Multiple large clinical trials have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors reduce the risk of renal events. However, the mechanism responsible for this outcome remains unknown. Here we investigated the effects of the SGLT2 inhibitor luseogliflozin on the development of renal fibrosis after renal ischemia/reperfusion injury in non-diabetic mice. Luseogliflozin significantly suppressed development of renal fibrosis, prevented peritubular capillary congestion/hemorrhage, attenuated CD31-positive cell loss, suppressed hypoxia, and increased vascular endothelial growth factor (VEGF)-A expression in the kidney after ischemia/reperfusion injury. Luseogliflozin failed to induce the above-mentioned protection in animals co-treated with sunitinib, a VEGF receptor inhibitor. Additionally, luseogliflozin reduced glucose uptake and increased VEGF-A expression in the kidneys of glucose transporter 2 (GLUT2)-downregulated mice following ischemia/reperfusion and in GLUT2-knock-down cells compared with those in normal controls. Withdrawal of glucose from cultured medium, to halt glucose uptake, remarkably increased VEGF-A expression and reversed the luseogliflozin-induced increase in VEGF-A expression in the proximal tubular cells. Thus, luseogliflozin prevented endothelial rarefaction and subsequent renal fibrosis after renal ischemia/reperfusion injury through a VEGF-dependent pathway induced by the dysfunction of proximal tubular glucose uptake in tubules with injury-induced GLUT2 downregulation.

Abstract. Metformin is a commonly used oral antihyperglycemic agent of the biguanide family. Recent studies suggest that metformin may reduce cancer risk and improve prognosis. However, the antitumor mechanism of metformin in several types of cancers, including hepatocellular carcinoma (HCC), has not been elucidated. The goal of the present study was to evaluate the effects of metformin on HCC cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with the antitumor effect of metformin in vitro. We used the cell lines Alex, HLE and Huh7, and normal hepatocytes to study the effects of metformin on human HCC cells. In an in vivo study, athymic nude mice bearing xenograft tumors were treated with metformin or left untreated. Tumor growth was recorded after 4 weeks, and the expression of cell cycle-related proteins was determined. Metformin inhibited the proliferation of Alex, HLE and Huh7 cells in vitro and in vivo. Metformin blocked the cell cycle in G0/G1 in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, cyclin E and cyclin-dependent kinase 4 (Cdk4). In addition, microRNA (miRNA) expression was markedly altered by the treatment with metformin in vitro and in vivo. In addition, various miRNAs induced by metformin also may contribute to the suppression of tumor growth. Our results demonstrate that metformin inhibits the growth of HCC, possibly by inducing G1 cell cycle arrest through the alteration of microRNAs.

The OTSC is effective for treating GI bleeding, fistulae as well as perforations, and the OTSC technique proofed effective treatment for perforation after ESD.

UMIN (UMIN000008487).

Endoscopic submucosal dissection (ESD) is not a common treatment for colorectal neoplasms because of its technical difficulties and has a higher incidence of complication. In particular, perforation is one of the severe complications and these patients require surgical intervention. However, whether prophylactic closure after colorectal ESD prevents perforation and other complications is not known. In the present study, we assessed the efficacy and safety of prophylactic closure for a large mucosal defect after colorectal ESD using a conventional clip and over-the-scope clip (OTSC) system. From April 2010 to December 2012, 68 patients with colorectal tumors were treated with ESD. The prohylactic closure was indicated for patients with excessive coagulation in the muscularis propria or larger resection size. The closure group reduced the peritoneal inflammatory reaction and abdominal symptoms without increasing complications. The closure group also had a significantly lower WBC count (post operative day 1), CRP (post operative day 4) and abdominal pain after colorectal ESD compared to the non-closure group. Perforation occurred in 1 case, and postoperative bleeding in 2 cases, with only 1 bleeding case needing an emergency endoscopy in the non-closure group. One perforation case needed emergency surgery because the endoscopic treatment was ineffective. Without increasing adverse effects, the prophylactic closure efficiently reduced the inflammatory reaction and abdominal symptoms of colorectal ESD in patients with large superficial colorectal neoplasms.