Herein we investigated the molecular mechanism of action of the citrus flavonoid, quercetin in skeletal muscle cells (L6 myotubes). Taking advantage of protein kinase inhibitors, we proved that the effect of quercetin on 2-NBDG uptake in L6 myotubes was not through insulin signaling pathway, but through adenosine monophosphate kinase (AMPK) pathway and its downstream target p38 MAPK. An increase in the cellular AMP to ATP ratio on pretreatment may account for AMPK activation which was coupled with a transient change in mitochondrial membrane potential. In addition, quercetin triggered a rise in intracellular calcium suggesting that calcium-calmodulin mediated protein kinase (CaMKK) may also be involved. Quercetin shared a similar mechanism with the well-known drug metformin, highlighting it as a promising compound for the management of type 2 diabetes. The AMPK signaling pathway could contribute to correction of insulin resistance through bypassing the insulin-regulated system for GLUT4 translocation.

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Enhanced oxidative stress contributes to pathological changes in diabetes and its complications. Thus, strategies to reduce oxidative stress may alleviate these pathogenic processes. Herein, we have investigated Naringin mediated regulation of glutathione (GSH) & intracellular free radical levels and modulation of glucose uptake under oxidative stress in L6 cell lines. The results from the study demonstrated a marked decrease in glutathione with a subsequent increase in free radical levels, which was reversed by the pretreatment of Naringin. We also observed that the increased malondialdehyde level, the marker of lipid peroxidation on induction of oxidative stress was retrieved on Naringin pretreatment. Addition of Naringin (100 μM) showed approximately 40% reduction in protein glycation in vitro. Furthermore, we observed a twofold increase in uptake of fluorescent labeled glucose namely 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2 - NBDG) on Naringin treatment in differentiated L6 myoblast. The increased uptake of 2-NBDG by L6 myotubes may be attributed due to the enhanced translocation of GLUT4. Our results demonstrate that Naringin activate GSH synthesis through a novel antioxidant defense mechanism against excessive Reactive Oxygen Species (ROS) production, contributing to the prevention of oxidative damage in addition to its effect on glycemic control.

The present study investigates the in vitro antidiabetic and antioxidant potential of hesperidin and hesperetin under oxidative stress induced in L6 myotubes. Also, the study attempts to reveal the effect of glycosylation (hesperetin) on the biological activities of hesperidin. Oxidative stress is the leading cause of complications associated with diabetes. Both hesperidin and hesperetin reduce oxidative stress directly by scavenging intracellular reactive oxygen species (ROS) and by up-regulating natural antioxidant defence system like glutathione. Hesperidin and hesperetin at 10μM inhibited the non-enzymatic glycation of proteins (65.57% and 35.6%, respectively), the critical reaction involved in the formation of advanced glycation end products (AGEs) which has a significant role in the pathogenesis of diabetes. Additionally, these compounds induced glucose uptake in L6 myotubes following acute and chronic treatment. The percentage 2-NBDG uptake shown by both the compounds was comparable with that of the antidiabetic drug, rosiglitazone (30.4%). Both the compounds downregulated PI3 kinase activity whereas GLUT4, IRS, and AKT were upregulated in L6 myotubes pointing to the possible overlapping with the insulin signalling pathway.Significance of the study: Evidence suggest that oxidative stress occurs in diabetes and could have a role in the development of insulin resistance. Oral hypoglycaemic agents which target on increasing insulin levels and improving insulin sensitivity or that reduce the rate of carbohydrate absorption from the gastrointestinal tract are used to manage type 2 diabetes. But these therapies rarely target the real cause of type 2 diabetes and have severe adverse effects. The observations from the present study provide significant evidence for hesperidin and hesperetin, to be considered as a dietary supplement to manage type 2 diabetes and to suppress oxidative stress mediated diabetic pathophysiology.

This account describes the developments in quinoneimide chemistry during the last two decades, emphasizing the addition of weak nucleophilic systems leading to cycloadducts in most cases.

The study quantified the major phenolics in different fractions of seeds and evaluated their cardioprotective efficacy. Gallic acid, ellagic acid, cinnamic acid, quercetin, syringic acid and ferulic acid were the major polyphenols present in different fractions of seeds. The cardioprotective effect of seed fractions in modulating angiotensin converting enzyme (ACE), HMG-CoA reductase, LDL oxidation and tertiary butyl hydrogen peroxide (TBHP) induced oxidative stress in H9c2 cardiac cell lines were investigated. effectively attenuated the cellular oxidative stress in H9c2 cardiomyoblasts. These fractions possessed inhibitory potential against ACE, HMG-CoA reductase and LDL oxidation. Molecular docking studies of the predominant polyphenols with ACE and HMG-CoA proteins revealed the binding interactions of these compounds, thus confirming their modulation of activity. The present study demonstrated the cardioprotective efficacy of seed fractions which can be attributed to the presence of phenolic acids and flavonoids.