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Sadasivan S.K.,Connexios Life science Private Ltd | Vasamsetti B.,Connexios Life science Private Ltd | Singh J.,Connexios Life science Private Ltd | Marikunte V.V.,Connexios Life science Private Ltd | And 3 more authors.
European Journal of Pharmacology | Year: 2014

Polyamines are highly charged low molecular weight aliphatic polycations and are ubiquitously present in all living cells. In addition to their previously reported role in cell proliferation and cancer, recent studies support their role in energy homeostasis and glucose metabolism. In the present study we have evaluated a polyamine - spermine for its effect on glycemic, lipid and body weight parameters. High fat diet induced obese mice (6 week old male C57B6/J mice fed on high fat diet for 22 weeks) were dosed with spermine intraperitoneally at two different doses (5 mg/kg and 10 mg/kg body weight) for 4 weeks and its effect on body weight, glycemic and lipid parameters was monitored. We found that at a dose of 10 mg/kg bodyweight, spermine treatment resulted in a 24% reduction in the body weight and 18% reduction in the fasting glucose compared to untreated controls. Besides, spermine treated mice exhibited improved glucose utilization associated with improved fat oxidation and loss of white adipose mass. Our study is promising in the direction of exploring the spermine and their analogs for treatment of metabolic syndrome. © 2014 Elsevier B.V. All rights reserved. Source

Verma M.K.,Connexios Life science Private Ltd | Chandravanshi B.,Connexios Life science Private Ltd | Biswas S.,Connexios Life science Private Ltd | Neelima K.,Connexios Life science Private Ltd | And 3 more authors.
BMC Research Notes | Year: 2014

Background: Elevated glucose concentrations lead to increased insulin secretion and suppression of glucagon secretion. In fact, insulin is a physiological inhibitor of glucagon secretion. Type 2 diabetes mellitus (T2DM) patients have defects in insulin secretion. In addition to this, lack of suppression of glucagon secretion under elevated glucose concentrations is also observed in T2DM patients. We have earlier shown that GPR40 activation by CNX-011-67 stimulates glucose stimulated insulin secretion (GSIS). Here we extended our studies to examine the impact of GPR40 activation by CNX-011-67 on glucagon secretion from intact islets under both normal and glucolipotoxic conditions.Findings: Glucagon secretion from intact rat islets was suppressed under elevated glucose concentration. Activation of GPR40 by CNX-011-67 further suppressed glucagon secretion. Culturing islets under chronic glucolipotoxic (GL) conditions, we have observed increased high glucose mediated glucagon secretion and content which were reduced with GPR40 activation by CNX-011-67. Interestingly, expression of pre-proglucagon gene (GCG) remained unchanged under glucolipotoxicity in the presence or absence of GPR40 activation.Conclusion: Activation of GPR40 by CNX-011-67 can reduce glucagon secretion from pancreatic islets. © 2014 Verma et al.;. Source

Sadasivan S.K.,Connexios Life science Private Ltd | Vasamsetti B.,Connexios Life science Private Ltd | Singh J.,Connexios Life science Private Ltd | Siddaraju N.,Connexios Life science Private Ltd | And 4 more authors.
Journal of Diabetes and Metabolic Disorders | Year: 2014

Background: AMP activated protein kinase (AMPK) regulates key metabolic reactions and plays a major role in glucose homeostasis. Activating the AMPK is considered as one of the potential therapeutic strategies in treating type-2 diabetes. However, targeting AMPK by small molecule mediated approach can be challenging owing to diverse isoforms of the enzyme and their varied combination in different tissues. In the current study we employ a novel strategy of achieving AMPK activation through increasing the levels of cellular AMP (an allosteric activator of AMPK) levels by activating the enzyme involved in AMP biosynthesis namely Adenylosuccinate lyase (ADSL).Methods: Rat primary hepatocytes were cultured under metabolic overload conditions (500 μM palmitate) to induce insulin resistance. ADSL was overexpressed in these hepatocytes and its effect on hepatic glucose output, and triglyceride accumulation was checked. In addition to this, ADSL was overexpressed in high fat diet induced obese mice by hydrodynamic tail vein injection and its effect on fasting glucose, glucose tolerance and pyruvate tolerance were checked.Results: Rat primary hepatocytes when cultured under metabolic overload conditions developed insulin resistance as measured in terms of failure of insulin to suppress the glucose output. Overexpressing the ADSL in these hepatocytes resulted in increased AMPK phosporylation and improved the insulin sensitivity and also resulted in reduced triglyceride accumulation and inflammatory cytokine levels. In addition to this, when ADSL was overexpressed in high fat diet induced obese mice, it resulted in reduced the fasting hyperglycemia (20% reduction), and increased glucose and pyruvate tolerance.Conclusions: This study indicates that activating ADSL can be a potential mechanism to achieve the activation of AMPK in the cells. This leads to a novel idea of exploring the purine nucleotide metabolic pathway as a promising therapeutic target for diabetes and metabolic syndrome. © 2014 Sadasivan et al.; licensee BioMed Central Ltd. Source

Sadasivan S.K.,Connexios Life science Private Ltd | Siddaraju N.,Connexios Life science Private Ltd | Khan K.M.,Connexios Life science Private Ltd | Vasamsetti B.,Connexios Life science Private Ltd | And 6 more authors.
Fibrogenesis and Tissue Repair | Year: 2015

Background: Precision-cut liver slices present different cell types of liver in a physiological context, and they have been explored as effective in vitro model systems to study liver fibrosis. Inducing fibrosis in the liver slices using toxicants like carbon tetrachloride is of less relevance to human disease conditions. Our aim for this study was to establish physiologically relevant conditions in vitro to induce fibrotic phenotypes in the liver slices.Results: Precision-cut liver slices of 150 μm thickness were obtained from female C57BL/6 J mice. The slices were cultured for 24 hours in media containing a cocktail of 10 nM each of TGF-β, PDGF, 5 μM each of lysophosphatidic acid and sphingosine 1 phosphate and 0.2 μg/ml of lipopolysaccharide along with 500 μM of palmitate and were analyzed for triglyceride accumulation, stress and inflammation, myofibroblast activation and extracellular matrix (ECM) accumulation. Incubation with the cocktail resulted in increased triglyceride accumulation, a hallmark of steatosis. The levels of Acta2, a hallmark of myofibroblast activation and the levels of inflammatory genes (IL-6, TNF-α and C-reactive protein) were significantly elevated. In addition, this treatment resulted in increased levels of ECM markers - collagen, lumican and fibronectin.Conclusions: This study reports the experimental conditions required to induce fibrosis associated with steatohepatitis using physiologically relevant inducers. The system presented here captures various aspects of the fibrosis process like steatosis, inflammation, stellate cell activation and ECM accumulation and serves as a platform to study the liver fibrosis in vitro and to screen small molecules for their antifibrotic activity. © 2015 Sadasivan et al.; licensee BioMed Central. Source

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