Genetic modification of human mesenchymal stem cells helps to reduce adiposity and improve glucose tolerance in an obese diabetic mouse model

INTRODUCTION: Human mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into fat, muscle, bone and cartilage cells. Exposure of subcutaneous abdominal adipose tissue derived AD-MSCs to high glucose (HG) leads to superoxide accumulation and up-regulation of inflammatory molecules. Our aim was to inquire how HG exposure affects MSCs differentiation and whether the mechanism is reversible. METHODS: We exposed human adipose tissue derived MSCs to HG (25 mM) and compared it to normal glucose (NG, 5.5 mM) exposed cells at 7, 10 and 14 days. We examined mitochondrial superoxide accumulation (Mitosox-Red), cellular oxygen consumption rate (OCR, Seahorse) and gene expression. RESULTS: HG increased reactive superoxide (ROS) accumulation noted by day 7 both in cytosol and mitochondria. The OCR between the NG and HG exposed groups however did not change until 10 days at which point OCR of HG exposed cells were reduced significantly. We noted that HG exposure upregulated mRNA expression of adipogenic (PPARG, FABP-4, CREBP alpha and beta), inflammatory (IL-6 and TNF alpha) and antioxidant (SOD2 and Catalase) genes. Next, we used AdSOD2 to upregulate SOD2 prior to HG exposure and thereby noted reduction in superoxide generation. SOD2 upregulation helped reduce mRNA over-expression of PPARG, FABP-4, IL-6 and TNFα. In a series of separate experiments, we delivered the eGFP and SOD2 upregulated MSCs (5 days post ex-vivo transduction) and saline intra-peritoneally (IP) to obese diabetic (db/db) mice. We confirmed homing-in of eGFP labeled MSCs, delivered IP, to different inflamed fat pockets, particularly omental fat. Mice receiving SOD2-MSCs showed progressive reduction in body weight and improved glucose tolerance (GTT) at 4 weeks, post MSCs transplantation compared to the GFP-MSC group (control). CONCLUSIONS: High glucose evokes superoxide generation, OCR reduction and adipogenic differentiation. Mitochondrial superoxide dismutase upregulation quenches excess superoxide and reduces adipocyte inflammation. Delivery of superoxide dismutase (SOD2) using MSCs as a gene delivery vehicle reduces inflammation and improves glucose tolerance in vivo. Suppression of superoxide production and adipocyte inflammation using mitochondrial superoxide dismutase may be a novel and safe therapeutic tool to combat hyperglycemia mediated effects

Conventional and Molecular Breeding Approaches for Biofortification of Pearl Millet

Pearl millet [Pennisetum glaucum (L.) R. Br.] is an essential diet of more than 90 million people in the semi-arid tropics of the world where droughts and low fertility of soils cause frequent failures of other crops. It is an important nutri-rich grain cereal in the drier regions of the world grown on 26 mha by millions of farmers (IFAD 1999; Yadav and Rai 2013). This makes pearl millet the sixth most important crop in the world and fourth most important food crop of the India, next to rice, wheat, and maize with annual cultivation over an area of ~8 mha. Pearl millet is also primary food crop in sub-Saharan Africa and is grown on 15 mha (Yadav and Rai 2013). The significant increase in productivity of pearl millet in India is attributed to development and adoption of hybrids of early to medium duration maturity. More than 120 diverse hybrids/varieties have been released till date for various production environments. The heterosis breeding and improved crop management technologies increased productivity substantially achieving higher increased production of 9.80 mt in 2016–2017 from 2.60 mt in 1950–1951 in spite of declined of area under the crop by 20–30% over last two decades (Yadav et al. 2012)

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