Toxicology and applied pharmacology最新文献

{"title":"Pulmonary effects of waterpipe generated smoke in adult diabetic rats","authors":"Rima Kamel ,&nbsp;Sibelle Kassouf ,&nbsp;Selim M. Nasser ,&nbsp;Amale Mcheik ,&nbsp;Nathalie Hayeck ,&nbsp;Elias Abi-Ramia ,&nbsp;Hanan ElKazzaz ,&nbsp;Christian Khalil ,&nbsp;Aniella Abi-Gerges","doi":"10.1016/j.taap.2025.117319","DOIUrl":"10.1016/j.taap.2025.117319","url":null,"abstract":"<div><div>Waterpipe smoking (WPS) is associated with pulmonary inflammation and DNA damage. Tobacco use among diabetic patients adds substantial clinical and public health burden. This study aims to investigate the combined pulmonary effects of diabetes and smoking. To achieve this goal, type 1 diabetes (T1D) was induced in adult male rats by Streptozotocin (65 mg/kg) injection. Rats were then exposed either to fresh air or WPS for one hour daily over five weeks (five days/week). Lung remodeling was evaluated by histology. Changes affecting inflammation, oxidative stress, apoptosis and survival pathways were characterized by real-time quantitative PCR and Western blot. Our findings showed that T1D was associated with pulmonary remodeling characterized by increases in lung weight/BW ratio, exacerbated by WPS, and elevated alveolar count. Both T1D and WPS exposure led to an accumulation of alveolar foamy macrophages and decreased alveolar septal thickness. Upregulation in the transcript levels of pro-inflammatory cytokine, TNF-α and anti-inflammatory marker, IL-10, were reported in diabetic lungs irrespective of WPS exposure. Moreover, diabetic lungs also displayed significant changes in the expression of mitochondrial complexes III and IV and antioxidant enzyme, SOD2, irrespective of the exposure condition. We also noted significant downregulation in the expression of caspases 3 and 9, p-P53/P53 ratio and JNK protein in diabetic lungs compared to control irrespective of the exposure condition. Lastly, diabetes and WPS exposure triggered significant decreases in EGFR expression. In conclusion, we show for the first time pulmonary remodeling and damages caused by the combined effects of T1D and smoking. Our findings highlight the pressing need for future better management of waterpipe consumption among patients with diabetes.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117319"},"PeriodicalIF":3.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of cytochrome P450 enzyme assays to predict p53 inducers and AChE inhibitors that require metabolic activation","authors":"Deborah K. Ngan ,&nbsp;Srilatha Sakamuru ,&nbsp;Jinghua Zhao ,&nbsp;Menghang Xia ,&nbsp;Stephen S. Ferguson ,&nbsp;David M. Reif ,&nbsp;Anton Simeonov ,&nbsp;Ruili Huang","doi":"10.1016/j.taap.2025.117315","DOIUrl":"10.1016/j.taap.2025.117315","url":null,"abstract":"<div><div>Metabolically active compounds can cause toxicity which would otherwise be undetected using traditional <em>in vitro</em> assays with limited proficiency for xenobiotic metabolism. Introduction of liver microsomes to assay systems enables enhanced identification of compounds that require biotransformation to induce toxicity. Previously, metabolically active compounds from the Tox21 10 K compound library were identified using assays probing two targets, p53 and acetylcholinesterase (AChE), in the presence and absence of human or rat liver microsomes, due to the established roles of cytochrome P450 (CYP) enzymes in human drug metabolism. To further explore the role of metabolic activation, the activities of the identified metabolically active compounds were evaluated against five CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. CYP bioactivities were found to be highly predictive (&gt;80 % accuracy) of compounds that required metabolic activation in these assays. Chemical features significantly enriched in metabolically active compounds, as well as chemical features that were specific for each of the five CYPs, were identified. Product use exposures of the metabolically active compounds were examined in this study, with “pesticides” appearing to be the largest category that may produce harmful metabolites. Additionally, the compound interactions with different CYPs were assessed and frequencies for both classes of compounds, drugs and environmental chemicals, were found to be proportionally similar across the five CYP isoforms.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117315"},"PeriodicalIF":3.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of arsenic exposure with PDGF-BB in vitro and in a South Texas population exposed through drinking water","authors":"Alexandra E. Svetlik ,&nbsp;Nishat Tasnim Hasan ,&nbsp;Nusrat Fahmida Trisha ,&nbsp;Daniel W. White ,&nbsp;Raj Satkunasivam ,&nbsp;Natalie M. Johnson ,&nbsp;Taehyun Roh","doi":"10.1016/j.taap.2025.117316","DOIUrl":"10.1016/j.taap.2025.117316","url":null,"abstract":"<div><div>Exposure to arsenic (As) from drinking water is a global public health concern, as As is a recognized carcinogen. Groundwater in South Texas, particularly in areas with Gulf Coast aquifers, contains high levels of As. Private wells are neither regulated nor regularly monitored, leaving residents vulnerable to arsenic exposure. This study aimed to investigate potential biomarkers of health effects for long-term, low-level As exposure among private well users in South Texas and to cross-validate findings using an in vitro model. Among 74 private well users, the association between urinary As levels and urinary LDH and 16 cytokine levels was assessed. After adjusting for covariates, linear regression analysis showed weak but significant associations between urinary total inorganic As levels and LDH (β = 0.37, <em>p</em> &lt; 0.01, R² = 0.23) and PDGF-BB (β = 0.22, <em>p</em> = 0.02, R² = 0.17). However, no significant associations were found with other cytokines. To compare findings from the population study, SV-HUC-1 uroepithelial cells were exposed to 0.1 or 0.5 μM NaAsO₂ subchronically for 5 weeks, corresponding to total arsenic levels of 7.5 and 37.5 μg/L in drinking water. As exposure was not cytotoxic at either dose, as indicated by lactate dehydrogenase (LDH) activity. However, platelet-derived growth factor (PDGF)-BB protein levels showed a statistically significant increase at a lower concentration of 0.1 μM. These findings suggest that PDGF-BB may serve as a potential biomarker for low-level As exposure, but further studies are required for confirmation.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117316"},"PeriodicalIF":3.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pectin-loaded ferulic acid nanoparticles: A potential therapeutic strategy for ulcerative colitis via modulation of the cGAS-STING pathway","authors":"Jingwen Xiao ,&nbsp;Shilin Zhou ,&nbsp;Fengshu Fei ,&nbsp;Lin Long ,&nbsp;Chuanlong Guo","doi":"10.1016/j.taap.2025.117317","DOIUrl":"10.1016/j.taap.2025.117317","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a persistent intestinal disorder featuring periodic flare-ups of the colon's inner lining inflammation. Current therapeutic strategies, while effective in managing symptoms, are often limited by side effects and high costs. This study investigates the potential of pectin-loaded ferulic acid (PC-FA) nanoparticles as a novel therapeutic approach for UC, focusing on their ability to modulate the cGAS-STING pathway, a key mediator in the inflammation associated with UC. PC-FA nanoparticles were prepared and characterized for their physicochemical properties, antioxidant capacity, biocompatibility, and influence on the cGAS-STING pathway. <em>In vitro</em> experiments demonstrated that PC-FA nanoparticles enhanced the solubility and bioavailability of ferulic acid (FA), reduced oxidative stress, and protected colon epithelial cells from damage caused by the administration of dextran sulfate sodium (DSS). <em>In vivo</em> studies in a DSS-induced colitis mouse model showed that PC-FA nanoparticles mitigated weight reduction, lowered disease activity index (DAI) scores, and sustained colon length, and ameliorated histopathological changes. Additionally, PC-FA nanoparticles effectively targeted DNA damage and inhibited the cGAS-STING pathway, leading to a significant reduction in pro-inflammatory cytokines. Pharmacokinetic studies revealed rapid absorption of PC-FA in the bloodstream, with a predominant distribution in the intestines. The study concludes that PC-FA nanoparticles are a promising therapeutic strategy for UC, offering targeted drug delivery, enhanced bioavailability, and anti-inflammatory effects.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117317"},"PeriodicalIF":3.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143773401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin ameliorates PM2.5-induced airway inflammation and apoptosis by PERK/eIF2α/ATF4/CHOP in chronic obstructive pulmonary disease mice","authors":"Meng Shi ,&nbsp;Kai Liu ,&nbsp;Xin Li ,&nbsp;Xiao-li Zeng ,&nbsp;Xiao-ju Liu","doi":"10.1016/j.taap.2025.117314","DOIUrl":"10.1016/j.taap.2025.117314","url":null,"abstract":"<div><div>Fine particulate matter (PM2.5) has been reported to exacerbate chronic airway inflammation, contributing to progression and acute exacerbation of chronic obstructive pulmonary disease (COPD). Persistent activated endoplasmic reticulum (ER) stress-related PERK/eIF2α/ATF4/CHOP pathway is critical in driving inflammation and cell death in a variety of inflammatory diseases. Melatonin (MEL) is well-recognized for its broad biological activities, such as anti-oxidative and anti-inflammatory effects However, the exact role of ER stress-related pathway and MEL in PM2.5-induced airway inflammation and apoptosis in COPD has not yet been elucidated. Therefore, we constructed the COPD mice model by cigarette smoke (CS) exposure to evaluate the mechanism by which PM2.5 exacerbate the development of COPD and the protective role of MEL. Results indicated that PM2.5 significantly impair lung function, disrupt emphysema, exacerbate inflammation and apoptosis and intensify the PERK/eIF2α/ATF4/CHOP pathway in COPD mice. Moreover, these changes caused by PM2.5 could be mitigated by MEL. In vitro, PM2.5 exposure notably reduced cell viability and triggered inflammation and apoptosis in BEAS-2B cells induced by cigarette smoke extract (CSE). These effects were reversed by the ER stress inhibitor 4-phenylbutyric acid (4-PBA), with MEL demonstrating similar effect. These findings demonstrate that PM2.5 aggravates airway inflammation and apoptosis via activating ER stress-related PERK/eIF2α/ATF4/CHOP pathways in COPD, which could be significantly restored by MEL.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117314"},"PeriodicalIF":3.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Solasodine binds to glucocorticoid receptor to ameliorate airway remodeling and excessive autophagy in bronchial smooth muscle cells for allergic asthma","authors":"Zhen Guo ,&nbsp;Jun-li Liu ,&nbsp;Yan-ni Fang ,&nbsp;Xiao-man Guo ,&nbsp;Chun-long Ma ,&nbsp;Jing-wei Wang","doi":"10.1016/j.taap.2025.117313","DOIUrl":"10.1016/j.taap.2025.117313","url":null,"abstract":"<div><div>This study was designed to analyze the potential mechanism of action of solasodine by which solasodine suppresses airway remodeling and autophagy in allergic asthma. Human bronchial smooth muscle cells (HBSMCs) were induced by 10 ng/mL of transforming growth factor (TGF)-β1 for 24 h and treated with a series of solasodine (10, 20, 40 μM) for another 24 h. In the TGF-β1-induced HBSMCs, solasodine treatment downregulated the α- smooth muscle actin (α-SMA) level but upregulated the glucocorticoid receptor (GR) level compared with the vehicle treatment (<em>P</em> &lt; 0.05). The binding of solasodine to GR was analyzed using molecular docking and MST measurement. As a result, a direct interaction between solasodine and GR was found. RU486, a GR antagonist, was used to verify that solasodine attenuates TGF-β1-induced fibrosis and autophagy by regulating GR. The RU486 treatment suppressed the effects of solasodine on the TGF-β1-induced FOXO3A, fibrosis and autophagy in the HBSMCs. Subsequently, C57BL/6 J mice were induced with ovalbumin (OVA) and treated with 10 mg/kg/d of solasodine or 2.5 mg/kg/d of dexamethasone (Dex). In the OVA-induced mice, solasodine or Dex treatment attenuated airway inflammation, airway remodeling, and abnormal autophagy compared with the vehicle treatment (<em>P</em> &lt; 0.05). Moreover, the solasodine or Dex treatment increased the expression of GR and FOXO3A in the OVA-induced mice compared with the vehicle treatment (<em>P</em> &lt; 0.01). This study showed that solasodine ameliorated airway remodeling and abnormal autophagy by binding to GR in the allergic model, presenting a possible therapeutic agent for the allergic asthma.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117313"},"PeriodicalIF":3.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Isopimaric acid, an ion channel regulator, regulates calcium and oxidative phosphorylation pathways to inhibit breast cancer proliferation and metastasis\" [Toxicology and applied Pharmacology, 2023, 462:116415].","authors":"Jiacheng Li, Xiaozhen Liu, Lin Chen, Xinping Zhu, Zhihong Yu, Liyao Dong, Xinyun Zhao, Hongling Zou, Qin Wei, Yongcai Feng, Yongqiang Zhu, Kequn Chai, Qun Li, Mingqian Li","doi":"10.1016/j.taap.2025.117311","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117311","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117311"},"PeriodicalIF":3.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of combined continuous renal replacement therapy and ulinastatin on cytokine levels and clinical outcomes in patients with sepsis","authors":"Anwaier Apizi,&nbsp;Jian Li,&nbsp;Wei Liu,&nbsp;Liangjie Dong,&nbsp;Yunfei Ding,&nbsp;Zhaoxia Yu","doi":"10.1016/j.taap.2025.117312","DOIUrl":"10.1016/j.taap.2025.117312","url":null,"abstract":"<div><div>This study aims to investigate the effects of continuous renal replacement therapy (CRRT) combined with ulinastatin on cytokine levels and prognosis in patients with sepsis. The control and study groups (40 cases each) were established. The control group received CRRT alone, while the study group received CRRT plus ulinastatin treatment, with both groups being treated for 7 days. We compared the following parameters before and after treatment between the two groups: Sequential Organ Failure Assessment (SOFA) scores, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, renal function indicators [cystatin C (CysC), blood urea nitrogen (BUN), and serum creatinine (SCr)], inflammatory factors [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and procalcitonin (PCT)], and immune function parameters (CD4+, CD8+, CD4+/CD8+ ratio). Additionally, we recorded adverse reactions and 28-day mortality rates in both groups. After 7 days of treatment, the study group showed significantly lower SOFA scores, APACHE II scores, serum levels of CysC, BUN, Scr, TNF-α, CRP, PCT, and peripheral blood CD8+ compared to the control group, while demonstrating higher peripheral blood CD4+ and CD4+/CD8+ ratio. During the treatment period, there was no significant difference in the incidence of adverse reactions between the two groups. However, the 28-day mortality rate was significantly lower in the study group compared to the control group. For patients with sepsis, the combination of CRRT and ulinastatin therapy can significantly improve disease severity, inflammatory factors, renal function, and immune function, while reducing mortality rate.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117312"},"PeriodicalIF":3.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brigatinib activates inflammasomes: Implication for immune-related adverse events","authors":"Takumi Noda,&nbsp;Saori Tanaka,&nbsp;Yuto Maruta,&nbsp;Moe Haruna,&nbsp;Serina Mizuguchi,&nbsp;Ayumi Fujimoto,&nbsp;Kazuya Urashima,&nbsp;Yuka Kohda,&nbsp;Ryuji Kato","doi":"10.1016/j.taap.2025.117310","DOIUrl":"10.1016/j.taap.2025.117310","url":null,"abstract":"<div><div>Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including brigatinib, are widely used to treat ALK-positive non-small cell lung cancer. However, severe adverse effects associated with brigatinib, such as interstitial pneumonia and liver dysfunction, may involve immune system activation. The precise mechanisms underlying these immune-related adverse effects remain unclear. In this study, we evaluated the direct activation of inflammasomes by brigatinib and other ALK TKI (crizotinib, alectinib, ceritinib) in differentiated THP-1 cells. Additionally, we analyzed the inflammasome-activating potential of supernatants from functional liver cell (FLC)-4 cells treated with these drugs. Our results demonstrate that brigatinib directly activates inflammasomes in THP-1 cells, inducing the production of interleukin-1β and the activation of caspase-1. In contrast, no inflammasome activation was observed with the other ALK TKIs. Furthermore, supernatants from FLC-4 cells, characterized by high drug-metabolizing activity, were shown to activate inflammasomes in differentiated THP-1 cells following treatment with brigatinib. Brigatinib treatment significantly increased the levels of damage-associated molecular patterns (DAMPs), including heat shock protein 90 and S100A6, in the supernatants of FLC-4 cells. These findings suggest that brigatinib induces the release of DAMPs from hepatocytes, which subsequently activate inflammasomes. This mechanism may be essential for brigatinib-induced immune system activation and the development of immune-related adverse events.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117310"},"PeriodicalIF":3.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Sitosterol protects against lithocholic acid-induced hepatotoxicity and cholestasis via farnesoid X receptor-mediated regulation of transporters and enzymes in vitro and in vivo","authors":"Wenyu Wang,&nbsp;Lin Li,&nbsp;Xia Li,&nbsp;Jiaqi Chen,&nbsp;Rui Wang,&nbsp;Qi Yang,&nbsp;Changyuan Wang,&nbsp;Qiang Meng","doi":"10.1016/j.taap.2025.117308","DOIUrl":"10.1016/j.taap.2025.117308","url":null,"abstract":"<div><div>Cholestasis arises as a clinical syndrome triggered by the accumulation and aggregation of bile acids. Currently, there are only a few treatment options available for cholestasis. Therefore, it is necessary to explore novel therapeutic strategies. β-sitosterol (SIT), the phytosterol most abundantly found in plants, exhibits diverse pharmacological activities. This study examined SIT's protective role against hepatotoxicity and cholestasis induced by lithocholic acid (LCA). LCA was administered twice a day to male C57BL/6 mice for four days to cause hepatotoxicity and cholestasis. Assessment of the improvement in cholestasis following SIT treatment used H&amp;E staining and serum biomarkers. Mice hepatocyte culture, real-time PCR, immunofluorescence staining, and Western blot were utilized to clarify the mechanisms of SIT hepatoprotection. Furthermore, molecular docking and dual-luciferase reporter gene analysis were utilized to show that SIT would activate the farnesoid X receptor (FXR). <em>In vivo</em>, SIT reduced bile acid accumulation by inducing the bile salt export pump (Bsep), multidrug resistance-related protein 2 (Mrp2), and reduced hepatic uptake of bile acids by inhibiting Na+/taurocholate <em>co</em>-transporting polypeptide (Ntcp), and cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1) while <em>in vitro</em>, it restored FXR expression and transcriptional activity. Besides, SIT decreased hepatic inflammation by suppressing the inflammatory genes NF-κB p65 and p-NF-κB p65, TNF-α, IL-6, and IL-1β. However, the hepatoprotective effects of SIT were abolished by the FXR antagonist guggulsterone <em>in vivo</em> and FXR siRNA <em>in vitro</em>, confirming FXR-dependent mechanisms. In conclusion, SIT protects against LCA-induced hepatotoxicity and cholestasis <em>via</em> FXR activation. These findings highlight SIT as a promising therapeutic candidate for cholestasis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117308"},"PeriodicalIF":3.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143686552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}