Recurrent hypoglycemia dampens functional regulation mediated via Neurexin-1, Neuroligin-2 and Mint-1 docking proteins: Intensified complications during diabetes.

Glycemic regulation is important for maintaining critical physiological functions. Extreme variation in levels of circulating glucose are known to affect insulin secretion. Elevated insulin levels result in lowering of circulating glycemic levels culminating into hypoglycemia. Recurrence of hypoglycemia are often noted owing to fasting conditions, untimely meals, irregular dietary consumption, or as a side-effect of disease pathophysiology. Such events of hypoglycemia threaten to hamper the patterns of insulin secretion in diabetic condition. Insulin vesicle docking is a prerequisite phase which ensures anchoring of the vesicles to the ß-cell membrane in order to expel the insulin cargo. Neurexin and Neuroligin are the marker docking proteins which assists in the tethering of the insulin granules to the secretory membrane. However, these cell adhesion molecules indirectly affect the glycemic levels by regulating insulin secretion. The effect of extreme levels of glycemic fluctuations on these molecules, and how it affects the docking machinery remains obscure. Our current study demonstrates down-regulated expression of Neurexin-1, Neuroligin-2 and Mint-1 molecules during hyperglycemia, hypoglycemia and diabetic hypoglycemia in rodents as well as for an in-vitro system using MIN6 cell-line. Studies with fluorescently labelled insulin revealed presence of lessened functional insulin secretory granules, concomitant with the alterations in morphology and as a result of hypoglycemia in control and diabetic condition which was found to be further deteriorating. Our studies indicate towards a feeble vesicular anchorage, which may partly be responsible for dwindled insulin secretion during diabetes. However, hypoglycemia poses as a potent diabetic complication in further deteriorating the docking machinery. To the best of our knowledge this is the first report which demonstrates the effect of hypoglycemic events in affecting insulin secretion by weakening insulin vesicular anchorage in normal and diabetic individuals.

Pathogenomic in silico approach identifies NSP-A and Fe-IIISBP as possible drug targets in Neisseria Meningitidis MC58 and development of pharmacophores as novel therapeutic candidates.

Meningitis creates a life-threatening clinical crisis. Moreover, the administered antibiotics result into multi-drug resistance, thereby necessitating development of alternative therapeutic strategies. This study aimed at identifying novel-drug targets in Neisseria meningitidis and therapeutic molecules which can be exploited for the treatment of meningitis. Novel targets were identified by applying a pathogenomic approach involving protein data-set mining, subtractive channel analysis and subsequent qualitative analysis comprising of in silico pharmacokinetics, molecular docking and pharmacophore generation. Pathogenomic studies revealed Neisserial Surface Protein A (NSP-A) and Iron-III-Substrate Binding Protein (Fe-IIISBP) as potential targets. Two pharmacophore models comprising of 2-(biaryl) carbapenems, efavirenz, praziquantel and pyrimethamine for NSP-A and 2-(biaryl) carbapenems, trimipramine and pyrimethamine for Fe-IIISBP, showed successful docking, followed drug-likeness criteria and generated pharmacophore model with a score of 8.08 and 8.818, respectively, which had further been docked to the target stably. Thus, our study identifies NSP-A and Fe-IIISBP as novel targets in Neisseria meningitidis for which 2-(biaryl) carbapenems, efavirenz, praziquantel, trimipramine and pyrimethamine may be employed for effective treatment of meningitis.

Extreme Glycemic Fluctuations Debilitate NRG1, ErbB Receptors and Olig1 Function: Association with Regeneration, Cognition and Mood Alterations During Diabetes.

Neuronal regeneration is crucial for maintaining intact neural interactions for perpetuation of cognitive and emotional functioning. The NRG1-ErbB receptor signaling is a key pathway for regeneration in adult brain and also associated with learning and mood stabilization by modulating synaptic transmission. Extreme glycemic stress is known to affect NRG1-ErbB-mediated regeneration in brain; yet, it remains unclear how the ErbB receptor subtypes are differentially affected due to such metabolic variations. Here, we assessed the alterations in NRG1, ErbB receptor subtypes to study the regenerative potential, both in rodents as well as in neuronal and glial cell models of hyperglycemia and hypoglycemic insults during hyperglycemia. The pro-oxidant and anti-oxidant status leading to degenerative changes in brain regions were determined. The spatial memory and anxiogenic behaviour of experimental rodents were tested using 'T' maze and Elevated Plus Maze. Our data revealed that the extreme glycemic discrepancies during diabetes and recurrent hypoglycemia lead to altered expression of NRG1, ErbB receptor subtypes, Syntaxin1 and Olig1 that shows association with impaired regeneration, synaptic dysfunction, demyelination, cognitive deficits and anxiety.