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Objective To investigate the expression of ENO3 gene in hepatocellular carcinoma and its effect on the sensitivity of hepatocellular carcinoma cell lines to OXA, and to explore the possible mechanism. Methods qRT-PCR and immunohistochemical analysis were used to detect the expression of ENO3 in 48 pairs of hepatocellular carcinoma tissues and normal liver tissues.Overexpression plasmid was constructed and transfected into MHCC97H and HepG2 cells.The experiments were divided into empty group (Vector group), ENO3 overexpression group (ENO3 group), empty+OXA group (Vector+OXA group) and ENO3 overexpression+OXA group (ENO3+OXA group).The proliferation ability of MHCC97H and HepG2 cells were detected by CCK-8 assay and cell colony formation assay.The apoptosis rate was determined by flow cytometry assay.Protein expressions of Bcl-2, Bax and Caspase-3 were detected by Western blot assay. Results The expression of ENO3 was significantly decreased in hepatocellular carcinoma tissues, compared with normal liver tissues adjacent to the carcinoma.The expression of ENO3 gene in the ENO3 overexpression group was significantly higher than that in the empty group.Compared with the Vector+OXA group, cell viability was decreased, apoptosis rate was increased, Bcl-2 protein expression was decreased, Bax and Caspase-3 protein expression were increased in the ENO3+OXA group. Conclusion The expression of ENO3 is down-regulated in hepatocellular carcinoma tissues, and the overexpression of ENO3 can enhance the sensitivity of hepatocellular carcinoma cell lines to oxaliplatin by promoting cell apoptosis.

ObjectiveTo compare the initial success rate, feasibility, and effectiveness of endoscopic retrograde cholangiopancreatography (ERCP) versus percutaneous transhepatic cholangiography (PTC) for anastomotic biliary stricture after liver transplantation (LT).MethodsWe retrospectively analyzed the data collected during January 2015 to December 2021 from liver transplantation recipients who developed anastomotic biliary stricture after liver transplantation and treated by ERCP and/or PTC. The success rate, complications and patients’ survival rate of ERCP and PTC procedures was evaluated.ResultsForty-eight patients who underwent LT and were confirmed to have the anastomotic biliary stricture were enrolled. Overall, 48/48 patients underwent single or multiple ERCP procedures as the first line therapy; 121 therapeutic ERCPs (3.36 ± 2.53 ERCPs per patient) were performed in 36/48 patients successfully. All the 12 patients who failed ERCP tend to have special bile duct conditions such as overlong, angle shaped, and/or extremely narrowed bile duct and underwent PTC as an alternative treatment. The initial success rate of ERCP was 75% (36/48) while the success rate of ERCP for the 12 patients with special bile duct was 0% (0/12). PTC was an effective second-line treatment for those 12 patients who failed ERCP, and 58.33% (7 of 12 cases) were treated successfully. The average procedure time in PTC group was significantly lower than ERCP group (t=2.292, P=0.027). The feasibility of ERCP was associated with the anatomical shape of bile duct and the severity of the stricture site. Finally, the cumulative survival rate was 100% (12/12) in PTC group compared to 86.11% (31/36) in ERCP group (χ2 =0.670, P=0.413).ConclusionERCP is the gold standard method for the diagnosis and effective intervention for the management of biliary complications after LT. However, its use in certain types of biliary complications (e.g., patients with severe anastomotic biliary stricture and those with overlong and angle shaped bile ducts) is not promising and associated with significant risk of complications. PTC and other interventions should be studied along with ERCP for patients for whom ERCP may not work. The feasibility and efficacy of primary management can be predicted by the noninvasive imaging examinations like Magnetic Resonance Cholangiopancreatography (MRCP) before the procedure, which may help with the choice of the most reasonable therapeutic modality and avoiding unnecessary financial burden and complications.

High aggressiveness is the main reason for the poor prognosis of hepatocellular carcinoma (HCC) patients. However, its molecular mechanisms still remain largely unexplored. ACADL, a mitochondrial enzyme that facilitates the primary regulated step in mitochondrial fatty acid oxidation, plays a role in HCC growth inhibition. However, the function of ACADL in tumor metastasis is not well elucidated. We found that the reduced expression of ACADL is closely associated with the loss of tumor encapsulation, extrahepatic metastasis, and poor prognosis in HCC patients. Upregulation of ACADL significantly inhibited HCC migration and invasion ability. Whereas knockdown of ACADL markedly enhanced cell invasive capability. Expression of matrix metalloproteinase-14 (MMP14) was negatively associated with the content of ACADL in HCC specimens. MMP14-positive patients with a low expression of ACADL showed worse outcome. Treatment with MMP14 agonist reversed the inhibitory effect of ACADL on HCC metastasis. In addition, ACADL negatively regulated MMP14 expression by inhibiting the STAT3 signaling pathway, as the sustained activation of STAT3 effectively restored the level of MMP14 in ACADL-overexpressed cells. Collectively, these findings disclose that ACADL represses HCC metastasis via STAT3-MMP14 pathway. This study may propose a promising strategy for the precise treatment of metastatic HCC patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate the reeonstitution and origin of mast cells and basophils in mice after bone marrow trans-plantation for 8 weeks. Methods: Total 5x1 Q6 whole bone marrow mononuclear cells (wBMMNC) from C57BL/6 homogeneic mice (CD45.1) were injected into the tail vein of recipient mice (CD45.2) which were received lethal irradiation. Eight weeks after trans-plantation, peripheral blood, peritoneal lavage fluid, spleen and bone marrow of control and transplantation groups were collected. Cell suspension were prepared and red blood cells were lysed, and the total number of nucleated cells were counted. Flow cytometry antibodies were used for staining, and the proportion and number of mast cells and basophils in different tissues were analyzed. Simultaneously, the cell origin was identified by analyzing the proportion of CD45.1 and CD45.2. Results: After 8 weeks of bone marrow transplantation, the proportion of mast cells in peritoneal cavity and basophils in bone marrow returned to the normal level, and there was no significant with control. The proportions of basophils in peripheral blood and spleen were also reconstituted, but it was different with control group (P<0.05). The percentage of CD45.2* mast cells in peritoneal was about 93.4%, and the percentage of CD45.1* basophils cells in peripheral blood, spleen and bone marrow were 87.6%, 96.4% and 90.8%, respectively. Conclusion: After 8 weeks of bone marrow transplantation, mast cells in peritoneal cavity and basophils in bone marrow have been reconstituted quickly, while basophils in peripheral blood and spleen reconstituted relatively slowly. Meanwhile, mast cells differentiate from host resident cells and basophils differentiate from donor bone marrow cells. [ABSTRACT FROM AUTHOR]

Background: Fostamatinib is the first spleen tyrosine kinase inhibitor approved for the treatment of chronic adult immune thrombocytopenia via blocking autoantibody-mediated platelet phagocytosis. Nevertheless, the potential of fostamatinib as therapeutic agent against acute inflammatory diseases has not been examined. This study aimed to investigate the effects of fostamatinib on the activation of macrophages and neutrophils and its therapeutic effects on SIRS. Methods: First, RT-qPCR and ELISA were used to detect the effects of fostamatinib on the expression and secretion of inflammatory factors by peritoneal macrophages (PMs) induced with TLR agonists. The activation and ROS release of neutrophils were detected by flow cytometry. Subsequently, the therapeutic effect of fostamatinib on LPS-induced SIRS in mice was examined. Finally, we also explored the underlying mechanisms of fostamatinib exerting pharmacodynamic effects by analyzing its effects on LPS-induced gene expression profile and the activation of signaling pathways in PMs through transcriptome sequencing and Western blot. Results: We found that fostamatinib inhibited the expression and secretion of TNF-α, IL-6, CCL2, CCL3, and CXCL10 (*P < 0.05) in PMs induced by LPS. Fostamatinib also reduced the activation of neutrophils stimulated by LPS, and suppressed the release of ROS by neutrophils. In SIRS mice, fostamatinib diminished the levels of inflammatory factors, and inhibited the excessive consumption of neutrophils in bone marrow. Transcriptome sequencing results showed that fostamatinib significantly inhibited the transcription of Cxcl10, Isg20, Mx1, Rsd2, etc. (*P < 0.05) in PMs induced by LPS. Meanwhile, fostamatinib selectively blocked the phosphorylation of STAT1 and STAT3 in PMs induced by LPS and cytokines (IFN-γ and IL-6). Conclusion: Fostamatinib can significantly inhibit LPS-induced inflammatory response through blocking STAT1/3 signaling pathways and has the potential to be used in the therapy of acute inflammatory diseases, especially SIRS and sepsis, which are resulting from the infection of Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose is a major cause of drug‐induced liver injury. Sirtuins 5 (SIRT5) has been implicated in the development of various liver diseases. However, its involvement in APAP‐induced acute liver injury (AILI) remains unclear. The present study aimed to explore the role of SIRT5 in AILI. SIRT5 expression is dramatically downregulated by APAP administration in mouse livers and AML12 hepatocytes. SIRT5 deficiency not only exacerbates liver injury and the inflammatory response, but also worsens mitochondrial oxidative stress. Conversely, the opposite pathological and biochemical changes are observed in mice with SIRT5 overexpression. Mechanistically, quantitative succinylome analysis and site mutation experiments revealed that SIRT5 desuccinylated aldehyde dehydrogenase 2 (ALDH2) at lysine 385 and maintained the enzymatic activity of ALDH2, resulting in the suppression of inflammation and mitochondrial oxidative stress. Furthermore, succinylation of ALDH2 at lysine 385 abolished its protective effect against AILI, and the protective effect of SIRT5 against AILI is dependent on the desuccinylation of ALDH2 at K385. Finally, virtual screening of natural compounds revealed that Puerarin promoted SIRT5 desuccinylase activity and further attenuated AILI. Collectively, the present study showed that the SIRT5‐ALDH2 axis plays a critical role in AILI progression and might be a strategy for therapeutic intervention. [ABSTRACT FROM AUTHOR]