Abstract
Diabetes represents a major health problem, involving a severe imbalance of blood sugar levels, which can disturb the nerves, eyes, kidneys, and other organs. Diabes management involves several synthetic drugs focused on improving insulin sensitivity, increasing insulin production, and decreasing blood glucose levels, but with unclear molecular mechanisms and severe side effects. Natural chemicals extracted from several plants such as Gymnema sylvestre, Momordica charantia or Ophiopogon planiscapus Niger have aroused great interest for their anti-diabetes activity, but also their hypolipidemic and anti-obesity activity. Here, we focused on the anti-diabetic activity of a few natural and synthetic compounds, in correlation with their pharmacokinetic/pharmacodynamic profiles, especially with their blood-brain barrier (BBB) permeability. We reviewed studies that used bioinformatics methods such as predicted BBB, molecular docking, molecular dynamics and quantitative structure-activity relationship (QSAR) to elucidate the proper action mechanisms of antidiabetic compounds. Currently, it is evident that BBB damage plays a significant role in diabetes disorders, but the molecular mechanisms are not clear. Here, we presented the efficacy of natural (gymnemic acids, quercetin, resveratrol) and synthetic (TAK-242, propofol, or APX3330) compounds in reducing diabetes symptoms and improving BBB dysfunctions. Bioinformatics tools can be helpful in the quest for chemical compounds with effective anti-diabetic activity that can enhance the druggability of molecular targets and provide a deeper understanding of diabetes mechanisms.
Highlights
Histone deacetylases (HDAC) modulation appears as an important direction in diabetes therapy, as their inhibition was associated with β cell development, proliferation, differentiation and function [40]
We discussed research on natural and synthetic compounds that operate on therapeutic target proteins in DM and on the blood-brain barrier (BBB)
We approached three current research directions, namely the modulation of proteins involved in glucose metabolism or in insulin response, of proteins involved in the development and preservation of pancreatic β cells, and of proteins involved in BBB permeability preservation
Summary
The molecular mechanisms involved in T2DM are incompletely explained, but insulin resistance and defects in insulin secretion are the main causes of this disease [5]. Macrovascular complications (cerebrovascular, coronary and arterial disease) [7] and microvascular complications (diabetic retinopathy, nephropathy, neuropathy) [8] affect the nervous system, suggesting an inflammatory process that permeates the BBB, leading to brain dysfunctions such as those in the psychiatric sphere [9]. We reviewed studies on natural compounds acting on DM protein targets and on BBB. We discussed the molecular targets in diabetes by considering proteins involved in the metabolism and uptake of glucose, proteins that control insulin secretion and proteins involved in pancreatic β cell development.
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