Keap1 degradation by autophagy for the maintenance of redox homeostasis

The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system is essential for cytoprotection against oxidative and electrophilic insults. Under unstressed conditions, Keap1 serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2, but Nrf2 is stabilized when Keap1 is inactivated under oxidative/electrophilic stress conditions. Autophagy-deficient mice show aberrant accumulation of p62, a multifunctional scaffold protein, and develop severe liver damage. The p62 accumulation disrupts the Keap1-Nrf2 association and provokes Nrf2 stabilization and accumulation. However, individual contributions of p62 and Nrf2 to the autophagy-deficiency-driven liver pathogenesis have not been clarified. To examine whether Nrf2 caused the liver injury independent of p62, we crossed liver-specific Atg7::Keap1-Alb double-mutant mice into p62- and Nrf2-null backgrounds. Although Atg7::Keap1-Alb::p62(-/-) triple-mutant mice displayed defective autophagy accompanied by the robust accumulation of Nrf2 and severe liver injury, Atg7::Keap1-Alb::Nrf2(-/-) triple-mutant mice did not show any signs of such hepatocellular damage. Importantly, in this study we noticed that Keap1 accumulated in the Atg7- or p62-deficient mouse livers and the Keap1 level did not change by a proteasome inhibitor, indicating that the Keap1 protein is constitutively degraded through the autophagy pathway. This finding is in clear contrast to the Nrf2 degradation through the proteasome pathway. We also found that treatment of cells with tert-butylhydroquinone accelerated the Keap1 degradation. These results thus indicate that Nrf2 accumulation is the dominant cause to provoke the liver damage in the autophagy-deficient mice. The autophagy pathway maintains the integrity of the Keap1-Nrf2 system for the normal liver function by governing the Keap1 turnover.     

Successful endoscopic transpapillary pancreaticobiliary drainage for omental panniculitis by hepatocellular carcinoma complicated by biliary fistula and pancreatic fistula

A 78-year-old man with hepatocellular carcinoma treated by chemoembolization and percutaneous ethanol injection was admitted to our hospital because of acute abdomen. The CT scan showed biliary fistula caused by hepatocellular carcinoma protruding from S3. Endoscopic retrograde cholangiopancreatography showed disruption of an intrahepatic duct and the main pancreatic duct, and contrast agent leaked into the peritoneal cavity from each duct. Omental panniculitis with biliary fistula and pancreatic fistula was diagnosed. The symptoms improved by endoscopic nasobiliary drainage and endoscopic pancreatic stenting. On the 13th day after admission, we added endoscopic nasopancreatic drainage because his abdominal pain had been exacerbated by pancreatic juice leakage. Omental panniculitis by hepatocellular carcinoma complicated by biliary fistula and pancreatic fistula is extremely rare. Endoscopic transpapillary pancreaticobiliary drainage was effective for omental panniculitis in this case.     

Modified Glasgow prognostic score in patients with incurable stage IV colorectal cancer

Background

The modified Glasgow prognostic score is an inflammation-based prognostic score. This study examined whether this score, measured before surgical procedures, could predict postoperative cancer-specific survival.

Methods

We retrospectively studied 79 colorectal cancer patients who underwent a surgical procedure for incurable stage IV disease. The modified Glasgow prognostic score (0 to 2) comprises C-reactive protein (≤10 vs >10 mg/L) and albumin (<35 vs ≥35 g/L) measurements.

Results

In terms of overall survival, univariate analysis revealed significant differences in the status of lung metastasis, peritoneal dissemination, distant metastasis, hemoglobin, C-reactive protein, albumin, tumor resection, adjuvant chemotherapy, and modified Glasgow prognostic score. Multivariate analysis revealed that hemoglobin (P = .019), adjuvant chemotherapy (P = .002), and modified Glasgow prognostic score (0 and 1, low; 2, high) (P = .0001) were significant predictive factors for postoperative mortality.

Conclusions

The modified Glasgow prognostic score is simple to obtain and useful in predicting survival in incurable stage IV colorectal cancer patients undergoing surgery.     

Plasma endoglin as a marker to predict cardiovascular events in patients with chronic coronary artery diseases

Recent clinical studies have revealed that the expression of endoglin, an accessory protein for the TGF-β receptor, is increased in patients with atherosclerotic diseases. The plasma endoglin level is thought to represent endothelial activation, inflammation, and senescence. To clarify the significance of plasma endoglin in chronic coronary artery disease. Human umbilical vein endothelial cells (HUVECs) were cultured to examine changes in soluble endoglin (s-endoglin) levels caused by atherogenic stimulation in vitro. We studied 318 patients with stable coronary artery disease who underwent a successful percutaneous coronary intervention (PCI). Patients with acute coronary syndrome were excluded. Major adverse cardiovascular events (MACE) were congestive heart failure, acute myocardial infarction, stroke, and sudden cardiac death. All patients were followed-up to examine MACE after the procedure. We confirmed that the levels of s-endoglin was increased in the culture medium of HUVECs by senescence, tumor necrosis factor-α and hydrogen peroxide. In a clinical study, mean follow-up period was 1055?±?612?days (49–2136?days) with 27 incidents of MACE (8.5%). We divided patients into three groups according to the plasma s-endoglin levels. Kaplan–Meier curves revealed that the highest endoglin group had a significantly higher MACE rate than the lowest endoglin group (log-rank test, p?=?0.009). A Cox proportional hazards model showed that chronic kidney disease, left ventricular ejection fraction and s-endoglin level were significant factors to predict MACE. Plasma endoglin could be a marker to predict cardiovascular events in patients with chronic coronary artery disease after PCI.     

Processed blood volume impacts clinical efficacy in patients with ulcerative colitis undergoing adsorptive depletion of myeloid lineage leucocytes

Background  

Hitherto, therapeutic depletion of granulocytes and monocytes by adsorption (GMA) has been associated with significant and insignificant efficacy in patients with ulcerative colitis (UC). Further, the processed blood volume in one GMA session has been fixed at 30 mL/min × 60 min, regardless of patients’ body weight (BW). We were interested to see the efficacy and safety of GMA when administered in relation to patients’ BW.