miR-381-3p knockdown improves intestinal epithelial proliferation and barrier function after intestinal ischemia/reperfusion injury by targeting nurr1.

Impairment in gut barrier function induced by intestinal ischemia/reperfusion (I/R) injury is associated with high morbidity and mortality. Intestinal barrier function requires the tight coordination of epithelial migration, proliferation and differentiation. We previously observed that nuclear receptor-related protein 1 (nurr1)-mediated proliferative pathway was impaired in intestinal I/R injury. Here, we aimed to assess the effect of nurr1 on intestinal barrier function and to evaluate microRNA (miRNA)-nurr1-mediated restoration of intestinal barrier function in intestinal I/R injury. We induced an in vivo intestinal I/R injury mouse model by clamping and then releasing the superior mesenteric artery. We also performed an in vitro study in which we exposed Caco-2 and IEC-6 cells to hypoxia/reoxygenation (H/R) conditions to stimulate intestinal I/R injury. Our results demonstrated that nurr1 regulated intestinal epithelial development and barrier function after intestinal I/R injury. miR-381-3p, which directly suppressed nurr1 translation, was identified by microarray and bioinformatics analysis. miR-381-3p inhibition enhanced intestinal epithelial proliferation and barrier function in vitro and in vivo and also attenuated remote organ injury and improved survival. Importantly, nurr1 played an indispensable role in the protective effect of miR-381-3p inhibition. Collectively, these findings show that miR-381-3p inhibition mitigates intestinal I/R injury by enhancing nurr1-mediated intestinal epithelial proliferation and barrier function. This discovery may lead to the development of therapeutic interventions for intestinal I/R injury.

Dexmedetomidine promotes liver regeneration in mice after 70% partial hepatectomy by suppressing NLRP3 inflammasome not TLR4/NFκB.

Inflammasome activation is mediated by NOD-like receptors (NLRs) that play important role in cellular proliferation. NLRP3 senses the widest array of stimuli. But its role in the liver regeneration after partial hepatectomy (PHx) is still unknown. Dexmedetomidine (Dex) has been documented to protect the liver against ischemia-reperfusion injury via the suppression of the TLR4/NF-κB pathway, which is important for NLRP3 inflammasome activation and liver regeneration. We tested whether Dex contributes to liver regeneration, and investigated its consequent effect on inflammasome activation. In vitro, L02 human liver cells were treated with Dex at different concentrations. The 70% PHx was performed in C57 BL/6 mice as PHx group, and sham-operated animals as Sham group, Dex-treated animals were assigned into two groups: Dex+PHx, which received single intraperitoneal injections of Dex (25µg/kg) before PHx 30mins; Dex+PHx+Dex, which received additional Dex (25µg/kg) after PHx for 3days. Dex significantly inhibited the proliferation of Lo2 cells in vitro and decreased the expression of TLR4/NFκB. In vivo, Dex+PHx exhibited promoted effect on liver regeneration and liver function recovery via inhibiting NLRP3 inflammasome activation. Dex+PH+Dex inhibited the liver regeneration, which may be associated with suppressed expression levels of TLR4/NFκB pathway. Though Dex pretreatment contributed to liver regeneration and function recovery via inflammation suppression, excessive inflammation suppression accompanied with TLR4 suppression could be related to the diminished liver regeneration, suggesting that TLR4/NFκB played important role in liver regeneration and Dex+PHx might be a useful therapeutic strategy to promote liver regeneration in clinical.

Resveratrol improves prostate fibrosis during progression of urinary dysfunction in chronic prostatitis by mast cell suppression.

Voiding dysfunction is the primary clinical manifestation of chronic prostatitis (CP), which is a common urological disease. The present study investigated whether prostate fibrosis was associated with urinary dysfunction in CP and if resveratrol improved urinary dysfunction, and the underlying molecular mechanism. A rat model of CP was established via subcutaneous injections of the pertussis­diphtheria­tetanus vaccine, which was followed by treatment with resveratrol. Bladder pressure and volume tests were performed to investigate the effect of resveratrol on urinary dysfunction in CP rats. Western blotting and immunohistochemical staining examined the expression levels of tryptase, chymase, transforming growth factor (TGF)­ß, Wnt and α­smooth muscle actin (α­SMA). The results demonstrated that the maximum capacity of the bladder, residual urine volume and maximum voiding pressure were increased significantly in the CP group compared with the control group. Mast cell (MC) activation, the activity of TGF­ß/Wnt/ß­catenin pathways, and the expression levels of tryptase and α­SMA in the CP group were increased significantly compared with the control group. Resveratrol treatment significantly reversed these factors. Therefore, the results indicate that MC infiltration may induce prostate fibrosis, which exhibits a close association with urinary dysfunction in CP. Resveratrol may improve fibrosis via the suppression of MC activation and TGF­ß/Wnt/ß­catenin pathway activities.

Resveratrol improved detrusor fibrosis induced by mast cells during progression of chronic prostatitis in rats.

To investigate the detrusor fibrosis and urinary dysfunction in chronic prostatitis (CP), and to investigate whether resveratrol can improve the urinary dysfunction and the underlying molecular mechanism. After rat model of CP is established by subcutaneously injecting DPT vaccine, rats are treated with resveratrol. Experiments of bladder pressure and volume test in rats are used to investigate the effect of resveratrol on urinary dysfunction in CP rats. To assess tissue fibrosis, picrosirius red staining is performed. H&E staining is performed to identify the histopathological changes. Western blot and immunohistochemical staining are used to examine the expression of c-kit, SCF，tryptase, TGF-ß, Wnt and α-SMA. The results of bladder pressure and volume test show that the maximum capacity of the bladder, residual urine volume and maximum voiding are increased significantly in CP rats. CP rats show significantly increased collagen deposition in the detrusor. H&E staining show that detrusor muscle arranged in disorder with fracture from CP rats. The results of western blot and immunohistochemical staining demonstrate that the activity of c-kit/SCF and TGF-ß/Wnt/ß-catenin pathway, expression levels of tryptase and α-SMA in bladder detrusor of CP group are significantly increased compared with the control group. However, resveratrol treatment significantly improved these factors. mast cell activation induced by the increased expression of c-kit/SCF in CP rats, may promote detrusor fibrosis which have a close relationship with urinary dysfunction. Resveratrol can improve the dysfunction by downregulating the mast cell activation and the activity of TGF-ß/Wnt/ß-catenin pathway.

Resveratrol improves smooth muscle carcinogenesis in the progression of chronic prostatitis via the downregulation of c-kit/SCF by activating Sirt1.

PURPOSE: Bladder smooth muscle cell death accompanied by hyperplasia and hypertrophy, as induced by inflammation, is the primary cause for poor bladder function. There are emerging evidences on the role of chronic inflammation as a factor involved in carcinogenesis and progression. We aim to determine the bladder smooth muscle pathological changes and dysfunction in chronic prostatitis (CP), to investigate whether resveratrol can improve the urinary dysfunction and the role of c-kit/SCF pathway, that has been associated with the smooth muscle carcinogenesis. METHOD: Rat model of CP was established via subcutaneous injections of DPT vaccine and subsequently treated with resveratrol. H&E staining was performed to identify the histopathological changes in prostates and bladders. Western blotting and immunohistochemical staining examined the expression level of C-kit, stem cell factor (SCF), Sirt1, apoptosis associated proteins. RESULTS: the model group exhibited severe diffuse chronic inflammation, characterized by leukocyte infiltration and papillary frond protrusion into the gland cavities, and a notable increase in prostatic epithelial height. Meanwhile, bladder muscle arranged in disorder with fracture, and cells appeared atypia. The activity of C-kit/SCF was up-regulated, the carcinogenesis associated proteins are dysregulated significantly in CP rats. Resveratrol treatment significantly improved these factors by Sirt1 activation. CONCLUSIONS: activated c-kit/SCF and bladder muscle carcinogenesis were involved in the pathological processes of CP, which was improved after resveratrol treatment via the downregulation of c-kit/SCF by activating Sirt1.

Resveratrol improves prostate fibrosis during progression of urinary dysfunction in chronic prostatitis.

AIM: We investigated whether prostate fibrosis was associated with urinary dysfunction in chronic prostatitis (CP) and whether resveratrol improved urinary dysfunction and the underlying molecular mechanism. METHODS: Rat model of CP was established via subcutaneous injections of DPT vaccine and subsequently treated with resveratrol. Bladder pressure and volume tests investigated the effect of resveratrol on urinary dysfunction in CP rats. Western blotting and immunohistochemical staining examined the expression level of C-kit/SCF and TGF-ß/Wnt/ß-catenin. RESULTS: Compared to the control group, the maximum capacity of the bladder, residual urine volume and maximum voiding pressure, the activity of C-kit/SCF and TGF-ß/Wnt/ß-catenin pathways were increased significantly in the CP group. Resveratrol treatment significantly improved these factors. CONCLUSION: CP induced significantly prostate fibrosis, which exhibits a close relationship with urinary dysfunction. Resveratrol improved fibrosis, which may be associated with the suppression of C-kit/SCF and TGF-ß/Wnt/ß-catenin pathway.

Resveratrol Improves Cell Cycle Arrest in Chronic Prostatitis Rats, by C-kit/SCF Suppression.

Chronic prostatitis (CP) with complex pathogenesis is difficult for treatment. c-kit has been associated with the control of cell proliferation of prostate cells. This study aims to evaluate the role of resveratrol, an activator of Sirt1, in regulating the expression of c-kit in CP and investigate the consequent effects on cell cycle. Rat model of CP was established through subcutaneous injections of diphtheria-pertussis-tetanus vaccine and subsequently treated with resveratrol. Hematoxylin and eosin staining was performed to identify the histopathological changes in prostates. Western blotting and immunohistochemical staining examined the expression level of c-kit, stem cell factor (SCF), Sirt1, and cell cycle-associated proteins. The model group exhibited severe diffuse chronic inflammation, characterized by leukocyte infiltration and papillary frond protrusion into the gland cavities, and a notable increase in prostatic epithelial height. Gland lumen diameter was also significantly smaller; the activity of c-kit/SCF in the CP rats was increased significantly compared to the control group. Meanwhile, the cell cycle proteins are dysregulated significantly in CP rats. Resveratrol treatment significantly improved these factors by Sirt1 activation. Dysregulation of cell cycle was involved in the pathological processes of CP, which was improved after resveratrol treatment by the downregulation of c-kit/SCF by activating Sirt1.

Resveratrol Improved the Progression of Chronic Prostatitis via the Downregulation of c-kit/SCF by Activating Sirt1.

The regulation mechanism of inflammation inducing prostate carcinogenesis remains largely unknown. Therefore, we investigated the role of the c-kit/SCF pathway, which has been associated with the control of prostate carcinogenesis, in chronic prostatitis (CP) rats and evaluated the anti-prostatitis effect of resveratrol. We performed hemolysin and eosin staining to evaluate the histopathological changes in prostates. Multiple approaches evaluated the expression levels of c-kit, stem cell factor (SCF), Sirt1, and carcinogenesis-associated proteins. The CP group exhibited severe diffuse chronic inflammation. Meanwhile, the prostate cells appeared atypia; the activity of c-kit/SCF was upregulated, and carcinogenesis-associated proteins are dysregulated significantly in CP rats. Resveratrol treatment significantly improved these factors by Sirt1 activation. In summary, CP could further cause prostate carcinogenesis, which may be associated with activated c-kit/SCF signaling. Resveratrol treatment could improve the progression of CP via the downregulation of c-kit/SCF by activating Sirt1.