Sirtuin 3 inhibits hepatocellular carcinoma growth through the glycogen synthase kinase-3ß/BCL2-associated X protein-dependent apoptotic pathway.

SIRT3 is a class III histone deacetylase that has been implicated in a variety of cancers. The role of SIRT3 in hepatocellular carcinoma (HCC) remains elusive. In this study, we found that SIRT3 expression was frequently repressed in HCC and its downregulation was closely associated with tumor grade and size. Ectopic expression of SIRT3 inhibited cell growth and induced apoptosis in HCC cells, whereas depletion of SIRT3 in immortalized hepatocyte promoted cell growth and decreased epirubicin-induced apoptosis. Mechanistic studies revealed that SIRT3 deacetylated and activated glycogen synthase kinase-3ß (GSK-3ß), which subsequently induced expression and mitochondrial translocation of the pro-apoptotic protein BCL2-associated X protein (Bax) to promote apoptosis. GSK-3ß inhibitor or gene silencing of BAX reversed SIRT3-induced growth inhibition and apoptosis. Furthermore, SIRT3 overexpression also suppressed tumor growth in vivo. Together, this study reveals a role of SIRT3/GSK-3ß/Bax signaling pathway in the suppression of HCC growth, and also suggests that targeting this pathway may represent a potential therapeutic approach for HCC treatment.

In Vitro and In Vivo Characterizations of Chiglitazar, a Newly Identified PPAR Pan-Agonist.

Solid rationales are still present for the identification of synthetic ligands to simultaneously target multiple PPAR subtypes for the treatment of T2DM. The purpose of this study was to characterize the in vitro and in vivo differential effects of chiglitazar, a non-TZD type of PPAR pan-agonist currently in phase III clinic development in China, from PPARγ-selective agonist like rosiglitazone. Chiglitazar showed transactivating activity in each PPARα, γ, and δ subtype and upregulated the expression of PPARα and/or PPARδ downstream genes involved in the key processes of lipid metabolism and thermogenesis. Comparable blood glucose lowering effect was observed between chiglitazar and rosiglitazone, but chiglitazar did not significantly increase the body weight in KKAy and fat pad weight in db/db mice. Chiglitazar had high distribution in liver, pancreas, and skeleton muscles but was less present in kidney, heart, and adipose in rats. Heart weight increase was not observed in rats treated with chiglitazar for 6 months at a dose as high as 45 mg kg(-1). The in vitro and in vivo differential features of chiglitazar are informative and encouraging for the further development of this synthetic ligand for the potential use in T2DM.

Generation and characterization of sodium-dicarboxylate cotransporter-deficient mice.

The sodium-dependent dicarboxylate cotransporter (NaDC1) has a proposed function of reabsorbing various Krebs cycle intermediates in the kidney and the small intestine. Since Krebs cycle intermediates have been suggested to be important for renal cell survival and recovery after hypoxia and reoxygenation, the transporter may play a role in the recovery of the kidney. Additionally, mutations in the transporter homolog in Drosophila led to fly longevity which was thought to be similar to that induced by caloric restriction (CR). To clarify the role of the sodium dicarboxylate cotransporter in vivo we generated cotransporter-deficient mice. These knockout mice excreted significantly higher amounts of various Krebs cycle intermediates in their urine; thus confirming the proposed function to reabsorb these metabolic intermediates in the kidney. No other phenotypic change was identified in these mice, however. Transporter deficiency did not affect renal function under normal physiological conditions, nor did it have an effect on renal damage and recovery from ischemic injury. Additionally, the absence of the transporter did not lead to metabolic or physiological changes associated with CR. Our results suggest that although the sodium dicarboxylate cotransporter is involved in regulating levels of various Krebs cycle intermediates in the kidney, impaired uptake of these intermediates does not significantly affect renal function under normal or ischemic stress.

Methanogen population in a marine biofilm corrosive to mild steel.

This study was conducted to analyze the methanogen population in a corrosive marine biofilm based on 16S rDNA analysis, using a PCR-cloning-sequencing approach. There were 80 methanogen clones developed from the PCR-amplified DNA extracted from the biofilm on the mild steel surface. All clones were categorized into one of five operational taxonomy units (OTUs). Two OTUs (comprising 57 clones) were affiliated with the acetotrophic Methanosaeta genus; the remaining three OTUs (23 clones) were affiliated with the hydrogenotrophic genera of Methanogenium, Methanoplanus and Methanocalculus. The hydrogenotrophic methanogens could directly cause metal corrosion through cathodic depolarization, whereas the acetotrophic methanogens grew syntrophically with corrosion-causing sulfate-reducing bacteria, as observed by fluorescent in situ hybridization, and thus contribute indirectly to metal corrosion.

Diabetic nephropathy is associated with the 5'-end dinucleotide repeat polymorphism of the aldose reductase gene in Chinese subjects with Type 2 diabetes.

AIMS: We investigated whether the promoter dinucleotide repeat polymorphism of the aldose reductase gene (5'-ALR2), implicated in the development of nephropathy in Type 1 diabetes, was associated with diabetic nephropathy in Type 2 diabetes. METHODS: In 265 Southern Chinese with Type 2 diabetes the 5' -ALR2 polymorphism was identified in genomic DNA using polymerase chain reaction and automated fluorescent scanning. They were classified as normoalbuminuric (n = 128), microalbuminuric (n = 85) or albuminuric (n = 52) according to the mean albumin excretion rate of two 12-h overnight collections. RESULTS: The 5' -ALR2 allele and genotype distributions differed significantly among the three groups of patients (P < 0.003 and P < 0.01, respectively). Normoalbuminuric patients had the lowest Z - 2 allele frequency: 17.6% vs. 28.2% and 23.1% for microalbuminuric and albuminuric patients, respectively, and the highest Z + 2 allele frequency: 36.7% vs. 21.2% and 23.1% in microalbuminuric and albuminuric patients, respectively. They also had the lowest Z - 2/X genotype frequency (X = any allele other than Z + 2): 18.8% vs. 36.5% in microalbuminuric (P < 0.01) and 38.5% in albuminuric patients (P < 0.02), respectively, but the highest Z + 2/Y genotype frequency (Y = any allele other than Z - 2): 50.7% vs. 27.0% and 34.6% in microalbuminuric (P < 0.001) and albuminuric patients, respectively. In a multiple logistic regression model, the Z - 2/X genotype (odds ratio 3.10; P < 0.025) was an independent risk factor of diabetic nephropathy, microalbuminuria or albuminuria, together with age, mean arterial pressure and body mass index. CONCLUSIONS: The 5' -ALR2 dinucleotide repeat polymorphism is associated with the development of diabetic nephropathy in Southern Chinese with Type 2 diabetes.