Anti-α-Glucosidase and Antiglycation Activities of α-Mangostin and New Xanthenone Derivatives: Enzymatic Kinetics and Mechanistic Insights through In Vitro Studies

Diabetes mellitus is characterized by chronic hyperglycemia that promotes ROS formation, causing severe oxidative stress. Furthermore, prolonged hyperglycemia leads to glycation reactions with formation of AGEs that contribute to a chronic inflammatory state. This research aims to evaluate the inhibitory activity of α-mangostin and four synthetic xanthenone derivatives against glycation and oxidative processes and on α-glucosidase, an intestinal hydrolase that catalyzes the cleavage of oligosaccharides into glucose molecules, promoting the postprandial glycemic peak. Antiglycation activity was evaluated using the BSA assay, while antioxidant capacity was detected with the ORAC assay. The inhibition of α-glucosidase activity was studied with multispectroscopic methods along with inhibitory kinetic analysis. α-Mangostin and synthetic compounds at 25 µM reduced the production of AGEs, whereas the α-glucosidase activity was inhibited only by the natural compound. α-Mangostin decreased enzymatic activity in a concentration-dependent manner in the micromolar range by a reversible mixed-type antagonism. Circular dichroism revealed a rearrangement of the secondary structure of α-glucosidase with an increase in the contents of α-helix and random coils and a decrease in β-sheet and β-turn components. The data highlighted the anti-α-glucosidase activity of α-mangostin together with its protective effects on protein glycation and oxidation damage.

Photocaged Dicarbonyl Probe Provides Spatiotemporal Control Over Protein Glycation

Protein glycation is a disease associated, non-enzymatic, posttranslational modification generated by endogenous dicarbonyl metabolites. Currently, there is a lack of chemical tools capable of studying protein adducts caused by this...

Potentially synergistic effects of melatonin and metformin in alleviating hyperglycaemia: a comprehensive review

High level of glucose is hazardous for organisms since it leads to lipid peroxidation, protein glycation and free radical generation. Insulin can lower the high blood glucose by promoting cell’s glucose up-taking. Thus, the impeded insulin secretion in type 1-diabetes and insensitivity of cells to insulin in type 2-diabetes cause hyperglycaemia. Hyperglycaemia impairs mitochondrial function of pancreas to trigger ROS generation. The malfunctional mitochondria cause endoplasmic reticulum to produce misfolded non-functional insulin, finally leading to diabetes. Melatonin, the mitochondria targeted antioxidant, provides protection against diabetes by multiple ways. These include balancing cellular redox status, lowering blood glucose level by modulating metabolic pathways and, finally protecting cells/organelles from high glucose induced injury. Moreover, this indoleamine preserves pancreatic physiological normalcy to facilitate insulin secretion. Thus, melatonin can effectively mitigate diabetes and diabetic complications. Metformin, the most prescribed medicine for type 2-diabetes, has similar antidiabetic activities as melatonin. Both the molecules share similar pathways to preserve stress-stricken pancreas and other organs, whereas, melatonin also potentiates the actions of metformin. The potentially synergistic actions of melatonin and metformin are expected and we strongly recommend a combined therapeutic application of these two molecules for treatment of diabetes.

Evaluation of Antioxidant and Antidiabetic Potential of Polyherbal Drug Made with Three Herbs: An In vitro Cell Culture Model

In diabetes, the postprandial phase is characterized by a rapid and large increase in blood glucose levels, and the possibility that the postprandial “hyperglycemic spikes” may be relevant to the onset of cardiovascular complications has recently received much attention. Medicinal use of herbal medicine in the treatment and prevention of diseases including diabetes has a long history compared to conventional medicine. These plants have no side effects and many existing medicines are derived from the plants. Hence, the current investigation was planned to make a poly herbal drug (PHD) through Punica granatum (fruits), Illicium verum (flowers) and Nyctanthes arbor (leaves) and assess their antioxidant and antidiabetic activities in vitro and in HepG2 cell line. The respective plant methanolic extracts and PHD are exposed to phytochemical assessment and to discriminate the bioactive factors by Gas Chromatography–Mass Spectrometry. We evaluated the antioxidant properties 2, 2-diphenyl-1-picrylhydrazyl scavenging, hydrogen peroxide scavenging, thiobarbituric acid reactive substances and total antioxidant activity of individual plant extracts and the PHD. At the same time, In vitro and cell culture approaches were used to assess the anti-diabetic activity. The PHD has a higher concentration of secondary metabolites than individual plant extracts, according to our findings. On the other hand, we also notice that PHD demonstrated higher antioxidant capability and considerable in vitro glucose-lowering effects along with noteworthy inhibition of ɑ-amylase, glucosidase, lipase, dipeptidyl peptidase-IV, collagenase and protein glycation in HepG2 cell line. In conclusion, this study clearly demonstrated the significant antioxidant and antidiabetic activities of the PHD. Hence, PHD may be used as a potential source in the management of diabetes, hyperglycemia and the related state of oxidative stress.

Gabapentin Antioxidant Derivatives with Anti-Inflammatory and Neuroprotective Potency

Aims: The aim of this work is to investigate the antioxidant and anti-inflammatory potency of novel gabapentin derivatives, which could be proven useful as neuroprotective agents. Background: Alzheimer’s Disease (AD) is one of the most common neurodegenerative disorders worldwide. Due to its multi-factorial character, no effective treatment has been obtained yet. In this direction, the multi-targeting compounds approach could be useful for the development of novel, more effective drugs against AD. Oxidative stress and inflammation are highly involved in the progression of neurodegeneration, while gabapentin has been investigated for the treatment of behavioral symptoms in AD. Objective: In this work, derivatives of cinnamic acid, trolox and 3,5-di-tertbutyl-4-hydroxybenzoic acid amidated with gabapentin methyl ester, were designed and studied. Compounds with these structural characteristics are expected to act in various biochemical pathways, affecting neurodegenerative processes. Methods: The designed compounds were synthesized with classical amidation methods, purified by flash column chromatography, and identified spectrometrically (1H-NMR and 13C-NMR). Their purity was determined by CHN elemental analysis. They were tested in vitro for their antioxidant and anti-inflammatory properties, and for their inhibitory effect on acetylcholinesterase. Their in vivo anti-inflammatory activity was also tested. Results: Those molecules incorporating an antioxidant moiety possessed inhibitory activity against rat microsomal membrane lipid peroxidation and oxidative protein glycation, as well as radical scavenging activity. Moreover, most of them presented moderate inhibition towards lipoxygenase (up to 51% at 100μΜ) and acetylcholinesterase (AchE) (IC50 up to 274μΜ) activities. Finally, all synthesized compounds presented in vivo anti-inflammatory activity, decreasing carrageenan-induced rat paw edema up to 53% and some of them could inhibit cyclooxygenase significantly. Conclusion: These results indicate that the designed compounds could be proven useful as multi-targeting molecules against AD, since they affect various biochemical pathways associated with neurodegeneration. Thus, more effective drugs can be obtained, and possible adverse effects of drug combination can be limited.

Mapping protein carboxymethylation sites provides insights into their role in proteostasis and cell proliferation

Posttranslational mechanisms play a key role in modifying the abundance and function of cellular proteins. Among these, modification by advanced glycation end products has been shown to accumulate during aging and age-associated diseases but specific protein targets and functional consequences remain largely unexplored. Here, we devise a proteomic strategy to identify sites of carboxymethyllysine modification, one of the most abundant advanced glycation end products. We identify over 1000 sites of protein carboxymethylation in mouse and primary human cells treated with the glycating agent glyoxal. By using quantitative proteomics, we find that protein glycation triggers a proteotoxic response and indirectly affects the protein degradation machinery. In primary endothelial cells, we show that glyoxal induces cell cycle perturbation and that carboxymethyllysine modification reduces acetylation of tubulins and impairs microtubule dynamics. Our data demonstrate the relevance of carboxymethyllysine modification for cellular function and pinpoint specific protein networks that might become compromised during aging.

Antidiabetic Potential of Selected Medicinal Plants: A Literature Review

Aims: To investigated for any scientific evidence indicating traditional use of different plant species in the management of diabetes. Study Design: Review Article. Place and Duration of Study: Conducted in Saudi Arabia from December 2020 to August 2021. Methodology: The literature was thoroughly investigated for any scientific evidence indicating traditional use of different plant species in the management of diabetes. The search was done in databases of Google Scholar, Saudi Digital Library and PubMed. Accordingly, the used plant species are classified into six groups. These are: Plants with antidiabetic activity, Plants with hypoglycemic activity, plants with alpha-glucosidase activity, Plants with alpha-amylase activity, Plants with glucose tolerance test, Plants with hypolipemic, anti-cholesterol, LDL and HDL activity. Conclusion: We have done in vitro and in vivo evaluation of M. arvensis L. for antidiabetic activity. The leaves extracts of M. arvensis L. showed significant antioxidant potential and significantly inhibited protein glycation, which correlated well with its phenolics along with other phytoconstituents. the methanolic extract of M. arvensis L.

Multi-Mechanistic In Vitro Evaluation of Antihyperglycemic, Antioxidant and Antiglycation Activities of Three Phenolic-Rich Indian Red Rice Genotypes and In Silico Evaluation of Their Phenolic Metabolites

The study evaluated the antidiabetic potential of three traditional Indian red rice genotypes/RR (Kattuyanam/KA, Chennangi/CH & Karungkuruvai/KU) using a combination of in vitro, metabolomics (Quadrupole-Time of Flight-Liquid chromatography-Mass spectrometry/Q-TOF-LC-MS/MS), and in silico techniques. In terms of antihyperglycemic potential, KA exhibited the highest inhibitory activity against α-amylase; CH against α-glucosidase; and KU against DPPIV and PTP1B enzymes. KA exhibited the highest antioxidant activity (DPPH, FRAP, and ABTS) and greater inhibition of protein glycation compared to other RR indicating its potential to mitigate diabetic complications. The metabolomic analysis confirmed the presence of 99 phenolics in the sample extracts (KU-71, KA-70, CH-68). Molecular docking studies revealed seven metabolites to be good inhibitors of the four target enzymes and activators of insulin receptor substrate/IRS. The antihyperglycemic and oxidation-glycation reduction composite index revealed KA to have the highest overall antidiabetic potential. Hence, the RR could be utilized in functional foods with a multi-barrelled strategy for diabetes prevention/management.

Protein glycation and drought response of pea (Pisum sativum L.) root nodule proteome: a proteomics approach

Because of ongoing climate change, drought is becoming the major factor limiting productivity of all plants, including legumes. As these protein-rich crops form symbiotic associations with rhizobial bacteria — root nodules — they readily lose their productivity under drought conditions. Understanding the underlying molecular mechanisms might give access to new strategies to preserve the productivity of legume crops under dehydration. As was shown recently, development of drought response is accompanied by alterations in the patterns of protein glycation and formation of advanced glycation end products (AGEs) that might be a part of unknown regulatory mechanisms. Therefore, here we address the effects of moderate drought on protein dynamics and AGE patterns in pea (Pisum sativum) root nodules. For this, plants inoculated with rhizobial culture were subjected to osmotic stress for one week, harvested, the total protein fraction was isolated from root nodules by phenol extraction, analyzed by bottom-up LC-MS-based proteomics, and AGE patterns were characterized. Surprisingly, despite the clear drought-related changes in phenotype and stomatal conductivity, only minimal accompanying expressional changes (14 rhizobial and 14 pea proteins, mostly involved in central metabolism and nitrogen fixation) could be observed. However, 71 pea and 97 rhizobial proteins (mostly transcription factors, ABC transporters and effector enzymes) were glycated, with carboxymethylation being the major modification type. Thereby, the numbers of glycated sites in nodule proteins dramatically decreased upon stress application. It might indicate an impact of glycation in regulation of transport, protein degradation, central, lipid and nitrogen metabolism. The data are available at Proteome Xchange (accession: PXD024042).