Emmanuel Mukwevho

Antioxidant strategies in the management of diabetic neuropathy.

Chronic hyperglycaemia (an abnormally high glucose concentration in the blood) resulting from defects in insulin secretion/action, or both, is the major hallmark of diabetes in which it is known to be involved in the progression of the condition to different complications that include diabetic neuropathy. Diabetic neuropathy (diabetes-induced nerve damage) is the most common diabetic complication and can be devastating because it can lead to disability. There is an increasing body of evidence associating diabetic neuropathy with oxidative stress. Oxidative stress results from the production of oxygen free radicals in the body in excess of its ability to eliminate them by antioxidant activity. Antioxidants have different mechanisms and sites of actions by which they exert their biochemical effects and ameliorate nerve dysfunction in diabetes by acting directly against oxidative damage. This review will examine different strategies for managing diabetic neuropathy which rely on exogenous antioxidants.

Potential Role of Sulfur-Containing Antioxidant Systems in Highly Oxidative Environments

All forms of life maintain a reducing environment (homeostasis) within their cells. Perturbations in the normal redox state can lead to an oxidative environment which has deleterious effects, especially in health. In biological systems, metabolic activities are dependent mainly on mitochondrial oxidative phosphorylation, a metabolic pathway that uses energy released by the oxidation of nutrients to produce ATP. In the process of oxidative phosphorylation, electrons are transferred from electron donors to electron acceptors such as oxygen in redox reactions and often results to the generation of reactive species. Reactive oxygen species consist of a class of radical and non-radical oxygen derivatives. The imbalance between the reactive oxygen species and antioxidant defence systems leads to oxidative burden and hence, damage biological molecules. Antioxidants help to prevent or fix the deleterious effects of reactive species. Sulfur is an important element in biological systems. This atom is usually integrated into proteins as the redox-active cysteine residue and in molecules such as glutathione, thioredoxin and glutaredoxin which are vital antioxidant molecules and are therefore essential for life. This review covers the role of sulfur containing antioxidant systems in oxidative environments.

Oleanolic Acid and Its Derivatives: Biological Activities and Therapeutic Potential in Chronic Diseases

The increasing demand for natural products as an alternative therapy for chronic diseases has encouraged research into the pharmacological importance of bioactive compounds from plants. Recently, there has been a surge of interest in the therapeutic potential of oleanolic acid (OA) in the prevention and management of chronic diseases. Oleanolic acid is a pentacyclic triterpenoid widely found in plants, including fruits and vegetables with different techniques and chromatography platforms being employed in its extraction and isolation. Several studies have demonstrated the potential therapeutic effects of OA on different diseases and their symptoms. Furthermore, oleanolic acid also serves as a framework for the development of novel semi-synthetic triterpenoids that could prove vital in finding therapeutic modalities for various ailments. There are recent advances in the design and synthesis of chemical derivatives of OA to enhance its solubility, bioavailability and potency. Some of these derivatives have also been therapeutic candidates in a number of clinical trials. This review consolidates and expands on recent reports on the biological effects of oleanolic acid from different plant sources and its synthetic derivatives as well as their mechanisms of action in in vitro and in vivo study models. This review suggests that oleanolic acid and its derivatives are important candidates in the search for alternative therapy in the treatment and management of chronic diseases.

Evaluation of the Influence of thiosemicarbazone–triazole hybrids on genes implicated in lipid oxidation and accumulation as potential anti-obesity agents

A series of thiosemicarbazone-triazole hybrids 1a-h are efficiently synthesised and evaluated for their influence on the expression of genes, cpt-1, acc-1 and pgc-1, which are essential in lipid metabolism. The test results show that hybrids 1c and 1g exhibited relatively high influence on the expression of cpt-1 and pgc-1 and suppression of acc-1 as desired.

Calmodulin dependent protein kinase II activation by exercise regulates saturated & unsaturated fatty acids and improves some metabolic syndrome markers

AIMS Activation of Calmodulin dependent protein kinase (CaMK)-II by exercise has a plethora of benefits in health. Fatty acids play a pivotal role in the pathogenesis of metabolic syndrome (MetS). Prevention of MetS and treatment of its main characteristics are very significant to fight against type 2 diabetes. CaMKII activation in the regulation of saturated and unsaturated fatty acids in relation to type 2 diabetes and MetS has not been studied, which became the focus of this present study. MAIN METHODS Using Gas chromatography-Mass spectrometry, we investigated saturated fatty acids and unsaturated fatty acids. Quantitative real time PCR was also used to assess the gene expression. KEY FINDINGS Results indicate that both palmitoleic acid and oleic acid which are monounsaturated fatty acids were increased in response to CaMKII activation. On the other hand, myristic acid and palmitic acid which are saturated fatty acids known to increase the risk factors of MetS and type 2 diabetes were decreased by exercise induction of CaMKII. Conversely, lauric acid also a saturated fatty acid was increased in response to CaMKII activation by exercise. This fatty acid is known to have beneficial effects in alleviating symptoms of both type 2 diabetes and MetS. SIGNIFICANCE According to our knowledge, this is the first study to show that CaMKII activation by exercise regulates fatty acids essential in type 2 diabetes and MetS. CaMKII can be an avenue of designing novel therapeutic drugs in the management and treatment of type 2 diabetes and MetS.

A Study on Neonatal Intake of Oleanolic Acid and Metformin in Rats (Rattus norvegicus) with Metabolic Dysfunction: Implications on Lipid Metabolism and Glucose Transport

Metabolic syndrome, a cluster of different disorders which include diabetes, obesity and cardiovascular diseases, is a global epidemic that is growing at an alarming rate. The origins of disease can be traced back to early developmental stages of life. This has increased mortalities and continues to reduce life expectancies of individuals across the globe. The aim of this study was to investigate the sub-acute and long term effects of neonatal oral administration of oleanolic acid and metformin on lipids (free fatty acids, FFAs) and genes associated with lipid metabolism and glucose transport using a neonatal rat experimental model. In the first study, seven days old pups were randomly grouped into control—distilled water (DW); oleanolic acid (60 mg/kg), metformin (500 mg/kg), high fructose diet (20% w/v, HF), oleanolic acid (OA) + high fructose diet (OA + HF), and Metformin + high fructose diet (MET + HF) groups. The pups were treated for 7 days, and then terminated on postnatal day (PD) 14. In the second study, rat pups were initially treated similarly to study 1 and weaned onto normal rat chow and plain drinking water on PD 21 till they reached adulthood (PD112). Tissue and blood samples were collected for further analyses. Measurement of the levels of free fatty acids (FFAs) was done using gas chromatography-mass spectrometry. Quantitative polymerase chain reaction (qPCR) was used to analyze the gene expression of glut-4, glut-5, fas, acc-1, nrf-1 and cpt-1 in the skeletal muscle. The results showed that HF accelerated accumulation of saturated FFAs within skeletal muscles. The HF fed neonatal rats had increased stearic acid, which was associated with decreased glucose, suppressed expression of glut-4, glut-5, nrf-1 and cpt-1 genes, and increased expression of acc-1 (p < 0.01) and fas. OA + HF and MET + HF treated groups had increased mono- and polyunsaturated FFAs; oleic, and octadecadienoic acids than the HF group. These unsaturated FFAs were associated with increased glut-4, glut-5 and nrf-1 (p < 0.01) and decreased acc-1 and fas (p < 0.05) in both OA + HF and MET + HF treated groups. Conclusions: The present study shows that neonatal oral administration of oleanolic acid and metformin potentially protects against the development of fructose-induced metabolic dysfunction in the rats in both short and long time periods.

Aqueous-Methanol Extracts of Orange-Fleshed Sweet Potato (Ipomoea batatas) Ameliorate Oxidative Stress and Modulate Type 2 Diabetes Associated Genes in Insulin Resistant C2C12 Cells

Edible plants such as sweet potato are sources of natural antioxidants that can be exploited in the management and treatment of insulin resistance. This present study investigated the effects of the extracts of an orange-fleshed sweet potato on oxidative stress biomarkers (glutathione status and lipid peroxidation) and activities of antioxidant enzymes (catalase, CAT and glutathione peroxidase, GPx) in palmitate-induced insulin resistant C2C12 cells. The intracellular antioxidant status of the cells was also measured using Ferric reducing antioxidant power (FRAP) and Trolox equivalent antioxidant capacity (TEAC) assays. Furthermore, this study determined the effect of the extracts on the regulation of some type 2 diabetes associated genes; glucose transporter 4 (glut4), Nuclear respiratory factor 1 (nrf1), Myocyte enhanced factor 2A (mef2a), Carnitine palmitoyltransferase 1 (cpt1) and Acetyl-CoA carboxylase 2 (acc2). The results showed a significant (p < 0.05) increase in intracellular GSH level, a significant reduction in the level of malonaldehyde and a significant improvement in the intracellular antioxidant status upon treatment of the insulin resistant cells with the extracts. The extracts were also able to positively modulate the expression levels of the type 2 diabetes associated genes. On the other hand, HPLC-MS analysis of the extracts showed the presence of polyphenols which could have contributed to the bioactivity of the extracts through their antioxidant effects.

Hybrid compounds from thiosemicarbazone and triazole as antidiabetic agents and their antioxidant potentials

W it is estimated that 220 million people suffer from Diabetes Mellitus and among all the diabetic patients, almost 90% suffer of Type 2 Diabetes. Twenty one million people in the United States, accounting for 7 % of the population, have Diabetes Mellitus (DM) according to the American Diabetes Association (ADA). One third of these people are not aware that they are diabetic as another 41 million people are pre‐diabetic. The total economic cost annually of Diabetes is approximately 132 billion dollars. Diabetes is more frequent among African Americans, Hispanic Americans, American Indians and Asian/Pacific Islanders. In people age 20 and older, 9.6% have Diabetes and in patients of 60 years or older 20.9 % have Diabetes. Diabetes is the sixth leading cause of death in the U.S, according to the center for disease control and prevention (CDC). The widespread occurrence of obesity supports the projection that cases of Diabetes will continue to grow. Diabetes causes a significant economic burden both in terms of direct and indirect costs to society. It is also responsible for increased morbidity and mortality. Three metabolic defects are responsible for the progression to Type 2 Diabetes Mellitus: peripheral insulin resistance, impaired -cell function, and increased hepatic glucose production. In modern age medicine, treatments are available for Diabetes Mellitus like Sulfonylureas, GLP-1 agonists, DPP4 inhibitors, PPAR-γ agonists, GPR119 agonists and SGLT2 inhibitors. The thiazolidinediones are a new class of agents that have been developed to treat Type 2 diabetic patients. Pioglitazone hydrochloride acts as an agonist at peroxisome proliferator-activated receptors (PPARs) in target tissues for insulin action, such as adipose tissue, skeletal muscle, and liver. Activation of the PPAR-g regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this manner, it enhances tissue sensitivity to insulin. Since there is a decrease in solubility with increase in pH and the half life being 3-5 hrs, so is incomplete absorption and eliminated quickly from the conventional tablets. Pioglitazone hydrochloride being a nonpolar drug and cannot effectively break down the lattice structure of water and hence its aqueous solubility is low. The objective of the present research work was to perform solubility studies in various oils and surfactants along with the cosolvents and to develop an optimum SEDDS for Pioglitazone HCl. SEDDS were characterized for size and zeta potential and in-vivo studies were performed to assess the bioavailability. Pioglitazone, a widely prescribed anti diabetic drug belongs to class IΙ under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility. Its oral absorption is dissolution rate limited and it requires enhancement in the solubility and dissolution rate for increasing its oral bioavailability. The rate and extent of release of pioglitazone Hcl from stable SEDDS (F1) was high in 1% SLS when compared to SGF. The FTIR spectra proved that there was on chemical interaction between excipients and drug. SEM studies confirmed that the size was small and spherical.Diabetes mellitus is a metabolic disease that threatens and reduces the quality of life. Eight hybrids (1ah) of thiosemicarbozone and triazole were screened for their effects on genes related to type 2 diabetes as well as their antioxidant activity. The influence of the hybrids on glucose transport genes (Glut-4, Mef2a and Nrf-1) was carried out using quantitative real time polymerase chain reaction (PCR). Antioxidant assays were carried out using established techniques. Hybrids 1b, 1d, 1e and 1g exhibited high expression of Glut-4 gene relative to insulin and control. All the hybrids tested except 1h and 1f expressed the Nrf-1 while only 1h did not express Mef-2a relative to control. Among all the compounds, 1b showed the highest 1-diphenyl-2-picryl- hydrazyl (DPPH) radical scavenging ability and Trolox Equivalent Antioxidant Capacity (TEAC) values. In terms of Ferric Reducing Antioxidant Power (FRAP) and Oxygen Radical Absorbance Capacity (ORAC), 1c and 1d had the highest values, respectively. In all the antioxidant assays carried out, 1a was shown to have the lowest antioxidant activities. Hybrids 1d and 1g showed consistent pattern of glucose transport pathway gene transcription with all the hybrids showing antioxidant potentials though at varying extents. These hybrids could be potential candidates eliciting antidiabetic and antioxidant effects.Objective: In this presentation we will give insight for novel evidence(s) raised from our research group studies in last five years about triggering central role of restoring as well as augmenting antioxidant defense by using adult bone marrow hematopoietic rich stem cells (HSCs), Silymarin (SM) and Silibinin (SB) to produce remarkable antidiabetic activities in STZ-diabetic rats. Two strategies were adopted to activate pancreatic cell therapy via possible regeneration of pancreatic cells, stimulation of β-cells, and enhancement of insulin release.