{"title":"Demethylzeylasteral alleviates inflammation and colitis via dual suppression of NF-κB and STAT3/5 by targeting IKKα/β and JAK2.","authors":"Tian Wen, Ting Liu, Hongqing Chen, Qi Liu, Xiaofei Shen, Qiongying Hu","doi":"10.1016/j.intimp.2024.113260","DOIUrl":"10.1016/j.intimp.2024.113260","url":null,"abstract":"<p><strong>Background: </strong>Ulcerative colitis (UC) is a common inflammatory bowel disease and a risk factor of colorectal cancer. Demethylzeylasteral (DZT), a bioactive component mainly isolated from Tripterygium wilfordii, has been shown to inhibit inflammation and cancer. However, its anti-UC function and molecular mechanisms have not been well characterized. This study aims to explore the therapeutic effect and functional targets of demethylzeylasteral against UC.</p><p><strong>Methods: </strong>RT-qPCR, Western blot and ELISA were used to detect the generation of pro-inflammatory cytokines and chemokines in murine macrophage cells. Luciferase reporter gene, Western blot, pull-down, CETSA, DARTS, and virtual docking were employed to detect the anti-inflammatory targets and molecular mechanisms of demethylzeylasteral. The anti-inflammatory and anti-colitis effects of demethylzeylasteral were further determined in DSS-challenged mice.</p><p><strong>Results: </strong>In vitro, demethylzeylasteral inhibited NO and PGE<sub>2</sub> production by suppressing the mRNA and protein expression of iNOS and COX-2, and suppressed the mRNA expression of TNF-α, IL-1β, IL-6, MCP-1, CXCL9, and CXCL10 in RAW264.7 macrophages stimulated by LPS/IFNγ. Furthermore, demethylzeylasteral was not only capable of inhibiting IKKα/β-NF-κB activation, but also able to block JAKs-STAT3/5 activation in LPS/INFγ-incubated RAW264.7 cells or DSS-exposed colon tissues of mice. Mechanistically, demethylzeylasteral was found to directly bind to IKKα/β and JAK2 kinases, leading to inactivation of pro-inflammatory signaling cascades and reduced generation of cytokines and chemokines. In vivo, oral administration of demethylzeylasteral significantly attenuated DSS-induced colitis, which was mainly manifested as mitigated symptoms of colitis, colonic mucosal barrier damage, and colonic inflammation.</p><p><strong>Conclusion: </strong>We demonstrated that demethylzeylasteral alleviated UC pathology by blocking NF-κB and STAT3/5 pathways via targeting IKKα/β and JAK2 kinases, raising the possibility that demethylzeylasteral could act as a candidate for the treatment of UC.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"142 Pt B","pages":"113260"},"PeriodicalIF":4.8,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ronghao Zou, Juan Lu, Xiaoyue Bai, Yuyao Yang, Shouyue Zhang, Shuai Wu, Zhixin Tang, Kang Li, Xiaohui Hua
{"title":"The epigenetic-modified downregulation of LOXL1 protein mediates EMT in bladder epithelial cells exposed to benzo[a]pyrene and its metabolite BPDE.","authors":"Ronghao Zou, Juan Lu, Xiaoyue Bai, Yuyao Yang, Shouyue Zhang, Shuai Wu, Zhixin Tang, Kang Li, Xiaohui Hua","doi":"10.1016/j.intimp.2024.113232","DOIUrl":"10.1016/j.intimp.2024.113232","url":null,"abstract":"<p><p>Benzo[a]pyrene (B[a]P) is a well-known polycyclic aromatic hydrocarbon (PAH) pollutant with high carcinogenicity, widespread environmental presence, and significant threat to public health. Epidemiological studies have linked exposure to B[a]P and its metabolite 7,8-dihydroxy-9,10-epoxybenzo[a]pyrene (BPDE) to the development and progression of various cancers, including bladder cancer. However, its underlying mechanism remains unclear. Our study revealed that B[a]P and BPDE induced epithelial-mesenchymal transition (EMT), a critical early event in cell malignant transformation, involving a decrease in E-Cadherin and upregulation of N-Cadherin protein levels, leading to increased cell motility and migration in bladder epithelial cells. Further studies have indicated that LOXL1 DNA undergoes methylation and modification influenced by methyltransferase 3a (DNMT3a) and DNMT3b, resulting in decreased LOXL1 protein levels. The decreased LOXL1 promotes the zinc finger transcription factor SLUG, which then inhibits E-Cadherin protein levels and initiates the EMT process. Moreover, DNMT3a/3b expression appears to be influenced by intracellular oxidative stress levels. These findings suggest that exposure to B[a]P/BPDE promotes the EMT process through the pivotal factor LOXL1, thereby contributing to bladder carcinogenesis. Our study provides a theoretical basis for considering LOXL1 as a potential biomarker for early diagnosis and a novel target for the precise diagnosis and treatment of bladder cancer.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"142 Pt B","pages":"113232"},"PeriodicalIF":4.8,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mehrdad Fathi, Simin Bahmanpour, Asal Barshidi, Hossein Rasouli, Fariba Karoon Kiani, Armin Mahmoud Salehi Khesht, Sepideh Izadi, Bentolhoda Rashidi, Shiva Kermanpour, Roya Mokhtarian, Vahid Karpisheh, Hadi Hassannia, Hamed Mohammadi, Ali Jalili, Farhad Jadidi-Niaragh
{"title":"Corrigendum to \"Simultaneous blockade of TIGIT and HIF-1α induces synergistic anti-tumor effect and decreases the growth and development of cancer cells\" [Int. Immunopharmacol. 101 (2021) 108288].","authors":"Mehrdad Fathi, Simin Bahmanpour, Asal Barshidi, Hossein Rasouli, Fariba Karoon Kiani, Armin Mahmoud Salehi Khesht, Sepideh Izadi, Bentolhoda Rashidi, Shiva Kermanpour, Roya Mokhtarian, Vahid Karpisheh, Hadi Hassannia, Hamed Mohammadi, Ali Jalili, Farhad Jadidi-Niaragh","doi":"10.1016/j.intimp.2024.113118","DOIUrl":"10.1016/j.intimp.2024.113118","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":" ","pages":"113118"},"PeriodicalIF":4.8,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142286378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eman Mohamed Faruk, Fatma Ibrahim, Dalia Ibrahim El-Wafaey, Yasmeen Mohammed Ismail El Sayed, Mohamed Ghazy Attia Hablas, Mahmoud M Hassan, Ahmed Mohammed Zaazaa, Kamal M Kamal
{"title":"Corrigendum to \"Spirulina platensis shields the submandibular gland from cadmium toxicity by bolstering antioxidant defenses and maintaining its structural integrity\" [Int. Immunopharmacol. 25 (2024) 112851].","authors":"Eman Mohamed Faruk, Fatma Ibrahim, Dalia Ibrahim El-Wafaey, Yasmeen Mohammed Ismail El Sayed, Mohamed Ghazy Attia Hablas, Mahmoud M Hassan, Ahmed Mohammed Zaazaa, Kamal M Kamal","doi":"10.1016/j.intimp.2024.113093","DOIUrl":"10.1016/j.intimp.2024.113093","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":" ","pages":"113093"},"PeriodicalIF":4.8,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142286379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}