Nicardipine-chitosan nanoparticles alleviate thioacetamide-induced acute liver injury by targeting NFκB/NLRP3/IL-1ß signaling in rats: Unraveling new roles beyond calcium channel blocking.

Liver inflammatory diseases are marked by serious complications. Notably, nicardipine (NCD) has demonstrated anti-inflammatory properties, but its benefits in liver inflammation have not been studied yet. However, the therapeutic efficacy of NCD is limited by its short half-life and low bioavailability. Therefore, we aimed to evaluate the potential of NCD-loaded chitosan nanoparticles (ChNPs) to improve its pharmacokinetic profile and hepatic accumulation. Four formulations of NCD-ChNPs were synthesized and characterized. The optimal formulation (NP2) exhibited a mean particle diameter of 172.6 ± 1.94 nm, a surface charge of +25.66 ± 0.93 mV, and an encapsulation efficiency of 88.86 ± 1.17 %. NP2 showed good physical stability as a lyophilized powder over three months. It displayed pH-sensitive release characteristics, releasing 77.15 ± 5.09 % of NCD at pH 6 (mimicking the inflammatory microenvironment) and 52.15 ± 3.65 % at pH 7.4, indicating targeted release in inflamed liver tissues. Pharmacokinetic and biodistribution studies revealed that NCD-ChNPs significantly prolonged NCD circulation time and enhanced its concentration in liver tissues compared to plain NCD. Additionally, the study investigated the protective effects of NCD-ChNPs in thioacetamide-induced liver injury in rats by modulating the NFκB/NLRP3/IL-1ß signaling axis. NCD-ChNPs effectively inhibited NFκB activation, reduced NLRP3 inflammasome activation, and subsequent release of IL-1ß, which correlated with improved hepatic function and reduced inflammation and oxidative stress. These findings highlight the potential of NCD-ChNPs as a promising nanomedicine strategy for the treatment of liver inflammatory diseases, warranting further investigation into their clinical applications, particularly in hypertensive patients with liver inflammatory conditions.

Innovative challenge for the inhibition of hepatocellular carcinoma progression by combined targeting of HSP90 and STAT3/HIF-1α signaling.

Hepatocellular carcinoma (HCC) is the third foremost cause of cancer-related deaths. HCC has a very bad prognosis because it is asymptomatic in the early stages, resulting in a late diagnosis, and it is highly resistant to conventional chemotherapy. Such chemotherapies have been proven disappointing because they provide extremely low survival benefits. This study discloses that the STAT3/HIF-1α is an auspicious therapeutic attack site for conceivable repression of HCC development. A site that can be targeted by simultaneous administration of a STAT3 inhibitor in the context of HSP90 inhibition. 17-DMAG binds to HSP90 and constrains its function, resulting in the degradation of HSP90 client proteins HIF-1α and STAT3. Hypoxia recruits STAT3/HIF-1α complex within the VEGF promoter. Additionally, it was acknowledged that STAT3 is an essential mediator of VEGF transcription by direct binding to its promoter. Furthermore, it induces HIF-1α stability and enhances its transcriptional activity. Herein, we revealed that the combination therapy using 17-DMAG and nifuroxazide, a STAT3 inhibitor, repressed the diethylnitrosamine-induced alterations in the structure of the liver. This effect was mediated via decreasing the levels of the HSP90 client proteins HIF-1α and pSTAT3 resulting in the suppression of the STAT3/HIF-1α complex transcriptional activity. To conclude, 17-DMAG/NFXZD combination therapy-induced disruption in the STAT3/HIF-1α loop led to a potential antiangiogenic activity and showed apoptotic potential by inhibiting autophagy and inducing ROS/apoptosis signaling. Additionally, this combination therapy exhibited promising survival prolongation in mice with HCC. Consequently, the use of 17-DMAG/NFXZD renders an inspirational perspective in managing HCC. However, further investigations are compulsory.

Diacetylrhein, an anthraquinone antiarthritic agent, suppresses dextran sodium sulfate-induced inflammation in rats: A possible mechanism for a protective effect against ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory life-threatening and premalignant disorder with no cure that even might end up with surgical removal of a large section or even all of the colon. It is characterized by relapsing-remitting courses of intestinal inflammation and mucosal damage in which oxidative stress and exaggerated inflammatory response play a significant role. Most of the current medications to maintain remission are symptomatic and have many adverse reactions. Therefore, the potential for improved management of patients with UC continues to increase. Yet, the benefits of using the antiarthritic agent diacetylrhein to counteract inflammation in UC are still obscure. Hence, our study was designed to explore its potential role in UC using a model of dextran sodium sulfate-induced acute colitis in rats. Our results revealed that diacetylrhein targeted the NLRP3 and inhibited the inflammasome assembly. Consequently, caspase-1 activity and the inflammatory cytokines IL-1ß and IL-18 were inhibited leading to a curbed pyroptosis process. Additionally, diacetylrhein revealed a significant antiapoptotic potential as revealed by the levels of pro-apoptotic and anti-apoptotic proteins. Concomitant to these effects, diacetylrhein also interrupted NFκB signals leading to improved microscopic features of inflamed colon and decreased colon weight to length ratio, indices of disease activity, and macroscopic damage. Additionally, a reduction in the myeloperoxidase activity, IL-6, and TGF-ß alongside an increase in the gene expression of Ocln and ZO-1 were detected. To conclude diacetylrhein showed a significant antioxidant and anti-inflammatory potential and therefore might represent a promising agent in the management of acute UC.

Pimitespib, an HSP90 inhibitor, augments nifuroxazide-induced disruption in the IL-6/STAT3/HIF-1α autocrine loop in rats with bleomycin-challenged lungs: Evolutionary perspective in managing pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a fatal lung disorder in which the etiology and pathogenesis are still unobvious. Effective treatments are urgently needed considering that lung transplantation is the only treatment that could improve outcomes. This study aimed to investigate the therapeutic significance of the dual administration of pimitespib, an HSP90 inhibitor, and nifuroxazide, a STAT3 inhibitor, against bleomycin-induced pulmonary fibrosis in rats. Our results revealed that pimitespib/nifuroxazide inhibited bleomycin-induced alterations in the structure and the function of the lungs. They demonstrated significant decreases in the BALF total and differential cell counts, LDH activity, and total protein. Concurrently, there was a reduction in the accumulation of collagen as proved by decreased hydroxyproline and the gene expression of COL1A1 accompanied by lower levels of PDGF-BB, TIMP-1, and TGF-ß. The levels of IL-6 were also downregulated. Pimitespib-induced inhibition of HSP90 led to subsequent inhibition of HIF-1α and STAT3 client proteins since the closed HSP90 would not enclose its client proteins. Therefore, pimitespib resulted in the repression of HIF-1α/CREB-p300 HAT as well as the STAT3/CREB-p300 HAT nuclear interactions. On the other hand, nifuroxazide resulted in a notable decline in pSTAT3 and HIF-1α levels. Subsequently, the combined effects of both drugs led to a substantial reduction in ECM deposition. Herein, pimitespib augmented nifuroxazide-induced disruption in the IL-6/STAT3/HIF-1α autocrine loop. Our findings also disclose that this novel loop is a promising therapeutic attack site for possible pulmonary fibrosis repression studies. Therefore, the use of pimitespib/nifuroxazide embodies an evolutionary perspective in managing pulmonary fibrosis.