Hepatic COX1 loss leads to impaired autophagic flux and exacerbates nonalcoholic steatohepatitis

The mechanisms underlying autophagic defects in nonalcoholic steatohepatitis (NASH) remain largely unknown. We aimed to elucidate the roles of hepatic cyclooxygenase 1 (COX1) in autophagy and the pathogenesis of diet-induced steatohepatitis in mice. Human nonalcoholic fatty liver disease (NAFLD) liver samples were used to examine the protein expression of COX1 and the level of autophagy. Cox1Δhepa mice and their wildtype littermates were generated and fed with 3 different NASH models. We found that hepatic COX1 expression was increased in patients with NASH and diet-induced NASH mice models accompanied by impaired autophagy. COX1 was required for basal autophagy in hepatocytes and liver specific COX1 deletion exacerbated steatohepatitis by inhibiting autophagy. Mechanistically, COX1 directly interacted with WD repeat domain, phosphoinositide interacting 2 (WIPI2), which was crucial for autophagosome maturation. Adeno-associated virus (AAV)-mediated rescue of WIPI2 reversed the impaired autophagic flux and improved NASH phenotypes in Cox1Δhepa mice, indicating that COX1 deletion-mediated steatohepatitis was partially dependent on WIPI2-mediated autophagy. In conclusion, we demonstrated a novel role of COX1 in hepatic autophagy that protected against NASH by interacting with WIPI2. Targeting the COX1-WIPI2 axis may be a novel therapeutic strategy for NASH.

Application value of triangular modal construed for planning approach of laparoscopic local resection of liver tumors located in superior part of central liver lobe / 中华消化外科杂志

Objective:To investigate the application value of triangular modal construed for planning approach of laparoscopic local resection of liver tumors located in superior part of central liver lobe.Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 10 patients who underwent local laparoscopic resection of liver tumors located in superior part of central liver lobe at the Affiliated Hospital of Qingdao University from January to June 2020 were collected. There were 6 males and 4 females, aged from 41 to 63 years, with a median age of 54 years. Preoperative triangular model was constructed for all patients to plan approach of laparoscopic local resection of liver tumors located in superior part of central liver lobe. Observation indicators: (1) preoperative general situations of patients; (2) surgical situations; (3) follow-up. Follow-up was conducted by outpatient examination or telephone interview to detect tumor recurrence and survival of patients up to February 2021. Measurement data with normal distribution were expressed as Mean± SD. Count data were expressed was absolute numbers. Results:(1) Preoperative general situations of patients: hepatocellular carcinoma was found in 7 cases, inthahepatic cholangiocarcinoma was found in 2 cases and ovarian cancer with liver metastasis was found in 1 case. Three cases had tumors located in S4a segment, 2 cases had tumors located in ventral subsegment of S8 segment, 2 cases had tumors located in dorsal subsegment of S8 segment, and 3 cases had tumors across the ventral segment of S4a+S8. The diameter of tumors was (3.4±1.0)cm. (2) Surgical situation: all the 10 patients underwent R 0 resection successfully, with no intraoperative blood transfusion or conversion to open surgery. The operation time of 10 patients was (149±59)minutes, the volume of intraoperative blood loss was (294±163)mL, the minimum surgical margin of specimen was (1.1±0.2)cm. The alanine aminotransferase was (324±151)U/L on the postoperative first day, the aspartic aminotransferase was (401±113)U/L on the postoperative first day, and the duration of postoperative hospital stay was (9±4)days. No bile leakage, hemorr-hage, reoperation or other complications occurred in all patients. (3) Follow-up: 10 patients were followed up for 7?13 months, with a median follow-up time of 11 months. All patients had no margin recurrence or distant metastasis. Conclusion:It is safe and feasible to construct triangular modal for planning approach of local laparoscopic resection of liver tumors located in superior part of central liver lobe.

Pseudolaric Acid B Inhibits Proliferation, Invasion and Epithelial-to-Mesenchymal Transition in Human Pancreatic Cancer Cell

PURPOSE: This study was aimed to investigate the effect of pseudolaric acid B (PAB) on proliferation, invasion and epithelial-to-mesenchymal transition (EMT) in pancreatic cancer cells and to explore the possible mechanism. MATERIALS AND METHODS: The pancreatic cancer cell line SW1990 was cultured and treated with PAB dose- and time-dependent manners. Cell proliferation and invasion ability were measured by MTT assay and Matrigel/Transwell test, respectively. Semi-quantitative real-time polymerase chain reaction and Western blotting were conducted to detect the expression of EMT markers and the key molecules. Finally, nude mice subcutaneous transplantation tumor model was used to confirm the therapy efficacy of PAB. RESULTS: PAB could inhibit SW1990 cell proliferation and invasion in time- and dose-dependent manners. Vimentin, fibronectin, N-cadherin, Snail, Slug, YAP, TEAD1, and Survivin were down-regulated (p < 0.01), while E-cadherin, caspase-9, MST1, and pYAP were up-regulated (p < 0.05). Combined PAB and gemcitabine treatment markedly restricted the tumor growth compared with gencitabin or PAB alone groups. CONCLUSION: PAB could inhibit the proliferation and invasion ability of pancreatic cancer cells through activating Hippo-YAP pathway and inhibiting the process of EMT.