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121.
Marsh SA Powell PC Agarwal A Dell'Italia LJ Chatham JC 《American journal of physiology. Heart and circulatory physiology》2007,293(1):H292-H298
Recent studies in our laboratory using the Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rat models resulted in unexpectedly high mortality rates in all genotypes including healthy homozygous lean Zucker rats, possibly because of renal dysfunction. Therefore, we evaluated left ventricular (LV) and kidney morphology and function in young ZO, Zucker diabetic fatty obese (ZDFO), homozygous Zucker/ZDF lean (ZL), and Sprague-Dawley (SD) rats. Hydronephrosis was evident in ZL, ZO, and ZDFO but not SD kidneys. ZDFO rats exhibited impaired LV shortening and relaxation with increased arterial stiffness. LV wall thickness was lower and LV end-systolic wall stress was higher in ZDFO compared with SD rats. Plasma ANG II was lower in ZO and ZDFO rats, which may be a result of reduced renal parenchyma with hydronephrosis; norepinephrine was higher in ZDFO rats than SD controls. Covariate analysis indicated that LV end-systolic wall stress was associated with renal dysfunction. The presence of hydronephrosis and its association with LV dysfunction potentially limits the ZDF model for study of the effects of diabetes on renal and cardiovascular function. 相似文献
122.
Closing in on the resting state of the Shaker K(+) channel 总被引:4,自引:0,他引:4
Pathak MM Yarov-Yarovoy V Agarwal G Roux B Barth P Kohout S Tombola F Isacoff EY 《Neuron》2007,56(1):124-140
Membrane depolarization causes voltage-gated ion channels to transition from a resting/closed conformation to an activated/open conformation. We used voltage-clamp fluorometry to measure protein motion at specific regions of the Shaker Kv channel. This enabled us to construct new structural models of the resting/closed and activated/open states based on the Kv1.2 crystal structure using the Rosetta-Membrane method and molecular dynamics simulations. Our models account for the measured gating charge displacement and suggest a molecular mechanism of activation in which the primary voltage sensors, S4s, rotate by approximately 180 degrees as they move "outward" by 6-8 A. A subsequent tilting motion of the S4s and the pore domain helices, S5s, of all four subunits induces a concerted movement of the channel's S4-S5 linkers and S6 helices, allowing ion conduction. Our models are compatible with a wide body of data and resolve apparent contradictions that previously led to several distinct models of voltage sensing. 相似文献
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Muthu Valliappan Dhaliwal Manpreet Sharma Arunima Nair Divya Kumar H. Mohan Rudramurthy Shivaprakash M. Sehgal Inderpaul Singh Choudhary Hansraj Panda Naresh Chakrabarti Arunaloke Agarwal Ritesh 《Mycopathologia》2022,187(4):355-362
Mycopathologia - In experimental models, the expression of glucose-regulated protein 78 (GRP78) in endothelial cells played a role in the pathogenesis of mucormycosis. However, the role of GRP78 in... 相似文献
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Vibrio cholerae MARTX toxin heterologous translocation of beta‐lactamase and roles of individual effector domains on cytoskeleton dynamics 下载免费PDF全文
Jazel S. Dolores Shivani Agarwal Martina Egerer Karla J. F. Satchell 《Molecular microbiology》2015,95(4):590-604
The Vibrio cholerae MARTXVc toxin delivers three effector domains to eukaryotic cells. To study toxin delivery and function of individual domains, the rtxA gene was modified to encode toxin with an in‐frame beta‐lactamase (Bla) fusion. The hybrid RtxA::Bla toxin was Type I secreted from bacteria; and then Bla was translocated into eukaryotic cells and delivered by autoprocessing, demonstrating that the MARTXVc toxin is capable of heterologous protein transfer. Strains that produce hybrid RtxA::Bla toxins that carry one effector domain in addition to Bla were found to more efficiently translocate Bla. In cell biological assays, the actin cross‐linking domain (ACD) and Rho‐inactivation domain (RID) are found to cross‐link actin and inactivate RhoA, respectively, when other effector domains are absent, with toxin autoprocessing required for high efficiency. The previously unstudied alpha‐beta hydrolase domain (ABH) is shown here to activate CDC42, although the effect is ameliorated when RID is also present. Despite all effector domains acting on cytoskeleton assembly, the ACD was sufficient to rapidly inhibit macrophage phagocytosis. Both the ACD and RID independently disrupted polarized epithelial tight junction integrity. The sufficiency of ACD but strong selection for retention of RID and ABH suggests these two domains may primarily function by modulating cell signaling. 相似文献
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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
130.
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