Dexmedetomidine administration before, but not after, ischemia dose-dependently protects against I/R-induced intestinal injury, partly by inhibiting inflammatory response and intestinal mucosal epithelial apoptosis via α2 adrenoreceptor activation.

Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor‐interacting protein kinase 1/3 (RIP1/3) and phosphorylated‐MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage‐depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What’s more, HMGB1 neutralization further protects against intestinal I/R‐associated liver damage in microbiota‐depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec‐1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R‐induced acute remote organ dysfunction.

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Background: A review of the evidence has indicated the critical role of long noncoding RNA (lncRNA) LSINCT5 in a large number of human cancers. However, the mechanistic involvement of LSINCT5 in endometrial carcinoma (EC) is still unknown. Here the authors aim to characterize the expression status of LSINCT5 and elucidate its mechanistic relevance to EC. Methods: Relative expression of LSINCT5 and HMGA2 were quantified by a real-time polymerase chain reaction. SiRNAs were employed to specifically knockdown endogenous LSINCT5 in EC cells. Cell proliferation was measured with Cell Count Kit-8 kit (CCK-8, Dojindo, Kumamoto, Japan) and cell growth was assessed by a colony formation assay. The cell cycle was analyzed with propidium iodide (PI) staining. Apoptotic cells were determined by flow cytometry after Annexin V/PI double-staining. Cell migration was evaluated by a wound-healing assay, and cell invasion was assessed using a transwell migration assay. The protein levels of HMGA2, Wnt3a, p-β-catenin, c-myc, β-actin, and GAPDH were determined by western blot. Results: The authors observed positively correlated and aberrantly up-regulated LSINCT5 and HMGA2 in EC. LSINCT5 deficiency significantly inhibited cell proliferation, cell cycle progression, and induced apoptosis. Meanwhile, cell migration and invasion were greatly compromised by the LSINCT5 knockdown. LSINCT5 stabilized HMGA2, which subsequently stimulated activation of Wnt/β-catenin signaling and consequently contributed to the oncogenic properties of LSINCT5 in EC. Conclusions: Our data uncovered the oncogenic activities and highlighted the mechanistic contributions of the LSINCT5-HMGA2-Wnt/β-catenin signaling pathway in EC.

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