N-Acetylcysteine in Combination with IGF-1 Enhances Neuroprotection against Proteasome Dysfunction-Induced Neurotoxicity in SH-SY5Y Cells

Ubiquitin proteasome system (UPS) dysfunction has been implicated in the development of many neuronal disorders, including Parkinson’s disease (PD). Previous studies focused on individual neuroprotective agents and their respective abilities to prevent neurotoxicity following a variety of toxic insults. However, the effects of the antioxidant N-acetylcysteine (NAC) on proteasome impairment-induced apoptosis have not been well characterized in human neuronal cells. The aim of this study was to determine whether cotreatment of NAC and insulin-like growth factor-1 (IGF-1) efficiently protected against proteasome inhibitor-induced cytotoxicity in SH-SY5Y cells. Our results demonstrate that the proteasome inhibitor, MG132, initiates poly(ADP-ribose) polymerase (PARP) cleavage, caspase 3 activation, and nuclear condensation and fragmentation. In addition, MG132 treatment leads to endoplasmic reticulum (ER) stress and autophagy-mediated cell death. All of these events can be attenuated without obvious reduction of MG132 induced protein ubiquitination by first treating the cells with NAC and IGF-1 separately or simultaneously prior to exposure to MG132. Moreover, our data demonstrated that the combination of the two proved to be significantly more effective for neuronal protection. Therefore, we conclude that the simultaneous use of growth/neurotrophic factors and a free radical scavenger may increase overall protection against UPS dysfunction-mediated cytotoxicity and neurodegeneration

Highly efficient maximum power point tracking control technique for PV system under dynamic operating conditions

publishedVersio

Acute maternal oxidant exposure causes susceptibility of the fetal brain to inflammation and oxidative stress

Background Maternal exposure to environmental stressors poses a risk to fetal development. Oxidative stress (OS), microglia activation, and inflammation are three tightly linked mechanisms that emerge as a causal factor of neurodevelopmental anomalies associated with prenatal ethanol exposure. Antioxidants such as glutathione (GSH) and CuZnSOD are perturbed, and their manipulation provides evidence for neuroprotection. However, the cellular and molecular effects of GSH alteration in utero on fetal microglia activation and inflammation remain elusive. Methods Ethanol (EtOH) (2.5 g/kg) was administered to pregnant mice at gestational days 16–17. One hour prior to ethanol treatment, N-acetylcysteine (NAC) and L-buthionine sulfoximine (BSO) were administered to modulate glutathione (GSH) content in fetal and maternal brain. Twenty-four hours following ethanol exposure, GSH content and OS in brain tissues were analyzed. Cytokines and chemokines were selected based on their association with distinctive microglia phenotype M1-like (IL-1β, IFN γ, IL-6, CCL3, CCL4, CCL-7, CCL9,) or M2-like (TGF-β, IL-4, IL-10, CCL2, CCL22, CXCL10, Arg1, Chi1, CCR2 and CXCR2) and measured in the brain by qRT-PCR and ELISA. In addition, Western blot and confocal microscopy techniques in conjunction with EOC13.31 cells exposed to similar ethanol-induced oxidative stress and redox conditions were used to determine the underlying mechanism of microglia activation associated with the observed phenotypic changes. Results We show that a single episode of mild to moderate OS in the last trimester of gestation causes GSH depletion, increased protein and lipid peroxidation and inflammatory responses inclined towards a M1-like microglial phenotype (IL-1β, IFN-γ) in fetal brain tissue observed at 6–24 h post exposure. Maternal brain is resistant to many of these marked changes. Using EOC 13.31 cells, we show that GSH homeostasis in microglia is crucial to restore its anti-inflammatory state and modulate inflammation. Microglia under oxidative stress maintain a predominantly M1 activation state. Additionally, GSH depletion prevents the appearance of the M2-like phenotype, while enhancing morphological changes associated with a M1-like phenotype. This observation is also validated by an increased expression of inflammatory signatures (IL-1β, IFN-γ, IL-6, CCL9, CXCR2). In contrast, conserving intracellular GSH concentrations eliminates OS which precludes the nuclear translocation and more importantly the phosphorylation of the NFkB p105 subunit. These cells show significantly more pronounced elongations, ramifications, and the enhanced expression of M2-like microglial phenotype markers (IL-10, IL-4, TGF-β, CXCL10, CCL22, Chi, Arg, and CCR2). Conclusions Taken together, our data show that maintaining GSH homeostasis is not only important for quenching OS in the developing fetal brain, but equally critical to enhance M2 like microglia phenotype, thus suppressing inflammatory responses elicited by environmental stressors

Serum Carotenoids and Pediatric Metabolic Index Predict Insulin Sensitivity in Mexican American Children

High concentrations of carotenoids are protective against cardiometabolic risk traits (CMTs) in adults and children. We recently showed in non-diabetic Mexican American (MA) children that serum α-carotene and β-carotene are inversely correlated with obesity measures and triglycerides and positively with HDL cholesterol and that they were under strong genetic influences. Additionally, we previously described a Pediatric Metabolic Index (PMI) that helps in the identification of children who are at risk for cardiometabolic diseases. Here, we quantified serum lycopene and β-cryptoxanthin concentrations in approximately 580 children from MA families using an ultraperformance liquid chromatography-photodiode array and determined their heritabilities and correlations with CMTs. Using response surface methodology (RSM), we determined two-way interactions of carotenoids and PMI on Matsuda insulin sensitivity index (ISI). The concentrations of lycopene and β-cryptoxanthin were highly heritable [h2 = 0.98, P = 7 × 10–18 and h2 = 0.58, P = 1 × 10–7]. We found significant (P ≤ 0.05) negative phenotypic correlations between β-cryptoxanthin and five CMTs: body mass index (− 0.22), waist circumference (− 0.25), triglycerides (− 0.18), fat mass (− 0.23), fasting glucose (− 0.09), and positive correlations with HDL cholesterol (0.29). In contrast, lycopene only showed a significant negative correlation with fasting glucose (− 0.08) and a positive correlation with HDL cholesterol (0.18). Importantly, we found that common genetic influences significantly contributed to the observed phenotypic correlations. RSM showed that increased serum concentrations of α- and β-carotenoids rather than that of β-cryptoxanthin or lycopene had maximal effects on ISI. In summary, our findings suggest that the serum carotenoids are under strong additive genetic influences and may have differential effects on susceptibility to CMTs in children

Serum carotenoids and Pediatric Metabolic Index predict insulin sensitivity in Mexican American children

High concentrations of carotenoids are protective against cardiometabolic risk traits (CMTs) in adults and children. We recently showed in non-diabetic Mexican American (MA) children that serum α-carotene and β-carotene are inversely correlated with obesity measures and triglycerides and positively with HDL cholesterol and that they were under strong genetic influences. Additionally, we previously described a Pediatric Metabolic Index (PMI) that helps in the identification of children who are at risk for cardiometabolic diseases. Here, we quantified serum lycopene and β-cryptoxanthin concentrations in approximately 580 children from MA families using an ultraperformance liquid chromatography-photodiode array and determined their heritabilities and correlations with CMTs. Using response surface methodology (RSM), we determined two-way interactions of carotenoids and PMI on Matsuda insulin sensitivity index (ISI). The concentrations of lycopene and β-cryptoxanthin were highly heritable [h2 = 0.98, P = 7 × 10-18 and h2 = 0.58, P = 1 × 10-7]. We found significant (P ≤ 0.05) negative phenotypic correlations between β-cryptoxanthin and five CMTs: body mass index (- 0.22), waist circumference (- 0.25), triglycerides (- 0.18), fat mass (- 0.23), fasting glucose (- 0.09), and positive correlations with HDL cholesterol (0.29). In contrast, lycopene only showed a significant negative correlation with fasting glucose (- 0.08) and a positive correlation with HDL cholesterol (0.18). Importantly, we found that common genetic influences significantly contributed to the observed phenotypic correlations. RSM showed that increased serum concentrations of α- and β-carotenoids rather than that of β-cryptoxanthin or lycopene had maximal effects on ISI. In summary, our findings suggest that the serum carotenoids are under strong additive genetic influences and may have differential effects on susceptibility to CMTs in children

United States Foreign Policy towards Pakistan Under the era of Trump and Obama

International audienceAt a glance into the tenure of Democrat's presidency, the president of USA Obama view was ironic because he tried his best to make relation between Washington and Islamabad. His administration came with the proposal to transform the relationship from transactional and security focused arranged into a deeper strategic partnership. Although US policy was not balanced in a year but in Republican's presidency US started to took side of Pakistan's rival that is India and limit the aids to Pakistan due to the emerging China. Under Trump's administration United States took help from Pakistan in Afghanistan and the relations are suitable

A New Species Of The Hermit Crab Genus Pagurus (Decapoda: Anomura: Paguridae) From Pakistan

Siddiqui, Feroz Akhtar, Komai, Tomoyuki (2008): A New Species Of The Hermit Crab Genus Pagurus (Decapoda: Anomura: Paguridae) From Pakistan. Raffles Bulletin of Zoology 56 (2): 317-325, DOI: 10.5281/zenodo.534064

Model for Fuel Droplet Evaporation in Combustion Chamber of Liquid Propellant Rocket Engines

Complete burning of liquid propellants droplets is very important to get higher specific impulse from liquid rocket engines. Required time must be provided to propellants droplets in combustion chamber for complete combustion. If required time is not provided then there will incomplete combustion of fuel which will reduce characteristic velocity and specific impulse. Combustion in liquid propellant rocket engine is non-premixed diffusion combustion. Combustion takes place in gaseous phase and reaction is very fast. So, the time consumed by a droplet for complete burning is the time taken by a droplet to get evaporate. Through modeling of droplets evaporation in combustion chamber of liquid propellant rocket engine, we can calculate time required for complete evaporation/ burning of propellants droplets and we can provide the required time in combustion chamber at design phase. An analytical mono component model is developed for the droplet evaporation in liquid rocket engine based on heat and mass transfer. The results of the model shows effects of the combustion chamber pressure, temperature, turbulence intensity, fuel droplet initial temperature, chamber diameter, droplet diameter and droplet relative velocity with hot gas on the life of droplet

Review of Blast Loading Models, Masonry Response, and Mitigation

Different models for prediction of blast loading, response of masonry structure against blast load, and various mitigation strategies are discussed. Variation of peak positive incident pressure with scale distance in free field spherical burst and surface burst scenarios, proposed by different researchers, is presented and compared. The variation is found significant in the region of small scaled distances. Blast wave parameters in urban environment have been found different from the free field scenario. Effects of geometry, boundary conditions, and material properties on response of masonry buildings were found significant. Different mitigation strategies such as blast wall, landscaping, architecture, and retrofitting techniques are presented

Acute maternal oxidant exposure causes susceptibility of the fetal brain to inflammation and oxidative stress

Background: Maternal exposure to environmental stressors poses a risk to fetal development. Oxidative stress (OS), microglia activation, and inflammation are three tightly linked mechanisms that emerge as a causal factor of neurodevelopmental anomalies associated with prenatal ethanol exposure. Antioxidants such as glutathione (GSH) and CuZnSOD are perturbed, and their manipulation provides evidence for neuroprotection. However, the cellular and molecular effects of GSH alteration in utero on fetal microglia activation and inflammation remain elusive. Methods: Ethanol (EtOH) (2.5 g/kg) was administered to pregnant mice at gestational days 16–17. One hour prior to ethanol treatment, N-acetylcysteine (NAC) and L-buthionine sulfoximine (BSO) were administered to modulate glutathione (GSH) content in fetal and maternal brain. Twenty-four hours following ethanol exposure, GSH content and OS in brain tissues were analyzed. Cytokines and chemokines were selected based on their association with distinctive microglia phenotype M1-like (IL-1β, IFN γ, IL-6, CCL3, CCL4, CCL-7, CCL9,) or M2-like (TGF-β, IL-4, IL-10, CCL2, CCL22, CXCL10, Arg1, Chi1, CCR2 and CXCR2) and measured in the brain by qRT-PCR and ELISA. In addition, Western blot and confocal microscopy techniques in conjunction with EOC13.31 cells exposed to similar ethanol-induced oxidative stress and redox conditions were used to determine the underlying mechanism of microglia activation associated with the observed phenotypic changes. Results: We show that a single episode of mild to moderate OS in the last trimester of gestation causes GSH depletion, increased protein and lipid peroxidation and inflammatory responses inclined towards a M1-like microglial phenotype (IL-1β, IFN-γ) in fetal brain tissue observed at 6–24 h post exposure. Maternal brain is resistant to many of these marked changes. Using EOC 13.31 cells, we show that GSH homeostasis in microglia is crucial to restore its anti-inflammatory state and modulate inflammation. Microglia under oxidative stress maintain a predominantly M1 activation state. Additionally, GSH depletion prevents the appearance of the M2-like phenotype, while enhancing morphological changes associated with a M1-like phenotype. This observation is also validated by an increased expression of inflammatory signatures (IL-1β, IFN-γ, IL-6, CCL9, CXCR2). In contrast, conserving intracellular GSH concentrations eliminates OS which precludes the nuclear translocation and more importantly the phosphorylation of the NFkB p105 subunit. These cells show significantly more pronounced elongations, ramifications, and the enhanced expression of M2-like microglial phenotype markers (IL-10, IL-4, TGF-β, CXCL10, CCL22, Chi, Arg, and CCR2). Conclusions: Taken together, our data show that maintaining GSH homeostasis is not only important for quenching OS in the developing fetal brain, but equally critical to enhance M2 like microglia phenotype, thus suppressing inflammatory responses elicited by environmental stressors