Browsing by Author "Kant, Shashi"

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    Exercise Rescues Gene Pathways Involved in Vascular Expansion and Promotes Functional Angiogenesis in Subcutaneous White Adipose Tissue
    Min, So Yun; Learnard, Heather; Kant, Shashi; Gealikman, Olga; Rojas-Rodriguez, Raziel; DeSouza, Tiffany; Desai, Anand; Keaney, John F.; Corvera, Silvia; Craige, Siobhan M. (MDPI, 2019-04-25)
    Exercise mitigates chronic diseases such as diabetes, cardiovascular diseases, and obesity; however, the molecular mechanisms governing protection from these diseases are not completely understood. Here we demonstrate that exercise rescues metabolically compromised high fat diet (HFD) fed mice, and reprograms subcutaneous white adipose tissue (scWAT). Using transcriptomic profiling, scWAT was analyzed for HFD gene expression changes that were rescued by exercise. Gene networks involved in vascularization were identified as prominent targets of exercise, which led us to investigate the vasculature architecture and endothelial phenotype. Vascular density in scWAT was found to be compromised in HFD, and exercise rescued this defect. Similarly, angiogenic capacity as measured by ex vivo capillary sprouting was significantly promoted with exercise. Together, these data demonstrate that exercise enhances scWAT vascularization and functional capacity for angiogenesis, and can prevent the detrimental effects of HFD. The improvement in these indices correlates with improvement of whole-body metabolism, suggesting that scWAT vascularization may be a potential therapeutic target for metabolic disease.
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    JNK and cardiometabolic dysfunction
    Craige, Siobhan M.; Chen, Kai; Blanton, Robert M.; Keaney, John F.; Kant, Shashi (Portland Press, 2019-07-19)
    Cardiometabolic syndrome (CMS) describes the cluster of metabolic and cardiovascular diseases that are generally characterized by impaired glucose tolerance, intra-abdominal adiposity, dyslipidemia, and hypertension. CMS currently affects more than 25% of the world's population and the rates of diseases are rapidly rising. These CMS conditions represent critical risk factors for cardiovascular diseases including atherosclerosis, heart failure, myocardial infarction, and peripheral artery disease (PAD). Therefore, it is imperative to elucidate the underlying signaling involved in disease onset and progression. The c-Jun N-terminal Kinases (JNKs) are a family of stress signaling kinases that have been recently indicated in CMS. The purpose of this review is to examine the in vivo implications of JNK as a potential therapeutic target for CMS. As the constellation of diseases associated with CMS are complex and involve multiple tissues and environmental triggers, carefully examining what is known about the JNK pathway will be important for specificity in treatment strategies.
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    Neural JNK3 regulates blood flow recovery after hindlimb ischemia in mice via an Egr1/Creb1 axis
    Kant, Shashi; Craige, Siobhan M.; Chen, Kai; Reif, Michaella M.; Learnard, Heather; Kelly, Mark; Caliz, Amada D.; Tran, Khanh-Van; Ramo, Kasmir; Peters, Owen M.; Freeman, Marc; Davis, Roger J.; Keaney, John F. Jr. (Springer Nature, 2019-09-17)
    Diseases related to impaired blood flow such as peripheral artery disease (PAD) impact nearly 10 million people in the United States alone, yet patients with clinical manifestations of PAD (e.g., claudication and limb ischemia) have limited treatment options. In ischemic tissues, stress kinases such as c-Jun N-terminal kinases (JNKs), are activated. Here, we show that inhibition of the JNK3 (Mapk10) in the neural compartment strikingly potentiates blood flow recovery from mouse hindlimb ischemia. JNK3 deficiency leads to upregulation of growth factors such as Vegfa, Pdgfb, Pgf, Hbegf and Tgfb3 in ischemic muscle by activation of the transcription factors Egr1/Creb1. JNK3 acts through Forkhead box O3 (Foxo3a) to suppress the activity of Egr1/Creb1 transcription regulators in vitro. In JNK3-deficient cells, Foxo3a is suppressed which leads to Egr1/Creb1 activation and upregulation of downstream growth factors. Collectively, these data suggest that the JNK3-Foxo3a-Egr1/Creb1 axis coordinates the vascular remodeling response in peripheral ischemia.
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    Non-Timber Forest Products Marketing Systems and Market Players in Southwest Virginia: A Case Study of Craft, Medicinal and Herbal, Specialty Wood, and Edible Forest Products
    Greene, Sarah Marsden (Virginia Tech, 1998-01-30)
    Non-timber forest products (NTFPs) are important in rural southwest Virginia as a source of household sustenance and supplemental income. The trade in NTFPs from this region is centuries old and now helps supply growing worldwide demands. Although marketing is a vital part of optimizing the value of these products, it has been ignored in rural natural resource development. This research analyzes marketing systems for selected NTFPs in southwest Virginia by describing marketing chains, interpreting data on important marketing elements, and comparing results within and between different groups of NTFPs. Product categories selected for emphasis are crafts (grapevine wreaths, baskets, furniture, and birdhouses), medicinal and herbal products, specialty wood products (musical instruments), and edible forest products. This qualitative, exploratory study utilizes direct interviews with fifty market players at various levels in marketing chains. Results provide information on NTFP products, value addition, market outlets, pricing, promotion, distribution, and marketing chains. Hundreds of people are involved with the NTFP trade in southwest Virginia and marketing can help ameliorate negative effects of job scarcity. The greatest opportunity for local level marketing exists for market players of crafts and specialty wood products. Medicinal and herbal products are the only category which very little local value addition takes place within the region and as a result, market players have minimal control over marketing. Edible forest products are not marketed but are collected only for consumption in the household. Several opportunities for marketing include improving market access for crafts and specialty wood products, increasing production through cultivation for medicinal and herbal products, and developing capacity for edible product cultivation.
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    Nox4 mediates skeletal muscle metabolic responses to exercise
    Specht, Kalyn S.; Kant, Shashi; Addington, Adele K.; McMillan, Ryan P.; Hulver, Matthew W.; Learnard, Heather; Campbell, Maura; Donnelly, Sarah R.; Caliz, Amada D.; Pei, Yongmei; Reif, Michaella M.; Bond, Jacob M.; DeMarco, Anthony; Craige, Branch; Keaney, John F. Jr.; Craige, Siobhan M. (2021-03)
    Objective: The immediate signals that couple exercise to metabolic adaptations are incompletely understood. Nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) produces reactive oxygen species (ROS) and plays a significant role in metabolic and vascular adaptation during stress conditions. Our objective was to determine the role of Nox4 in exercise-induced skeletal muscle metabolism. Methods: Mice were subjected to acute exercise to assess their immediate responses. mRNA and protein expression responses to Nox4 and hydrogen peroxide (H2O2) were measured by qPCR and immunoblotting. Functional metabolic flux was measured via ex vivo fatty acid and glucose oxidation assays using C-14-labeled palmitate and glucose, respectively. A chronic exercise regimen was also utilized and the time to exhaustion along with key markers of exercise adaptation (skeletal muscle citrate synthase and beta-hydroxyacyl-coA-dehydrogenase activity) were measured. Endothelial-specific Nox4-deficient mice were then subjected to the same acute exercise regimen and their subsequent substrate oxidation was measured. Results: We identified key exercise-responsive metabolic genes that depend on H2O2 and Nox4 using catalase and Nox4-deficient mice. Nox4 was required for the expression of uncoupling protein 3 (Ucp3), hexokinase 2 (Hk2), and pyruvate dehydrogenase kinase 4 (Pdk4), but not the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1 alpha). Global Nox4 deletion resulted in decreased UCP3 protein expression and impaired glucose and fatty acid oxidization in response to acute exercise. Furthermore, Nox4-deficient mice demonstrated impaired adaptation to chronic exercise as measured by the time to exhaustion and activity of skeletal muscle citrate synthase and beta-hydroxyacyl-coA-dehydrogenase. Importantly, mice deficient in endothelial-Nox4 similarly demonstrated attenuated glucose and fatty acid oxidation following acute exercise. Conclusions: We report that H2O2 and Nox4 promote immediate responses to exercise in skeletal muscle. Glucose and fatty acid oxidation were blunted in the Nox4-deficient mice post-exercise, potentially through regulation of UCP3 expression. Our data demonstrate that endothelial-Nox4 is required for glucose and fatty acid oxidation, suggesting inter-tissue cross-talk between the endothelium and skeletal muscle in response to exercise. (C) 2021 The Authors. Published by Elsevier GmbH.