Poly(ADP‑ribose) polymerase‑1 inhibitor ameliorates dextran sulfate sodium‑induced colitis in mice by regulating the balance of Th17/Treg cells and inhibiting the NF‑κB signaling pathway

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a critical role in inflammatory pathways. The PARP-1 inhibitor, 5-aminoisoquinolinone (5-AIQ), has been demonstrated to exert significant pharmacological effects. The present study aimed to further examine the potential mechanisms of 5-AIQ in a mouse model of dextran sodium sulfate (DSS)-induced colitis. Colitis conditions were assessed by changes in weight, disease activity index, colon length, histopathology and pro-inflammatory mediators. The colonic expression of PARP/NF-κB and STAT3 pathway components was measured by western blot analysis. Flow cytometry was used to analyze the proportion of T helper 17 cells (Th17) and regulatory T cells (Tregs) in the spleen. Western blot analysis and reverse transcription-quantitative PCR were employed to determine the expression of the transcription factors retinoic acid-related orphan receptor and forkhead box protein P3. The results demonstrated that 5-AIQ reduced tissue damage and the inflammatory response in mice with experimental colitis. Moreover, 5-AIQ increased the proportion of Treg cells and decreased the percentage of Th17 cells in the spleen. Furthermore, following 5-AIQ treatment, the main components of the PARP/NF-κB and STAT3 pathways were downregulated. Collectively, these results demonstrate that the PARP-1 inhibitor, 5-AIQ, may suppress intestinal inflammation and protect the colonic mucosa by modulating Treg/Th17 immune balance and inhibiting PARP-1/NF-κB and STAT3 signaling pathways in mice with experimental colitis.

Olaparib: A Clinically Applied PARP Inhibitor Protects from Experimental Crohn’s Disease and Maintains Barrier Integrity by Improving Bioenergetics through Rescuing Glycolysis in Colonic Epithelial Cells

“…PARP-1 has been long involved in cancer development and inflammation. Accordingly, PARP-1 −/− mice were protected in 2,4,6-trinitrobenzene sulphonic acid- (TNBS-) induced colitis [ 26 ] and pharmacological inhibitors of PARP-1 improved dextran sodium sulfate-induced [ 27 ] and TNBS-induced colitis [ 28 ] in rodents. PARP-1 is activated by DNA damage and catalyzes polyADP-ribosylation (PARylation) of numerous nuclear proteins using NAD + as a substrate [ 29 ].…”

Stanniocalcin‐1 Promotes PARP1‐Dependent Cell Death via JNK Activation in Colitis

“…These results were concordant with the anti‐inflammatory effect of PARP inhibitors in mouse models of colitis, suggesting that PARP inhibitors might be used in the treatment of inflammatory diseases. [ 26 , 27 ] Therefore, we anticipate the application of PARP inhibitors being applied in other non‐oncological diseases, particularly CD.…”

“…[25] Furthermore, Parp1 inhibition markedly alleviates colonic inflammation and protects the intestinal barrier in dextran sulfate sodium (DSS)-induced and interleukin (IL)−10-deficient spontaneous mouse models of colitis. [26,27] Based on existing evidence, the functions of STC1 and PARP1 in the CD pathogenesis remain unclear. Thus, in the current study, we investigate whether parthanatos contribute to the pathogenesis of oxidative damage in CD.…”

“…[ 25 ] Furthermore, Parp1 inhibition markedly alleviates colonic inflammation and protects the intestinal barrier in dextran sulfate sodium (DSS)‐induced and interleukin (IL)−10‐deficient spontaneous mouse models of colitis. [ 26 , 27 ]…”

Research progress of phenolic compounds regulating IL‐6 to exert antitumor effects

“…Inflammation is an important risk factor for the development and progression of cancer, including cancer of the respiratory system, cancer of the digestive system, etc (Cui et al, 2019). The role of IL-6 and STAT3 signaling in inflammation and cancer has long been established (Jung et al, 2019;Peng, Shen, Tian, Li, & Wang, 2021).IL-6 is produced during both acute and chronic inflammation, significantly higher than levels found in normal human tissues. Zheng et al (2018)'s cell and mouse experiments show that silybin reduced levels of inflammatory cytokines, including IL-6, TNF-α, and IL-1β, in inflammationassociated enteritis (CAC).…”