Toxicology and applied pharmacology最新文献

{"title":"Fangchinoline alleviates the progression of osteoarthritis through the nuclear factor kappa B signaling pathway","authors":"Wei He ,&nbsp;Xinhuo Li ,&nbsp;Qiannan Ding ,&nbsp;Tan Zhang ,&nbsp;Jiewen Zheng ,&nbsp;Xuanyuan Lu ,&nbsp;Jianlei Li ,&nbsp;Cong Jin ,&nbsp;Yangjun Xu","doi":"10.1016/j.taap.2025.117241","DOIUrl":"10.1016/j.taap.2025.117241","url":null,"abstract":"<div><div>Osteoarthritis is a progressive, chronic joint disease characterized by pain, stiffness, and limited mobility, which can lead to physical disability in severe cases. Owing to its complex pathological features, effective treatments for osteoarthritis are lacking. Fangchinoline is a natural alkaloid found in the tuberous roots of plants belonging to the Menispermaceae family. Fangchinoline reportedly possesses anti-inflammatory, antioxidant, and anticancer properties; however, its role in osteoarthritis progression remains unclear. In this study, we investigated the protective effects and potential mechanisms of fangchinoline against osteoarthritis. In vitro, we confirmed that fangchinoline alleviates interleukin-1β-induced cartilage inflammation, reduces the levels of metabolic factors, such as inducible nitric oxide synthase and matrix metalloproteinase-3, and modulates the expression of aggrecan, which enhances extracellular matrix synthesis. In vivo, we demonstrated that fangchinoline can ameliorate articular cartilage degeneration and reduce inflammatory destruction in a destabilization of the medial meniscus mouse model. The nuclear factor kappa B (NF-κB) signaling pathway in osteoarthritis has been a primary target for drug development, and our results suggest that fangchinoline exerts anti-inflammatory effects by inhibiting the activity of IKKα/β. Using an in vitro human cartilage culture model, we further validated that fangchinoline significantly mitigates cartilage degeneration and inflammation by modulating the NF-κB signaling pathway. This evidence highlights its dual action in preserving cartilage integrity and suppressing inflammatory responses. These findings collectively underscore fangchinoline as a potent inhibitor of NF-κB, capable of attenuating key pathological processes associated with osteoarthritis. Therefore, fangchinoline emerges as a promising therapeutic candidate for slowing the progression of osteoarthritis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117241"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081140","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":"Dehydrodiisoeugenol inhibits PDGF-BB-induced proliferation and migration of human pulmonary artery smooth muscle cells via the mTOR/HIF1-α/HK2 signaling pathway","authors":"Shishun Xie ,&nbsp;Jianjun Zhao ,&nbsp;Fan Zhang ,&nbsp;Xiangjun Li ,&nbsp;Xiaoyan Yu ,&nbsp;Zhiyun Shu ,&nbsp;Hongyuan Cheng ,&nbsp;Siyao Liu ,&nbsp;Shaomin Shi","doi":"10.1016/j.taap.2024.117212","DOIUrl":"10.1016/j.taap.2024.117212","url":null,"abstract":"<div><div>Abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) leading to pulmonary vascular remodeling are critical factors in the development of pulmonary hypertension (pH). Dehydrodiisoeugenol (DEH), a natural phenolic compound, is renowned for its antioxidant and anti-inflammatory properties. However, the precise role and mechanisms of DEH in PH remain unclear. In this study, human PASMCs were exposed to PDGF-BB for 48 h to establish an in vitro model. Subsequently, cells were treated with DEH, and assessments of cell proliferation, migration, and apoptosis were performed using CCK-8/EdU assays, scratch/transwell assays, and flow cytometry. The results showed that PDGF-BB induced phenotypic modulation, proliferation, and migration of PASMCs while reducing apoptosis. Treatment with DEH effectively reversed these effects. Bioinformatics analysis identified mTOR as a target of DEH action. Western blot experiments were conducted to evaluate the expression of proteins involved in the mTOR/HIF1-α/HK2 signaling pathway, suggesting that DEH modulates this pathway by targeting and inhibiting mTOR. After treating cells with mTOR inhibitors, cellular glycolysis was assessed using the extracellular acidification rate (ECAR) assay. The results indicated that inhibition of mTOR phosphorylation decreased aerobic glycolysis in PASMCs and suppressed cell proliferation, migration, and apoptosis resistance, regardless of PDGF-BB treatment. Activation of mTOR reversed the inhibition of PDGF-BB-induced PASMC-related protein expression by DEH. These findings suggest that DEH inhibits aerobic glycolysis in PDGF-BB-induced PASMCs through the mTOR/HIF1-α/HK2 signaling pathway, thereby suppressing cell proliferation, migration, and resistance to apoptosis. Consequently, DEH holds promise as a novel therapeutic agent for treating pulmonary arterial hypertension.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117212"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884846","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 ,&nbsp;Daniel Issac Alcántara-Jara ,&nbsp;Diana Moroni-González ,&nbsp;Alfonso Diaz ,&nbsp;Rubén Antonio Vázquez-Roque ,&nbsp;Eduardo Brambila ,&nbsp;Samuel Treviño","doi":"10.1016/j.taap.2024.117203","DOIUrl":"10.1016/j.taap.2024.117203","url":null,"abstract":"<div><div>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 (<em>n</em> = 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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117203"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shikonin modulates activated fibroblast apoptosis in silicosis fibrosis via the PI3K/Akt signaling pathway: A network pharmacology approach","authors":"Shengpeng Wen ,&nbsp;Sirong Chang ,&nbsp;Huning Zhang ,&nbsp;Wenyue Zhang ,&nbsp;Yi Guo ,&nbsp;Na Zhang ,&nbsp;Anning Yang ,&nbsp;Yue Sun ,&nbsp;Zhihong Liu","doi":"10.1016/j.taap.2025.117236","DOIUrl":"10.1016/j.taap.2025.117236","url":null,"abstract":"<div><h3>Background</h3><div>Silicosis is a lung disease caused by the inhalation of free crystalline silica and is characterized mainly by lung inflammation and progressive pulmonary fibrosis. Shikonin, a biologically active compound isolated from the traditional Chinese medicine Comfrey, has been shown to have significant antifibrotic effects. However, the molecular mechanisms underlying the antifibrotic effects of SHK in silicosis remain unclear.</div></div><div><h3>Methods</h3><div>This study used a combination of network pharmacology, molecular docking, molecular dynamics simulation, and in vitro experimental validation to investigate the potential targets of SHK in silicosis.</div></div><div><h3>Results</h3><div>Network pharmacology analysis identified 208 cross genes associated with disease drugs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis show that these intersecting genes are significantly associated with the PI3K/Akt signaling pathway. Protein protein interaction (PPI) network analysis further revealed 10 core crossover genes, namely ALB, Akt1, STAT3, CASP3, EGFR, MMP9, Bcl-2, ESR1, HSP90AA1, and NF-κB1. Among them, Akt1 and Bcl-2 have the strongest binding ability to SHK. The in vitro experimental results showed that SHK can significantly inhibit the activation of fibroblasts and promote apoptosis of activated fibroblasts through the PI3K/Akt signaling pathway.</div></div><div><h3>Conclusion</h3><div>SHK alleviates silica induced silicosis fibrosis by inhibiting the transformation of fibroblasts into myofibroblasts through the PI3K/Akt signaling pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117236"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041987","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":"Peripheral inflammation enhances opioid-induced gastrointestinal motility inhibition via up-regulating spinal mu opioid receptor","authors":"Zhonghua Zhang ,&nbsp;Yaofeng Zhao ,&nbsp;Dingnian Gou ,&nbsp;Pengtao Li ,&nbsp;Hao Wang ,&nbsp;Yanfang Li ,&nbsp;Chenxi Li ,&nbsp;Zhanyu Niu ,&nbsp;Tong Yang ,&nbsp;Lanxia Zhou ,&nbsp;Shouliang Dong","doi":"10.1016/j.taap.2025.117225","DOIUrl":"10.1016/j.taap.2025.117225","url":null,"abstract":"<div><div>Opioids are potent analgesics in clinical pain management but exert variable analgesia in different pain types. Opioid-induced constipation is a common side effect of opioid therapy, and whether opioids induce different gastrointestinal motility inhibitions in different pain types is unknown. In this study, we evaluated the antinociceptive effects and inhibition of upper gastrointestinal transit and colonic bead expulsion of morphine, DAMGO, and Deltorphin in mouse CFA chronic inflammatory pain, SNI chronic neuropathic pain, and carrageenan chronic inflammatory pain models. Furthermore, quantitative PCR and immunofluorescence were used to investigate the mechanisms underlying the altered inhibition. Results showed that intrathecal administration of morphine, DAMGO, and Deltorphin produced higher antinociceptive effects in the CFA and carrageenan groups than in the SNI group. Upper gastrointestinal transit inhibition was significantly enhanced in the carrageenan group by morphine and DAMGO; colonic bead expulsion inhibition was also enhanced in the CFA and carrageenan groups by morphine and DAMGO, but not in Deltorphin treatment. Additionally, mu (MOR) opioid receptor mRNA and MOR-expressing cell density in the lumbar spinal cord of CFA and carrageenan mice were increased, whereas delta opioid receptor expression remained unchanged in these groups. Finally, the pharmacological blockade of MOR completely prevented the enhanced upper gastrointestinal transit inhibition in the carrageenan group by morphine and DAMGO. Altogether, our results indicate that gastrointestinal motility inhibition induced by MOR agonists can be enhanced with upregulated spinal MOR expression in chronic inflammatory pain.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117225"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955634","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":"A computational model of the crosstalk between hepatocyte fatty acid metabolism and oxidative stress highlights the key enzymes, metabolites, and detoxification pathways in the context of MASLD","authors":"Yuki Miura ,&nbsp;Cosmin Voican ,&nbsp;Yasuyuki Sakai ,&nbsp;Masaki Nishikawa ,&nbsp;Eric Leclerc","doi":"10.1016/j.taap.2024.117185","DOIUrl":"10.1016/j.taap.2024.117185","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as NAFLD) is a common liver disease worldwide and carries the risk of progressing to severe liver conditions, such as fibrosis and liver cancer. In the context of MASLD, evaluating fat accumulation in the liver and the subsequent production of oxidative stress is essential to understand the disease propagation. However, clinical studies using human patients to investigate the fat accumulation and the onset of oxidative stress in MASLD face ethical and technical challenges, highlighting the importance of alternative methods. To understand the relationship between fatty acid metabolism, lipid accumulation, oxidative stress generation, and antioxidant mechanisms in hepatocytes, we proposed a new mathematical model. The importance of this model lies in its ability to track the time-dependent changes in oxidative stress and glutathione concentration in response to the input of fatty acids. Furthermore, the model allows for the evaluation of the effects of altering the activity of the key enzymes involved in those mechanisms. Our model is anticipated to provide new insights into MASLD therapy strategies by identifying key pathways and predicting the effects of drug-induced changes in enzyme activity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117185"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781126","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 ,&nbsp;Yingying Shi ,&nbsp;Lishuang Zhao ,&nbsp;Rong Wang ,&nbsp;Lan Luo ,&nbsp;Zhimin Yin","doi":"10.1016/j.taap.2024.117206","DOIUrl":"10.1016/j.taap.2024.117206","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>In vivo mice models and in vitro cell models were established to examine the therapeutic effects and molecular mechanisms of γ-GC.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>Our results support the use of γ-GC as an inhibitor of ER stress for prevention and treatment of T2DM in the future.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117206"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","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":"Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity and the underlying mechanism","authors":"Yi Chen ,&nbsp;Wei Luo ,&nbsp;Yanqing Wu","doi":"10.1016/j.taap.2024.117179","DOIUrl":"10.1016/j.taap.2024.117179","url":null,"abstract":"<div><h3>Background</h3><div>Ferroptosis is a key process in doxorubicin (DOX)-induced cardiotoxicity and is a potentially important therapeutic target. Thymoquinone (TQ) is a monoterpenoid compound isolated from black cumin extract that exhibits antitumor effects and acts as a powerful mitochondrial-targeted antioxidant. In this study, we investigated the effect of TQ on DOX-induced cardiotoxicity and the potential underlying mechanisms.</div></div><div><h3>Methods and results</h3><div>Mice were randomly assigned to the control (CON) group, DOX (20 mg/kg) group, TQ10 (10 mg/kg/d) group, and TQ20 (20 mg/kg/d) group and intraperitoneally injected with DOX and different doses of TQ. The electrocardiogram, blood pressure, and cardiac ultrasound changes during the experiments showed that TQ exerted a protective effect against DOX-induced cardiotoxicity. The glutathione (GSH), malondialdehyde (MDA), and total antioxidant capacity (T-AOC) levels in the mouse heart tissue were significantly different from those in the CON group. Western blot analysis revealed that the expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) in the DOX group was lower than that in the control group. TQ treatment decreased these changes, indicating that TQ alleviated DOX-induced cardiotoxicity and increased the antioxidant capacity of murine cardiomyocytes. The mechanism might involve activating the Nrf2/HO-1 signaling pathway and reducing iron-mediated death. Immunohistochemical staining revealed similar effects on the expression levels of NQO1, COX-2, and NOX4. Moreover, transmission electron microscopy indicated that TQ protected murine cardiomyocytes against DOX-induced mitochondrial damage.</div></div><div><h3>Conclusion</h3><div>The results of this study suggested that TQ can decrease oxidative stress levels and DOX-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway to alleviate ferroptosis in murine cardiomyocytes.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117179"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792339","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":"Betaine alleviates methomyl-triggered oxidative stress-mediated cardiopulmonary inflammation in rats through iNOS/Cox2 and Nrf2/HO1/Keap1 signaling pathway","authors":"Eman I. Hassanen ,&nbsp;Neven H. Hassan ,&nbsp;Ahmed M. Hussien ,&nbsp;Marwa A. Ibrahim ,&nbsp;Merhan E. Ali","doi":"10.1016/j.taap.2024.117223","DOIUrl":"10.1016/j.taap.2024.117223","url":null,"abstract":"<div><div>Methomyl (MET), a universally used insecticide, has many adverse effects on various organs in both humans and animals including the liver, kidneys, and heart. Betaine (BET), a natural antioxidant, has a protective role against many toxicants-induced cardiovascular disorders. The present study was designed to elucidate the molecular mechanistic way underlying the mitigating effect of BET against MET-induced cardiopulmonary injury and inflammation in rats. Four groups of rats were used and orally administered the consequent materials daily for 28 days: normal saline, BET (250 mg/kg bwt), MET (2 mg/kg bwt), MET + BET. Blood and tissue (heart &amp; lungs) samples were collected to assess the oxidative stress markers, lipid profile, biochemical markers, microscopic appearance, and inflammatory gene regulations. The results proved that MET induced oxidant/antioxidant imbalance, elevation of serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels, and deterioration in lipid profile. The histopathological inspection showed severe myocardial necrosis and interstitial pneumonia along with bronchitis and alveolar damage. There was a marked increase in the intensity of cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) immunostaining with marked upregulation of the transcriptase levels of <em>keap-1</em>gene and downregulation of nuclear factor erythroid 2-related factor-2 <em>(Nrf-2) and</em> heme oxygenase-1 <em>(HO-1)</em> genes in both heart and lung tissues of MET group. Otherwise, the coadministration of BET with MET markedly alleviated the abovementioned toxicological parameters. We can conclude that BET was able to reduce the MET-induced oxidative stress-mediated cardiovascular injury and pulmonary inflammation by modulating Keap-1/Nrf-2 signaling pathway and inactivating Cox-2 and iNOS expression which therefore reduced further cellular damage and inflammatory response.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117223"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915639","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 ,&nbsp;Ahmed A. Elnfarawy ,&nbsp;Asmaa E. Nashy ,&nbsp;Ramy A. Abdelsalam ,&nbsp;Marwa S. Zaghloul","doi":"10.1016/j.taap.2024.117208","DOIUrl":"10.1016/j.taap.2024.117208","url":null,"abstract":"<div><div>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).</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117208"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","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}