Programmed cell death (PCD) refers to the way in which cells die depending on specific genes encoding signals or activities. Apoptosis, autophagy, and pyroptosis are all mechanisms of PCD. Among these mechanisms, pyroptosis is mediated by the gasdermin family, accompanied by inflammatory and immune responses. The relationship between pyroptosis and cancer is complex, and the effects of pyroptosis on cancer vary in different tissues and genetic backgrounds. On one hand, pyroptosis can inhibit the occurrence and development of tumors; on the other hand, as a type of proinflammatory death, pyroptosis can form a suitable microenvironment for tumor cell growth and thus promote tumor growth. In addition, the induction of tumor pyroptosis is also considered a potential cancer treatment strategy. Studies have shown that DFNA5 (nonsyndromic hearing impairment protein 5)/GSDME (Gasdermin-E) mRNA methylation results in lower expression levels of DFNA5/GSDME in most tumor cells than in normal cells, making it difficult to activate the pyroptosis in most tumor cells. During the treatment of malignant tumors, appropriate chemotherapeutic drugs can be selected according to the expression levels of DFNA5/GSDME, which can be upregulated in tumor cells, thereby increasing the sensitivity to chemotherapeutic drugs and reducing drug resistance. Therefore, induced pyroptosis may play a predominant role in the treatment of cancer. Here, we review the latest research on the anti-and protumor effects of pyroptosis and its potential applications in cancer treatment. Facts Open questions 1. Does pyroptosis play differential roles in normal and tumor tissues? 2. What are the key signals that initiate pyroptosis? 3. What are the key signaling pathways impacted by pyroptosis in tumors? 4. How can pyroptosis be manipulated to drive tumor fate?
The short-term effects of laparoscopic splenectomy and esophagogastric devascularization were better than those for open surgery, and the medium-term effects were similar between these two surgical approaches. Prospective randomized studies with a greater number of cases are needed to confirm the role of laparoscopy in splenectomy and esophagogastric devascularization.
Drug-resistant bacteria are a serious threat to global public health. Gram-positive bacterial endolysin preparations have been successfully used to fight Gram-positive bacteria as a novel antimicrobial replacement strategy. However, Gram-negative bacterial phage endolysins cannot be applied directly to destroy Gram-negative strains due to the externally inaccessible peptidoglycan layer of the cell wall; this has seriously hampered the development of endolysin-like antibiotics against Gram-negative bacteria. In this study, 3–12 hydrophobic amino acids were successively added to the C-terminus of Escherichia coli phage endolysin Lysep3 to create five different hydrophobic-modified endolysins. Compared with endogenous Lysep3, endolysins modified with hydrophobic amino acids surprisingly could kill E. coli from outside of the cell at the appropriate pH and endolysin concentration. The lysis ability of modified endolysins were enhanced with increasing numbers of hydrophobic amino acids at the C-terminus of endolysin. Thus, these findings demonstrate that the enhancement of hydrophobicity at the C-terminus enables the endolysin to act upon E. coli from the outside, representing a novel method of lysing Gram-negative antibiotic-resistant bacteria.
Cirrhosis and portal hypertension (PH) has a high incidence in China. Laparoscopic splenectomy and esophagogastric devascularization (LS + ED) was confirmed as an effective and safe surgical approach. But compared to open surgery (OS + ED), the rate of portal vein system thrombosis (PVST) was found to be higher after LS + ED. PVST is a common and potentially life-threatening complication after LS + ED in patients with cirrhosis and PH. Anti-coagulation therapy should be given early, but no standard plan for PSVT prophylaxis has been developed for all patients. In this study, the efficacy and safety of early use of low molecular weight heparin (LMWH) to prevent PVST were retrospectively evaluated compared with conventional anti-coagulant therapy. Of 219 patients with cirrhosis and PH undergoing LS + ED at our hospital from January 2008 to June 2013, 139 received early anti-coagulant therapy with LMWH, and 80 received conventional anti-coagulant therapy. The rates and types of PVST, perioperative coagulation function, intra-abdominal active bleeding, and esophagogastric variceal bleeding (EGVB) were compared in these two groups. Of the 139 patients in the early anti-coagulation group, 42 (30.2 %) experienced postoperative PVST, including two (1.4 %) with main trunk. Of the 80 patients in the conventional anti-coagulation group, 40 (50.0 %) experienced postoperative PVST, including 12 (15.0 %) with main trunk; three (3.8 %) experienced recurrent EGVB due to main trunk thrombosis, and one (1.3 %) underwent an immediate second laparotomy for uncontrollable active bleeding. The rates of postoperative PVST (P = 0.004), main trunk thrombosis (P = 0.000), and EGVB (P = 0.048) were significantly lower in the early than in the conventional anti-coagulant group, but all tested perioperative indices of coagulation function and rates of intraperitoneal active bleeding were similar. Early anti-coagulation with LMWH is safe and effective in patients with LS + ED for cirrhosis and PH.
ObjectiveTo investigate the role(s) of Trps1 in non-anastomotic biliary stricture (NABS) following liver transplantation.MethodsImmunohistochemical and histological techniques were used to detect Trps1, E-cadherin, CK19, vimentin, α-SMA, and collagen deposition. Human intrahepatic biliary epithelial cells (HIBECs) were infected with a Trps1 adenovirus, or transfected with Trps1 short-interfering RNAs (siRNAs). Reverse transcription polymerase chain reaction (RT-PCR) assays and western blotting were used to determine expression levels of epithelial and mesenchymal markers, and Trps1 in HIBECs.ResultsExpression of Trps1 and epithelial markers was down-regulated or absent in NABS liver samples. Mesenchymal markers were seen in biliary epithelial cells (BECs), with collagen deposited around the bile duct. Trps1 expression positively correlated with epithelial markers. Expression of epithelial marker mRNAs and proteins in HIBECs decreased with prolonged cold preservation (CP), while mesenchymal marker expression increased. A 12-h CP period led to increased Trps1 mRNA and protein levels. Expression of E-cadherin was increased in HIBECs following Trps1 adenovirus infection and CP/reperfusion injury (CPRI), with vimentin expression levels reduced and CPRI-mediated epithelial-mesenchymal transition (EMT) inhibited. Transfection of HIBECs with Trps1 siRNAs in conjunction with CPRI revealed that E-cadherin expression was decreased, vimentin expression was increased, and CPRI-mediated EMT was promoted.ConclusionTrps1 is involved in NABS pathogenesis following liver transplantation and negatively correlates with BEC EMT and biliary fibrosis in liver grafts. Trps1 demonstrates antagonistic effects that could reverse EMT.
Background Accumulating evidence indicated that necroptosis plays an essential role in the pathogenesis of inflammatory bowel disease (IBD). The O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) of necroptotic signal molecule receptor-interacting serine-threonine kinase 3 (RIPK3) was reported to exert a protective effect in gut inflammation. Our recent study suggested traditional Chinese herbal formula Wu-Mei-Wan (WMW) as an effective prescription in mouse colitis. However, the potential mechanisms are not fully understood. Considering the crucial role of necroptosis in the pathogenesis of IBD, therefore, this study was designed to explain whether the anti-colitis effect of WMW is mediated by modulating necroptosis and its related mechanisms. Methods The protective effects of WMW on colitis have been determined by detecting colitis mice body weight, disease activity index (DAI), survival rate and colon length. Colonic inflammation was examined by inflammatory cells infiltration and local cytokines levels. After then, we measured the levels of necroptosis and O-GlcNAcylation. C O-immunoprecipitation experiments were used to address whether elevated O-GlcNAcylation can inhibit necroptotic signal transduction in the treatment of WMW. Finally, the key enzymes in O-GlcNAcylation: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) were examined and molecular docking analysis was used to determine effective natural compounds in the regulation on OGT and OGA activities. Results Our results showed that WMW significantly improved mice body weight, survival rate and colon length, decreased DAI in TNBS-induced colitis. WMW obviously alleviated colonic inflammatory responses with reduced macrophages, neutrophils infiltration and local IL-1β, IL-6, TNF-α and IFN-γ levels. It was found that WMW increased colonic O-GlcNAcylation level and inhibited the activation of RIPK1, RIPK3 and MLKL. Then, further experiments revealed that WMW enhanced OGT activity and suppressed OGA activity, thereby increasing RIPK3 O-GlcNAcylation and inhibiting the binding of RIPK3 and MLKL, which led to the inhibition of necroptosis. Additionally, docking analysis demonstrated that hesperidin, coptisine and ginsenoside Rb1 may exert a major role in the regulation on OGT and OGA activities by WMW. Conclusion Our work demonstrated that WMW can alleviate TNBS-induced colitis in mice by inhibiting necroptosis through increasing RIPK3 O-GlcNAcylation.
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