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In the previous report (Sonia Angeline et al., 2012), we showed an altered expression of protective proteins in rotenone-induced Parkinson's disease (PD)-like rat model. This model exhibited a marked attenuation in the expression of parkin, C terminus Hsp70 interacting protein (CHIP) and PARK 7 protein (DJ1) while enhanced levels of caspases and ubiquitin were seen. Herein, we confirmed the neuroprotective role of sesamol and naringenin individually on rotenone-induced rodent model of PD. Rotenone administration was given for 11days to generate the PD model (Sonia Angeline et al., 2012). From 11th day onward individual doses of sesamol (15mg/kg) and naringenin (10mg/kg) drugs were given orally to the rotenone PD rat model for 10 consecutive days. The impact of drugs markedly improved the motor skills, body weight, expression of parkin, DJ1, tyrosine hydroxylase and CHIP compared to the group treated with rotenone alone in the striatum and substantia nigra. These results were correlated with the reduction in caspase and ubiquitin levels by immunostaining and immunoblotting. Moreover, improved morphology and survivability of neurons were seen upon sesamol and naringenin treatment in the same rat PD model. Further we confirmed the efficacy of neuroprotective biomolecule administration on muscle from the above PD model and observed the restoration in muscle morphology, elevated level of parkin, DJ1, differential expression of heat shock proteins and reduced cell death. To conclude, for the first time we are demonstrating the comprehensive role of sesamol and naringenin (rotenone-induced PD model) in neuro and myoprotection that would have great clinical significance.

Mounting evidence suggests a link between metabolic syndrome (MetS) such as diabetes, obesity, non-alcoholic fatty liver disease in the progression of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDDs). For instance, accumulated Aβ oligomer is enhancing neuronal Ca2+ release and neural NO where increased NO level in the brain through post translational modification is modulating the level of insulin production. It has been further confirmed that irrespective of origin; brain insulin resistance triggers a cascade of the neurodegeneration phenomenon which can be aggravated by free reactive oxygen species burden, ER stress, metabolic dysfunction, neuorinflammation, reduced cell survival and altered lipid metabolism. Moreover, several studies confirmed that MetS and diabetic sharing common mechanisms in the progression of AD and NDDs where mitochondrial dynamics playing a critical role. Any mutation in mitochondrial DNA, exposure of environmental toxin, high-calorie intake, homeostasis imbalance, glucolipotoxicity is causative factors for mitochondrial dysfunction. These cumulative pleiotropic burdens in mitochondria leads to insulin resistance, increased ROS production; enhanced stress-related enzymes that is directly linked MetS and diabetes in neurodegeneration. Since, the linkup mechanism between mitochondrial dysfunction and disease phenomenon of both MetS and NDDs is quite intriguing, therefore, it is pertinent for the researchers to identify and implement the therapeutic interventions for targeting MetS and NDDs. Herein, we elucidated the pertinent role of MetS induced mitochondrial dysfunction in neurons and their consequences in NDDs. Further, therapeutic potential of well-known biomolecules and chaperones to target altered mitochondria has been comprehensively documented. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

The convergent endeavors of the neuroscientist to establish a link between clinical neurology, genetics, loss of function of an important protein, and channelopathies behind neurological disorders are quite intriguing. Growing evidence reveals the impact of ion channels dysfunctioning in neurodegenerative disorders (NDDs). Many neurological/neuromuscular disorders, viz, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and age-related disorders are caused due to altered function or mutation in ion channels. To maintain cell homeostasis, ion channels are playing a crucial role which is a large transmembrane protein. Further, these channels are important as it determines the membrane potential and playing critically in the secretion of neurotransmitter. Behind NDDs, losses of pathological proteins and defective ion channels have been reported and are found to aggravate the disease symptoms. Moreover, ion channel dysfunctions are eliciting a range of symptoms, including memory loss, movement disabilities, neuromuscular sprains, and strokes. Since the possible mechanistic role played by aberrant ion channels, their receptor and associated factors in neurodegeneration remained elusive; therefore, it is a challenging task for the neuroscientist to implement the therapeutics for targeting NDDs. This chapter reviews the potential role of the ion channels in membrane physiology and brain homeostasis, where ion channels and their associated factors have been characterized with their functional consequences in neurological diseases. Moreover, mechanistic role of perturbed ion channels has been identified in various NDDs, and finally, ion channel modulators have been investigated for their therapeutic intervention in treating common NDDs.

The convergent endeavors of the neuroscientist to establish a link between clinical neurology, genetics, loss of function of an important protein, and channelopathies behind neurological disorders are quite intriguing. Growing evidence reveals the impact of ion channels dysfunctioning in neurodegenerative disorders (NDDs). Many neurological/neuromuscular disorders, viz, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and age-related disorders are caused due to altered function or mutation in ion channels. To maintain cell homeostasis, ion channels are playing a crucial role which is a large transmembrane protein. Further, these channels are important as it determines the membrane potential and playing critically in the secretion of neurotransmitter. Behind NDDs, losses of pathological proteins and defective ion channels have been reported and are found to aggravate the disease symptoms. Moreover, ion channel dysfunctions are eliciting a range of symptoms, including memory loss, movement disabilities, neuromuscular sprains, and strokes. Since the possible mechanistic role played by aberrant ion channels, their receptor and associated factors in neurodegeneration remained elusive; therefore, it is a challenging task for the neuroscientist to implement the therapeutics for targeting NDDs. This chapter reviews the potential role of the ion channels in membrane physiology and brain homeostasis, where ion channels and their associated factors have been characterized with their functional consequences in neurological diseases. Moreover, mechanistic role of perturbed ion channels has been identified in various NDDs, and finally, ion channel modulators have been investigated for their therapeutic intervention in treating common NDDs.

Colorectal cancer, one of the most common cancers occurring worldwide, is a heterogeneous disease described by progressive and parallel histological and molecular alterations. It evolves from a benign polyp, called the adenoma, to become a malignant adenocarcinoma. At the molecular level, genetic mutations and epigenetic alterations, both play a dual role as an initiator of the tumor formation and as progressor of the malignant tumor. Moreover, their key events regulate the tumor’s ability to metastasize and proliferate exponentially. The epigenetic silencing and activation of cancer critical gene is prominently observed in the pathogenesis of colorectal cancer. In the last decade, rapid advancement in identification of epigenetic mechanisms took place that involves DNA methylation, histone modifications, micro and non coding RNAs and nucleosome repositioning. Genes that are epigenetically silenced or activated are generally tumor suppressor genes (TP53, CDK2NA, Retinoblastoma) or oncogenes (Wnt, KRAS, BRAF, PIK3CA) respectively that play a crucial role in cell cycle regulation. Furthermore, epigenetic alteration of mismatch repair genes can contribute to cancer through the phenomenon of micro satellite instability. Therefore, unraveling of epigenetic alterations and their mechanisms is necessary in order to better understand the prognosis of colorectal cancer and to evolve new therapeutic strategies for targeting it.

Cancer is a most common and lethal disease in which certain cells in our body grow in an uncontrolled way. The growth of new vascular network is essential for sustained growth of tumor to adequately supply nutrients and oxygen. These requirements are mainly fulfilled by formation of fresh blood vessels. Angiogenesis plays a pivotal role in various physiological conditions within the human body, including, embryonic development and tissue repair after trauma or surgery. Angiogenesis is a hallmark feature of cancer, inflammatory diseases, and wound healing. Different growth factors and vascular genes mediate the angiogenic process, which is regulated by epigenetic states of gene especially through small RNAs. Epigenetic modification of tumor cells includes diverse reinforcing and converging signals, including histone modifications, DNA methylation, and non-coding RNAs. This chapter is focused on highlighting the role of angiogenesis in vasculogenesis process and epigenetic modifications in cancer progression. Moreover, we reported the importance of various angiogenic factors and their epigenetic modifications together with a novel therapeutic window towards the treatment of most common cancers using epigenetic regulators.

Epigenetics referred to the hereditary changes in gene expression at the level of mitosis, which are different from the changes in DNA sequences whereas epigenetic variation involves CpG Island (CGI) hypermethylation along with the silencing of tumor suppressor genes in case of brain tumors. In DNA methylation, cytosine nucleotides are methylated at fifth position of the pyrimidine ring when they are part of the symmetrical dinucleotide CpG. Each post-embryonic cell has a specific level of DNA methylation whereas an overall decrease in the methylation level in the genome is termed as hypomethylation. As repeated sequences (such as CpG) are ideal recombination sites, hypomethylation promotes mitotic recombination, but it increases with aging process. However, some CpG sites such as CpG islands (CGI) are not methylated in normal cells whereas in cancer cells, methylation of CGI is frequently observed in the promoter region of various genes dispersed throughout the genome. This state of methylation is known as hypermethylation and it induces silencing of the corresponding gene (usually tumor suppressor genes) either by directly inhibiting the binding of transcription factors or changing the chromatin structure by recruiting histone deacetylases. DNA hypomethylation and hypermethylation usually coexist in the same genome but at different sequences in a tumor cell.

The aim of this study is to examine clinical management of lipid profile, renal and liver function versus HbA1c value correlation in diabetic population of Vellore district in South India. A total of 1300 cases from three different diabetic clinics in Vellore were taken for the study. 25% of populations were selected as control.Parameters such as age, sex, fasting blood glucose, postprandial blood glucose, lipid profile, mean plasma glucose, urine micro albumin, and HbA1c were taken into consideration. A correlation between blood glucose levels and other parameters such as lipid profile, renal and liver functionand HbA1c levels were established using meta analysis. Analysis suggests people of age group from 40 to 60 years and male population were highly affected from diabetes. Also HbA1canalysis showed only 25% of the cases had HbA1c levels between 7-7.5%, while 57% cases had HbA1c levels above 7.5%. Further, a significant positive correlation was found between postprandial blood sugar levels, total cholesterol and triglyceride levels (p

Exposure to high-altitude results in hypobaric hypoxia which is considered as an acute physiological stress. This condition often leads to high-altitude illnesses such as high-altitude cerebral edema, high altitude pulmonary edema and hypoxic muscle weakness. Hypoxic injuries can be prevented by either preconditioning with cobalt chloride or treatment with drugs. The aim of current investigation was to evaluate the effect of naringenin (NGEN) and quercetin (QUR) against behavioral impairment and neuronal damage in hypoxia induced murine model. An oral administration of NGEN or QUR (10 mg/kg each) was given to the animal prior to every hypoxic treatment. Behavioral changes were evaluated along with the hypoxia exposure for all the groups. After hypoxia exposure and drug administration, the mice were euthanized; brains were harvested and stored for further analysis. Expressions of hypoxia induced proteins were ensured by Western blotting. Our results demonstrate expression of hypoxia inducible factor 1α (HIF1α), vascular endothelial growth factor (VEGF), active caspase 3 and ubiquitin levels were significantly reduced upon drug treatment. However, expressions of chaperones (Hsp70, Hsp90 and C-terminus Hsp70 interacting protein) were moderately changed. We established our findings based on behavioral test, hematoxylin and eosin as well as amino-cupric silver stainings. In addition, the protective nature of these drugs was corroborated with immunoblot and immunofluorescence results, where we confirmed the down regulation of caspase 3 and ubiquitinated proteins. To conclude, treatment with NGEN and QUR alone substantially ameliorated hypoxia induced brain dysfunction and acts like a neuroprotectant.

—Rotenone is a pesticide that inhibits mitochon-drial complex I activity, thus creating an environment of oxi-dative stress in the cell. Many studies have employedrotenone to generate an experimental animal model of Par-kinson’s disease (PD) that mimics and elicits PD-like symp-toms, such as motor and cognitive decline. Cytoprotectiveproteins including parkin and heat shock proteins (HSPs)play major roles in slowing PD progression. Moreover, evi-dence suggests that mitochondrial dysfunction and oxida-tive stress-dependent apoptotic pathways contribute todopaminergic neuron degeneration in PD. Here, rats werechronically exposed to rotenone to confirm that it causesa debilitating phenotype and various behavioral defects.We also performed histopathological examinations of nigro-striatal, cortical and cerebellar regions of rotenone-treatedbrain to elucidate a plausible neurodegenerative mecha-nism. The results of silver, tyrosine hydroxylase (TH), par-kin, ubiquitin and caspase staining of brain tissuesections further validated our findings. The stress responseis known to trigger HSP in response to pharmacologicalinsult. These protective proteins help maintain cellularhomeostasis and may be capable of rescuing cells fromdeath. Therefore, we assessed the levels of different HSPsin the rotenone-treated animals. Collectively, our studiesindicated the following findings in the striatum and substan-tia nigra following chronic rotenone exposure in an experi-mental PD model: (i) behavioral deficit that correlated withhistopathological changes and down regulation of TH sig-naling, (ii) decreased levels of the cytoprotective proteinsparkin, DJ1 and Hsp70 and robust expression of mitochon-drial chaperone Hsp60 according to Western blot, (iii)increased immunoreactivity for caspase 9, caspase 3 andubiquitin and decreased parkin immunoreactivity. 2012 IBRO. Published by Elsevier Ltd. All rights reserved.Key words: Parkinson’s disease (PD), rotenone, neurodegen-eration, parkin, heat shock proteins (HSPs).

The study of neurodegenerative disorders has had a major impact on our understanding of more fundamental mechanisms underlying neurobiology. Breakthroughs in the genetics of Alzheimer's (AD) and Parkinson's diseases (PD) has resulted in new knowledge in the areas of axonal transport, energy metabolism, protein trafficking/clearance and synaptic physiology. The major neurodegenerative diseases have in common a regional or network pathology associated with abnormal protein accumulation(s) and various degrees of motor or cognitive decline. In AD, β-amyloids are deposited in extracellular diffuse and compacted plaques as well as intracellularly. There is a major contribution to the disease by the co-existence of an intraneuronal tauopathy. Additionally, PD-like Lewy Bodies (LBs) bearing aggregated α-synuclein is present in 40-60% of all AD cases, especially involving amygdala. Amyloid deposits can be degraded or cleared by several mechanisms, including immune-mediated and transcytosis across the blood-brain barrier. Another avenue for disposal involves the lysosome pathway via autophagy. Enzymatic pathways include insulin degradative enzyme and neprilysin. Finally, the co-operative actions of C-terminus Hsp70 interacting protein (CHIP) and Parkin, components of a multiprotein E3 ubiquitin ligase complex, may be a portal to proteasome-mediated degradation. Mutations in the Parkin gene are the most common genetic link to autosomal recessive Parkinson's disease. Parkin catalyzes the post-translational modification of proteins with polyubiquitin, targeting them to the 26S proteasome. Parkin reduces intracellular Aβ(1-42) peptide levels, counteracts its effects on cell death, and reverses its effect to inhibit the proteasome. Additionally, Parkin has intrinsic cytoprotective activity to promote proteasome function and defend against oxidative stress to mitochondria. Parkin and CHIP are also active in amyloid clearance and cytoprotection in vivo. Parkin has cross-functionality in additional neurodegenerative diseases, for instance, to eliminate polyglutamine-expanded proteins, reducing their aggregation and toxicity and reinstate proteasome function. The dual actions of CHIP (molecular co-chaperone and E3 ligase) and Parkin (as E3-ubiquitin ligase and anti-oxidant) may also play a role in suppressing inflammatory reactions in animal models of neurodegeneration. In this review, we focus on the significance of CHIP and Parkin as inducers of amyloid clearance, as cytoprotectants and in the suppression of reactive inflammation. A case is made for more effort to explore whether neurodegeneration associated with proteinopathies can be arrested at early stages by promoting their mutual action.

The bulk Mg/3%Al/0.1%GNP alloy-nano composite was fabricated using powder metallurgy route assisted with microwave sintering and followed by hot extrusion. The microstructural and Raman spectroscopy studies were performed to characterize the graphene nano-platelet(GNP).EDX tests confirmed the presence and the homogeneous distribution of Al and graphene nano-platelets in the magnesium alloy-nanocomposite. The addition of 3 wt% Al and 0.1wt%GNP to the Mg changed Vicker hardness, ultimate tensile strength and failure strain by +46.15%,+17.6% and -5% respectively. The fabricated composite offers higher resistance to the local deformation than monolithic Mg and Mg/3%Al alloy, revealed by the load/unload-indentation depth curve.

The significance of intracellular beta-amyloid (Abeta(42)) accumulation is increasingly recognized in Alzheimer's disease (AD) pathogenesis. Abeta removal mechanisms that have attracted attention include IDE/neprilysin degradation and antibody-mediated uptake by immune cells. However, the role of the ubiquitin-proteasome system (UPS) in the disposal of cellular Abeta has not been fully explored. The E3 ubiquitin ligase Parkin targets several proteins for UPS degradation, and Parkin mutations are the major cause of autosomal recessive Parkinson's disease. We tested whether Parkin has cross-function to target misfolded proteins in AD for proteasome-dependent clearance in SH-SY5Y and primary neuronal cells. Wild-type Parkin greatly decreased steady-state levels of intracellular Abeta(42), an action abrogated by proteasome inhibitors. Intracellular Abeta(42) accumulation decreased cell viability and proteasome activity. Accordingly, Parkin reversed both effects. Changes in mitochondrial ATP production from Abeta or Parkin did not account for their effects on the proteasome. Parkin knock-down led to accumulation of Abeta. In AD brain, Parkin was found to interact with Abeta and its levels were reduced. Thus, Parkin is cytoprotective, partially by increasing the removal of cellular Abeta through a proteasome-dependent pathway.

The C-terminus Hsp70 interacting protein (CHIP) has dual function as both co-chaperone and ubiquitin ligase. CHIP is increasingly implicated in the biology of polyglutamine expansion disorders, Parkinson's disease and tau protein in Alzheimer's disease. We investigated the involvement of CHIP in the metabolism of the beta-amyloid precursor protein and its derivative beta-amyloid (Abeta). Using immunoprecipitation, fluorescence localization and crosslinking methods, endogenous CHIP and betaAPP interact in brain and cultured skeletal myotubes as well as when they are expressed in stable HEK cell lines. Their interaction is confined to Golgi and ER compartments. In the presence of the proteasome inhibitor with MG132, endogenous and expressed betaAPP levels are significantly increased and accordingly, the interaction with CHIP enhanced. Concurrently, levels of Hsp70 were most consistently induced by proteasome inhibition among the various heat shock proteins (HSPs) tested. Thus, complexes of CHIP, Hsp70 and holo-betaAPP (as well as C-terminal fragments) were stabilized by the action of MG132. Moreover, CHIP itself is shown to both increase cellular holo-betaAPP levels and protect it from oxidative stress and degradation. Interestingly, CHIP also promotes the association of ubiquitin with betaAPP, implying that a smaller pool of betaAPP is destined for proteasomal processing. In neuronal cultures, CHIP and Hsp70/90 expression reduce steady-state cellular Abeta levels and hasten its degradation in pulse-chase experiments. The functional significance of CHIP and HSP interactions, especially with Hsp70, was tested using siRNA and in neuronal cells where protection from Abeta-induced toxicity is shown. We conclude that CHIP, as a bimolecular switch, interacts with HSP to stabilize normal holo-betaAPP on the one hand while also assisting in the ubiquitination of a subpopulation of betaAPP molecules that are destined for proteasome degradation. CHIP also hastens the clearance of Abeta in a manner consistent with its known neuroprotective properties.

Background Angiogenesis is a hallmark feature in the initiation, progression and growth of tumour. There are various factors for promotion of angiogenesis on one hand and on the other hand, biomolecules have been reported to inhibit cancer through anti-angiogenesis mechanism. Biomolecules, for instance, luteolin, lectin and lupeol are known to suppress cancer. This study aims to compare and evaluate the biomolecule(s) like luteolin, lupeol and lectin on CAM assay and HT-29 cell culture to understand the efficacy of these drugs. Method The biomolecules have been administered on CAM assay, HT-29 cell culture, cell migration assay. Furthermore, bioinformatics analysis of the identified targets of these biomolecules have been performed. Result Luteolin has been found to be better in inhibiting angiogenesis on CAM assay in comparison to lupeol and lectin. In line with this study when biomolecules was administered on cell migration assay via scratch assay method. We provided evidence that Luteolin was again found to be better in inhibiting HT-29 cell migration. In order to identify the target sites of luteolin for inhibition, we used software analysis for identifying the best molecular targets of luteolin. Using software analysis best target protein molecule of these biomolecules have been identified. VEGF was found to be one of the target of luteolin. Studies have found several critical point mutation in VEGF A, B and C. Hence docking analysis of all biomolecules with VEGFR have been performed. Multiple allignment result have shown that the receptors are conserved at the docking site. Conclusion Therefore, it can be concluded that luteolin is not only comparatively better in inhibiting blood vessel in CAM assay, HT-29 cell proliferation and cell migration assay rather the domain of VEGFR is conserved to be targeted by luteolin, lupeol and lectin.

Obesity has become a major health problem in the last few decades, mainly due to change of society towards sedentary lifestyle, intake of high-calorie diets and reduction in physical activity. Obesity is characterized by excess storage of fat in muscles and adipose tissues. It brings along with it physiological changes to the body such as insulin resistance, hyperinsulinemia, dyslipidemia, adipokine secretion by adipose tissues. These physiological changes have a stark impact on proper brain functioning and may induce oxidative stress, ER stress and mitochondrial dysfunction. Obesity affects the glucose and energy metabolism of the brain cells and through the secretion of pro-inflammatory agents like TNF-α, IL-1, IL-6 induces neuroinflammation mainly in the hypothalmic region of the brain. The overall effect is impairment of neuronal function and its internal molecular machinery, resulting in aberrant protein depositions either intracellularly or extracellularly or both, thus leading to neurodegeneration. Obesity and neurodegenerative diseases (NDDs) are linked by alterations in molecular pathways such as PI3K/Akt signaling pathway and IKKβ/NF-κB pathway, which may change expression profiles of genes or activate or deactivate molecular mediators and thereby drift them away from normal cell functioning. Herein, we have discussed

Advantages of Cu based shape memory alloy include amongst other features, high transformation temperature, low cost of production, ease in manufacturing processes and ability to vary the achieved properties through alloying additions. It has been often reported that these alloys are very sensitive to the alloying additions in terms of properties achieved and phase precipitation necessary for development of shape memory properties. This behaviour in Cu based shape memory alloys i.e. being very sensitive to its constituents can be used positively to design alloys with pre set properties if the alloying additions and their percentages are properly controlled. In an attempt to understand the effect of different alloying additions, 2% of different elements [Zn, Si, Mg & Cr] were added to a known Cu-based shape memory alloy [Cu-12.5 wt% of Al-5 wt % of Mn]. The objective was to ascertain changes or improvements achieved due to the additions in terms of microstructural changes, hardness, phase precipitation and transformation temperatures. Attempts have been made to analyze the changes in properties achieved in the base Cu-Al-Mn alloys due to the quaternary additions. Grain structure with α+β phases, which is a pre requisite for martensite formation on quenching is seen in all the alloys indicating that all the alloys have potential to exhibit the shape memory behaviour. The martensite formation with different morphologies is observed in the quenched samples however. XRD results have identified the precipitated phases to be the martensitic phases. The DSC results indicate clear transformation peaks in most of the samples with significantly high transformation temperatures. The findings confirm the variation in properties achieved due to different additions and improvements achieved in terms of higher transformation temperatures and martensite formation due to the alloying additions. An attempt has been made to understand the findings.

Parkinson's disease (PD) is a chronic neurodegenerative condition which has the second largest incidence rate among all other neurodegenerative disorders barring Alzheimer's disease (AD). Currently there is no cure and researchers continue to probe the therapeutic prospect in cell cultures and animal models of PD. Out of the several factors contributing to PD prognosis, the role of p38 MAPK (Mitogen activated protein-kinase) and PI3K/AKT signalling module in PD brains is crucial because the impaired balance between the pro- apoptotic and anti-apoptotic pathways trigger unwanted phenotypes such as microglia activation, neuroinflammation, oxidative stress and apoptosis. These factors continue challenging the brain homeostasis in initial stages thereby essentially assisting the dopaminergic (DA) neurons towards progressive degeneration in PD. Neurotherapeutics against PD shall then be targeted against the misregulated accomplices of the p38 and PI3K/AKT cascades. In this review, we have outlined many such established mechanisms involving the p38 MAPK and PI3K/AKT pathways which can offer therapeutic windows for the rectification of aberrant DA neuronal dynamics in PD brains.

In contrast with the class A heat stress transcription factors (HSFs) of plants, a considerable number of HSFs assigned to classes B and C have no evident function as transcription activators on their own. However, in the following article, we provide evidence that tomato (Lycopersicon peruvianum) HsfB1 represents a novel type of coactivator cooperating with class A HSFs (e.g., with tomato HsfA1). Provided the appropriate promoter architecture, the two HSFs assemble into an enhanceosome-like complex, resulting in strong synergistic activation of reporter gene expression. Moreover, HsfB1 also cooperates in a similar manner with other activators, for example, with the ASF1/2 enhancer binding proteins of the 35S promoter of Cauliflower mosaic virus or with yet unidentified activators controlling housekeeping gene expression. By these effects, HsfB1 may help to maintain and/or restore expression of certain viral or housekeeping genes during ongoing heat stress. The coactivator function of HsfB1 depends on a histone-like motif in its C-terminal domain with an indispensable Lys residue in the center (GRGKMMK). This motif is required for recruitment of the plant CREB binding protein (CBP) ortholog HAC1. HsfA1, HsfB1, and HAC1/CBP form ternary complexes in vitro and in vivo with markedly enhanced efficiency in promoter recognition and transcription activation in plant and mammalian (COS7) cells. Using small interfering RNA–mediated knock down of HAC1 expression in Arabidopsis thaliana mesophyll protoplasts, the crucial role for the coactivator function of HsfB1 was confirmed.

Objective: Neurodegenerative diseases are a debilitating age-related disorder manifested by memory loss, impaired motor activity, and loss of muscle tone due to the accumulation of toxic metabolites in the brain. Despite the knowledge of factors causing neurodegenerative disorders, it remains irreversible and incurable. Growing evidence have currently advocated the physiological and pathological contribution of hypoxia-induced vascular endothelial growth factor (VEGF) in neuronal loss. The objective of this research report highlights biomolecules mediated targeting of VEGF activity based on in silico approaches that could establish a potential therapeutic window for the treatment of different abnormalities associated with impaired VEGF.Methods: We employed various in silico methods such as drug-likeness parameters, namely, Lipinski filter analysis, Pock Drug tool for active site prediction, AUTODOCK 4.2.1, and LigPlot1.4.5 for molecular docking studiesResults: Three-dimensional structure of VEGF was generated and Ramachandran plot obtained for quality assessment. RAMPAGE displayed 99.5% of residues in the most favored regions, 0.5% residues in additionally allowed, and no residues in disallowed regions in VEGF, showing that stereochemical quality of protein structure is good. Further, initial screenings of the molecules were done based on Lipinski’s rule of five. Finally, we have found Naringenin to be most effective among three biomolecules in modulating VEGF activity based on minimum inhibition constant, Ki, and highest negative free energy of binding with the maximum interacting surface area during docking studies.Conclusion: The present study outlines the novel potential of biomolecules in regulating VEGF activity for the treatment of different abnormalities associated with impaired VEGF.

Objective: Hypoxia plays a significant role in governing many vital signalling molecules in the central nervous system (CNS). Hypoxic exposure has also been depicted as a stimulus for oxidative stress, increase in lipid peroxidation, DNA damage, blood-brain dysfunction, impaired calcium (Ca 2+ ) homoeostasis and agglomeration of oxidized biomolecules in neurons, which act as a novel signature in diverse neurodegenerative and oncogenic processes. On the contrary, the presence of abnormally impaired expression of HIF-1α under hypoxic insult could serve as an indication of the existence of tumors and neuronal dysfunction as well. For instance, under hypoxic stress, amyloid-β protein precursor (AβPP) cleavage is triggered due to the higher expression of HIF-1α and thus leads to synaptic loss. The objective of this research is to perform comparative studies of biomolecules in regulating HIF-1α activity based on in silico approaches that could establish a potential therapeutic window for the treatment of different abnormalities associated with impaired HIF-1α. Methods: We employed various in silico methods such as drug-likeness parameters namely Lipinski filter analysis, Muscle tool, SWISS-MODEL, active site prediction, Auto Dock 4.2.1 and LigPlot1.4.5for molecular docking studies. Results: 3D structure of HIF-1α was generated and Ramachandran plot obtained for quality assessment. RAMPAGE displayed 99.5% of residues in the most favoured regions. 0% residues in additionally allowed and 0.5% disallowed regions of the HIF-1α protein. Further, initial screenings of the molecules were done based on Lipinski’s rule of five. Cast P server used to predict the ligand binding site suggests that this protein can be utilised as a potential drug target. Finally, we have found Naringenin to be most effective amongst three biomolecules in modulating HIF-1α based on minimum inhibition constant, Ki and highest negative free energy of binding with the maximum interacting surface area during docking studies. Conclusion: The present study outlines the novel potential of Biomolecules in regulating HIF-1α activity for the treatment of different abnormalities associated with impaired HIF-1α.

Objective: The objective of this study was to explore the therapeutic role of biomolecules in targeting the altered expression of Parkin in PD pathogenesis.Methods: We employed various in silico tools such as drug-likeness parameters, namely, Lipinski filter analysis, Muscle tool for phylogenetic analysis, Castp Server for active site prediction, molecular docking studies using AutoDock 4.2.1 and LIGPLOT1.4.5 were carried out.Results: Our results show that neuroprotective activity of Quercetin to be most effective and can provide their possible clinical relevance in PD. Further, initial screenings of the molecules were done based on Lipinski’s rule of five. CastP server used to predict the ligand binding site suggests that this protein can be utilized as a potential drug target. Finally, we have found Quercetin to be most effective amongst four biomolecules in modulating Parkin based on minimum inhibition constant, Ki and highest negative free energy of binding with the maximum interacting surface area in a course of docking studies.Conclusion: This research could provide a potential therapeutic window for the treatment of PD.

Objective: Parkinson’s disease (PD) is a debilitating age-related neurodegenerative disease characterized by the canonical formation of intracellular Lewy bodies comprising α-synuclein protein. Despite the knowledge of factors causing PD, it remains irreversible and incurable. Recent studies have highlighted the physiological and pathological involvement of cell cycle proteins in PD. The intriguing relationship between PARK2 and cyclin E which leads to upregulation of cyclin E in the absence of functional PARK2 contributes heavily in the onset and progression of PD. The objective of this study is to explore neuroprotective action of bimoclomol in attenuating the level of cyclin E and inhibiting post-mitotic cell division led neurodegeneration in PD. Methods: We employed various in silico methods such as drug-likeness parameters, namely, Lipinski filter analysis, Ghose parameters, Veber rules, absorption, distribution, metabolism, and excretion - toxicity analysis, pharmacophore based target prediction, active site prediction, and molecular docking studies. Results: The binding of bimoclomol inhibited cyclin E, thereby, attenuating post-mitotic cell division led neurodegeneration in PD. Conclusion: This study outlines the novel potential of bimoclomol in attenuating cyclin E led neuronal death in PD which may be mediated by heat shock proteins (HSP70).

Neurodegenerative disorders (NDDs) are progressive and chronic disorders characterized by destruction of neurons in sensory, motor and cognitive systems. Free radical’s accumulation, oxidative stress, ER stress and a dysfunctional ubiquitin proteasome system can regulate prognosis in NDDs. Oxidative trauma in the brain can result from high rate of oxidative metabolism in contrast to the diminished functional levels of the antioxidant enzymes responsible for detoxification. Endoplasmic Reticulum (ER) advocates a degree of control on cellular parameters such as proper protein folding, posttranslational modification and subsequent protein trafficking in order to maintain normal cellular homeostasis. However, an abnormal ER functioning can lead to loss of integrity of the ER thus resulting in ER stress. In addition to this impairment in the ubiquitin proteasome system (UPS) machinery results in the accumulation of toxic proteins in the brain thus resulting in severe neuronal trauma and subsequent damage. This review explores the disease critical interactions and roles of three critical NDD determinants viz. oxidative stress, ER stress and UPS dysfunction in neurodegenerative conditions.

Inclusion body myositis (IBM), a degenerative and inflammatory disorder of skeletal muscle, and Alzheimer's disease share protein derangements and attrition of postmitotic cells. Overexpression of cyclins and proliferating cell nuclear antigen (PCNA) and evidence for DNA replication is reported in Alzheimer's disease brain, possibly contributing to neuronal death. It is unknown whether aberrant cell cycle reentry also occurs in IBM. We examined cell cycle markers in IBM compared with normal control, polymyositis (PM) and non-inflammatory dystrophy sample sets. Next, we tested for evidence of reentry and DNA synthesis in C2C12 myotubes induced to express β-amyloid (Aβ42). We observed increased levels of Ki-67, PCNA and cyclins E/D1 in IBM compared with normals and non-inflammatory conditions. Interestingly, PM samples displayed similar increases. Satellite cell markers did not correlate with Ki-67-affected myofiber nuclei. DNA synthesis and cell cycle markers were induced in Aβ-bearing myotubes. Cell cycle marker and cyclin protein expressions were also induced in an experimental allergic myositis-like model of PM in mice. Levels of p21 (Cip1/WAF1), a cyclin-dependent kinase inhibitor, were decreased in affected myotubes. However, overexpression of p21 did not rescue cells from Aβ-induced toxicity. This is the first report of cell cycle reentry in human myositis. The absence of rescue and evidence for reentry in separate models of myodegeneration and inflammation suggest that new DNA synthesis may be a reactive response to either or both stressors.

The aim of this study was to investigate the early onset effects of diabetes on pro-angiogenic signaling pathway, total number of bone marrow cells, organs (pancreas and kidney) damage and the reversal effect of diabetes by combinatorial treatment of curcumin and bone marrow transplantation in streptozotocin (STZ) induced diabetic mice.In the present study, Streptozotocin induced diabetic mice were transplanted with bone marrow cells (2 × 10(6) ) followed by the administration of curcumin (80 mg/kg bodyweight). Effect of diabetes on the different organs was studied by HE, Western blotting and immunofluorescence using vascular endothelial growth factor (VEGF), platelet/endothelial cell adhesion molecule (PECAM), insulin, Caspase-9 and Caspase-3 antibodies.The effect of diabetes results in the reduction of the total cell number and viability of the bone marrow cells, organ degeneration and lower VEGF/PECAM expression. However, transplantation with normal bone marrow cells significantly reduced the blood glucose levels (above normal range) and initiated the organ regeneration via the VEGF/PECAM mediated manner. Curcumin treatment further reduced the blood glucose level (near normal); and accelerated the organ regeneration, enhanced VEGF/PECAM expression and decreased caspase expression level in the organs. Curcumin also had a protective role against the glucotoxicity test performed on the bone marrow cells.This study suggests that bone marrow transplantation and curcumin administration is an effective treatment in reversing the early onset effects of diabetes via the VEGF/PECAM signaling pathway.

Curcumin has long been used as an antioxidative, antiinflammatory, and modulator of pathological angiogenesis, whereas naringenin is a well-known immunomodulator. In this report, we investigated the effect of curcumin and naringenin on the growth of Ehrlich ascites carcinoma tumor model. To achieve this, Swiss albino mice were implanted intraperitoneally with 1 × 10⁶ Ehrlich ascites carcinoma cells followed by the administration of oral doses of naringenin and curcumin either individually (50 mg/kg body weight) or in combination (20 mg/kg body weight each). A marked reduction has been seen in the total number of cells (80%) and accumulation of ascetic fluid (55%) when these drugs were administered together. These drugs proved to be an effective angio-inhibitory compound and confirmed by different in vivo assay systems, viz. peritoneal/skin angiogenesis and chorioallantoic membrane assay. Antiangiogenic and antiproliferative effect of these compounds alone or in combination was further corroborated with immunoblot results where we confirmed the downregulation of vascular endothelial growth factor, Hif1α, heat shock protein 90, and p-Akt. Furthermore, treatment with naringenin and curcumin alone or in combination substantially improved hepatocellular architecture and no noticeable neoplastic lesions or cellular alteration were reported. These outcomes put forward a plausible clinical application of these diet-derived compounds, as both angioinhibitory and antitumor in association with conventional therapy.

Diabetes is a rapidly growing health problem; however, there is currently no effective therapy for diabetes. We know that prolonged diabetes leads to damage of various organs apart from pancreas such as kidney and liver and the role of bone marrow mononuclear cells (BMMNCs) is not clearly understood in regeneration of these organs. In this study, we transplanted chloromethylbenzamido-1,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanine perchlorate (CM-DiI) labeled BMMNCs in streptozotocin (STZ) induced mice and tracked them in various affected organs. We observed, through histological studies that intravenously transplanted CM-DiI labeled BMMNCs were found in acinar regions of the pancreas and not in islet regions, but regenerated islets in diabetic mice. Interestingly, these cells were not found in the kidney and liver of diabetic mice, but these organs regenerated. Also, there was a significant drop in blood glucose levels after the transplantation. We concluded that transplanted BMMNCs incorporated in the acinar region of the pancreas and not in any other organs, but aided in the regeneration of pancreas, liver and kidney. The transplanted BMMNCs also helped in reduction of blood glucose levels. Key words: Bone marrow mononuclear cells, diabetes, transplantation, organ regeneration.

Diet-derived flavonoids, in particular quercetin, may play advantageous roles by preventing or/and inhibiting oncogenesis. Evidence suggests that quercetin can elicit various properties depending on the cell type. The aim of this study was to evaluate its effects on Dalton's lymphoma ascites (DLA) induced solid tumours and to identify the target(s) of action. We addressed this question by inducing subcutaneous solid tumours in Swiss albino mice and investigated whether the quercetin affects essential biological processes that are responsible for tumour growth, morphology, angiogenesis and apoptosis. We also studied influence on several heat shock proteins (HSPs). Our findings demonstrate that intra-tumour administration of quercetin results in decreased volume/weight. Furthermore, we demonstrate that quercetin promotes apoptosis of cancer cells by down-regulating the levels of Hsp90 and Hsp70. Depletion of these two chaperones by quercetin might result in triggering of caspase-3 in treated tumours. Moreover, it also down-regulated the expression of major key angiogenic or pro-angiogenic factors, like HIF-1α and VEGF In addition, H and E staining together with immunofluorescence of fixed tumour tissue provided evidence in support of increased cell death in quercetin-treated mice.

The study of neurodegenerative disorders has had a major impact on our understanding of more fundamental mechanisms underlying neurobiology. Breakthroughs in the genetics of Alzheimer's (AD) and Parkinson's diseases (PD) has resulted in new knowledge in the areas of axonal transport, energy metabolism, protein trafficking/clearance and synaptic physiology. The major neurodegenerative diseases have in common a regional or network pathology associated with abnormal protein accumulation(s) and various degrees of motor or cognitive decline. In AD, β-amyloids are deposited in extracellular diffuse and compacted plaques as well as intracellularly. There is a major contribution to the disease by the co-existence of an intraneuronal tauopathy. Additionally, PD-like Lewy Bodies (LBs) bearing aggregated α-synuclein is present in 40-60% of all AD cases, especially involving amygdala. Amyloid deposits can be degraded or cleared by several mechanisms, including immune-mediated and transcytosis across the blood-brain barrier. Another avenue for disposal involves the lysosome pathway via autophagy. Enzymatic pathways include insulin degradative enzyme and neprilysin. Finally, the co-operative actions of C-terminus Hsp70 interacting protein (CHIP) and Parkin, components of a multiprotein E3 ubiquitin ligase complex, may be a portal to proteasome-mediated degradation. Mutations in the Parkin gene are the most common genetic link to autosomal recessive Parkinson's disease. Parkin catalyzes the post-translational modification of proteins with polyubiquitin, targeting them to the 26S proteasome. Parkin reduces intracellular Aβ(1-42) peptide levels, counteracts its effects on cell death, and reverses its effect to inhibit the proteasome. Additionally, Parkin has intrinsic cytoprotective activity to promote proteasome function and defend against oxidative stress to mitochondria. Parkin and CHIP are also active in amyloid clearance and cytoprotection in vivo. Parkin has cross-functionality in additional neurodegenerative diseases, for instance, to eliminate polyglutamine-expanded proteins, reducing their aggregation and toxicity and reinstate proteasome function. The dual actions of CHIP (molecular co-chaperone and E3 ligase) and Parkin (as E3-ubiquitin ligase and anti-oxidant) may also play a role in suppressing inflammatory reactions in animal models of neurodegeneration. In this review, we focus on the significance of CHIP and Parkin as inducers of amyloid clearance, as cytoprotectants and in the suppression of reactive inflammation. A case is made for more effort to explore whether neurodegeneration associated with proteinopathies can be arrested at early stages by promoting their mutual action.

Intraneuronal β-amyloid (Aβi) accumulates early in Alzheimer's disease (AD) and inclusion body myositis. Several organelles, receptor molecules, homeostatic processes, and signal transduction components have been identified as sensitive to Aβ. Although prior studies implicate the insulin-PI3K-Akt signaling cascade, a specific step within this or any essential metabolic or survival pathway has not emerged as a molecular target. We tested the effect of Aβ42 on each component of this cascade. In AD brain, the association between PDK and Akt, phospho-Akt levels and its activity were all decreased relative to control. In cell culture, Aβiexpression inhibited both insulin-induced Akt phosphorylation and activity. In vitro experiments identified that β-amyloid (Aβ), especially oligomer preparations, specifically interrupted the PDK-dependent activation of Akt. Aβialso blocked the association between PDK and Akt in cell-based and in vitro experiments. Importantly, Aβ did not interrupt Akt or PI3K activities (once stimulated) nor did it affect more proximal signal events. These results offer a novel therapeutic strategy to neutralize Aβ-induced energy failure and neuronal death.

In the present study, Cu-12.5 wt. %Al-5 wt. %Mn-80.5 wt. % shape memory alloy is chosen as the base alloy and 2 wt. % of quaternary additions of Fe, Ni, and Ti added to the base alloy. The effects of these additions on in terms of feasibility, microstructure, hardness, and transformation temperature were studied. The findings suggest the possibility to improve martensite formation, attain higher transitions temperatures, and longer retention over the base alloy through such additions.

Intracellular deposition of the beta-amyloid (Abeta) peptide is an increasingly recognized pathological hallmark associated with neurodegeneration and muscle wasting in Alzheimer's disease (AD) and inclusion body myositis (IBM), respectively. Previous reports have implicated dysregulation of beta-amyloid precursor protein (betaAPP) expression in IBM. Accumulation of full-length betaAPP, its various proteolytic derivatives including Abeta, and phospho-tau into vacuolated inclusions is an early pathogenic event. We previously reported on a statistical tendency favoring fast twitch fiber involvement in IBM, reminiscent of the tissue specific patterns of misfolded protein deposition seen in neurodegenerative diseases. To test this principle, we generated an animal model in which human wild-type (WT) betaAPP expression was limited to postnatal type II skeletal muscle. Hemizygous transgenic mice harboring increased levels of holo betaAPP751 and Abeta in skeletal muscle fibers became significantly weaker with age compared with nontransgenic littermates and exhibited typical myopathic features. A subpopulation of dissociated muscle fibers from transgenic mice exhibited a 2-fold increase in resting calcium and membrane depolarization compared with nontransgenic littermates. Taken together, these data indicate that overexpression of human betaAPP in fast twitch skeletal muscle of transgenic mice is sufficient for the development of some features characteristic of IBM, including abnormal tau histochemistry. The increase in resting calcium and depolarization are novel findings, suggesting both a mechanism for the weakness and an avenue for therapeutic intervention in IBM.

Nox1 and Nox4, homologues of the leukocyte NADPH oxidase subunit Nox2 (gp91phox) mediate superoxide anion formation in various cell types. However, their interactions with other components of the NADPH oxidase are poorly defined. We determined whether a direct interaction of Nox1 and Nox4 with the p22phox subunit of the NADPH oxidase occurs. Using confocal microscopy, co-localization of p22phox with Nox1, Nox2, and Nox4 was observed in transiently transfected vascular smooth muscle cells (VSMC) and HEK293 cells. Plasmids coding for fluorescent fusion proteins of p22phox and the Nox proteins with cyan- and yellow-fluorescent protein (cfp and yfp, respectively) were constructed and expressed in VSMC and HEK293 cells. The cfp-tagged p22phox expression level increased upon cotransfection with Nox1 or Nox4. Protein-protein interaction between the fluorescent fusion proteins of p22phox and the Nox partners was observed using the fluorescence resonance energy transfer technique. Immunoprecipitation of native Nox1 from human VSMC revealed co-precipitation of p22phox. Immunoprecipitation from transfected HEK293 cells revealed co-precipitation of native p22phox with yfp-tagged Nox1, Nox2, and Nox4. Following mutation of a histidine (corresponding to the position 115 in human Nox2) to leucine, this interaction was abolished. Transfection of rat p22phox (but not Noxo1 and Noxa1) increased the radical generation in cells expressing Nox4. We provide evidence that p22phox directly interacts with Nox1 and Nox4, to form an superoxide-generating NADPH oxidase and demonstrate that mutation of the potential heme binding site in the Nox proteins disrupts the complex formation of Nox1 and Nox4 with p22phox.

This paper applies Autoregressive Conditional Heteroskedasticity (ARCH) methodology to model volatality and its persistence based on daily returns(1992-96) of 30 blue-chip securities traded in Bombay Stock Exchange. The results of the Study show that the variance of returns varies over time and that the ARCH and GARCH models capture the volatility persistence.

a b s t r a c t The paper discusses the attempt made to improve upon the transition temperatures and amount of martensite formation in Cu–Al alloys with alloying additions of Mn, Ni and Zn in varying proportions and combinations. The alloys have been subjected to heat treatment cycles to improve upon the microstructure and precipitate the required martensite phase. The effect of these ternary and/or quaternary additions has been studied on the phases precipitated through micro-structural analysis and X-ray diffraction and Differential Scanning Calorimetric studies. The findings confirm the possibility of improvement on the shape memory properties like martensite formation, higher transitions temperatures and longer retention in selected alloys based on the properties exhibited through proper alloying additions and heat treatments. © 2014 Brazilian Metallurgical, Materials and Mining Association. Published by Elsevier Editora Ltda.