ER stress and ASK1-JNK activation contribute to oridonin-induced apoptosis and growth inhibition in cultured human hepatoblastoma HuH-6 cells

Workers who are exposed to extreme heat or work in hot environments may be at risk of heat stress. Exposure to extreme heat can result in occupational illnesses and injuries. On the other hand, local and regional heat therapy has been used for the treatment of some cancers, such as liver cancer, lung cancer, and kidney cancer. Although heat stress has been shown to induce the accumulation of p53 protein, a key regulator of cell cycle, apoptosis, DNA repair, and autophagy, how it regulates p53 protein accumulation and what the p53 targets are remain unclear. Here, we show that, among various genotoxic stresses, including ionizing radiation (IR) and ultraviolet (UV) radiation, heat stress contributes significantly to increase p53 protein levels in normal liver cells and liver cancer cells. Heat stress did not increase p53 mRNA expression as well as p53 promoter activity. However, heat stress enhanced the half-life of p53 protein. Moreover, heat stress increased the expression of puma and light chain 3 (LC-3), which are associated with the apoptotic and autophagic function of p53, respectively, whereas it did not change the expression of the cell cycle regulators p21, 14-3-3δ, and GADD45α, suggesting that heat-triggered alteration of p53 selectively modulates the downstream targets of p53. Our study provides a novel mechanism by which heat shock stimulates p53 protein accumulation, which is different from common DNA damages, such as IR and UV, and also provides new molecular basis for heat injuries or heat therapy.     

Association between rs10118757(A/G) in methylthioadenosine phosphorylase gene and coronary artery disease in Chinese Hans

Studies focusing on the association of gene methylthioadenosine phosphorylase (MTAP) with the risk of coronary artery disease (CAD) and myocardial infarction (MI) are limited.     

Evaluation of glutathione S-transferase genetic variants affecting type 2 diabetes susceptibility: A meta-analysis

Genetic polymorphisms of glutathione S-transferases (GSTs) and type 2 diabetes mellitus (T2DM) risk have been widely studied, however, the results were somewhat conflicting. To evaluate the association of GSTs (GSTM1, GSTT1 and GSTP1) gene polymorphisms with T2DM, a meta-analysis was performed before October, 2012. ORs were pooled according to random-effects model. There were a total of 1354/1666 (n = 9) cases/controls (studies) for GSTM1, 1271/1470 (n = 8) for GSTT1, and 1205/1250 (n = 7) for GSTM1. There were significant associations between GSTM1 polymorphism, GSTT1 polymorphism and T2DM in the contrast of present genotype vs. null genotype, with pooled OR = 1.99 (95%CI = 1.46–2.71) and OR = 1.61 (95%CI = 1.19–2.17), respectively. Yet no significant association of GSTP1 polymorphism and T2DM was showed. When stratified by ethnicity, the significant associations were also existed in Asians for GSTM1 and GSTT1, but not GSTP1. No publication bias but some extent of heterogeneity was observed. Finally, the accumulated evidence proved the obvious associations of GSTM1 and GSTT1 polymorphisms with an increased risk of T2DM.     

Preparative Separation of Enantiomers Based on Functional Nucleic Acids Modified Gold Nanoparticles

The preparative‐scale separation of chiral compounds is vitally important for the pharmaceutical industry and related fields. Herein we report a simple approach for rapid preparative separation of enantiomers using functional nucleic acids modified gold nanoparticles (AuNPs). The separation of _DL‐tryptophan (_DL‐Trp) is demonstrated as an example to show the feasibility of the approach. AuNPs modified with enantioselective aptamers were added into a racemic mixture of _DL‐Trp. The aptamer‐specific enantiomer (_L‐Trp) binds to the AuNPs surface through aptamer‐_L‐Trp interaction. The separation of _DL‐Trp is then simply accomplished by centrifugation: the precipitate containing _L‐Trp bounded AuNPs is separated from the solution, while the _D‐Trp remains in the supernatant. The precipitate is then redispersed in water. The aptamer is denatured under 95 °C and a second centrifugation is then performed, resulting in the separation of AuNPs and _L‐Trp. The supernatant is finally collected to obtain pure _L‐Trp in water. The results show that the racemic mixture of _DL‐Trp is completely separated into _D‐Trp and _L‐Trp, respectively, after 5 rounds of repeated addition of fresh aptamer‐modified AuNPs to the _DL‐Trp mixture solution. Additionally, the aptamer‐modified AuNPs can be repeatedly used for at least eight times without significant loss of its binding ability because the aptamer can be easily denatured and renatured in relatively mild conditions. The proposed approach could be scaled up and extended to the separation of other enantiomers by the adoption of other enantioselective aptamers. Chirality 25:751–756, 2013. © 2013 Wiley Periodicals, Inc.     

Modeling the synergy between HSV-2 and HIV and potential impact of HSV-2 therapy

Mounting evidence indicates that genital HSV-2 infection may increase susceptibility to HIV infection and that co-infection may increase infectiousness. Accordingly, antiviral treatment of people with HSV-2 may mitigate the incidence of HIV in populations where both pathogens occur. To better understand the epidemiological synergy between HIV and HSV-2, we formulate a deterministic compartmental model that describes the transmission dynamics of these pathogens. Unlike earlier models, ours incorporates gender and heterogeneous mixing between activity groups. We derive explicit expressions for the reproduction numbers of HSV-2 and HIV, as well as the invasion reproduction numbers via next generation matrices. A qualitative analysis of the system includes the local and global behavior of the model. Simulations reinforce these analytical results and demonstrate epidemiological synergy between HSV-2 and HIV. In particular, numerical results show that HSV-2 favors the invasion of HIV, may dramatically increase the peak as well as reducing the time-to-peak of HIV prevalence, and almost certainly has exacerbated HIV epidemics. The potential population-level impact of HSV-2 on HIV is demonstrated by calculating the fraction of HIV infections attributable to HSV-2 and the difference between HIV prevalence in the presence and absence of HSV-2. The potential impact of treating people with HSV-2 on HIV control is demonstrated by comparing HIV prevalence with and without HSV-2 therapy. Most importantly, we illustrate that the aforementioned aspects of the population dynamics can be significantly influenced by the sexual structure of the population.     

Effects of blood-feeding on olfactory sensitivity of the malaria mosquito Anopheles gambiae: Application of mixed linear models to account for repeated measurements

Olfaction plays an important role in the host-seeking behavior of the malaria mosquito Anopheles gambiae. After a complete blood meal, female mosquitoes will not engage in host-seeking behavior until oviposition has occurred. We investigated if peripheral olfactory sensitivity changed after a blood meal by recording electroantennograms (EAGs) of female mosquitoes at three time points (2 h, 48 h and 72 h) to 15 volatile kairomones of either human origin or documented to emanate from oviposition sites. The EAG-sensitivity was compared with that of females of similar age post eclosion. As is common practice in electrophysiological studies, the EAG recordings were obtained by repeated stimulation of the same antennal preparations. We introduce mixed linear modeling as an improved statistical analysis for electrophysiological data. Two hours after blood ingestion, olfactory sensitivity as quantified through EAG-recording increased significantly and selectively, i.e. for seven compounds, compared to unfed females of the same age. Such short-term electrophysiological sensitization in the olfactory system as a result of feeding has not been documented before for insects. Sensitization to six compounds persisted until 48 h or 72 h post-blood meal at one or more concentrations. Desensitization was observed at 48 and 72 h pbm in response to two and three kairomones, respectively. For several compounds, sensitization at the EAG-level corresponded with sensitization found previously in single sensillum studies on olfactory neurons in antennal sensilla trichodea of An. gambiae females. These effects are likely to reflect sensitization to oviposition cues, as eggs have matured 48–72 h pbm. Knowledge of changes in olfactory sensitivity to kairomones can be applied to increase trap catches of malaria mosquitoes that have taken a blood meal and need to locate oviposition sites.     

Up-regulation of protein tyrosine nitration in methamphetamine-induced neurotoxicity through DDAH/ADMA/NOS pathway

Protein tyrosine nitration is an important post-translational modification mediated by nitric oxide (NO) associated oxidative stress, occurring in a variety of neurodegenerative diseases. In our previous study, an elevated level of dimethylarginine dimethylaminohydrolase 1 (DDAH1) protein was observed in different brain regions of acute methamphetamine (METH) treated rats, indicating the possibility of an enhanced expression of protein nitration that is mediated by excess NO through the DDAH1/ADMA (Asymmetric Dimethylated l-arginine)/NOS (Nitric Oxide Synthase) pathway. In the present study, proteomic methods, including stable isotope labeling with amino acids in cell culture (SILAC) and two dimensional electrophoresis, were used to determine the relationship between protein nitration and METH induced neurotoxicity in acute METH treated rats and PC12 cells. We found that acute METH administration evokes a positive activation of DDAH1/ADMA/NOS pathway and results in an over-production of NO in different brain regions of rat and PC12 cells, whereas the whole signaling could be repressed by DDAH1 inhibitor N^ω-(2-methoxyethyl)-arginine (l-257). In addition, enhanced expressions of 3 nitroproteins were identified in rat striatum and increased levels of 27 nitroproteins were observed in PC12 cells. These nitrated proteins are key factors for Cdk5 activation, cytoskeletal structure, ribosomes function, etc. l-257 also displayed significant protective effects against METH-induced protein nitration, apoptosis and cell death. The overall results illustrate that protein nitration plays a significant role in the acute METH induced neurotoxicity via the activation of DDAH1/ADMA/NOS pathway.     

Glyphosate effects on the gene expression of the apical bud in soybean (Glycine max)

Glyphosate is a broad spectrum, non-selective herbicide which has been widely used for weed control. Much work has focused on elucidating the high accumulation of glyphosate in shoot apical bud (shoot apex). However, to date little is known about the molecular mechanisms of the sensitivity of shoot apical bud to glyphosate. Global gene expression profiling of the soybean apical bud response to glyphosate treatment was performed in this study. The results revealed that the glyphosate inhibited tryptophan biosynthesis of the shikimic acid pathway in the soybean apical bud, which was the target site of glyphosate. Glyphosate inhibited the expression of most of the target herbicide site genes. The promoter sequence analysis of key target genes revealed that light responsive elements were important regulators in glyphosate induction. These results will facilitate further studies of cloning genes and molecular mechanisms of glyphosate on soybean shoot apical bud.     

Design,synthesis, and biological evaluation of novel 3-pyrrolo[b]cyclohexylene-2-dihydroindolinone derivatives as potent receptor tyrosine kinase inhibitors

A novel series of 3-pyrrolo[b]cyclohexylene-2-dihydroindolinone derivatives targeting VEGFR-2, PDGFR-β and c-Kit kinases were designed and synthesized. The molecular design was based on the SAR features of indolin-2-ones as kinase inhibitors. SAR study of the series allowed us to identify compounds possessing more potent inhibitory activities against the three kinases than sunitinb with IC₅₀ values in the low nanomolar range in vitro. Additionally, some compounds also showed favorable antiproliferative activities against a panel of cancer cell lines (BXPC-3, T24, BGC, HEPG2 and HT29).