The anti-alcoholism drug disulfiram effectively ameliorates ulcerative colitis through suppressing oxidative stresses-associated pyroptotic cell death and cellular inflammation in colonic cells

Chi, Fengxu; Zhang, Guangquan; Ren, Niansheng; Zhang, Jian; Du, F.; Zheng, Xiyan; Zhang, Cong; Lin, Zhiqun; Li, Ruixi; Shi, Xiaorui; Zhu, Yuekun

doi:10.1016/j.intimp.2022.109117

Cited by 8 publications

(3 citation statements)

References 44 publications

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“…Disulfiram appeared to influence the reduction of malondialdehyde levels in the colonic tissues of rats with colitis. 56 , 57 This reduction might be linked to disulfiram’s function as an inhibitor of acetaldehyde dehydrogenase. 58 …”

Section: Discussionmentioning

confidence: 99%

“…Disulfiram appeared to influence the reduction of malondialdehyde levels in the colonic tissues of rats with colitis. 56,57 This reduction might be linked to disulfiram's function as an inhibitor of acetaldehyde dehydrogenase. 58 The sensitivity analysis further confirmed and strengthened our findings regarding the association of clopidogrel, glucosamine, fluticasone, and glyceryl trinitrate with a reduced risk of the study outcome.…”

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confidence: 99%

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Drug Repurposing in Crohn’s Disease Using Danish Real-World Data

Shakibfar,

Allin,

Jess

et al. 2024

POR

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Aim Drug repurposing, utilizing electronic healthcare records (EHRs), offers a promising alternative by repurposing existing drugs for new therapeutic indications, especially for patients lacking effective therapies. Intestinal fibrosis, a severe complication of Crohn’s disease (CD), poses significant challenges, increasing morbidity and mortality without available pharmacological treatments. This article focuses on identifying medications associated with an elevated or reduced risk of fibrosis in CD patients through a population-wide real-world data and artificial intelligence (AI) approach. Methods Patients aged 65 or older with a diagnosis of CD from 1996 to 2019 in the Danish EHRs were followed for up to 24 years. The primary outcome was the need of specific surgical procedures, namely proctocolectomy with ileostomy and ileocecal resection as proxies of intestinal fibrosis. The study explored drugs linked to an increased or reduced risk of the study outcome through machine-learning driven survival analysis. Results Among the 9179 CD patients, 1029 (11.2%) underwent surgery, primarily men (58.5%), with a mean age of 76 years, 10 drugs were linked to an elevated risk of surgery for proctocolectomy with ileostomy and ileocecal resection. In contrast, 10 drugs were associated with a reduced risk of undergoing surgery for these conditions. Conclusion This study focuses on repurposing existing drugs to prevent surgery related to intestinal fibrosis in CD patients, using Danish EHRs and advanced statistical methods. The findings offer valuable insights into potential treatments for this condition, addressing a critical unmet medical need. Further research and clinical trials are warranted to validate the effectiveness of these repurposed drugs in preventing surgery related to intestinal fibrosis in CD patients.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Drug Repurposing in Crohn’s Disease Using Danish Real-World Data

Shakibfar,

Allin,

Jess

et al. 2024

POR

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“…Inflammation and oxidative stress-induced cell death, including pyroptosis (Xie et al, 2020). Notably, inflammatory response and oxidative damage are important links in NLRP3mediated pyroptosis (Chi et al, 2022). There are increasing studies on pyroptosis in gastrointestinal diseases, and researchers are gradually realizing the particular connection between pyroptosis and UC (Zhang et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

The potential mechanism of huazhuojiedu decoction in the treatment of ulcerative colitis based on network pharmacology and experimental validation

Jia

Guo

et al. 2022

Front. Pharmacol.

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Huazhuojiedu decoction (HZJDD), a traditional Chinese medicine prescription, has been clinically proven to be an effective treatment for ulcerative colitis (UC). However, the mechanism of HZJDD in the treatment of UC remains unclear. This study combined network pharmacology with experimental validation to explore the potential mechanism of HZJDD on UC. First, the relationship network diagrams between HZJDD and UC were established based on multiple databases. Then, the HZJDD-UC intersection genes target network was constructed and Gene Ontology-Biological processes (GO-BP) analysis was performed to discover the potential pharmacological mechanism. Finally, the results of GO-BP were verified in dextran sulfate sodium salt (DSS) induced UC rats. The network pharmacology results showed that 119 active components and 146 potential targets were screened for HZJDD, and six of the top 15 biological processes belonged to inflammatory response, cellular response to hypoxia, and cellular response to lipopolysaccharide (LPS). The GO-BP results indicated that the mechanism of HZJDD treatment of UC was related to inflammation, oxidative stress, and the regulation of LPS. Animal experiments showed that HZJDD could significantly reduce the disease activity index (DAI) score, improve colon length, and effectively repair the histomorphological and micromorphological changes in DSS-induced UC rats. Moreover, HZJDD reduced the expressions of CRP, TNF-α, IL-6, LPS, IL-1β, and IL-18; downregulated the activity of MDA; and upregulated the activities of CAT, GSH, and SOD in DSS-induced UC rats. Furthermore, HZJDD suppressed the expression of the NLRP3/caspase-1 signaling pathway at the gene and protein levels to inhibit pyroptosis. Network pharmacology and animal experiments showed that HZJDD exerted a therapeutic effect on DSS-induced UC rats by reducing inflammation, oxidative stress, and restraining the NLRP3/caspase-1 signaling pathway to inhibit pyroptosis.

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Targeting programmed cell death in inflammatory bowel disease through natural products: New insights from molecular mechanisms to targeted therapies

Wang,

et al. 2024

Phytotherapy Research

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Inflammatory bowel disease (IBD) is an autoimmune disorder primarily characterized by intestinal inflammation and recurrent ulceration, leading to a compromised intestinal barrier and inflammatory infiltration. This disorder's pathogenesis is mainly attributed to extensive damage or death of intestinal epithelial cells, along with abnormal activation or impaired death regulation of immune cells and the release of various inflammatory factors, which contribute to the inflammatory environment in the intestines. Thus, maintaining intestinal homeostasis hinges on balancing the survival and functionality of various cell types. Programmed cell death (PCD) pathways, including apoptosis, pyroptosis, autophagy, ferroptosis, necroptosis, and neutrophil extracellular traps, are integral in the pathogenesis of IBD by mediating the death of intestinal epithelial and immune cells. Natural products derived from plants, fruits, and vegetables have shown potential in regulating PCD, offering preventive and therapeutic avenues for IBD. This article reviews the role of natural products in IBD treatment by focusing on targeting PCD pathways, opening new avenues for clinical IBD management.

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The anti-alcoholism drug disulfiram effectively ameliorates ulcerative colitis through suppressing oxidative stresses-associated pyroptotic cell death and cellular inflammation in colonic cells

Cited by 8 publications

References 44 publications

Drug Repurposing in Crohn’s Disease Using Danish Real-World Data

Drug Repurposing in Crohn’s Disease Using Danish Real-World Data

The potential mechanism of huazhuojiedu decoction in the treatment of ulcerative colitis based on network pharmacology and experimental validation

Targeting programmed cell death in inflammatory bowel disease through natural products: New insights from molecular mechanisms to targeted therapies

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