Histone deacetylase inhibitors: a novel class of therapeutic agents in diabetic nephropathy

Histone deacetylase (HDAC) inhibitors are currently being tested as anticancer agents in clinical trials. Chromatin remodeling, such as through histone acetylation, is a fundamental phenomenon in eukaryotic cell biology, bearing implications to numerous physiological and pathological phenomena. Here, we discuss recent data from our own laboratory and those of others demonstrating antifibrotic and renoprotective effect of HDAC inhibitors in diabetic kidneys, and the possible mechanisms including the role of reactive oxygen species. HDAC inhibitors may prove to be a novel class of multitarget agents in the treatment of diabetic nephropathy.     

Yoga Training Improves Metabolic Parameters in Obese Boys

Yoga has been known to have stimulatory or inhibitory effects on the metabolic parameters and to be uncomplicated therapy for obesity. The purpose of the present study was to test the effect of an 8-week of yoga-asana training on body composition, lipid profile, and insulin resistance (IR) in obese adolescent boys. Twenty volunteers with body mass index (BMI) greater than the 95th percentile were randomly assigned to yoga (age 14.7±0.5 years, n=10) and control groups (age 14.6±1.0 years, n=10). The yoga group performed exercises three times per week at 40~60% of heart-rate reserve (HRR) for 8 weeks. IR was determined with the homeostasis model assessment of insulin resistance (HOMA-IR). After yoga training, body weight, BMI, fat mass (FM), and body fat % (BF %) were significantly decreased, and fat-free mass and basal metabolic rate were significantly increased than baseline values. FM and BF % were significantly improved in the yoga group compared with the control group (p<0.05). Total cholesterol (TC) was significantly decreased in the yoga group (p<0.01). HDL-cholesterol was decreased in both groups (p<0.05). No significant changes were observed between or within groups for triglycerides, LDL-cholesterol, glucose, insulin, and HOMA-IR. Our findings show that an 8-week of yoga training improves body composition and TC levels in obese adolescent boys, suggesting that yoga training may be effective in controlling some metabolic syndrome factors in obese adolescent boys.     

Lycopene supplementation suppresses oxidative stress induced by a high fat diet in gerbils

The effect of lycopene supplementation on the antioxidant system was investigated by analyzing lipid peroxide levels, glutathione contents, and antioxidant enzyme activities in Mongolian gerbils fed a high fat diet. Gerbils were fed on each experimental diet for 6 weeks; normal diet (NC), normal diet with 0.05% lycopene (NL), high fat diet (HF), and a high fat diet with 0.05% lycopene (HFL). Dietary supplementation of lycopene increased hepatic lycopene level in gerbils fed a normal or high fat diet (P < 0.05). Liver and erythrocyte concentrations of lipid peroxide increased in gerbils fed a high fat diet, whereas lycopene supplementation decreased liver and erythrocyte concentrations of lipid peroxide (P < 0.05). Hepatic total glutathione content was higher in the NL group than that in the NC group (P < 0.05). Total antioxidant status in plasma increased following lycopene supplementation compared with that of the non-lycopene supplemented groups (P < 0.05). Hepatic catalase activity increased following dietary lycopene supplementation (P < 0.05). Superoxide dismutase activity in liver remained unchanged with lycopene supplementation, but erythrocyte superoxide dismutase activity increased in NL group compared with NC group (P < 0.05). Glutathione-S-transferase activity increased in the NL group compared to NC group (P < 0.05). Liver and erythrocyte glutathione peroxidase activity increased significantly in the NL group compared to that in the HF group (P < 0.05). Liver glutathione reductase activity was higher in the NL group than that in the NC group (P < 0.05). These results suggest that lycopene supplementation may be efficient for preventing chronic diseases induced by oxidative stress related to high fat diet.     

Reversible oxidant-induced increases in albumin transfer across cultured endothelium: alterations in cell shape and calcium homeostasis

To determine whether reactive oxygen molecules could directly and reversibly increase the transfer of albumin across an endothelial barrier, we measured albumin transfer across monolayers of endothelium cultured on micropore filters before and after exposure to xanthine and xanthine oxidase. Xanthine and xanthine oxidase increased endothelial albumin transfer in a dose-dependent fashion. Parallel phase contrast and fluorescence microscopy demonstrated retraction of adjacent cells from one another and disruption of the actin filaments. The oxidant- induced increases in albumin transfer and changes in cell shape were reversed by removing xanthine oxidase and then incubating the monolayers for 3 1/2 hours in tissue culture media enriched with fetal bovine serum. However, incubation in tissue culture media without serum resulted in progressive injury and cell death. Hence, the brief exposure to oxidants initiated a progressive injury process that was reversed by incubation in serum. Because intracellular and extracellular calcium are important determinants of cell shape, and because some oxidized membrane lipids act as calcium ionophores, we asked whether oxidants altered endothelial calcium homeostasis. Xanthine-xanthine oxidase increased release of 45Ca++ from preloaded cells. The calcium antagonist lanthanum chloride prevented xanthine- xanthine oxidase increases in endothelial albumin transfer and prevented the changes in cell shape; chelation of extracellular calcium inhibited lysis of endothelium by xanthine-xanthine oxidase; and the calcium ionophore A23187 increased endothelial albumin transfer and mimicked the oxidant-induced changes in cell shape. Lanthanum chloride inhibited these effects of A23187. These data suggest that oxygen radicals can reversibly increase endothelial permeability to macromolecules, that this is associated with reversible changes in endothelial cell shape and actin filaments, and that the changes in cell shape are related to oxidant-induced changes in endothelial calcium homeostasis.     

Gastric duplication communicating with the left hepatic duct: a rare case of recurrent hemobilia in a child.

Gastric duplication is a rare anomaly, usually manifested as an abdominal mass or gastric outlet obstruction mimicking congenital hypertrophic pyloric stenosis during the first year of life. Occasionally, it communicates with the pancreatic duct and causes pancreatitis. However, communication with the intrahepatic bile duct has not been described. The authors report a rare case of gastric duplication that communicated with the left hepatic duct and caused recurrent hemobilia in a 2-year-old girl. Left hepatectomy and excision of the duplication were curative.     

Morphological investigation of the enteric nervous system in Hirschsprung's disease and hypoganglionosis using whole-mount colon preparation

BACKGROUND/PURPOSE: A suction rectal mucosal biopsy with positive staining for acetylcholinesterase is a useful test for diagnosis of Hirschsprung's disease (HD). However, hypoganglionosis has not been diagnosed by a rectal mucosal biopsy. The authors morphologically examined the enteric nervous systems in HD and hypoganglionosis patients using whole-mount preparations. METHODS: Six HD patients, two hypoganglionosis patients, and 10 with normally innervated colons were examined. Colonic specimens were incubated with the primary antibodies against protein gene product 9.5 (PGP 9.5) mixed with S-100b protein, tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), substance P (SP), and neurofilament protein 200 kDa (NFH). They were observed by histochemical technique using light-microscopy in whole-mount preparations. RESULTS: The aganglionic distal colon had thick nerve strands stained with PGP 9.5 mixed with S100 or NFH located in the layer between the longitudinal muscle and the circular one, and the submucosal layer. The nerve strands in the myenteric layer contained few CGRP- and SP-positive fibers and ran along the long axis of the intestine. Ganglion cells appeared along with those thick nerve strands in the transitional zone of HD. In hypoganglionosis, we found small myenteric ganglia with no thick nerve strands. CONCLUSIONS: The enteric nervous system in oligoganglionic segments of HD morphologically differed from the one in hypoganglionosis. A suction rectal mucosal biopsy would be of no use in the diagnosis of hypoganglionosis.