Toxicology and applied pharmacology最新文献

{"title":"Dysregulation of mRNA expression by hsa-miR-186 overexpression in arsenic-induced skin carcinogenesis.","authors":"Mayukh Banerjee, Angeliki Lykoudi, Jae Y Hwang, Jianmin Pan, Shesh N Rai, Juw W Park, J Christopher States","doi":"10.1016/j.taap.2024.117209","DOIUrl":"10.1016/j.taap.2024.117209","url":null,"abstract":"<p><p>Dysregulated miRNA expression contributes to development of arsenic-induced cutaneous squamous cell carcinoma (cSCC). hsa-miR-186 (miR-186) is overexpressed in arsenical cSCC tissues as well as in preclinical cell line model of arsenical cSCC. Simultaneous miR-186 overexpression and chronic inorganic trivalent arsenite (iAs; 100 nM) exposure transformed human HaCaT cell line preferentially over miR-186 overexpression or iAs exposure alone. Both iAs and miR-186 regulate the expression of wide range of mRNA targets. However, how their interaction impacts the transcriptome-wide mRNA expression landscape ushering in cancer is unknown. We performed longitudinal RNA-seq analysis in passage-matched HaCaT cell clones (±miR-186 overexpression) with simultaneous chronic iAs exposure (0/100 nM) at 12 and 29 weeks. We determined the impact of each factor and their interaction towards differential gene expression and pathway dysregulation employing two different statistical approaches (t-statistic and 2-factor ANOVA). We show that a core set of pathways are dysregulated deterministically irrespective of the statistical approach chosen, possibly representing necessary changes for transformation. The data suggest that each clonal line could take a unique route to dysregulate this core set of pathways necessary for transformation, highlighting the possible role of stochasticity in cancer development. Evidence is presented to sift the strengths and weaknesses of each statistical methodology in providing biological understanding of events that play crucial roles in carcinogenesis in large datasets with multiple contributing variables.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117209"},"PeriodicalIF":3.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885344","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":"Targeting angiogenic and proliferative mediators by montelukast & trimetazidine Ameliorates thioacetamide-induced liver fibrosis in rats.","authors":"Rehab S Abdelrahman, Ahmed A Elnfarawy, Asmaa E Nashy, Ramy A Abdelsalam, Marwa S Zaghloul","doi":"10.1016/j.taap.2024.117208","DOIUrl":"10.1016/j.taap.2024.117208","url":null,"abstract":"<p><p>Liver fibrosis is a significant health complication with the potential to result in serious mortality and morbidity. However, there is no standard treatment due to its complex pathogenesis. The drug montelukast reversibly and selectively antagonizes the cysteinyl-leukotrienes-1 receptor and reduces inflammation; thus, it is used in the treatment of asthma. Trimetazidine, an anti-anginal agent, selectively inhibits the activity of mitochondrial long-chain 3-ketoacyl-CoA thiolase, inhibition of free fatty acid (FFA) oxidation. This study explores the efficacy of montelukast (5 and 10 mg/kg) and trimetazidine (10-20 mg/kg) against liver fibrosis induced by thioacetamide (TAA) in rats. Impaired liver function tests were significantly improved by montelukast and trimetazidine. The antioxidant and anti-inflammatory effects of montelukast and trimetazidine were proved by the inhibition of malondialdehyde (MDA) and nitric oxide (NO) accumulation, with elevation of glutathione (GSH) and superoxide dismutase activity, decreased heat shock protein (HSP-70) expression, and a decline in interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) levels in liver tissue. Also, the antifibrotic effects were explored by reducing levels of hydroxyproline and alpha-smooth muscle actin (α-SMA) expression in liver tissue and attenuating hepatic expression of hepatic expression of angiogenic mediator vascular endothelium growth factor (VEGF) and proliferative mediator Antigen Kiel 67 (Ki-67).</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117208"},"PeriodicalIF":3.3,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883031","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":"Knockdown of regulator of Calcineurin 2 promotes transcription factor EB-mediated lipophagy to prevent non-alcoholic fatty liver disease.","authors":"Lei Shan, Pengzhan Guo, Mumeike Wen, Yue Sun, Fei Gao, Kai Zhang, Ning Zhang, Baoshan Yang","doi":"10.1016/j.taap.2024.117210","DOIUrl":"10.1016/j.taap.2024.117210","url":null,"abstract":"<p><p>Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. The present work aimed to explore the function of regulator of Calcineurin 2 (RCAN2) in NAFLD and its related mechanisms. Mice were fed with high-fat diet (HFD) to construct NAFLD model. Adeno-associated virus injection was performed to interference with RCAN2 in mice. RCAN2 knockdown meliorated HFD-induced NAFLD and impaired glucose metabolism. Abnormal lipid metabolism and inflammation in HFD-fed mice were relieved when RCAN2 was downregulated. Besides, hepatocyte Huh-7 cells, treated with free fatty acids (oleic acid and palmitic acid), were used as NAFLD models in vitro. We found that knockdown of RCAN2 inhibited the accumulation of lipid droplets and inflammation induced by free fatty acids. RCAN2 interference increased the activity of calcineurin (CaN), which enhanced the nuclear translocation of Transcription factor EB (TFEB). Autophagosome and lysosome biogenesis was augmented, and autophagy-dependent lipid degradation (lipophagy) was promoted. Collectively, we demonstrate that RCAN2 insufficiency protects against NAFLD by promoting TFEB-mediated lipophagy.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117210"},"PeriodicalIF":3.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877926","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":"Didecyldimethylammonium chloride-induced lung fibrosis may be associated with phospholipidosis.","authors":"Wonkyun Jung, Mi-Jin Yang, Min-Sung Kang, Jiyun Lim, Hyosun Choi, Ji Ae Lee, Kyung-Sik Yoon, Jin-Bae Kim, Eun-Jung Park","doi":"10.1016/j.taap.2024.117211","DOIUrl":"10.1016/j.taap.2024.117211","url":null,"abstract":"<p><p>In the current study, we dosed didecyldimethylammonium chloride (DDAC) in mice by pharyngeal aspiration for 28 days or 90 days (weekly) and tried to elucidate the relationship between lamellar body formation and the lesions. When exposed for 28 days (0, 5, 10, 50, and 100 μg/head), all the mice in the 50 and 100 μg/head groups died since Day 2 after the third dosing (Day 16 after the first dosing). Edema, necrosis of bronchiolar and alveolar epithelium, and fibrinous exudate were observed in the lungs of all the dead mice, and chronic inflammatory lesions were observed in the lung tissues of alive mice. When dosed with DDAC of 0, 1, 4, and 8 μg/head for 13 weeks, the total number of pulmonary cells and the pulmonary levels of pro- and anti-inflammatory cytokines significantly increased, and chronic inflammatory lesions were detected with the production of collagen, collagen fibers, and lamellar body-like structures. Swelling of the nuclear envelope and nucleoplasmic components and generation of lipid droplets were also notably observed in the lung tissues of DDAC (8 μg/head)-treated mice. Furthermore, transcriptomic analysis performed using human bronchial epithelial cells showed that DDAC affected the expression of DNA damage, ER stress, lipid metabolism, and transcription regulation-related genes at 6 h after treatment, as it did 24 h treatment and that early growth response factor 1 gene was added to a list of the most up-regulated genes. Meanwhile, cytokines that are associated with the pathology of chronic lung diseases (IL-11, IL-24, and TGF-β) were slightly increased in the lung of DDAC-treated mice, and only the pulmonary level of CCL-2, but not CXCL-1 and CCL-3, increased in both sexes of mice. More importantly, the GM-CSF level increased dose-dependently in the lungs of both sexes of mice exposed to DDAC. Considering that the wound-healing process can take several weeks to complete, we suggest that DDAC-induced pulmonary fibrosis may be attributable to disruption of the wound-healing process due to continuous exposure to DDAC. We also hypothesize that the formation of lamellar bodies may be attributable to lysosomal accumulation of phospholipids separated from the destroyed lung tissue membrane.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117211"},"PeriodicalIF":3.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877922","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":"Chronic cadmium exposure to minimal-risk doses causes dysfunction of epididymal adipose tissue and metabolic disorders.","authors":"Victor Enrique Sarmiento-Ortega, Daniel Issac Alcántara-Jara, Diana Moroni-González, Alfonso Diaz, Rubén Antonio Vázquez-Roque, Eduardo Brambila, Samuel Treviño","doi":"10.1016/j.taap.2024.117203","DOIUrl":"10.1016/j.taap.2024.117203","url":null,"abstract":"<p><p>Cadmium (Cd) is among the top seven most hazardous environmental contaminants. Minimal risk levels for daily exposure have been established, such as no observable adverse effect level (NOAEL) and lowest observable adverse effect level (LOAEL). Chronic exposure to Cd, at both NOAEL and LOAEL doses, causes toxicity in diverse tissues. However, Cd toxicity in adipose tissue, an endocrine and metabolic organ, remains relatively understudied. We aimed to investigate the potentially toxic effects of chronic Cd exposure (at NOAEL and LOAEL doses) on epidydimal adipose tissue of adult male Wistar rats. Ninety male Wistar rats were divided into three groups (n = 30): Control Cd-free, NOAEL, and LOAEL that received CdCl₂ in drinking water for 15 days to 5 months. We evaluated over time zoometry, serum and adipose Cd concentration, redox balance, GLUT4 and Nrf2 expression, histology, leptin, adiponectin, adipose insulin resistance index, free fatty acids, and glucose tolerance. The higher dose group showed a more pronounced and sustained increase in serum and adipose tissue of Cd concentration. Zoometry was similarly affected in both Cd-exposed groups with adipocyte hypertrophy. The redox balance was maintained due to the augmenting of Nrf2 expression. Leptin concentration augmented, while adiponectin diminished. Adipose insulin resistance increased simultaneously to lipolysis and glucose intolerance despite high GLUT4 expression. In conclusion, this study provides strong evidence that chronic Cd exposure, even at minimal risk levels (LOAEL and NOAEL doses), has toxic effects, disrupting the function of epididymal adipose tissue and contributing to metabolic disorders.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117203"},"PeriodicalIF":3.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865549","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":"γ-Glutamylcysteine restores glucolipotoxicity-induced islet β-cell apoptosis and dysfunction via inhibiting endoplasmic reticulum stress.","authors":"Jinyi Zhou, Yingying Shi, Lishuang Zhao, Rong Wang, Lan Luo, Zhimin Yin","doi":"10.1016/j.taap.2024.117206","DOIUrl":"10.1016/j.taap.2024.117206","url":null,"abstract":"<p><strong>Purpose: </strong>The impaired function of islet β-cell is associated with the pathogenesis of type 2 diabetes mellitus (T2DM). γ-glutamylcysteine (γ-GC), an immediate precursor of glutathione (GSH), has antioxidant and neuroprotective functions. Its level has been reported to be down-regulated in hyperglycemia. However, whether γ-GC has a protective effect on islet β-cell dysfunction remains elusive. Recently, we explore the molecular mechanism by which γ-GC protects islet β-cell from glucolipotoxicity-induced dysfunction.</p><p><strong>Methods: </strong>In vivo mice models and in vitro cell models were established to examine the therapeutic effects and molecular mechanisms of γ-GC.</p><p><strong>Results: </strong>db mice develop impaired glucose-stimulated insulin secretion (GSIS) due to reduced islet number and damaged islet microstructure. Serious oxidative damage, apoptosis and lipid accumulation are also observed in β-cell stimulated by glucolipotoxicity. Mechanistic studies suggest that glucolipotoxicity inhibits PDX-1 nuclear translocation by inducing endoplasmic reticulum (ER) stress, which leads to impaired insulin (INS) secretion in β-cell. Nevertheless, γ-GC as an inhibitor of ER stress can alleviate the damage of islet microstructure in db mice. Importantly, γ-GC promotes INS gene expression and GSIS through driving nuclear translocation of PDX-1, thereby enhancing intracellular INS content. Moreover, treatment with γ-GC can also mitigate oxidative damage, apoptosis and lipid accumulation of β-cell, resulting in ameliorating islet β-cell dysfunction induced by glucolipotoxicity.</p><p><strong>Conclusion: </strong>Our results support the use of γ-GC as an inhibitor of ER stress for prevention and treatment of T2DM in the future.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117206"},"PeriodicalIF":3.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865556","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":"Metabolomics based early warning model for acute kidney injury risk in patients exposed to diquat.","authors":"Shengkai Zhu, Xinyu Li, Chengzhao Wu, Xu Zhao, Shuiying Xu, Yujing Zhao, Xiaobo Peng, Xiaohe Xiao, Ming Niu","doi":"10.1016/j.taap.2024.117207","DOIUrl":"10.1016/j.taap.2024.117207","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is one of the most important indications of severe clinical symptoms in patients with diquat poisoning and is closely related to poor prognosis. However, current studies have rarely focused on early warnings of diquat-related AKI, which is not conducive to the treatment of patients with early clinical diquat poisoning. In this study, untargeted plasma metabolomics was employed to reveal the differences between diquat-poisoned patients with and without AKI, as well as between patients and healthy volunteers. The results showed that 48 metabolites were significantly changed in the patients, among which 3-hydroxybutyrylcarnitine, SAICAR, dodecanoic acid, and tetrahydrofolyl-[Glu](2) could be used to effectively differentiate the above three groups. Based on the ratios of the first two metabolites and the ratios of the last two metabolites, a decision tree model for the early warning of diquat-induced AKI was established with an accuracy rate of 88.7 %. This model provides great support for accurate clinical diagnosis and intervention regarding the AKI risk of diquat-exposed patients.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117207"},"PeriodicalIF":3.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855223","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":"Neuregulin 1 improved gastric motility and reduced gastric inflammation by activating the α7nAChR through the cholinergic anti-inflammatory pathway in diabetic rats.","authors":"Weigang Cui, Yuqi Ma, Libin Zhang, Lei Zhang, Qianyin Yao, Jie Zhang, Yatao Cheng, Wenqin Zeng, Qin Liu, Fengyun Liu, Chunyan Liang","doi":"10.1016/j.taap.2024.117205","DOIUrl":"10.1016/j.taap.2024.117205","url":null,"abstract":"<p><p>Diabetic gastroparesis (DGP), a prevalent complication of diabetes, is characterized by delayed gastric emptying and inflammation. The dorsal motor nucleus of the vagus (DMV) plays a crucial role in modulating gastric function via the vagus nerve. Neuregulin 1 (NRG1), which is present in the DMV and influences the autonomic nervous system, has an unclear role in DGP. This study aimed to investigate the expression of NRG1 in the DMV of Zucker diabetic fatty (ZDF) rats and to evaluate the impact of centrally administered NRG1 on gastric motility and inflammation, as well as the underlying mechanisms. Our findings revealed a decrease in NRG1 and choline acetyltransferase (ChAT) expression in the DMV of ZDF rats, corresponding to weakened gastric motility. Microinjection of AAV-NRG1 (overexpressed NRG1 by means of an adeno-associated viral vector delivery of NRG1) into the DMV enhanced gastric motility and increased vagal nerve discharge frequency. Moreover, AAV-NRG1 upregulated acetylcholine (Ach) and α7 nicotinic acetylcholine receptor (α7nAChR) expression in the gastric body, mitigating gastric inflammation. The beneficial effects of AAV-NRG1 were partially reversed by vagotomy or α7nAChR antagonism. These findings provide novel evidence that NRG1 in the DMV can stimulate Ach release and activate α7nAChRs, thereby reducing inflammation and restoring gastric motility via the vagus nerve. This implicates the NRG1 as a potential therapeutic target for DGP.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117205"},"PeriodicalIF":3.3,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847990","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":"MMP13 as an effective target of an active trifluoromethyl quinazoline compound against osteosarcoma.","authors":"Chang-Hua Zhou, Ting Zhang, Jia Yu, Gang Yu, Sha Cheng, Hui Wu, Bi-Xue Xu, Heng Luo, Xiao-Bin Tian","doi":"10.1016/j.taap.2024.117204","DOIUrl":"10.1016/j.taap.2024.117204","url":null,"abstract":"<p><p>Osteosarcoma (OS) is a highly fatal malignant tumor with a high metastatic rate and poor prognosis. Matrix metalloproteinase-13 (MMP13) is involved in OS metastasis. Its increased expression is closely related to distant metastasis and poor prognosis. The trifluoromethyl quinazoline compound KZL-201 was designed and synthesized, and its inhibitory effect on the progression of OS cells was investigated. The aim of this study was to investigate the underlying mechanism of action of KZL-201 in OS using a combination of bioinformatics analysis, molecular biology, cytology, and zoology. The in vitro experiments showed that KZL-201 inhibited OS cell proliferation, invasion, and migration; KZL-201 induced apoptosis and arrested the cell cycle at the G2/M phase. The results of molecular docking, the cellular thermal shift assay, and gene silencing experiments showed that KZL-201 had a strong affinity for MMP13. KZL-201 inhibited the progression of 143B cells by regulating the TGF-β1/Smad2/3 pathway. Thus, MMP13 is an important target gene of KZL-201 in inhibiting 143B cell progression. The in vivo experiments showed that KZL-201 inhibited the growth of OS tissues and the expression of MMP13 in OS tissues. In summary, KZL-201 targeted MMP13 and inhibited its expression, consequently suppressing the progression of OS by regulating the TGF-β1/Smad2/3 pathway.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117204"},"PeriodicalIF":3.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824502","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":"Desloratadine mitigates hepatocellular carcinoma in rats: Possible contribution of TLR4/MYD88/NF-κB pathway.","authors":"Heba A Bahriz, Rania R Abdelaziz, Dalia H El-Kashef","doi":"10.1016/j.taap.2024.117202","DOIUrl":"10.1016/j.taap.2024.117202","url":null,"abstract":"<p><p>Chemotherapeutic medication-induced systemic toxicity makes cancer treatment less effective. Thus, the need for drug repurposing, which aids in the development of safe and efficient cancer therapies, is urgent. The primary goal of this research was to assess desloratadine hepatoprotective abilities and its capacity to attenuate TLR4/MyD88/NF-κB inflammatory pathway in hepatocellular carcinoma (HCC) induced by thioacetamide (TAA). Male Sprague Dawely rats received TAA injections (200 mg/kg, i.p., 2 times/week) for 16 weeks. To confirm the development of HCC, liver function biomarkers and histopathological analysis were evaluated. Desloratadine (5 mg/kg, p.o.) was administered to rats in 2 treatment groups; HCC + DES 1 group received desloratadine with TAA for 1 month from week 13-16, HCC + DES 2 group received desloratadine with TAA for 2 months from week 9-16. Chronic TAA administration resulted in considerable overexpression of the profibrogenic cytokine TGF-β and elevation in protein expression of NF-κB besides levels of TLR4, MyD88, TRAF6, TAK1 and IL-1β. Desloratadine administration showed a significant improvement in liver function tests, as well as an increase in tissue antioxidant enzymes and an improvement in the liver's histopathological features. Collectively, desloratadine through modulating TLR4/MyD88/TRAF6/TAK1/NF-κB and acting as an antioxidant, is a promising treatment for HCC induced by TAA.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117202"},"PeriodicalIF":3.3,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822628","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}