Gaber F. Ali, Emad H. M. Hassanein, Mustafa Ahmed Abdel-Reheim, El-shaimaa A. Arafa, Wafaa R. Mohamed
{"title":"IL-6/JAK/STAT3/SOCS3、SIRT1和细胞红蛋白信号参与双乙酰甲氨蝶呤对肠道损伤的保护作用","authors":"Gaber F. Ali, Emad H. M. Hassanein, Mustafa Ahmed Abdel-Reheim, El-shaimaa A. Arafa, Wafaa R. Mohamed","doi":"10.1002/jbt.70339","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Despite its wide applications, methotrexate (MTX) causes significant intestinal toxicity by inducing oxidative stress, inflammatory cascades, and apoptosis. Diacerein (DIA) is a pain-relieving and anti-inflammatory medication with favorable antioxidant properties. We investigated DIA protective effects on MTX-induced intestinal toxicity. Rats were divided into five groups: Control, DIA (50 mg/kg), MTX (single dose of 20 mg/kg; i.p. on 5th day), DIA (25 mg/kg) + MTX, and DIA (50 mg/kg) + MTX. Compared to the MTX-treated group, DIA alleviated MTX-induced intestinal histopathological abrasions and inflammatory cell infiltration, improving average villous length and crypt depth. Furthermore, DIA exhibited potent antioxidative properties, evident by decreasing lipid peroxidation and increasing SOD activity and GSH content, and upregulating the expression of SIRT1 and cytoglobin. In addition, DIA ameliorated MTX-induced intestinal inflammation demonstrated by decreasing IL-6 and TNF-α mediated via suppressing NF-κBp65, phosphorylation of JAK1/STAT3, and upregulation of SOCS3 expression compared to the MTX-treated group. Furthermore, DIA inhibited intestinal apoptotic alterations by reducing cleaved caspase-3 protein expression. These results suggest that DIA, in a dose-dependent manner, could be an effective treatment for reducing intestinal toxicity by MTX via exerting an antioxidant effect, anti-inflammatory properties, and antiapoptotic activity with possible involvement of NF-κBp65, IL-6/JAK1/STAT3/SOCS3, SIRT1, and cytoglobin signaling.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 6","pages":""},"PeriodicalIF":3.2000,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Involvement of IL-6/JAK/STAT3/SOCS3, SIRT1, and Cytoglobin Signaling in Diacerein Protective Effect against Intestinal Injury Induced by Methotrexate\",\"authors\":\"Gaber F. Ali, Emad H. M. Hassanein, Mustafa Ahmed Abdel-Reheim, El-shaimaa A. Arafa, Wafaa R. Mohamed\",\"doi\":\"10.1002/jbt.70339\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>Despite its wide applications, methotrexate (MTX) causes significant intestinal toxicity by inducing oxidative stress, inflammatory cascades, and apoptosis. Diacerein (DIA) is a pain-relieving and anti-inflammatory medication with favorable antioxidant properties. We investigated DIA protective effects on MTX-induced intestinal toxicity. Rats were divided into five groups: Control, DIA (50 mg/kg), MTX (single dose of 20 mg/kg; i.p. on 5th day), DIA (25 mg/kg) + MTX, and DIA (50 mg/kg) + MTX. Compared to the MTX-treated group, DIA alleviated MTX-induced intestinal histopathological abrasions and inflammatory cell infiltration, improving average villous length and crypt depth. Furthermore, DIA exhibited potent antioxidative properties, evident by decreasing lipid peroxidation and increasing SOD activity and GSH content, and upregulating the expression of SIRT1 and cytoglobin. In addition, DIA ameliorated MTX-induced intestinal inflammation demonstrated by decreasing IL-6 and TNF-α mediated via suppressing NF-κBp65, phosphorylation of JAK1/STAT3, and upregulation of SOCS3 expression compared to the MTX-treated group. Furthermore, DIA inhibited intestinal apoptotic alterations by reducing cleaved caspase-3 protein expression. 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Involvement of IL-6/JAK/STAT3/SOCS3, SIRT1, and Cytoglobin Signaling in Diacerein Protective Effect against Intestinal Injury Induced by Methotrexate
Despite its wide applications, methotrexate (MTX) causes significant intestinal toxicity by inducing oxidative stress, inflammatory cascades, and apoptosis. Diacerein (DIA) is a pain-relieving and anti-inflammatory medication with favorable antioxidant properties. We investigated DIA protective effects on MTX-induced intestinal toxicity. Rats were divided into five groups: Control, DIA (50 mg/kg), MTX (single dose of 20 mg/kg; i.p. on 5th day), DIA (25 mg/kg) + MTX, and DIA (50 mg/kg) + MTX. Compared to the MTX-treated group, DIA alleviated MTX-induced intestinal histopathological abrasions and inflammatory cell infiltration, improving average villous length and crypt depth. Furthermore, DIA exhibited potent antioxidative properties, evident by decreasing lipid peroxidation and increasing SOD activity and GSH content, and upregulating the expression of SIRT1 and cytoglobin. In addition, DIA ameliorated MTX-induced intestinal inflammation demonstrated by decreasing IL-6 and TNF-α mediated via suppressing NF-κBp65, phosphorylation of JAK1/STAT3, and upregulation of SOCS3 expression compared to the MTX-treated group. Furthermore, DIA inhibited intestinal apoptotic alterations by reducing cleaved caspase-3 protein expression. These results suggest that DIA, in a dose-dependent manner, could be an effective treatment for reducing intestinal toxicity by MTX via exerting an antioxidant effect, anti-inflammatory properties, and antiapoptotic activity with possible involvement of NF-κBp65, IL-6/JAK1/STAT3/SOCS3, SIRT1, and cytoglobin signaling.
期刊介绍：
The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.
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