Fructose-induced ROS generation impairs glucose utilization in L6 skeletal muscle cells.

High fructose consumption has implicated in insulin resistance and metabolic syndrome. Fructose is a highly lipogenic sugar that has intense metabolic effects in liver. Recent evidences suggest that fructose exposure to other tissues has substantial and profound metabolic consequences predisposing toward chronic conditions such as type 2 diabetes. Since skeletal muscle is the major site for glucose utilization, in the present study we define the effects of fructose exposure on glucose utilization in skeletal muscle cells. Upon fructose exposure, the L6 skeletal muscle cells displayed diminished glucose uptake, glucose transporter type 4 (GLUT4) translocation, and impaired insulin signaling. The exposure to fructose elevated reactive oxygen species (ROS) production in L6 myotubes, accompanied by activation of the stress/inflammation markers c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2), and degradation of inhibitor of NF-κB (IκBα). We found that fructose caused impairment of glucose utilization and insulin signaling through ROS-mediated activation of JNK and ERK1/2 pathways, which was prevented in the presence of antioxidants. In conclusion, our data demonstrate that exposure to fructose induces cell-autonomous oxidative response through ROS production leading to impaired insulin signaling and attenuated glucose utilization in skeletal muscle cells.

Glucose uptake stimulatory effect of 4-hydroxypipecolic acid by increased GLUT 4 translocation in skeletal muscle cells.

Peganum harmala Linn, commonly known as 'harmal' belonging to the family Zygophyllaceae, is one of the most important medicinal plants of India. In continuation of our drug development program on Indian medicinal plants we discovered antihyperglycemic activity in 4-hydroxypipecolic acid (4-HPA), isolated from the seed of P. harmala. Effect of 4-HPA on glucose uptake and glucose transporter-4 (GLUT-4) translocation was investigated in L6 skeletal muscle cell lines. Treatment with 4-HPA stimulated both glucose uptake and GLUT4 translocation from intracellular to cell surface in skeletal muscle cells in a concentration-dependent manner, which might be leading to antihyperglycemic effect.

Synthesis of propiophenone derivatives as new class of antidiabetic agents reducing body weight in db/db mice.

A series of propiophenone derivatives (6-23) have been synthesized and evaluated for their in vivo antihyperglycemic activities in sucrose loaded model (SLM), sucrose challenged streptozotocin (STZ-S) induced diabetic rat model and C57BL/KsJ db/db diabetic mice model. Compound 15 and 16 were emerged as potent antihyperglycemics and lipid lowering agents. These compounds (15, 16) further validate the potency by reducing body weight and food intake in db/db mice model. Possible mechanism of action for the propiophenone derivatives was established by the evaluation in various in vitro models. Interestingly some of the compounds were efficiently inhibiting PTP-1B.

Design and synthesis of 2,4-disubstituted polyhydroquinolines as prospective antihyperglycemic and lipid modulating agents.

A series of 2,4-disubstituted polyhydroquinoline were synthesized and evaluated for their in vivo antihyperglycemic as well as antidyslipidemic activities. Several synthesized compounds have exhibited promising in vivo antihyperglycemic in SLM, STZ-S, and db/db mice model along with significant lipid and TG modulating activity. All these compounds were evaluated in various in vitro models of diabetes to know the possible mechanism of their antihyperglycemic action. Interestingly, compounds 3a-r (diaryl substitution) have exhibited promising protein-tyrosine phosphatase 1B (PTP1B) inhibitory activity whereas, compounds 5a-d (acid substituted) have shown significant glycogen phosphorylase activity.

Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents.

We have designed 1,3-disubstituted-5-membered heteroaromatic ring system as a common core motif from known anti-hyperglycemic agents. Designed compounds were synthesized and screened for in vivo anti-hyperglycemic activity in sucrose loaded model (SLM), sucrose-challenged streptozotocin-induced diabetic rat model (STZ-S) as well as db/db mice model. Some of the synthesized compounds showed promising in vivo anti-hyperglycemic as well as moderate lipid lowering activity. Synthesized Compounds were screened in various in vitro models of type-2 diabeties such as DPP-4, PTP1B and PPARgamma to know the mechanism of their anti-hyperglycemic action. None of the synthesized compounds showed DPP-4 inhibitory as well as PPARgamma activity. These compounds have shown promising PTP-1B inhibitory activity there by revealing that compounds exhibit anti-diabetic activity by PTP1B pathway.

Direct immunofluorescence assay for rapid environmental detection of Vibrio cholerae O1.

An immunofluorescence assay for direct detection of V. cholerae O1 was developed using polyclonal antibodies raised against outer membrane proteins (OMPs) of V. cholerae O1. Production of OMPs varied with growth media used; maximum production was found in tryptic soy broth. The detection system was specific because no cross-reactivity was observed with other bacteria including V. cholerae O139, E. coli, S. dysenteriae and Salmonella enterica subsp. enterica serovar Typhi. The technique was able to detect 240 CFU/mL of V. cholerae O1 suspended in phosphate-buffered saline. The assay coupled with bacterial enrichment in APW for 6 h detected as few as 5 CFU of V. cholerae in spiked samples. Moreover, a 2-h incubation of enriched bacterial cells in 0.1% yeast extract with 10 ppm nalidixic acid enhanced the bacterial size and helped in morphological identification of V. cholerae. Among 32 potable water samples from afflicted hand pumps and wells collected from a cholera-plagued area 12 were found to be contaminated with V. cholerae by immunofluorescence assay as well as by conventional culture methods. The proposed method could thus be employed in environmental surveillance of V. cholerae O1.