Molecular diagnostics provide a powerful method to detect and diagnose various neurological diseases such as Alzheimer's and Parkinson's disease. The confirmation of such diagnosis allows early detection and subsequent medical counseling that help specific patients to undergo clinically important drug trials. This provides a medical pathway to have better insight of neurogenesis and eventual cure of the neurodegenerative diseases. In this short review, we present recent advances in molecular diagnostics especially biomarkers and imaging spectroscopy for neurological diseases. We describe advances made in Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), and finally present a perspective on the future directions to provide a framework for further developments and refinements of molecular diagnostics to combat neurodegenerative disorders.
Resveratrol, a natural stilbene present at relatively high concentrations in grape skin and seeds and red wine, is known for its purported antioxidant activity in the vascular and nervous systems. In contrast to its direct antioxidant role within the central nervous system, recent research supports a protective mechanism through increasing endogenous cellular antioxidant defenses, which triggers a cascade of parallel neuroprotective pathways. A growing body of in vitro and in vivo evidence indicates that resveratrol acts through multiple pathways and reduces ischemic damage in vital organs, such as the heart and the brain, in various rodent models. Most of the protective biological actions of resveratrol have been associated with its antioxidative, anti-inflammatory, and antiapoptotic properties and other indirect pathways. Continued public interest and increasing resveratrol supplements on the market warrant a review of the available in vitro and in vivo science reported in the stroke-related literature. Rigorous clinical trials evaluating the effects of resveratrol in stroke are absent, though the general population consumption appears to be relatively safe. Resveratrol has shown potential for treating stroke in laboratory animals and in vitro human cell studies, yet there is still a need for human research in preclinical settings. This review summarizes many of the findings on the neuroprotective potential of resveratrol in cerebral stroke, focusing on both the in vitro and in vivo experimental models and some proposed mechanisms of action.
Monocrotophos (MCP) is a widely used organophosphate (OP) pesticide. We studied apoptotic changes and their correlation with expression of selected cytochrome P450s (CYPs) in PC12 cells exposed to MCP. A significant induction in reactive oxygen species (ROS) and decrease in glutathione (GSH) levels were observed in cells exposed to MCP. Following the exposure of PC12 cells to MCP (10−5 M), the levels of protein and mRNA expressions of caspase-3/9, Bax, Bcl2, P53, P21, GSTP1-1 were significantly upregulated, whereas the levels of Bclw, Mcl1 were downregulated. A significant induction in the expression of CYP1A1/1A2, 2B1/2B2, 2E1 was also observed in PC12 cells exposed to MCP (10−5 M), whereas induction of CYPs was insignificant in cells exposed to 10−6 M concentration of MCP. We believe that this is the first report showing altered expressions of selected CYPs in MCP-induced apoptosis in PC12 cells. These apoptotic changes were mitochondria mediated and regulated by caspase cascade. Our data confirm the involvement of specific CYPs in MCP-induced apoptosis in PC12 cells and also identifies possible cellular and molecular mechanisms of organophosphate pesticide-induced apoptosis in neuronal cells.
Zymomonas mobilis is a superb ethanol producer with productivity exceeding yeast strains by several fold. Although metabolic engineering was successfully applied to expand its substrate range to include xylose, xylose fermentation lagged far behind glucose. In addition, xylose fermentation was often incomplete when its initial concentration was higher than 5%. Improvement of xylose fermentation is therefore necessary. In this work, we applied adaptation to improve xylose fermentation in metabolically engineered strains. As a result of adaptation over 80 days and 30 serial transfers in a medium containing high concentration of xylose, a strain, referred as A3, with markedly improved xylose metabolism was obtained. The strain was able to grow on 10% (w/v) xylose and rapidly ferment xylose to ethanol within 2 days and retained high ethanol yield. Similarly, in mixed glucose-xylose fermentation, a total of 9% (w/v) ethanol was obtained from two doses of 5% glucose and 5% xylose (or a total of 10% glucose and 10% xylose). Further investigation reveals evidence for an altered xylitol metabolism in A3 with reduced xylitol formation. Additionally xylitol tolerance in A3 was increased. Furthermore, xylose isomerase activity was increased by several times in A3, allowing cells to channel more xylose to ethanol than to xylitol. Taken together, these results strongly suggest that altered xylitol metabolism is key to improved xylose metabolism in adapted A3 strain. This work further demonstrates that adaptation and metabolic engineering can be used synergistically for strain improvement.
Mixtures of NaBr and NaBrO 3 in two different ratios have been used for highly stereoselective bromination of alkenes and alkynes, and regioselective bromine substitution at the a-carbon of ketones and at the benzylic position of toluene derivatives. The reactions were conducted in an aqueous acidic medium under ambient conditions. The solid reagents were prepared from the intermediate obtained in the ''cold process'' of bromine manufacture and are stable, nonhazardous and inexpensive to prepare. This procedure provides an efficient and practical alternative to conventional procedures using liquid bromine directly or indirectly.
An in vitro model of ischemic cerebral stroke [oxygen-glucose deprivation (OGD) for 6 h followed by 24 h reoxygenation (R)] with PC12 cells increases Ca(2+) influx by upregulating native L-type Ca(2+) channels and reactive oxygen species (ROS) generation. This reactive oxygen species generation and increase in intracellular Ca(2+) triggers the expression of hypoxic homeostasis transcription factors such as hypoxia induced factor-1 alpha (HIF-1α), Cav-beta 3 (Cav β3), signal transducer and activator of transcription 3 (STAT3), heat shock protein 27 (hsp-27), and cationic channel transient receptor potential melastatin 7 (TRPM7). OGD insulted PC12 cells were subjected to biologically safe doses (5, 10, and 25 μM) of trans-resveratrol in three different treatment groups: 24 h prior to OGD (pre-treatment); 24 h post OGD (post-treatment); and from 24 h before OGD to end of reoxygenation period (whole-treatment). Here, we demonstrated that OGD-R-induced neuronal injury/death is by reactive oxygen species generation, increase in intracellular calcium levels, and decrease in antioxidant defense enzymes. trans-Resveratrol increases the viability of OGD-R insulted PC12 cells, which was assessed by using MTT, NRU, and LDH release assay. In addition, trans-resveratrol significantly decreases reactive oxygen species generation, intracellular Ca(2+) levels, and hypoxia associated transcription factors and also increases the level of antioxidant defense enzymes. Our data shows that the whole-treatment group of trans-resveratrol is most efficient in decreasing hypoxia induced cell death through its antioxidant properties.
The submission of my dissertation marks the culmination of my long and fruitful journey of being a student. I have, through the last four years of my graduate study, been the beneficiary of an amazing amount of support from a large number of people to whom I owe all my success. I would first like to thank my parents, who have been supportive of me throughout my entire life and encouraged me to succeed in everything I attempt. I am deeply indebted to them for their continued support, love and generosity. I will forever be grateful to my graduate advisor, Dr. Willian Koros, for supporting me through my graduate studies. His passion in research and trust on people set a superb role for me to follow in my future life. My gratitude extends to all my committee members, Dr.
Consumption of flavan-3-ols, notably (−)-epicatechin (EC), has been highly recommended in complementary and alternative medicine (CAM) due to reports that flavan-3-ols boost antioxidant activity, support vascular function, and prevent cardiovascular disease. To date, in vivo efficacy and mechanisms of action for many CAM therapies, including EC, remain elusive in brain ischemia. In contrast to its purported direct antioxidant role, we hypothesized protection through activation of the endogenous transcriptional factor Nrf2. To screen cellular protection and investigate Nrf2 activation, we adopted a pretreatment paradigm using enriched primary neuronal cultures from mice and washed out EC prior to oxygen glucose deprivation to attenuate direct antioxidant effects. EC protected primary neurons from oxygen glucose deprivation by increasing neuronal viability (40.2 ± 14.1%) and reducing protein oxidation, effects that occurred concomitantly with increased Nrf2-responsive antioxidant protein expression. We also utilized wildtype and Nrf2 C57BL/6 knockout mice in a permanent model of focal brain ischemia to evaluate glial cell regulation and complex sensorimotor functioning. EC-treated wildtype mice displayed a reduction or absence of forelimb motor coordination impairments that were evident in vehicle-treated mice. This protection was associated with reduced anatomical injury (54.5 ± 8.3%) and microglia/macrophage activation/recruitment (56.4 ± 13.0%). The protective effects elicited by EC in both model systems were abolished in tissues and neuronal cultures from Nrf2 knockout mice. Together, these data demonstrate EC protection through Nrf2 and extend the benefits to improved performance on a complex sensorimotor task, highlighting the potential of flavan-3-ols in CAM approaches in minimizing subsequent stroke injury.
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