p38 MAPK pathway is involved in high glucose-induced thioredoxin interacting protein induction in mouse mesangial cells

Excessive reactive oxygen species (ROS) play a key role in the pathogenesis of diabetic nephropathy. The thioredoxin (TRX) system, a major thiol antioxidant system, regulates the reduction of intracellular ROS. Here we show that high glucose (HG) inhibits TRX ROS-scavenging function through p38 mitogen-activated protein kinase (MAPK)-mediated induction of thioredoxin interacting protein (TXNIP) in mouse mesangial cells (MMCs). Knockdown of TXNIP in MMCs reversed HG-induced reduction of TRX activity and inhibited HG-induced activation of p38 MAPK and increased synthesis of TGF-β1 and fibronectin. These data suggest that HG-induced overexpression of TXNIP in MMCs, which may be via the p38 MAPK pathway.     

NF-κB inhibitory action of resveratrol: A probable mechanism of neuroprotection in experimental diabetic neuropathy

Resveratrol has shown array of biological actions, and is under clinical development for various disease conditions. The etiology of diabetic neuropathy revolves around oxidative stress, AGE formation, lipid peroxidation etc. All these stimulate inflammatory processes and NF-κB cascade is considered as one of the major players of inflammatory response. Activation of NF-κB results in elevated levels of inflammatory mediators. COX-2 and TNF-α activity have also been correlated with inflammatory damage in the pathophysiology of diabetic neuropathy (DN). Therefore we investigated the effect of resveratrol on NF-κB inflammatory cascade, COX-2, TNF-α and IL-6 levels in experimental DN.We found that resveratrol protected against various functional and behavioral deficits in diabetic neuropathy in line with our earlier published reports. In this study we found that the resveratrol treatment decreased the expression of p65 and IκB-α in treated rats. Treatment also ameliorated the elevated levels of TNF-α, IL-6 and COX-2. Resveratrol treatment produced significant decrease in nerve MDA levels in treated animals which may also be contributing to reduction in neuro-inflammation. This study confirms the NF-κB inhibitory activity and anti-inflammatory activity of resveratrol which may contribute to neuroprotection in diabetic neuropathy apart from its antioxidant effect.     

烟碱降解细菌Ochrobactrum intermedium DN2生长培养基及培养条件的优化研究

在烟碱生物降解的研究和实际应用中,需要在较短的时间内获得大量O.intermediumDN2菌体。为了提高菌株DN2的菌体浓度,缩短其培养时间,本研究采用PlackettBurman设计对影响O.intermediumDN2生长的内在和外在相关因素进行了评价。结果表明,影响菌株DN2生长的显著因素有胰蛋白胨、MgSO₄·7H₂O、初始pH值、温度、装液量和培养时间。在此基础上,采用响应曲面法分别对该菌生长培养基的组成和培养条件进行优化,得到最佳培养基组成为(g/L):胰蛋白胨11.34、牛肉膏3.00、NaCl5.00、MgSO₄·7H₂O3.71,pH值7.23;最佳培养条件为温度32℃、转速120r/min、装液量88ml/250ml三角瓶、培养时间34h。5L发酵罐验证实验表明,菌株DN2达到最大生长量的时间为36h,与预测值34h基本一致,比优化前缩短约12h;最大菌体浓度为6.49×10₉cfu/ml,与预测值6.73×10₉cfu/ml接近,比优化前高近一个数量级。     

B → A → B Transitions in a Molecular Dynamics Trajectory of Low Salt DNA Solution

A molecular dynamics simulation of the DNA dodecamer d(CGCATATATGCG) has been performed with AMBER 5.0 under low salt conditions. Both B A and A B transitions are observed. This may have biological significance for the formation of complexes between DNA and TATA-box binding proteins.Supplementary material to this paper is available in electronic form at http://dx.doi.org/10.1007/s0089400060654     

Intermittent fasting prevents the progression of type I diabetic nephropathy in rats and changes the expression of Sir2 and p53

Diabetic nephropathy (DN) is one of the main causes of end stage renal disease (ESRD) and a leading cause of diabetes mellitus related morbidity and mortality. Recently, sirtuin are reported to have emerging pathogenetic roles in cancer, muscle differentiation, heart failure, neurodegeneration, diabetes and aging. The aim of the present study was to study the role of intermittent fasting (IF) on DN and studying the expression of Sir2 and p53. At biochemical level, we found that IF causes significant improvement in blood urea nitrogen (BUN), creatinine, albumin and HDL cholesterol, parameters that are associated with the development of DN. Diabetic rats on IF also show significant improvement in onset of hypertension. Interestingly, the expression of Sir2, a NAD dependent histone deacetylase, decreases in diabetic rat kidney and this decrease is overcome by IF. Moreover, we provide evidence for involvement of mitogen activated protein kinases (MAPK) cascade in mediating the effects of IF as there is reduction in the expression of p38 which gets induced under diabetic condition. This was further accompanied by the concomitant decrease in cleavage of caspase3 and p53 expression. These findings suggest that IF significantly improves biochemical parameters associated with development of DN and changes the expression of Sir2 and p53.     

Involvement of a Rho-ROCK-JNK pathway in arsenic trioxide-induced apoptosis in chronic myelogenous leukemia cells

The apoptotic signals activated by As(2)O(3) in the chronic myelogenous leukemia (CML) cell lines K562 and KCL22 were investigated. As(2)O(3) was found to induce apoptosis in these cells via the intrinsic pathway. As(2)O(3) also induced a sustained c-Jun NH2-terminal kinase (JNK) activation which preceded and was necessary for caspase-9 activation. We established that Rho and its effector, the kinase ROCK, are activated by As(2)O(3). Inhibition of either Rho or ROCK prevented JNK activation and protected against apoptosis. Thus, in CML cells, apoptosis induced by As(2)O(3) is mediated, at least in part, via a Rho-ROCK-JNK axis. These findings define a novel signaling pathway for As(2)O(3)-induced apoptosis.     

Constructing an Ion-Wall to Achieve Excellent Lithium Anodes in Li–O2 Batteries with High DN Electrolytes

For the lithium (Li) metal anode, constructing a strong and durable protective layer with lithium-ion permeability is crucial, especially in high donor number (DN) solvent system. High DN solvent-based electrolytes can support both higher capacity and lower charge overpotential in the rechargeable lithium–oxygen batteries (LOBs). However, Li anodes in high DN solvent system suffer from severe corrosion and uncontrolled dendrite growth due to the unstable solid-electrolyte interphase (SEI). Typically, this interface is formed in situ through electrochemical processes with complicated component and spatial distribution. Here, a functional molecule is introduced to construct an ion-wall (IW) on Li surface by prechemical sequential reactions (p-CSRs), through which the crystalline nanoparticles as bricks and amorphous hybrid compounds as the mortar can be produced to build such a “wall.” Different from the conventional SEI, this wall is not only compact and uniform, but also possess high strength, excellent passivation properties and high ionic conductivity. With these properties, the IW could suppress Li dendrites and inhabit the side reaction, supporting highly reversible Li plating/stripping behavior in high DN solvent system. As a result, the cycle stability of LOBs based on the IW protected Li anode is significantly improved.     

A Disintegrin and Metalloproteinase-10 (ADAM-10) Mediates DN30 Antibody-induced Shedding of the Met Surface Receptor

Met, the tyrosine kinase receptor for the hepatocyte growth factor is a prominent regulator of cancer cell invasiveness and has emerged as a promising therapeutic target. Binding of the anti-Met monoclonal antibody DN30 to its epitope induces the proteolytic cleavage of Met, thereby impairing the invasive growth of tumors. The molecular mechanism controlling this therapeutic shedding process has so far been unknown. Here, we report that A Disintegrin And Metalloproteinase (ADAM)-10, but not ADAM-17, is required for DN30-induced Met shedding. Knockdown of ADAM-10 in different tumor cell lines or abrogation of its proteolytic activity by natural or synthetic inhibitors abolished Met down-regulation on the cell surface as well as reduction of Met activation. Moreover, hepatocyte growth factor-induced tumor cell migration and invasion were impaired upon ADAM-10 knockdown. Thus, the therapeutic effect of DN30 involves ADAM-10-dependent Met shedding, linking for the first time a specific metalloprotease to target therapy against a receptor tyrosine kinase.