Diabetes is considered as a risk factor for the severity of coronavirus disease 2019 (COVID-19). The mortality rate of COVID-19 was found to be high among patients with diabetes. The exact molecular mechanism involved in diabetes-associated COVID-19 severity is not established. In this review, we discuss the exacerbated formation of advanced glycation end products (AGEs), AGE-receptor for AGE (RAGE) signaling induced spike in inflammatory cytokines, and the role of metformin, an antidiabetic drug with glycation inhibition property. The commonality between these two diseases is exacerbated immune response. AGEs interact with RAGE, leading to oxidative stress, activation of the pro-inflammatory pathway, and production of inflammatory cytokines, which may aberrantly activate the immune response. Based on these pieces of evidence, we propose a role for glycation in the pathogenesis of COVID-19 severity.

Nanoparticles or similar, nanoscale objects such as proteins or biological fibrils usually have to be deposited from aqueous suspension onto a solid support surface for further characterization by atomic force microscopy (AFM) and related methods such as Kelvin-probe force microscopy (KFM). Here we show, on the examples of functionalized nanoparticles and collagen fibrils, that water desorption after sample preparation affects their electrostatic potential determined by KFM in a predictable manner. We explain this effect with a simple, analytical model based on the capacitance of the partially dielectric-filled tip-sample system. We also propose practical measures to avoid false interpretation of electrical AFM-based experiments. As the phenomenon is very generic it may have significant implications in the application of AFM to nanoparticles and other nanostructures including biological ones.

Crosslinking and aggregation of proteins has been related to several disorders such as diabetes, Alzheimer’s and other neuronal diseases. Glycation is known to accelerate protein cross-linking and aggregation. The crosslinked and aggregated proteins plays a major role in the pathogenesis of diseases. Therefore this thesis mainly focuses on the identification, characterisation of crosslinked proteins and inhibition of this process. In addition to glycation, drugs that promote glycation were also studied. Proteomic analysis of cross-linked protein aggregates in diabetes- Glycation induced protein aggregation has been implicated in the development of diabetic complications and neurodegenerative diseases. These aggregates are known to be resistant to proteolytic digestion. Here we report the identification of protease resistant proteins from the streptozotocin induced diabetic rat kidney, which included enzymes in glucose metabolism and stress response proteins. These protease resistant proteins were characterized to be advanced glycation end products modified and ubiquitinated by immunologicaland mass spectrometry analysis. Further, diabetic rat kidney exhibited significantly impaired proteasomal activity. The functional analysis of identified physiologically important enzymes showed that their activity was reduced in diabetic condition. Loss of functional activity of these proteins was compensated by enhanced gene expression. Aggregation prone regions were predicted by in silico analysis and compared with advanced glycation end products modification sites. These findings suggested that the accumulation of protein aggregates is an inevitable consequence of impaired proteasomal activity and protease resistance due to advanced glycation end products modification. Protriptyline, an anti-depressant inhibits protein cross linking and multiple targets of Alzheimer’s disease- Alzheimer’s disease (AD) is a complex neurodegenerative disorder involving multiple cellular and molecular processes. The discovery of drug molecules capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. The repositioning of existing non-toxic drugs could dramatically reduce the time and costs involved in developmental and clinical trial stages. In this study, preliminary screening of 140 FDA approved nervous system drugs by docking suggested the viability of the tricyclic group of antidepressants against three major AD targets, viz. Acetylcholinesterase (AChE), β-secretase (BACE-1), and amyloid β (Aβ) aggregation, with one member, protriptyline, showing highest inhibitory activity. Detailed biophysical assays, together with isothermal calorimetry, fluorescence quenching experiments, kinetic studies and atomic force microscopy established the strong inhibitory activity of protriptyline against all three major targets. The molecular basis of inhibition was supported with comprehensive molecular dynamics simulations. Further, the drug inhibited glycation induced amyloid aggregation, another important causal factor in AD progression. This study has led to the discovery of protriptyline as a potent multi target directed ligand and established its viability as a promising candidate for AD treatment. Tolbutamide, an anti-diabetic drug promotes glycation- In this study, we have investigated the effect of tolbutamide on albumin confirmation using BSA as a model protein. We have found that the binding of tolbutamide, a first generation sulfonylurea, induces significant conformational change in the albumin, which was proved by Thioflavin T assay, ANS assay, and CD analysis. Molecular dynamic simulations suggested that the binding of tolbutamide increases the solvent accessibility of lysine residues, the hotspots of glycation of albumin. Furthermore, the change in conformation of albumin facilitates increased glycation, which was observed by AGE fluorescence and the results were corroborated by mass spectrometric analysis. This study suggested that tolbutamide enhances albumin glycation by inducing conformational change in the protein and hence it could be a risk factor if used for prolonged period.