1 agonist and RORγt inverse agonist and modulates intestinal immunity, although is not yet known whether allo-LCA exerts regulatory functions outside the intestine. In the present study we have therefore investigated whether administration of allo-LCA, 10 mg/kg/day, to mice administered a high fat/high fructose diet (HFD-F) and carbon tetrachloride (Ccl4), a model for metabolic dysfunction-associated steatohepatitis (MASH), protects from development of liver damage. In vitro allo-LCA functions as GPBAR1 agonist and RORγt inverse agonist and prevents macrophages M1 polarization and Th17 polarization of CD4 cells. In vivo studies, while exposure to a HFD-F/Ccl4 promoted insulin resistance and development of a pro-atherogenic lipid profile and liver steatosis and fibrosis, allo-LCA reversed this pattern by improving insulin sensitivity and liver lipid accumulation. The liver transcriptomic profile demonstrated that allo-LCA reversed the dysregulation of multiple pathways associated with immunological, inflammatory and metabolic signaling. Allo-LCA also restored bile acid homeostasis, reversing HFD/Ccl4-induced shifts in bile acid pool composition and restored adipose tissue histopathology and function by reducing the expression of leptin and resistin, two pro-inflammatory adipokines, and restored a healthier composition of the intestinal microbiota. In conclusion, present results expand on the characterization of entero-hepatic signaling and suggest that allo-LCA, a microbial metabolite, might have therapeutic potential in liver diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116883"},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672967","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}