A Novel Combination Therapy Using Rosuvastatin and Lactobacillus Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition.

Inflammasome targeting and controlling dysbiosis are promising therapeutic approaches to control ulcerative colitis. This report is the first to investigate the mechanisms underlying the coloprotective effects of rosuvastatin and Lactobacillus and their combined therapy on dextran sodium sulfate (DSS)-induced colitis in high-fat diet (HFD)-fed rats. Our results demonstrate the aggravation of intestinal inflammation as a consequence of an HFD following DSS administration. An association between dyslipidemia, LDL oxidation, CD36 expression, ROS generation, thioredoxin-interacting protein (TXNIP) upregulation, and NLRP3 inflammasome activation was demonstrated by DSS exposure in HFD-fed rats. We demonstrated that rosuvastatin/Lactobacillus significantly suppressed the DSS/HFD-induced increase in colon weight/length ratio, DAI, MDI, and myeloperoxidase, as well as corrected dysbiosis and improved histological characteristics. Additionally, caspase-1 activity and IL-1ß-driven pyroptotic activity was significantly reduced. Rosuvastatin/Lactobacillus showed prominent anti-inflammatory effects as revealed by the IL-10/IL-12 ratio and the levels of TNF-α and IL-6. These latter effects may be attributed to the inhibition of phosphorylation-induced activation of NF-κB and a concomitant reduction in the expression of NLRP3, pro-IL-1ß, and pro-IL-18. Furthermore, rosuvastatin/Lactobacillus reduced Ox-LDL-induced TXNIP and attenuated the inflammatory response by inhibiting NLRP3 inflammasome assembly. To conclude, rosuvastatin/Lactobacillus offers a safe and effective strategy for the management of ulcerative colitis.

Arsenic trioxide and curcumin attenuate cisplatin-induced renal fibrosis in rats through targeting Hedgehog signaling.

Renal fibrosis is a progressive process resulting from a sustained injury that may ultimately cause renal failure. Cisplatin is an antitumor drug that induces renal injury and nephrotoxicity and is widely employed as a model for acute and chronic renal injury. Several signaling pathways are implicated in fibrogenic cell activation among which is Hedgehog (Hh) signaling. We here investigated the effects of arsenic trioxide (Ars) and curcumin in ameliorating cisplatin-induced kidney fibrosis via regulating Hh signaling. Cisplatin (4.5 mg/kg) was administered in Sprague-Dawley rats for two consecutive days and renal fibrosis was induced after 21 days. Once renal fibrosis was confirmed, Ars (3.5 mg/kg/day, orally) and curcumin (200 mg/kg/day, orally) were administered daily for another 21 days. Ars and curcumin corrected kidney function markers as creatinine clearance and urea nitrogen. Both agents ameliorated fibrosis as shown by lowered TGF-ß1 mRNA levels, α-SMA protein levels, and hydroxylproline content. Cisplatin-activated Hh signaling which was blocked by both Ars and curcumin as demonstrated by decreased mRNA levels of Shh, Smo, and Ptch and suppressed renal Gli1 and Gli2 protein levels. Our results indicate new therapeutic roles for Ars and curcumin and suggest that blocking Hh signaling may be a promising approach for alleviating renal fibrosis. Symbols indicate α-SMA, alpha-smooth muscle actin; TGF-ß, transforming growth factor-beta; Ptch, patched; Smo, smoothened; Shh, sonic hedgehog; Ihh, Indian hedgehog; Dhh, desert hedgehog; and SUFU, suppressor of fused.