Toxicology and applied pharmacology最新文献

{"title":"Exploring the role of Bisphenol A in obesity-driven colorectal cancer progression: network toxicology and multi-organ pathology in animal models.","authors":"Muhamad Fikri Shazlan Saad, Muhammad Nazrul Hakim Abdullah, Vuanghao Lim, Hasnah Bahari, Boon Yin Khoo, Jun Jie Tan, Yoke Keong Yong","doi":"10.1016/j.taap.2025.117227","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117227","url":null,"abstract":"<p><p>Bisphenol A (BPA), an endocrine disruptor, is linked to cancer progression in estrogen-responsive tissues, but its role in promoting colorectal cancer (CRC) progression in the context of obesity remains underexplored. This study examines BPA's influence on CRC in obese Sprague-Dawley rats using network toxicology and experimental models. Computational analysis using the Database for Annotation, Visualization, and Integrated Discovery identified pathways such as \"CRC\" and \"chemical carcinogenesis-receptor activation\", implicating the PI3K-AKT pathway in IL-1 beta upregulation and BPA's role in CRC during obesity. Thirty male rats were grouped (n = 6) as follows: N (normal diet), NC (normal diet + CRC), HC (high-fat diet + CRC), NCB (normal diet + CRC + BPA), and HCB (high-fat diet + CRC + BPA). CRC was induced with 1,2-dimethylhydrazine (40 mg/kg), and BPA (25 mg/kg) was administered for 19 weeks. Although BPA exposure did not affect body weight or biochemical parameters, the HCB group exhibited significant histopathological changes in the colon, including lymphoid hyperplasia, liver damage, and increased IL-1β levels. Furthermore, diet influenced adipocyte size, exacerbating BPA's effects on CRC progression. Findings suggest BPA may worsen CRC progression in obese rats through identified pathways, promoting multi-organ pathology and underscoring the need for stricter regulations, especially for vulnerable populations. ENVIRONMENTAL IMPLICATION: Bisphenol A (BPA), a widespread environmental contaminant, is increasingly linked to serious health issues, including cancer, in susceptible populations. Our study highlights BPA's role in promoting obesity-driven colorectal cancer (CRC) progression, demonstrating its carcinogenic potential in high-risk contexts. These findings emphasize the urgent need for regulatory scrutiny of BPA exposure, particularly in obese individuals, and support the development of safer alternatives. Addressing BPA's impact can contribute to preventive health strategies and inform policies aimed at reducing environmental and public health risks associated with endocrine-disrupting chemicals.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117227"},"PeriodicalIF":3.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955579","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":"The SGLT2 inhibitor remogliflozin induces vasodilation in the femoral artery of rabbits via activation of a Kv channel, the SERCA pump, and the cGMP signaling pathway.","authors":"Minju Park, Wenwen Zhuang, Junsu Jeong, Hye Ryung Kim, YeEun Jang, Mi Seon Seo, Jin Ryeol An, Hongzoo Park, Eun-Taek Han, Jin-Hee Han, Wanjoo Chun, Won Sun Park","doi":"10.1016/j.taap.2025.117228","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117228","url":null,"abstract":"<p><p>This study explored the vasodilatory mechanisms of the sodium-glucose cotransporter-2 inhibitor remogliflozin using femoral arteries of rabbits. Remogliflozin dilated femoral arterial rings pre-contracted with phenylephrine in a concentration-dependent manner. Pretreatment with the Ca²⁺-sensitive K⁺ channel inhibitor (paxilline), the ATP-sensitive K⁺ channel inhibitor (glibenclamide), or the inwardly rectifying K⁺ channel inhibitor (Ba²⁺) did not alter the vasodilatory effect. However, vasodilation was significantly reduced by pretreatment with the voltage-dependent K⁺ (Kv) channel inhibitor (4-AP) and with the Kv1.5 subtype inhibitor (DPO-1) but not with Kv2.1 or Kv7 subtype inhibitor. Neither endothelium removal nor the inhibition of nitric oxide production altered the vasodilatory effect of remogliflozin. However, pretreatment with the sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid effectively reduced the remogliflozin effect, as did pretreatment with cGMP/PKG-related but not cAMP/PKA-related signaling pathway inhibitors. These results indicate that remogliflozin-mediated dilation of the femoral artery occurs via the activation of Kv channels, mainly the Kv1.5 subtype, SERCA pump, and cGMP/PKG-related signaling pathways.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117228"},"PeriodicalIF":3.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955676","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":"Network pharmacological mechanism and molecular experimental validation of artemisinin in the treatment of lung adenocarcinoma.","authors":"Zhimin Lu, Jialu Jiang, Xuming Yao, Guoxin Hou","doi":"10.1016/j.taap.2025.117226","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117226","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer is a medical ailment with high mortality and prevalence rates. Artemisinin (ART) and its derivatives exhibit anti-cancer properties against various malignancies, including lung cancer. However, further research is required to determine the precise anti-cancer mechanisms of ART. Hence, this study aimed to utilize network pharmacology to preliminarily investigate the therapeutic effectiveness and mode of action of this medication.</p><p><strong>Methods: </strong>Using a bioinformatics approach, five target proteins with the strongest connections were selected for docking. Gene enrichment analysis was performed, and the ART target proteins were predicted. Various methods, including methyl thiazolyl tetrazolium (MTT) assays, colony formation assays, microsphere formation assays, flow cytometry, and western blotting analysis, were employed to assess the impact of ART on the malignant characteristics of lung cancer cells.</p><p><strong>Results: </strong>Bioinformatic analysis identified 51 ART target genes in lung adenocarcinoma for further analysis. Pathway enrichment analysis of target genes revealed 639 enriched Gene Ontology-Biological Process (GO BP) and 17 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. These findings imply that ART may control the IL-6 signaling pathway by focusing on important molecules such as CDK4 and IL-6. The ART-treated group experienced apoptosis induction, cell cycle arrest, and inhibition of cell proliferation and microsphere formation compared with the control group (p < 0.05, p < 0.01). Additionally, ART reduced the protein expression of CDK4, COX-2, ERBB2, CD44, and EpCAM while increasing that of caspase3, IL-6, P-53, and SRC (p < 0.01).</p><p><strong>Conclusion: </strong>ART inhibited the growth and stemness of HCC827 cells.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117226"},"PeriodicalIF":3.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955675","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, Yaofeng Zhao, Dingnian Gou, Pengtao Li, Hao Wang, Yanfang Li, Chenxi Li, Zhanyu Niu, Tong Yang, Lanxia Zhou, Shouliang Dong","doi":"10.1016/j.taap.2025.117225","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117225","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"117225"},"PeriodicalIF":3.3,"publicationDate":"2025-01-05","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":"The effects of UGT1A4 and ABCB1 polymorphisms on clozapine and N- desmethyl clozapine plasma levels in Turkish schizophrenia patients.","authors":"Fezile Ozdemir, Merve Demirbugen Oz, Kenan Can Tok, Emrah Dural, Yagmur Kır, Mehmet Gumustas, Bora Baskak, H Sinan Suzen","doi":"10.1016/j.taap.2024.117219","DOIUrl":"https://doi.org/10.1016/j.taap.2024.117219","url":null,"abstract":"<p><p>Clozapine (CLZ) is an antipsychotic which is particularly used in treatment resistant schizophrenia patients who do not respond to other agents. It is preferred because it reduces suicidal behaviours and attempts, reducing aggression and violent behaviour. The aim of the study is to evaluate the effects of ABCB1 rs1045642 and UGT1A4 rs2011425 polymorphisms on CLZ and its major metabolite N- desmethly clozapine (DCLZ) plasma concentrations in patients with schizophrenia. A total 109 of Turkish patients with schizophrenia on continually administered CLZ monotherapy were included. The plasma concentrations of CLZ and DCLZ were measured using an HPLC after liquid-liquid extraction while, transporter gene ABCB1 and phase two enzyme UGT1A4 polymorphisms were identified using PCR- RFLP method. Results showed that UGT1A4*3 polymorphism has statistically significant effects on CLZ C/D and DCLZ C/D levels in patients with sub/supra therapeutic levels while ABCB1 C3435T polymorphism has a significant effect on CLZ/DCLZ ratio among patients who have subtherapeutic levels. This study indicates the influence of genetic differences on plasma levels and highlights the importance of pharmacogenetic studies in clinic. Using the obtained results as pharmacogenetic biomarkers will help clinicians provide effective treatment in individual patients and reduce the undesirable side effects.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"117219"},"PeriodicalIF":3.3,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955563","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":"Investigating the anticancer properties of urolithin B in triple negative breast cancer: In vivo and in vitro insights.","authors":"Saeide Mansoori, Seyed Isaac Hashemy, Moein Eskandari, Azar Khorrami, Masoud Homayouni, Atefeh Ghahremanloo","doi":"10.1016/j.taap.2024.117224","DOIUrl":"https://doi.org/10.1016/j.taap.2024.117224","url":null,"abstract":"<p><p>Breast cancer (BC) is a leading cause of cancer-related mortality among women worldwide, with incidence rates rising globally. Urolithin B (UB), a bioactive metabolite of ellagic acid, has demonstrated promising anticancer effects in various cancer models. This study aimed to evaluate the effects of UB on the growth, angiogenesis, and metastasis of BC cells using both in vivo and in vitro approaches. Cytotoxic effects of UB were assessed on MDA-MB-231 cells and normal HFF cells using the MTT assay. Scratch assays and gelatin zymography demonstrated UB's suppression of cell migration and reduced enzymatic activities of MMP-2 and MMP-9. In a xenograft mouse model, UB significantly reduced tumor growth, enhanced necrosis, and decreased vascularity in tumor tissues. It downregulated mRNA expression levels of VEGF, VEGFR, MMP-2, and MMP-9, indicating potent anti-angiogenic and anti-metastatic properties. Additionally, UB exhibited antioxidant effects by increasing total thiol content and the activities of superoxide dismutase (SOD) and catalase (CAT) while reducing malondialdehyde (MDA) levels in tumor tissues. In conclusion, our results highlight the anticancer potential of UB, through its ability to suppress the proliferation, angiogenesis, and metastatic properties of BC both in vitro and in vivo. Coupled with its antioxidant properties, UB emerges as a promising and safe candidate for further pre-clinical and clinical research and therapeutic applications in BC management.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117224"},"PeriodicalIF":3.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928291","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":"PPARβ/δ agonist GW0742 mitigates acute liver damage induced by acetaminophen overdose in mice.","authors":"Lin Wang, Jing-Hui Chen, Yan-Jing Zhang, Ming-Bao Zhang, Tao Zeng","doi":"10.1016/j.taap.2024.117180","DOIUrl":"10.1016/j.taap.2024.117180","url":null,"abstract":"<p><p>Liver damage caused by acetaminophen (APAP) overdose remains a worldwide medical problem. New therapeutic medicines for APAP poisoning are needed as the efficacy of the only antidote, N-acetyl-cysteine (NAC), significantly decreases if administered after 8 h of APAP intake and massive APAP overdose remains to induce hepatotoxicity despite the timely administration of NAC. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) possesses versatile roles including regulation of lipid homeostasis and anti-inflammation in the liver. This study aimed to investigate the effects of GW0742, one specific PPARβ/δ agonist, on APAP-caused liver damage in mice. We found that GW0742 (40 mg/kg, i.p.) pretreatment completely blocked the increase of serum aminotransferase activities, hepatocyte necrosis, oxidative stress, and liver inflammation in mice exposed to 300 mg/kg APAP (i.p.). Mechanistically, GW0742 pretreatment significantly suppressed the M1 polarization of liver Kupffer cells and activation of NLRP3 inflammasome. Interestingly, GW0742 remained effective when administered 6 h after APAP exposure, although its efficacy was less pronounced than that administered 6 h before the APAP challenge. Notably, GW0742 exhibited a more profound effect than NAC evidenced by the lower serum alanine transaminase (ALT) level and the improved histopathological manifestation. Furthermore, exposure to APAP for 6 h had resulted in dramatic liver inflammation, while pretreatment with GW0742 prior to APAP exposure did not influence the increase in serum aminotransferase activity and oxidative stress at 2 h after APAP exposure. These results highlight that PPARβ/δ may be a promising therapeutic target for treating APAP-caused acute liver damage probably acting on liver macrophages.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"117180"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772649","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":"Salidroside exerts neuroprotective effects on retrograde neuronal death following neonatal axotomy via activation of PI3K/Akt pathway and deactivation of p38 MAPK pathway.","authors":"Shengtao Ji, Daiyue Chen, Fei Ding, Xiaosong Gu, Qiu Xue, Chun Zhou, Maohong Cao, Shu Yu","doi":"10.1016/j.taap.2024.117178","DOIUrl":"10.1016/j.taap.2024.117178","url":null,"abstract":"<p><p>Salidroside, a glucoside of tyrosol, is a powerful active ingredient extracted from the Chinese herb medicine Rhodiola rosea L.. As a neuroprotective agent, the application of salidroside in combination with neural tissue engineering has recently attracted much attention in peripheral nerve repair and reconstruction. However, the cellular and molecular mechanisms by which salidroside promotes nerve regeneration remain to be elucidated. We aim to evaluate the long-term neuroprotective potential of salidroside in an experimental rat model of neonatal sciatic nerve crush injury, with a focus on target-deprived neuronal death and the mechanisms involved. Behavioral analysis showed that salidroside dose-dependently improved voluntary hindlimb behavior and rod rotation ability following neonatal axotomy during an 8-week observation period. According to electrophysiology, Fluoro-Gold retrograde tracing, histological and immunohistochemical analyses, salidroside significantly improved nerve regeneration and reinnervation. Nissle and TUNEL staining, as well as caspase-3 activation assay indicated a beneficial effect of salidroside on retrograde loss and apoptosis of motoneurons within 2 weeks after axotomy. qPCR, ELISA and oxidative stress experiments revealed that salidroside improved the imbalance of spinal microenvironment, including oxidative stress and down-regulation of neurotrophic factors. Western blotting analysis showed that salidroside enhanced the activation of PI3K/Akt and inhibited the p38 MAPK signaling pathway following axotomy. The oxidative stress and axonal disconnection/regeneration models of primary motoneurons in vitro further confirmed the involvement of these two pathways in the neuroprotective effects of salidroside. These data provide a theoretical basis for the application of salidroside in peripheral nerve repair and reconstruction.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"117178"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772651","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":"Centromere protein K enhances the activation of YAP1/TAZ signal cascade to drive the progression of clear cell renal cell carcinoma.","authors":"Ning Nan","doi":"10.1016/j.taap.2024.117181","DOIUrl":"10.1016/j.taap.2024.117181","url":null,"abstract":"<p><p>Centromere protein K (CENPK) is a newly identified malignancy-related gene that exhibits differential expression in various cancers and plays a crucial role in carcinogenesis. However, it remains uncertain whether CENPK is involved in clear cell renal cell carcinoma (ccRCC). This work aimed to unveil the expression, clinical significance, biological functions, and regulatory mechanisms of CENPK in ccRCC. Through analysis of RNA-seq data obtained from TCGA, a high expression pattern of CENPK was identified in ccRCC, which was found to be associated with pathologic stage, histologic grade, and clinical outcome. The enrichment of CENPK in ccRCC was further verified through the analysis of clinical samples. By conducting cellular functional experiments, we showed an inhibitory effect of CENPK knockdown on the malignant behavior of ccRCC cells. GSEA revealed a close relationship between CENPK and the Hippo-YAP1/TAZ signal cascade. The following experiments demonstrated that the activation of YAP1/TAZ was strongly inhibited by CENPK knockdown, and this change was accompanied by a decrease in the levels of CTGF and CYR61. Blockade of the MST1/2-LATS1/2 axis reversed the suppressive impact of CENPK knockdown on YAP1/TAZ. The tumor-promoting impact observed upon CENPK overexpression was diminished in YAP1 knockout cells. Notably, ccRCC cells with reduced CENPK expression exhibited a diminished capability to form tumors in nude mice. This report highlights the importance of CENPK in ccRCC and sheds new light on the underlying mechanism of this cancer type. Therefore, CENPK has the potential to serve as a viable candidate target for treating ccRCC.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117181"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772647","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, Neven H Hassan, Ahmed M Hussien, Marwa A Ibrahim, Merhan E Ali","doi":"10.1016/j.taap.2024.117223","DOIUrl":"https://doi.org/10.1016/j.taap.2024.117223","url":null,"abstract":"<p><p>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 & 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 keap-1gene and downregulation of nuclear factor erythroid 2-related factor-2 (Nrf-2) and heme oxygenase-1 (HO-1) 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.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117223"},"PeriodicalIF":3.3,"publicationDate":"2024-12-30","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}