Glucose Metabolism,Neural Cell Senescence and Alzheimer’s Disease

Alzheimer’s disease (AD), an elderly neurodegenerative disorder with a high incidence and progressive memory decline, is one of the most expensive, lethal, and burdening diseases. To date, the pathogenesis of AD has not been fully illustrated. Emerging studies have revealed that cellular senescence and abnormal glucose metabolism in the brain are the early hallmarks of AD. Moreover, cellular senescence and glucose metabolism disturbance in the brain of AD patients may precede amyloid-β deposition or Tau protein phosphorylation. Thus, metabolic reprogramming targeting senescent microglia and astrocytes may be a novel strategy for AD intervention and treatment. Here, we recapitulate the relationships between neural cell senescence and abnormal glucose metabolism (e.g., insulin signaling, glucose and lactate metabolism) in AD. We then discuss the potential perspective of metabolic reprogramming towards an AD intervention, providing a theoretical basis for the further exploration of the pathogenesis of and therapeutic approach toward AD.     

Differential In Vitro Effects of SGLT2 Inhibitors on Mitochondrial Oxidative Phosphorylation,Glucose Uptake and Cell Metabolism

(1) The cardio-reno-metabolic benefits of the SGLT2 inhibitors canagliflozin (cana), dapagliflozin (dapa), ertugliflozin (ertu), and empagliflozin (empa) have been demonstrated, but it remains unclear whether they exert different off-target effects influencing clinical profiles. (2) We aimed to investigate the effects of SGLT2 inhibitors on mitochondrial function, cellular glucose-uptake (GU), and metabolic pathways in human-umbilical-vein endothelial cells (HUVECs). (3) At 100 µM (supra-pharmacological concentration), cana decreased ECAR by 45% and inhibited GU (IC5o: 14 µM). At 100 µM and 10 µM (pharmacological concentration), cana increased the ADP/ATP ratio, whereas dapa and ertu (3, 10 µM, about 10× the pharmacological concentration) showed no effect. Cana (100 µM) decreased the oxygen consumption rate (OCR) by 60%, while dapa decreased it by 7%, and ertu and empa (all 100 µM) had no significant effect. Cana (100 µM) inhibited GLUT1, but did not significantly affect GLUTs’ expression levels. Cana (100 µM) treatment reduced glycolysis, elevated the amino acids supplying the tricarboxylic-acid cycle, and significantly increased purine/pyrimidine-pathway metabolites, in contrast to dapa (3 µM) and ertu (10 µM). (4) The results confirmed cana´s inhibition of mitochondrial activity and GU at supra-pharmacological and pharmacological concentrations, whereas the dapa, ertu, and empa did not show effects even at supra-pharmacological concentrations. At supra-pharmacological concentrations, cana (but not dapa or ertu) affected multiple cellular pathways and inhibited GLUT1.     

Exploring the Physiological Role of Transthyretin in Glucose Metabolism in the Liver

Transthyretin (TTR), a 55 kDa evolutionarily conserved protein, presents altered levels in several conditions, including malnutrition, inflammation, diabetes, and Alzheimer’s Disease. It has been shown that TTR is involved in several functions, such as insulin release from pancreatic β-cells, recovery of blood glucose and glucagon levels of the islets of Langerhans, food intake, and body weight. Here, the role of TTR in hepatic glucose metabolism was explored by studying the levels of glucose in mice with different TTR genetic backgrounds, namely with two copies of the TTR gene, TTR+/+; with only one copy, TTR+/−; and without TTR, TTR−/−. Results showed that TTR haploinsufficiency (TTR+/−) leads to higher glucose in both plasma and in primary hepatocyte culture media and lower expression of the influx glucose transporters, GLUT1, GLUT3, and GLUT4. Further, we showed that TTR haploinsufficiency decreases pyruvate kinase M type (PKM) levels in mice livers, by qRT-PCR, but it does not affect the hepatic production of the studied metabolites, as determined by 1H NMR. Finally, we demonstrated that TTR increases mitochondrial density in HepG2 cells and that TTR insufficiency triggers a higher degree of oxidative phosphorylation in the liver. Altogether, these results indicate that TTR contributes to the homeostasis of glucose by regulating the levels of glucose transporters and PKM enzyme and by protecting against mitochondrial oxidative stress.     

高温液态水中葡萄糖分解反应动力学

研究了压力10 MPa,温度453.15～493.15 K下葡萄糖在高温液态水中分解反应动力学,考察了不同温度下反应时间对葡萄糖异构化产物果糖和进一步分解的主要产物5-羟甲基糠醛收率的影响.实验结果表明,在无外加催化剂情况下,葡萄糖能顺利进行分解反应,实验数据与2级反应动力学方程吻合较好.随着温度的升高,分解反应速率常数显著增大,葡萄糖分解反应的活化能为140.97 kJ/mol.     

葡萄糖和蔗糖热分解过程的动力学分析

对葡萄糖和蔗糖的热分解过程进行了TG-DTA研究,采用Kissinger法、Friedman法及非线性拟合法获得了分解过程的反应机理和动力学参数. 结果表明,葡萄糖比蔗糖更易分解. 葡萄糖的分解过程分别为二级和一级反应,蔗糖的分解过程分别为n级和一级反应. 利用非线性拟合法给出了葡萄糖与蔗糖热分解过程的完整反应途径和动力学参数,葡萄糖三阶段的活化能分别为132, 150和253 kJ/mol,指前因子分别为11.6, 11.1和19.6 s-1;蔗糖两阶段的活化能分别为105和229 kJ/mol,指前因子分别为8.2和18.6 s-1.     

Kinetics of glucose ethanolysis catalyzed by extremely low sulfuric acid in ethanol medium简

The kinetics for production of ethyl levulinate from glucose in ethanol medium was investigated. The experiments were performed in various temperatures （433-473 K） and initial glucose concentrations （0.056-0.168 mol·L-1） with extremely low sulfuric acid as the catalyst. The results show that higher temperature can improve the conversion of glucose to ethyl levulinate, with higher yield of ethyl levulinate （44.79%, by mole） obtained at 473 K for 210 min. The kinetics follows a simplified first-order kinetic model. For the main and side reactions, the values of activation energy are 122.64 and 70.97 kJ·mo1-1, and the reaction orders are 0.985 and 0.998, respectively.     

流加培养过程中杂交瘤细胞的摄氧率与生长代谢之间的关联

摄氧率(OUR)不仅易于在线检测而且可以快速反映细胞的物质和能量代谢状况。为此,利用2 L B.Braun反应器的恒速流加培养工艺,考察了杂交瘤细胞的摄氧率与生长、代谢之间的关系。OUR与活细胞密度成良好的正相关性,但由于氧比消耗速率不是常数,所以二者不呈线性关系,从而利用OUR只能估测,而不能准确计算细胞密度。随着葡萄糖浓度降至低水平,氧比消耗速率、ATP比生成速率下降,而氧与葡萄糖的消耗计量比、细胞对氧的消耗逐增,由氧化磷酸化生成的ATP比例上升,说明葡萄糖代谢途径逐渐从糖酵解途径迁移到三羧酸循环,被氧化程度提高,能量利用率增强。     

C50株抗CEA杂交瘤细胞抗体生成动力学及体外培养条件的优化

目的　研究C5 0株抗CEA杂交瘤细胞的抗体生成动力学 ,确定优化体外培养条件。方法　体外静态培养C5 0细胞 ,采用ELISA和细胞计数的方法检测培养上清抗体浓度和细胞数量 ,分析细胞生长与抗体分泌的关联性。采用体内复壮和添加新型免疫增强剂CpGODN的方法 ,尝试恢复长期体外培养的C5 0细胞的抗体生成能力。结果　C5 0细胞的抗体生成动力学为非生长关联型 ,经过体内复壮 ,C5 0细胞体外培养上清中抗体浓度显著提高 ,但活细胞密度或细胞活力均未发生明显变化。在培养基中添加一定浓度的CpGODN ,可以恢复长期体外培养的C5 0细胞的抗体生成能力。结论　根据细胞的抗体生成动力学特征 ,通过调节细胞的生长状态 ,可提高上清抗体浓度。根据抗体基因的组织特异性表达的机制 ,通过优化杂交瘤细胞的体外培养条件 ,能保持细胞正常的抗体生成能力 ,维持细胞高且稳定的上清抗体浓度     

基于发酵动力学模型的小球藻高密度发酵培养

构建了50 L发酵罐小球藻分批培养动力学模型,采用补料策略高密度发酵培养小球藻,考察了补料发酵过程中碳源的利用情况,采用实时荧光定量PCR技术分析了蛋白质合成关键酶二氨基庚二酸异构酶(dapF)、柠檬酸合成酶(CS)和葡萄糖?6-磷酸脱氢酶(G6PDH)的基因表达情况. 结果表明,小球藻经补料培养120 h,细胞生物量达106.65 g/L,平均生长速率为0.89 g/(L?h),葡萄糖的细胞得率为0.56 g/g,发酵过程中葡萄糖和尿素浓度对小球藻的dspF, CS和G6PDH基因表达量有重要影响.     

Vitamin C Suppresses Pancreatic Carcinogenesis through the Inhibition of Both Glucose Metabolism and Wnt Signaling

Cumulative studies have indicated that high-dose vitamin C has antitumor effects against a variety of cancers. However, the molecular mechanisms underlying these inhibitory effects against tumorigenesis and metastasis, particularly in relation to pancreatic cancer, are unclear. Here, we report that vitamin C at high concentrations impairs the growth and survival of pancreatic ductal adenocarcinoma (PDAC) cells by inhibiting glucose metabolism. Vitamin C was also found to trigger apoptosis in a caspase-independent manner. We further demonstrate that it suppresses the invasion and metastasis of PDAC cells by inhibiting the Wnt/β-catenin-mediated epithelial-mesenchymal transition (EMT). Taken together, our results suggest that vitamin C has therapeutic effects against pancreatic cancer.     

Chemical Elicitor-Induced Modulation of Antioxidant Metabolism and Enhancement of Secondary Metabolite Accumulation in Cell Suspension Cultures of Scrophularia kakudensis Franch

Scrophularia kakudensis is an important medicinal plant with pharmaceutically valuable secondary metabolites. To develop a sustainable source of naturaceuticals with vital therapeutic importance, a cell suspension culture was established in S. kakudensis for the first time. Friable calli were induced from the leaf explants cultured on a Murashige and Skoog (MS) medium containing 3.0 mg·L⁻¹ 6-benzyladenine (BA) in a combination with 2 mg·L⁻¹ 2,4-dichlorophenoxy acetic acid (2,4-D). From the callus cultures, a cell suspension culture was initiated and the cellular differentiation was investigated. In addition, the effect of biotic elicitors such as methyl jasmonate (MeJa), salicylic acid (SA), and sodium nitroprusside (SNP) on the accumulation of secondary metabolites and antioxidant properties was demonstrated. Among the elicitors, the MeJa elicited the accumulation of total phenols, flavonoids, and acacetin, a flavonoid compound with multiple pharmaceutical values. Similarly, the higher concentrations of the MeJa significantly modulated the activities of antioxidant enzymes and enhanced the scavenging potentials of free radicals of cell suspension extracts. Overall, the outcomes of this study can be utilized for the large scale production of pharmaceutically important secondary metabolites from S. kakudensis through cell suspension cultures.     

Lithium Enhances Hippocampal Glucose Metabolism in an In Vitro Mice Model of Alzheimer’s Disease

Impaired cerebral glucose metabolism is an early event that contributes to the pathogenesis of Alzheimer’s disease (AD). Importantly, restoring glucose availability by pharmacological agents or genetic manipulation has been shown to protect against Aβ toxicity, ameliorate AD pathology, and increase lifespan. Lithium, a therapeutic agent widely used as a treatment for mood disorders, has been shown to attenuate AD pathology and promote glucose metabolism in skeletal muscle. However, despite its widespread use in neuropsychiatric disorders, lithium’s effects on the brain have been poorly characterized. Here we evaluated the effect of lithium on glucose metabolism in hippocampal neurons from wild-type (WT) and APPSwe/PS1ΔE9 (APP/PS1) mice. Our results showed that lithium significantly stimulates glucose uptake and replenishes ATP levels by preferential oxidation of glucose through glycolysis in neurons from WT mice. This increase was also accompanied by a strong increase in glucose transporter 3 (Glut3), the major carrier responsible for glucose uptake in neurons. Similarly, using hippocampal slices from APP-PS1 mice, we demonstrate that lithium increases glucose uptake, glycolytic rate, and the ATP:ADP ratio in a process that also involves the activation of AMPK. Together, our findings indicate that lithium stimulates glucose metabolism and can act as a potential therapeutic agent in AD.     

Membrane Microfiltration Fermentation of Glucose Oxidase with Cell Recycling

Membrane microfiltration fermentation(MMF) with cell recycling was successfully ap-plied to the production of glucose oxidase(GOD).A plate microfiltration module was found suitablefor such purpose.By feeding whole medium in MMF,the productivity of GOD was much higherthan that by feeding glucose alone.With increasing dilution rate the enzyme productivity increasedand average enzyme activity decreased.The enzyme productivity of MMF under D=0.12h~(-1)and0.2Oh~(-1) were 3871 and 3945 U.h~(-1)respectively,which was about 3 times as that of batch fermen-tation(BF)and the average enzyme activity was still as high as 37 U.mL~(-1)under D=0.12h~(-1).The relative efficiency of MMF applied to low yield strain was higher than that applied to high yieldstrain.     

Lack of TRPV1 Channel Modulates Mouse Gene Expression and Liver Proteome with Glucose Metabolism Changes

To investigate the role of the transient receptor potential channel vanilloid type 1 (TRPV1) in hepatic glucose metabolism, we analyzed genes related to the clock system and glucose/lipid metabolism and performed glycogen measurements at ZT8 and ZT20 in the liver of C57Bl/6J (WT) and Trpv1 KO mice. To identify molecular clues associated with metabolic changes, we performed proteomics analysis at ZT8. Liver from Trpv1 KO mice exhibited reduced Per1 expression and increased Pparα, Pparγ, Glut2, G6pc1 (G6pase), Pck1 (Pepck), Akt, and Gsk3b expression at ZT8. Liver from Trpv1 KO mice also showed reduced glycogen storage at ZT8 but not at ZT20 and significant proteomics changes consistent with enhanced glycogenolysis, as well as increased gluconeogenesis and inflammatory features. The network propagation approach evidenced that the TRPV1 channel is an intrinsic component of the glucagon signaling pathway, and its loss seems to be associated with increased gluconeogenesis through PKA signaling. In this sense, the differentially identified kinases and phosphatases in WT and Trpv1 KO liver proteomes show that the PP2A phosphatase complex and PKA may be major players in glycogenolysis in Trpv1 KO mice.     

细胞培养技术在化妆品工业中的应用

综述了生物技术在化妆品工业领域的广泛应用,其中包括植物细胞、动物细胞培养技术在化妆品原料生产、筛选以及产品评估等方面的应用。