Combining the HSP90 inhibitor TAS-116 with metformin effectively degrades the NLRP3 and attenuates inflammasome activation in rats: A new management paradigm for ulcerative colitis.

Ulcerative colitis (UC) is a prevalent type of inflammatory bowel diseases that may predispose patients to acquire colitis-related cancer if treatment was not effective. Despite the presence of an array of established treatment options, current modalities are not successful for a substanial number of patients. The activation of the NLRP3 inflammasome is critical in the development of inflammatory processes in the colon. Additionally, the regulation of NLRP3 via HSP90 inhibition is a potential target to treat UC. Moreover, during inflammation, autophagy allows the turnover of malfunctioning proteins and therefore stands as a viable strategy for inactivating NLRP3 inflammasomes and halting hyperinflammation. Herein, we evaluated the effect of autophagy induction using metformin in the context of HSP90 inhibition by TAS-116 in the dextran sodium sulfate (DSS)-induced UC in rats. We revealed that TAS-116-induced interruption of the protein complex containing HSP90 and NLRP3 might hamper and delay the start of the inflammatory cascade ensued by the NLRP3 inflammasome oligomerization. In such circumstances, the unprotected NLRP3 is subjected to autophagic degradation in an environment of metformin-promoted autophagic signaling. As a result, such dynamic synergy was efficient in combating colon damage and immune-cell infiltration. This was confirmed by the macroscopic and microscopic investigations. Further, biochemical analysis revealed subdued inflammation cascade and oxidative injury. Therefore, simultaneous administration of TAS-116 and metformin is a new management paradigm aimed at inducing malfunction in the NLRP3 followed by augmenting its autophagic degradation, respectively. However, further studies should be conducted to assess the reliability and consistency of this novel approach.

Shaaban AA ，Abdelhamid AM ，Shaker ME ，Cavalu S ，Maghiar AM ，Alsayegh AA ，Babalghith AO ，El-Ahwany E ，Amin NA ，Mohammed OA ，Eissa H ，Gaafar AGA ，Batiha GE ，Saber S ... -  《-》

Novel complementary coloprotective effects of metformin and MCC950 by modulating HSP90/NLRP3 interaction and inducing autophagy in rats.

Saber S ，El-Kader EMA 《-》

Oroxindin inhibits macrophage NLRP3 inflammasome activation in DSS-induced ulcerative colitis in mice via suppressing TXNIP-dependent NF-κB pathway.

Liu Q ，Zuo R ，Wang K ，Nong FF ，Fu YJ ，Huang SW ，Pan ZF ，Zhang Y ，Luo X ，Deng XL ，Zhang XX ，Zhou L ，Chen Y ... -  《-》

Roseburia intestinalis‑derived flagellin ameliorates colitis by targeting miR‑223‑3p‑mediated activation of NLRP3 inflammasome and pyroptosis.

Wu X ，Pan S ，Luo W ，Shen Z ，Meng X ，Xiao M ，Tan B ，Nie K ，Tong T ，Wang X ... -  《-》

Sanguinarine ameliorates DSS induced ulcerative colitis by inhibiting NLRP3 inflammasome activation and modulating intestinal microbiota in C57BL/6 mice.

Sanguinarine (SAN) is an important natural anti-inflammatory constitutes and dietary supplementation with SAN could improve the relative length of the intestine, alter gut microbiota, and enhance growth performance of pigs, broiler chickens, and cattle. However, it is unclear whether it has the therapeutic effect on ulcerative colitis (UC). This study aimed to investigate the therapeutic effect of SAN on UC and explore its mechanisms of action. Several efficacy indexes of SAN on dextran sulfate sodium (DSS)-induced C57BL/6 mice were evaluated. ELISA kit and western blot analysis were used to evaluate it's anti-inflammatory effect and the mechanism of action. 16S rDNA sequencing detection was used to determine the impact of SAN on gut microbiota. SAN and Sulfasalazine could significantly improve the colon length, the weight loss, the symptoms and the pathological injury of colon in DSS-induced mice. Meanwhile, SAN could decrease the levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-13 and IL-18) and increase the levels of anti-inflammatory cytokines (IL-4 and IL-10) in colon, and suppress DSS-induced high expressions of NLRP3, caspase-1 and IL-1β. In addition, SAN (0.5, 1 μM) could inhibit the expression level of NLRP3 and the activation of caspase-1 and IL-1β in lipopolysaccharide-stimulated THP-1 cells in non-cytotoxic doses, which was similar to that of MCC950, a specific inhibitor of NLRP3 inflammasome activation. The abundance changes of many genera such as Muribaculaceae_unclassified, Escherichia-Shigella, Lachnospiraceae_NK4A136_group and Helicobacter were also closely related to the improvement of SAN on intestinal inflammatory response. SAN exhibited therapeutic effect on DSS-induced colitis by blocking NLRP3-(Caspase-1)/IL-1β pathway and improving intestinal microbial dysbiosis. SAN might be developed to treat UC and other disorders associated with microbial dysbiosis.

Li X ，Wu X ，Wang Q ，Xu W ，Zhao Q ，Xu N ，Hu X ，Ye Z ，Yu S ，Liu J ，He X ，Shi F ，Zhang Q ，Li W ... -  《-》