Antioxidant Activities of Natural Compounds from Caribbean Plants to Enhance Diabetic Wound Healing.

Diabetic wound healing is a global medical challenge. Several studies showed that delayed healing in diabetic patients is multifactorial. Nevertheless, there is evidence that excessive production of ROS and impaired ROS detoxification in diabetes are the main cause of chronic wounds. Indeed, increased ROS promotes the expression and activity of metalloproteinase, resulting in a high proteolytic state in the wound with significant destruction of the extracellular matrix, which leads to a stop in the repair process. In addition, ROS accumulation increases NLRP3 inflammasome activation and macrophage hyperpolarization in the M1 pro-inflammatory phenotype. Oxidative stress increases the activation of NETosis. This leads to an elevated pro-inflammatory state in the wound and prevents the resolution of inflammation, an essential step for wound healing. The use of medicinal plants and natural compounds can improve diabetic wound healing by directly targeting oxidative stress and the transcription factor Nrf2 involved in the antioxidant response or the mechanisms impacted by the elevation of ROS such as NLRP3 inflammasome, the polarization of macrophages, and expression or activation of metalloproteinases. This study of the diabetic pro-healing activity of nine plants found in the Caribbean highlights, more particularly, the role of five polyphenolic compounds. At the end of this review, research perspectives are presented.

Polyphenolic compounds of Phyllanthus amarus Schum & Thonn. (1827) and diabetes-related activity of an aqueous extract as affected by in vitro gastrointestinal digestion.

ETHNOPHARMACOLOGICAL RELEVANCE: Extracts of the aerial part of Phyllanthus amarus have been extensively used in several countries to cure diabetes. No data is available on the impact of gastrointestinal digestion of such crude extracts on their antidiabetic activity. AIM OF THE STUDY: The aim of this study was to identify active fractions and compounds of fresh aerial parts of P. amarus extracted by an infusion method that are responsible for antidiabetic effects occurring at the level of glucose homeostasis. MATERIALS AND METHODS: An aqueous extract was obtained by an infusion method and its polyphenolic composition was analysed by reverse phase UPLC-DAD-MS. The influence of in vitro gastrointestinal digestion was evaluated both on the chemical composition and on the antidiabetic effect of P. amarus infusion extract using glucose-6-phosphatase enzyme inhibition and stimulation of glucose uptake. RESULTS: Analysis of the chemical composition of the crude extract revealed the presence of polysaccharides and various families of polyphenols such as phenolic acids, tannins, flavonoids and lignans. After simulated digestion, the total content of polyphenols decreased by about 95%. Caffeoylglucaric acid derivates and lignans exhibited strong stimulation of glucose uptake similar to metformin with an increase of 35.62 ± 6.14% and 34.74 ± 5.33% respectively. Moreover, corilagin, geraniin, the enriched polysaccharides fraction and the bioaccessible fraction showed strong anti-hyperglycemic activity with about 39-62% of glucose-6-phosphatase inhibition. CONCLUSION: Caffeoylglucaric acid isomers, tannin acalyphidin M1 and lignan demethyleneniranthin were reported for the first time in the species. After in vitro gastroinstestinal digestion, the composition of the extract changed. The dialyzed fraction showed strong glucose-6-phosphatase inhibition.

Receptor for advanced glycation end products modulates oxidative stress and mitochondrial function in the soleus muscle of mice fed a high-fat diet.

Accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) are implicated in the progression of pathologies associated with aging, chronic inflammation, diabetes, and cellular stress. RAGE activation is also implicated in cardiovascular complications of type 2 diabetes, such as nephropathy, retinopathy, accelerated vascular diseases, and cardiomyopathy. Studies investigating the effects of AGE/RAGE axis activation on skeletal muscle oxidative stress and metabolism are more limited. We tested whether a high-fat diet (HFD) would alter circulating AGE concentration, skeletal muscle AGE accumulation, and oxidative stress in wild-type and RAGE-deficient mice. The physiological significance of AGE/RAGE axis activation in HFD-fed mice was evaluated in terms of exercise tolerance and mitochondrial respiratory chain complex activity. HFD elicited adiposity, abnormal fat distribution, and oral glucose intolerance. HFD also induced accumulation of Nε-carboxymethyl-l-lysine, increased protein carbonyl levels, and impaired respiratory chain complex activity in soleus muscle. Ablation of RAGE had no effects on weight gain and oral glucose tolerance in HFD-fed mice. Peak aerobic capacity and mitochondrial cytochrome-c oxidase activity were restored in HFD-fed RAGE-/- mice. We concluded that RAGE signaling plays an important role in skeletal muscle homeostasis of mice under metabolic stress. Novelty HFD in mice induces accumulation of AGEs, oxidative stress, and mitochondrial dysfunction in the soleus muscle. RAGE, the multi-ligand receptor for AGEs, modulates oxidative stress and mitochondrial electron transport chain function in the soleus muscle of HFD-fed mice.

Theoretical investigation of the effect of sugar substitution on the antioxidant properties of flavonoids.

Natural flavonoids are secondary phenolic plant metabolites known for their bioactivity as antioxidants. The evaluation of this property is generally done by the estimation of their direct free radical-scavenging activity as hydrogen or electron donating compounds. This paper reviews experimental results available in the literature for a selection of flavonoids and compares them with calculated quantities characteristic of the hydrogen or electron donation. For that purpose, bond dissociation energies, ionization potentials and electron transfer enthalpies are computed by using DFT methods and the ONIOM procedure implemented in the ab initio program Gaussian. This process has been chosen because it can be extended to the study of large molecules. When acid dissociation and interaction with the solvent are taken into account, the results present very good concordance with experimental results, enlightening the complexity of the processes involved in the classical assays which measure the ability of compounds to scavenge the (2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt) radical cation (ABTS (+)) or the 2,2-diphenyl-1-picryl-hydrazyl radical (DPPH(·)). This study demonstrates the good accuracy of theoretical calculations in obtaining the relative energies involved in free radical scavenging abilities and its capacity for predictive behaviour. It also highlights the necessity to take into account the pK(a) of the compounds and the solvent interaction. The ability of the method to calculate the antioxidant properties of larger molecules are tested on glycosylated flavonoids and the effects of sugar substitution on the antioxidant properties of flavonoids are investigated, pointing out the importance of the charges on the oxygen atoms.

Theoretical study of the mechanism of inhibition of xanthine oxidase by flavonoids and gallic acid derivatives.

Xanthine oxidase is a flavoprotein enzyme which catalyzes the oxidative hydroxylation of purine substrates. Because of its availability, it has become a model for structural molybdoenzymes in general. The enzyme is a well-established target of drugs against gout and hyperuricemia and exists in two forms: oxidase and deshydrogenase. In some pathologies, its level increases in oxidase form, being the source of free radicals which can cause damage to surrounding tissues. It is important to understand the mechanisms of the enzyme inhibition to help in the search of new inhibitors. The main active center is a molybdopterin buried in a cavity. Theoretical calculations can be of some help for distinguishing the important aspects in the inhibition: attraction inside the cavity and anchorage. In this paper, the molybdopterin molecule geometry has been optimized by ab initio with the DFT method and the results have been shown to be very similar to the X-ray coordinates. In order to evaluate the attraction inside the cavity, the electrostatic potential between the charged molybdopterin molecule and two series of inhibitors, some flavonoids, and some gallic acid derivatives have been calculated using the multipolar development supplied by the Gaussian package. The good concordance between the electrostatic force and IC(50) indicates that the attraction is an important factor in the inhibition and must be taken into account in the designing of new drugs.

Isoflavones from Ficus nymphaefolia.

A new isoflavone, 5,7-dihydroxy-4'-methoxy-3'-(2,3-dihydroxy-3-methylbutyl)isoflavone (1) was isolated from the stem bark of Ficus nymphaefolia Mill. (Moraceae) together with eight known isoflavones: genistein, erycibenin A, cajanin, 5,7,2'-trihydroxy-4'-methoxyisoflavone, erythrinin C, alpinumisoflavone, derrone and 3'-(3-methylbut-2-enyl)biochanin A. Their structures were established by spectral analysis including 1D and 2D NMR experiments.

A new alpha-methylene gamma-lactone sesquiterpene from Hedyosmum arborescens.

A new sesquiterpene lactone, 7alpha,10alpha-epoxy-1alpha(H),5alpha(H)-guaia-3,11(13)-dien-8alpha,12-olide, was isolated from the leaves of Hedyosmum arborescens. The structure of this unusual 7,10-epoxy-guaianolide was determined by spectroscopic methods, particularly one- and two-dimensional 1H and 13C NMR.