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131.
David W. Frederick James G. Davis Antonio Dávila Jr. Beamon Agarwal Shaday Michan Michelle A. Puchowicz Eiko Nakamaru-Ogiso Joseph A. Baur 《The Journal of biological chemistry》2015,290(3):1546-1558
The NAD biosynthetic precursors nicotinamide mononucleotide and nicotinamide riboside are reported to confer resistance to metabolic defects induced by high fat feeding in part by promoting oxidative metabolism in skeletal muscle. Similar effects are obtained by germ line deletion of major NAD-consuming enzymes, suggesting that the bioavailability of NAD is limiting for maximal oxidative capacity. However, because of their systemic nature, the degree to which these interventions exert cell- or tissue-autonomous effects is unclear. Here, we report a tissue-specific approach to increase NAD biosynthesis only in muscle by overexpressing nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in the salvage pathway that converts nicotinamide to NAD (mNAMPT mice). These mice display a ∼50% increase in skeletal muscle NAD levels, comparable with the effects of dietary NAD precursors, exercise regimens, or loss of poly(ADP-ribose) polymerases yet surprisingly do not exhibit changes in muscle mitochondrial biogenesis or mitochondrial function and are equally susceptible to the metabolic consequences of high fat feeding. We further report that chronic elevation of muscle NAD in vivo does not perturb the NAD/NADH redox ratio. These studies reveal for the first time the metabolic effects of tissue-specific increases in NAD synthesis and suggest that critical sites of action for supplemental NAD precursors reside outside of the heart and skeletal muscle. 相似文献
132.
Swati Agarwal Shashi Kant Tiwari Brashket Seth Anuradha Yadav Anshuman Singh Anubha Mudawal Lalit Kumar Singh Chauhan Shailendra Kumar Gupta Vinay Choubey Anurag Tripathi Amit Kumar Ratan Singh Ray Shubha Shukla Devendra Parmar Rajnish Kumar Chaturvedi 《The Journal of biological chemistry》2015,290(34):21163-21184
The human health hazards related to persisting use of bisphenol-A (BPA) are well documented. BPA-induced neurotoxicity occurs with the generation of oxidative stress, neurodegeneration, and cognitive dysfunctions. However, the cellular and molecular mechanism(s) of the effects of BPA on autophagy and association with oxidative stress and apoptosis are still elusive. We observed that BPA exposure during the early postnatal period enhanced the expression and the levels of autophagy genes/proteins. BPA treatment in the presence of bafilomycin A1 increased the levels of LC3-II and SQSTM1 and also potentiated GFP-LC3 puncta index in GFP-LC3-transfected hippocampal neural stem cell-derived neurons. BPA-induced generation of reactive oxygen species and apoptosis were mitigated by a pharmacological activator of autophagy (rapamycin). Pharmacological (wortmannin and bafilomycin A1) and genetic (beclin siRNA) inhibition of autophagy aggravated BPA neurotoxicity. Activation of autophagy against BPA resulted in intracellular energy sensor AMP kinase (AMPK) activation, increased phosphorylation of raptor and acetyl-CoA carboxylase, and decreased phosphorylation of ULK1 (Ser-757), and silencing of AMPK exacerbated BPA neurotoxicity. Conversely, BPA exposure down-regulated the mammalian target of rapamycin (mTOR) pathway by phosphorylation of raptor as a transient cell''s compensatory mechanism to preserve cellular energy pool. Moreover, silencing of mTOR enhanced autophagy, which further alleviated BPA-induced reactive oxygen species generation and apoptosis. BPA-mediated neurotoxicity also resulted in mitochondrial loss, bioenergetic deficits, and increased PARKIN mitochondrial translocation, suggesting enhanced mitophagy. These results suggest implication of autophagy against BPA-mediated neurodegeneration through involvement of AMPK and mTOR pathways. Hence, autophagy, which arbitrates cell survival and demise during stress conditions, requires further assessment to be established as a biomarker of xenoestrogen exposure. 相似文献
133.
Nisha Singh Tomar Malini Sharma R. M. Agarwal 《Physiology and Molecular Biology of Plants》2015,21(1):83-92
Jatropha curcas shows invasive characters and is a significant source of many phytochemicals with varying biological activities. Different plant parts of Jatropha curcas L exhibited variation in their phytochemical constituents. Leaves and ovary walls were found to contain higher contents of total phenols, tannins and phytic acid whereas free amino acids were greater in leaves. Young leaves of Jatropha show greater contents of all these metabolites. Further, plants exhibit seasonal differences as leaves collected during summer (May-June) have greater accumulation of total phenols, tannins and free amino acids however, phytic acid was more during rainy season. Leachates and extracts in their higher concentrations adversely affected the germination and growth of wheat seedlings however, lower concentrations were more or less stimulatory. These treatments not only decreased the length, fresh and dry weight of seedlings but also affected the chlorophyll contents and activity of enzymes such as nitrate reductase, aminotransferases in wheat seedlings however, the activity of superoxide dismutase and ascorbate peroxidases increased. Experiments indicate harmful allelopathic effects of Jatropha leachates /extracts on wheat seedlings, hence further experimentation and analysis is recommended before continued plantation of Jatropha particularly on fertile soils. However. Growth of Jatropha plants on saline soils and their potential for accumulating sodium, potassium and chloride are the attributes suggesting the possibility of use of Jatropha plants in improving saline soils. 相似文献
134.
Ambreen Asim Ashok Kumar Srinivasan Muthuswamy Shalu Jain Sarita Agarwal 《Journal of biomedical science》2015,22(1)
Down syndrome (DS) is one of the commonest disorders with huge medical and social cost. DS is associated with number of phenotypes including congenital heart defects, leukemia, Alzeihmer’s disease, Hirschsprung disease etc. DS individuals are affected by these phenotypes to a variable extent thus understanding the cause of this variation is a key challenge. In the present review article, we emphasize an overview of DS, DS-associated phenotypes diagnosis and management of the disease. The genes or miRNA involved in Down syndrome associated Alzheimer’s disease, congenital heart defects (AVSD), leukemia including AMKL and ALL, hypertension and Hirschprung disease are discussed in this article. Moreover, we have also reviewed various prenatal diagnostic method from karyotyping to rapid molecular methods - MLPA, FISH, QF-PCR, PSQ, NGS and noninvasive prenatal diagnosis in detail. 相似文献
135.
S. Agarwal, R. Gupta, V. K. Iyer, S. R. Mathur and R. Ray Cytopathological diagnosis of alveolar soft part sarcoma, a rare soft tissue neoplasm Objective: Alveolar soft part sarcoma (ASPS) is a rare soft tissue neoplasm, having various morphological mimics, especially on fine needle aspiration cytology (FNAC). Because no definite immunohistochemical markers are available to aid a correct diagnosis, knowledge of the cytomorphological features is essential for correct patient management. Cytological features of five cases of ASPS are discussed, along with the ultrastructural findings available in one of them. Methods: Cytology records from 1997 to 2009 were reviewed for cases with a diagnosis of ASPS on cytology. The histology slides of the cases were also assessed for confirmation of the diagnosis. All the slides were reviewed by three pathologists. Results: There were five cases of ASPS diagnosed on FNAC. Their cytological features were noted in detail. The diagnoses in all the cases were confirmed on histology, and ultrastructural findings available in one of them were also assessed. Conclusions: The knowledge of cytological features may aid in diagnosing this rare tumour correctly on FNA smears, thus enabling correct patient management. 相似文献
136.
Nepali K Agarwal A Sapra S Mittal V Kumar R Banerjee UC Gupta MK Satti NK Suri OP Dhar KL 《Bioorganic & medicinal chemistry》2011,19(18):5569-5576
A series of forty two N-(1,3-diaryl-3-oxopropyl)amides were synthesized via an efficient, modified Dakin-West reaction and were evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Structure-activity relationship analyses have been presented. Selected active xanthine oxidase inhibitors (3r, 3s, and 3zh) were assessed in vivo to study their anti-hyperuricemic effect in potassium oxonate induced hyperuricemic mice model. Compound 3s emerged as the most potent xanthine oxidase inhibitor (IC(50)=2.45 μM) as well as the most potent anti-hyperuricemic agent. The basis of significant inhibition of xanthine oxidase by 3s was rationalized by its molecular docking into catalytic site of xanthine oxidase. 相似文献
137.
138.
Linfang Shen Xudong Chen Xufeng Zhang Krishna Agarwal 《Plasmonics (Norwell, Mass.)》2011,6(2):301-305
In this paper, we show that surface plasmon polaritons (SPPs) can be sustained by a single row of holes periodically drilled
on a perfect electric conductor surface. These SPPs can be strongly confined in the transverse plane and they possess an excellent
modal shape. In the terahertz regime, large propagation length is available for highly confined SPPs on a real-metal surface
waveguide. As the dispersion characteristics of such SPPs can be controlled by the surface geometry, unusual total reflection
phenomenon occurs when waves travel along a nonuniform surface waveguide with gradually increasing hole depths. 相似文献
139.
Hamza TH Chen H Hill-Burns EM Rhodes SL Montimurro J Kay DM Tenesa A Kusel VI Sheehan P Eaaswarkhanth M Yearout D Samii A Roberts JW Agarwal P Bordelon Y Park Y Wang L Gao J Vance JM Kendler KS Bacanu SA Scott WK Ritz B Nutt J Factor SA Zabetian CP Payami H 《PLoS genetics》2011,7(8):e1002237
Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson''s disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP''s main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10−6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10−7) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: ORReplication = 0.59, PReplication = 10−3; ORPooled = 0.51, PPooled = 7×10−8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10−3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10−13). Imputation revealed a block of SNPs that achieved P2df<5×10−8 in GWAIS, and OR = 0.41, P = 3×10−8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients. 相似文献
140.