Novel role of TRPV2 in promoting the cytotoxicity of H2O2-mediated oxidative stress in Human hepatoma cells

Oxidative stress is important for the initiation and progression of cancers, which confers the cells with a survival advantage by inducing oxidative adaption and drug resistance. Therefore, developing strategies to promote oxidative stress-induced cytotoxicity could be important for cancer therapy. Herein, we found that H₂O₂-mediated oxidative stress increases TRPV2 expression in human hepatoma (HepG2 and Huh-7) cells. This occurred at the mRNA and protein levels in a dose-dependent manner. The significance of TRPV2 in promoting H₂O₂-induced cell death was demonstrated in gain and loss of function studies with overexpression and knockdown of TRPV2, respectively. Mechanistically, H₂O₂-induced cell death involves inhibition of pro-survival signaling proteins (Akt, Nrf2) and activation of pro-death signaling proteins (p38, JNK1). Overexpression of TRPV2 in H₂O₂-treated hepatoma cells aggravates the inhibition of Akt and Nrf2, while it enhances the activation of p38 and JNK1 at the early stage of cell death. Interestingly, increased expression of TRPV2 in HepG2 cells improved the efficacy of stress-associated chemicals to induce cell death. Our findings suggest that TRPV2 acts as an important enhancer for H₂O₂-induced cytotoxicity. This process occurred by the inhibition of Akt and Nrf2 as well as the early activation of p38 and JNK1. These findings have important implications for inhibition of oxidative adaption and drug resistance.     

The xanthophyll cycle and sustained thermal energy dissipation activity in Vinca minor and Euonymus kiautschovicus in winter

The influence of low temperature on the operation of the xanthophyll cycle and energy dissipation activity, as ascertained through measurements of chlorophyll fluorescence, was examined in two broad-leaved evergreen species, Vinca minor L. and Euonymus kiautschovicus Loessner. In leaves examined under laboratory conditions, energy dissipation activity developed more slowly at lower leaf temperatures, but the final, steady-state level of such activity was greater at lower temperatures where the rate of energy utilization (through photosynthetic electron transport) was much lower. The rate at which energy dissipation activity increased was similar to that of the de-epoxidation of violaxanthin to antheraxanthin and zea-xanthin at different temperatures. However, leaves in the field examined prior to sunrise on mornings following cold days and nights exhibited a retention of antheraxanthin and zeaxanthin that was associated with sustained decreases in photosystem II efficiency. We therefore suggest that this phenomenon of ‘photoinhibition’ in response to light and cold temperatures during the winter results from sustained photoprotective thermal energy dissipation associated with the xanthophyll cycle. Such retention of the de-epoxidized components of the xanthophyll cycle responded to day-to-day changes in temperature, being greatest on the coldest mornings (when photoprotective energy dissipation might be most required) and less on warmer mornings when photosynthesis could presumably proceed at higher rates.     

Monoamine oxidase-A is an important source of oxidative stress and promotes cardiac dysfunction,apoptosis, and fibrosis in diabetic cardiomyopathy

Oxidative stress is closely associated with the pathophysiology of diabetic cardiomyopathy (DCM). The mitochondrial flavoenzyme monoamine oxidase A (MAO-A) is an important source of oxidative stress in the myocardium. We sought to determine whether MAO-A plays a major role in modulating DCM. Diabetes was induced in Wistar rats by single intraperitoneal injection of streptozotocin (STZ). To investigate the role of MAO-A in the development of pathophysiological features of DCM, hyperglycemic and age-matched control rats were treated with or without the MAO-A-specific inhibitor clorgyline (CLG) at 1 mg/kg/day for 8 weeks. Diabetes upregulated MAO-A activity; elevated markers of oxidative stress such as cardiac lipid peroxidation, superoxide dismutase activity, and UCP3 protein expression; enhanced apoptotic cell death; and increased fibrosis. All these parameters were significantly attenuated by CLG treatment. In addition, treatment with CLG substantially prevented diabetes-induced cardiac contractile dysfunction as evidenced by decreased QRS, QT, and corrected QT intervals, measured by ECG, and LV systolic and LV end-diastolic pressure measured by microtip pressure transducer. These beneficial effects of CLG were seen despite the persistent hyperglycemic and hyperlipidemic environments in STZ-induced experimental diabetes. In summary, this study provides strong evidence that MAO-A is an important source of oxidative stress in the heart and that MAO-A-derived reactive oxygen species contribute to DCM.     

Modulation of the immune response by Middle East respiratory syndrome coronavirus

Coronavirus (CoV) infections are commonly associated with respiratory and enteric disease in humans and animals. In 2012, a new human disease called Middle East respiratory syndrome (MERS) emerged in the Middle East. MERS was caused by a virus that was originally called human coronavirus-Erasmus Medical Center/2012 but was later renamed as Middle East respiratory syndrome coronavirus (MERS-CoV). MERS-CoV causes high fever, cough, acute respiratory tract infection, and multiorgan dysfunction that may eventually lead to the death of the infected individuals. The exact origin of MERS-CoV remains unknown, but the transmission pattern and evidence from virological studies suggest that dromedary camels are the major reservoir host, from which human infections may sporadically occur through the zoonotic transmission. Human to human transmission also occurs in healthcare facilities and communities. Recent studies on Middle Eastern respiratory continue to highlight the need for further understanding the virus-host interactions that govern disease severity and infection outcome. In this review, we have highlighted the major mechanisms of immune evasion strategies of MERS-CoV. We have demonstrated that M, 4a, 4b proteins and Plppro of MERS-CoV inhibit the type I interferon (IFN) and nuclear factor-κB signaling pathways and therefore facilitate innate immune evasion. In addition, nonstructural protein 4a (NSP4a), NSP4b, and NSP15 inhibit double-stranded RNA sensors. Therefore, the mentioned proteins limit early induction of IFN and cause rapid apoptosis of macrophages. MERS-CoV strongly inhibits the activation of T cells with downregulation of antigen presentation. In addition, uncontrolled secretion of interferon ɣ-induced protein 10 and monocyte chemoattractant protein-1 can suppress proliferation of human myeloid progenitor cells.     

Effect of natural exogenous antioxidants on aging and on neurodegenerative diseases

Abstract

Aging and neurodegenerative diseases share oxidative stress cell damage and depletion of endogenous antioxidants as mechanisms of injury, phenomena that are occurring at different rates in each process. Nevertheless, as the central nervous system (CNS) consists largely of lipids and has a poor catalase activity, a low amount of superoxide dismutase and is rich in iron, its cellular components are damaged easily by overproduction of free radicals in any of these physiological or pathological conditions. Thus, antioxidants are needed to prevent the formation and to oppose the free radicals damage to DNA, lipids, proteins, and other biomolecules. Due to endogenous antioxidant defenses are inadequate to prevent damage completely, different efforts have been undertaken in order to increase the use of natural antioxidants and to develop antioxidants that might ameliorate neural injury by oxidative stress. In this context, natural antioxidants like flavonoids (quercetin, curcumin, luteolin and catechins), magnolol and honokiol are showing to be the efficient inhibitors of the oxidative process and seem to be a better therapeutic option than the traditional ones (vitamins C and E, and β-carotene) in various models of aging and injury in vitro and in vivo conditions. Thus, the goal of the present review is to discuss the molecular basis, mechanisms of action, functions, and targets of flavonoids, magnolol, honokiol and traditional antioxidants with the aim of obtaining better results when they are prescribed on aging and neurodegenerative diseases.     

Modelling HIV immune response and validation with clinical data

A system of ordinary differential equations is formulated to describe the pathogenesis of HIV infection, wherein certain features that have been shown to be important by recent experimental research are incorporated in the model. These include the role of CD4+memory cells that serve as a major reservoir of latently infected cells, a critical role for T-helper cells in the generation of CD8 memory cells capable of efficient recall response, and stimulation by antigens other than HIV. A stability analysis illustrates the capability of this model in admitting multiple locally asymptotically stable (locally a.s.) off-treatment equilibria. We show that this more biologically detailed model can exhibit the phenomenon of transient viremia experienced by some patients on therapy with viral load levels suppressed below the detection limit. We also show that the loss of CD4+T-cell help in the generation of CD8+memory cells leads to larger peak values for the viral load during transient viremia. Censored clinical data is used to obtain parameter estimates. We demonstrate that using a reduced set of 16 free parameters, obtained by fixing some parameters at their population averages, the model provides reasonable fits to the patient data and, moreover, that it exhibits good predictive capability. We further show that parameter values obtained for most clinical patients do not admit multiple locally a.s off-treatment equilibria. This suggests that treatment to move from a high viral load equilibrium state to an equilibrium state with a lower (or zero) viral load is not possible for these patients.     

Pre-exposure affects the olfactory response of Drosophila melanogaster to menthol

A modification of the trap assay (Woodard et al., 1989) was used to evaluate the response of Drosophila melanogaster (Meigen) to food media containing menthol. Dose-response curves for flies to mentholic foods were produced for flies that had been pre-exposed to menthol, during development and adult life, and flies that had not been exposed to menthol before the assay. Mentholic food media were less attractive to Drosophila than plain food medium. Rearing flies on a medium containing menthol reduced their aversion to some concentrations of menthol. The rearing effect was not simply due to lowered general activity levels resulting from developing in a medium containing menthol. There was a threshold concentration of menthol in the rearing medium below which we found no induced behavioural change.     

Proteomic Analysis of Specific Proteins in the Root of Salt-Tolerant Barley

Comparative two-dimensional electrophoresis showed six proteins, which were significantly produced in the root of salt-tolerant barley. These proteins were identified as stress/defense-related proteins that do not scavenge reactive oxygen species directly, suggesting that salt-tolerant barley develops not only an antioxidative system, but also physical and biochemical changes to cope with salt stress.