SREBF2 triggers endoplasmic reticulum stress and Bax dysregulation to promote lipopolysaccharide-induced endothelial cell injury.

An increased lipopolysaccharide (LPS) level in patients with cirrhosis induced the dysregulation of sterol regulatory element-binding transcription factor 2 (SREBF2), which participated in the modulation of tumor inflammatory microenvironment. However, the role of SREBF2 in the LPS-induced injury of portal vein endothelium was scarcely reported. This study aimed to investigate the effects of SREBF2 on the LPS-induced injury to endothelial cells (ECs) in vitro and in vivo and explore the underlying mechanism. In this study, we found that LPS increased SREBF2 expression through activating the TLR4/JNK/c-Jun pathway and suppressed UBE2I-mediated SREBF2 sumoylation to enhance its transcriptional activity. The dysregulation of SREBF2 induced ER stress by increasing the intracellular cholesterol level and facilitated Bax expression to cause additional damage to LPS-induced ECs. As a potential intervention, miR590-3p negatively regulated SREBF2 expression and upregulated UBE2I expression by targeting TLR4, thus alleviating LPS-induced injury. These results suggest that LPS-induced SREBF2 triggered ER stress and promoted Bax expression to injure ECs, which was reversed by miR590-3p. The mechanisms of SREBF2 mediated LPS-induced endothelial injury of portal vein, which might be the therapeutic target for PVT development in cirrhosis patients. 1. LPS promoted SREBF2 expression by activating the TLR4/JNK/c-Jun pathway and suppressed UBE2I-mediated SREBF2 sumoylation to upregulate SREBF2 transcriptional activity 2. SREBF2-mediated ER stress and Bax expression involved in LPS-induced EC injury 3. miR590-3p decreased SREBF2 expression by targeting TLR4 and mitigated LPS-induced EC injury.

Risk stratification for secondary prophylaxis of gastric varices due to portal hypertension.

BACKGROUND: Gastroesophageal variceal hemorrhage is a common complication associated with portal hypertension. Current guidelines provide well-established recommendations for esophageal varices, while that of gastric varices remain scarce and lack evidential strength. The aim of the study is to identify a feasible risk stratification method based on imaging findings to evaluate patient response to cyanoacrylate injection for the treatment of gastric varices. METHODS: A prospective cohort study including patients diagnosed with gastric varices admitted for initial secondary prophylactic treatment for GV was conducted. Routine endoscopic examination and endoscopic ultrasound (EUS) were performed on all subjects to evaluate extraluminal collaterals. All patients with gastric varices were treated uniformly with cyanoacrylate injection. Patients were prospectively followed for at least 12 months and any occurrence of variceal rebleed was recorded. RESULTS: 102 subjects were enrolled in the study, 66.7% had GOV Type 2, 27.5% had GOV Type 1 and 5.9% had IGV Type 1. During the 12 months follow-up, 33.3% patients experienced variceal rebleed. A risk assessment scoring system was proposed based on endoscopic and EUS findings. A Cox regression analysis demonstrated a significant association between the merited risk score and incidence of variceal rebleed (P < 0.001). CONCLUSIONS: Presence of red wales sign, size of varix, and presence of para-gastric vein were all independent risk factors for variceal rebleed after endoscopic therapy for the treatment of gastric varices. Early identification of this subgroup, especially those with higher risk scores, necessitates a change in course of treatment, which can improve prognosis and overall patient outcome.