Molecular basis of hippocampal energy metabolism in diabetic rats: The effects of SOD mimic

Hippocampal structural changes associated with diabetes-related cognitive impairments are well described, but their molecular background remained vague. We examined whether/how diabetes alters molecular basis of energy metabolism in hippocampus readily after diabetes onset, with special emphasis on its redox-sensitivity.To induce diabetes, adult Mill Hill hybrid hooded rats received a single alloxan dose (120 mg/kg). Both non-diabetic and diabetic groups were further divided in two subgroups receiving (i) or not (ii) superoxide dismutase (SOD) mimic, [Mn(II)(pyane)Cl₂] for 7 days, i.p. Treatment of the diabetic animals started after blood glucose level ≥12 mM.Diabetes decreased protein levels of oxidative phosphorylation components: complex III and ATP synthase. In contrast, protein amounts of glyceraldehyde-3-phosphate dehydrogenase, pyruvate dehydrogenase, and hypoxia-inducible factor-1α – the key regulator of energy metabolism in stress conditions, were higher in diabetic animals. Treatment with SOD mimic restored/increased the levels of oxidative phosphorylation components and returned hypoxia-inducible factor-1α to control level, while diabetes-induced up-regulation of glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase, was additionally stimulated.To conclude, our results provide insight into the earliest molecular changes of energy-producing pathways in diabetes that may account for structural/functional disturbance of hippocampus, seen during disease progression. Also, data suggest [Mn(II)(pyane)Cl₂] as potential therapeutic agent in cutting-edge approaches to threat this widespread metabolic disorder.     

Loss of ATP13A2 impairs glycolytic function in Kufor-Rakeb syndrome patient-derived cell models

BackgroundKufor-Rakeb syndrome (KRS) is an autosomal recessive, juvenile-onset Parkinson's disease (PD) caused by loss-of-function mutations in ATP13A2 (PARK9). Impaired energy metabolism is considered a pathogenic mechanism in PD and mitochondrial dysfunction resulting from Zn²⁺ dyshomeostasis has been found in KRS patient-derived cells. In addition to mitochondrial energy production, glycolysis plays an important role in cellular energy metabolism and glucose hypometabolism has been reported in PD. However, glycolytic status in KRS remains undetermined despite its potential importance.MethodsWe assessed glycolytic function in ATP13A2-deficient KRS patient-derived human olfactory neurosphere cells and fibroblasts and determined the effect of pyruvate supplementation on improving cellular energy production.ResultsWe found impaired extracellular acidification, reduction in pyruvate production and a decrease in the NAD⁺/NADH ratio, indicative of glycolytic dysfunction. In addition, gene expression analysis revealed an altered expression profile for several glycolytic enzymes. Glycolytic dysfunction was aggravated when the intracellular Zn²⁺ concentration was increased, while ATP13A2 overexpression and pyruvate supplementation blocked the observed Zn²⁺-mediated toxicity. Moreover, supplementation with pyruvate significantly increased basal mitochondrial ATP production and abolished Zn²⁺-induced cell death.ConclusionsThese findings indicate that glycolytic dysfunction contributes to pathogenesis and pyruvate supplementation improves overall cellular bioenergetics in our KRS patient-derived cell model, highlighting a therapeutic potential.     

鼻咽癌代谢重编程与放疗抵抗

鼻咽癌是一种具有地域分布性的鼻咽上皮恶性肿瘤,放疗抵抗是鼻咽癌患者治疗失败的主要原因。代谢重编程是调控肿瘤发生发展的核心,代谢变化能够影响肿瘤的发生、发展及治疗抵抗。糖酵解、氧化磷酸化、脂肪酸氧化等代谢途径均参与肿瘤放疗敏感性的调控。肿瘤微环境变化、基因突变或基因异常表达、基因表观遗传修饰或某些信号通路异常激活是调控鼻咽癌放疗抵抗的主要机制。近年来,越来越多的研究显示,代谢重编程在鼻咽癌放疗抵抗中扮演了重要角色,可通过调控DNA损伤修复、细胞周期、凋亡与自噬、肿瘤细胞干性和免疫反应等来调节鼻咽癌细胞的放疗抗性。靶向代谢重编程可为鼻咽癌放疗增敏提供新的策略和思路。     

Long non-coding RNA MSC-AS1 facilitates the proliferation and glycolysis of gastric cancer cells by regulating PFKFB3 expression

Long non-coding RNA musculin antisense RNA 1 (lncRNA MSC-AS1) has been recognized as an oncogene in pancreatic cancer, hepatocellular carcinoma, nasopharyngeal carcinoma, and renal cell carcinoma. However, the functional significance of MSC-AS1 and its underlying mechanism in gastric cancer (GC) progression remain unclear. In this study, we demonstrated that the expression of MSC-AS1 in GC tissues was significantly higher than that in non-tumor tissues. Moreover, the elevated level of MSC-AS1 was detected in GC cells (MKN-45, AGS, SGC-7901, and MGC-803) compared to normal GES-1 gastric mucosal cells. The cancer genome atlas (TCGA) data further indicated that the high level of MSC-AS1 was closely correlated with advanced tumor stage and poor prognosis of GC. Next, we revealed that MSC-AS1 knockdown inhibited the proliferation, glucose consumption, lactate production, and pyruvate production of MGC-803 cells. Conversely, MSC-AS1 overexpression enhanced the proliferation and glycolysis of AGC cells. Mechanistically, modulating MSC-AS1 level affected the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), but did not impact the levels of hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2) in GC cells. Based on this, we reversed the MSC-AS1 knockdown-induced the inhibition of cell proliferation and glycolysis by restoring PFKFB3 expression in MGC-803 cells. In conclusion, MSC-AS1 facilitated the proliferation and glycolysis of GC cells by maintaining PFKFB3 expression.     

葡萄糖代谢调控T细胞功能的研究进展

T细胞接受复杂的信号后激活、增殖和分化成不同的细胞亚型.研究表明,葡萄糖代谢可影响T细胞的激活、分化和免疫功能.因此,了解T细胞葡萄糖代谢特点和部分调控葡萄糖代谢的信号分子,探讨葡萄糖代谢的改变如何影响T细胞功能很有必要,深入探索T细胞的葡萄糖代谢特点和调控机制,有助于研究炎症条件下T细胞的功能,从而为炎症的治疗提供新的方法和思路.     

Trypanosoma brucei: The effect of glycerol on the anaerobic metabolism of glucose

Studies measuring the glycolytic intermediate and adenine nucleotide concentrations in Trypanosoma brucei metabolising glucose either aerobically or under conditions where glycerol-3-phosphate oxidase is inactive have shown the following: 1. Inhibition with 0.5 mM salicylhydroxamic acid (SHAM) accurately simulates anaerobic conditions in T. brucei; 2. On inhibition of respiring cells with 0.5 mM SHAM, the concentrations of most glycolytic intermediates decreases; they decrease further as the concentration of glycerol, an end product, increases. Only the concentration of sn-glycerol-3-phosphate is increased. This increase depends upon the method of preparation but is independent of time and glycerol concentration; 3. Glycerol formation from sn-glycerol-3-phosphate is coupled to the phosphorylation of another compound. The results of these studies are consistent with this compound being ADP; 4. The degree of inhibition of the anaerobic metabolism of glucose exerted by glycerol varies with the sn-glycerol-3-phosphate concentration, implying that the effect of glycerol is at the site of sn-glycerol-3-phosphate: ADP transphosphorylation.     

The evolution of the Calvin cycle from prokaryotic to eukaryotic chromosomes: a case study of functional redundancy in ancient pathways through endosymbiosis

The evolutionary histories of the 12 enzymes that catalyze the reactions of the Calvin cycle in higher-plant chloroplasts are summarized. They are shown to be encoded by a mixture of nuclear genes of cyanobacterial and proteobacterial origin. Moreover, where cytosolic isoforms of these enzymes are found they are almost invariably encoded by genes of clearly endosymbiont origin. We infer that endosymbiosis resulted in functional redundancy that was eliminated through differential gene loss, with intruding eubacterial genes repeatedly replacing pre-existing nuclear counterparts to which they were either functionally or structurally homologous. Our findings fail to support the `product-specificity corollary', which predicts re-targeting of nuclear-encoded gene products to the organelle from whose genome they originated. Rather it would appear that the enzymes of central carbohydrate metabolism have evolved novel targeting possibilities regardless of their origins. Our findings suggest a new hypothesis to explain organelle genome persistence, based on the testable idea that some organelle-encoded gene products might be toxic when present in the cytosol or other inappropriate cellular compartments. Received: 8 January / 20 May 1997     

肿瘤细胞的“瓦博格效应”与抗肿瘤药物的研发

“瓦博格效应”即指肿瘤细胞对糖酵解通路产能依赖增强的现象。这一现象为设计各种抗肿瘤代谢的药物提供了生物化学基础。介绍肿瘤细胞所具有的“瓦博格效应”及其主要机制，并总结了近年来基于该效应的抗肿瘤药物的研发状况。