Saroj S. Ghaskadbi

Indian Herbs and Herbal Drugs Used for the Treatment of Diabetes

Traditional Medicines derived from medicinal plants are used by about 60% of the world’s population. This review focuses on Indian Herbal drugs and plants used in the treatment of diabetes, especially in India. Diabetes is an important human ailment afflicting many from various walks of life in different countries. In India it is proving to be a major health problem, especially in the urban areas. Though there are various approaches to reduce the ill effects of diabetes and its secondary complications, herbal formulations are preferred due to lesser side effects and low cost. A list of medicinal plants with proven antidiabetic and related beneficial effects and of herbal drugs used in treatment of diabetes is compiled. These include, Allium sativum, Eugenia jambolana, Momordica charantia Ocimum sanctum, Phyllanthus amarus, Pterocarpus marsupium, Tinospora cordifolia, Trigonella foenum graecum and Withania somnifera. One of the etiologic factors implicated in the development of diabetes and its complications is the damage induced by free radicals and hence an antidiabetic compound with antioxidant properties would be more beneficial. Therefore information on antioxidant effects of these medicinal plants is also included.

Islets and their antioxidant defense

Pancreatic β-cells secrete insulin in response to changes in extracellular glucose concentration. Persistent hyperglycemia during diabetes exerts toxic effects on islets by creating redox imbalance arising from overproduction of reactive oxygen species (ROS). ROS accumulation disturbs the integrity and physiological function of cellular biomolecules impairing viability and functionality of cells. Susceptibility of an organ to oxidative stress (OS) is determined by its defense mechanism and ability to repair DNA damage caused by ROS. Weak defense status of islets along with its inefficiency to repair oxidative DNA damage as compared to other tissues renders it extraordinarily sensitive to OS. Realizing the vulnerability of islet cells to oxidative damage, several efforts to boost their defense mechanism in the form of oral administration of antioxidants and overexpression of genes responsible for antioxidant enzymes have proven successful. Recently accountability for this low antioxidant defense of islets have been given by correlating it with its metabolic evolution.

Antioxidant activity of some polyphenol constituents of the medicinal plant Phyllanthus amarus Linn

Abstract Phyllanthus amarus Linn is a widely distributed tropical medicinal plant highly valued for its therapeutic properties. The antioxidant activity of some of its principal constituents, namely amariin, 1-galloyl-2,3-dehydrohexahydroxydiphenyl (DHHDP)-glucose, repandusinic acid, geraniin, corilagin, phyllanthusiin D, rutin and quercetin 3-O-glucoside were examined for their ability to scavenge free radicals in a range of systems including 2,2-diphenyl-2-picrylhydrazyl (DPPH), 2,2-azobis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS)/ferrylmyoglobin, ferric reducing antioxidant power (FRAP) and pulse radiolysis. In addition, their ability to protect rat liver mitochondria against oxidative damage was determined by measuring the ROO• radical induced damage to proteins and lipids and •OH radical induced damage to plasmid DNA. The compounds showed significant antioxidant activities with differing efficacy depending on the assays employed. Amariin, repandusinic acid and phyllanthusiin D showed higher antioxidant activity among the ellagitannins and were comparable to the flavonoids, rutin and quercetin 3-O-glucoside.

Molecular Characterization and Meta-Analysis of Gut Microbial Communities Illustrate Enrichment of Prevotella and Megasphaera in Indian Subjects

The gut microbiome has varied impact on the wellbeing of humans. It is influenced by different factors such as age, dietary habits, socio-economic status, geographic location, and genetic makeup of individuals. For devising microbiome-based therapies, it is crucial to identify population specific features of the gut microbiome. Indian population is one of the most ethnically, culturally, and geographically diverse, but the gut microbiome features remain largely unknown. The present study describes gut microbial communities of healthy Indian subjects and compares it with the microbiota from other populations. Based on large differences in alpha diversity indices, abundance of 11 bacterial phyla and individual specific OTUs, we report inter-individual variations in gut microbial communities of these subjects. While the gut microbiome of Indians is different from that of Americans, it shared high similarity to individuals from the Indian subcontinent i.e., Bangladeshi. Distinctive feature of Indian gut microbiota is the predominance of genus Prevotella and Megasphaera. Further, when compared with other non-human primates, it appears that Indians share more OTUs with omnivorous mammals. Our metagenomic imputation indicates higher potential for glycan biosynthesis and xenobiotic metabolism in these subjects. Our study indicates urgent need of identification of population specific microbiome biomarkers of Indian subpopulations to have more holistic view of the Indian gut microbiome and its health implications.

Differential susceptibility of chick and mouse islets to streptozotocin and its co-relation with islet antioxidant status

Species differences in susceptibility of islets to STZ in different mammals have been well documented. Likewise, failure of diabetes induction in birds by streptozotocin has been reported. We hypothesized that the susceptibility of islets to STZ treatment may be related to generation of reactive oxygen species (ROS) and their antioxidant defense mechanisms. To test this hypothesis, we measured the total ROS generated and estimated the damage caused to the chick islets due to STZ treatment, in terms of lipid peroxidation, protein carbonyl formation and DNA strand breaks and compared it with that of mouse islets. We also compared the activities of antioxidant enzymes like catalase, superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reductase (GR) and amount of antioxidant molecules like reduced glutathione (GSH) and uric acid under control and STZ-treated conditions. These studies coupled with viability, functionality and presence of glucose transporter GLUT2 in chick and mouse islets clearly indicated that STZ treatment neither affects viability nor functionality of chick islets whereas those of mouse islets are affected significantly. Here we demonstrate for the first time a correlation between the generation of ROS on STZ treatment and antioxidant status with insensitivity of chick islets to STZ resulting into failure of diabetes induction in chick.

Geraniin and amariin, ellagitannins from Phyllanthus amarus, protect liver cells against ethanol induced cytotoxicity.

Ethanol mediated free radical generation plays an important role in the pathogenesis of liver injuries and alcoholic liver diseases. In the present study two ellagitannins namely geraniin and amariin isolated from Phyllanthus amarus were examined for their ability to protect mouse liver slices against ethanol induced toxicity and possible mechanism of its protection. Oxidative stress markers such as, lipid peroxidation, protein carbonyl formation, amount of 8-hydroxy-2-deoxyguanosine and antioxidant enzymes levels were measured using specific biochemical assays. Poly (ADP-ribose) polymerase (PARP), Bax and Bcl2 were checked to assess the induction of apoptosis using western blots. The results showed that geraniin and amariin protected mouse liver slices against ethanol induced cytotoxicity. Both compounds inhibited oxidation of lipid, protein and formation of 8-hydroxy-2-deoxyguanosine, all of which were found to be elevated on exposure to ethanol. These compounds restored the antioxidant enzymes altered on ethanol exposure. Compounds also inhibited the cleavage of PARP and bax and restored Bcl2, induced on exposure to ethanol. In summary, both ellagitannins effectively protected mouse liver slices against ethanol induced cytotoxicity and apoptosis by reducing oxidative damage to biological molecules and modulating Bax/Bcl-2 ratio respectively, thus minimizing liver injury.

Bark and Fruit Extracts of Gmelina arborea. Protect Liver Cells from Oxidative Stress

Abstract The effect of Gmelina arborea Roxb. (Verbenaceae) bark and fruit aqueous extracts on paraquat- and hydrogen peroxide–induced oxidative stress was investigated using liver slice culture. Both paraquat and hydrogen peroxide were found to be cytotoxic as measured by release of lactate dehydrogenase from liver slice culture. Addition of bark and fruit extracts along with these cytotoxic agents led to a decrease in lactate dehydrogenase release. Activities of three antioxidant enzymes, namely super-oxide dismutase, catalase, and glutathione reductase, were found to increase on treatment with these pro-oxidants. Addition of the plant extracts along with the pro-oxidants suppressed the enzyme activities. The extracts also displayed antioxidant activity in in vitro radical scavenging assays. Results indicate that Gmelina bark and fruit extracts protected liver slice culture cells by alleviating oxidative stress–induced damage to liver cells.

Bis(quercetinato)oxovanadium IV Reverses Metabolic Changes in Streptozotocin-Induced Diabetic Mice

Organic vanadium compounds offer several advantages in the treatment of diabetes, yet they are impractical to use because of known side effects. In order to ameliorate the side effects of vanadium, we conjugated it with quercetin to form bis(quercetinato)oxovanadium IV (BQOV). This study evaluates the effect of BQOV treatment on carbohydrate metabolism and overall oxidative stress in streptozotocin-induced (STZ) diabetic mice. Administration of BQOV orally to diabetic mice for 3 weeks led to a reduction of blood glucose levels and the animals exhibited normal glucose tolerance at the end of the study period. The increase in glucose uptake by skeletal muscle and liver as well as the normalization of mRNA levels of G-6-Pase and glucokinase in the liver after BQOV treatment pointed to improvements in carbohydrate metabolism. The analysis of the antioxidant status of serum, liver and pancreas revealed reduced oxidative stress in BQOV-treated animals compared to untreated diabetic controls. Serum analyses for kidney and liver function showed that BQOV treatment provoked total protection of the kidney and partial protection of the liver from diabetogenic insults. The number of insulin-positive cells and the amount of pancreatic insulin in treated mice (1.2038 +/- 0.34 ng/mg tissue) did not account for pancreatic regeneration but suggested an insulin-mimetic action on the part of BQOV. Moreover, administration of BQOV for 3 weeks did not show any visible side-effects. This data indicate that BQOV is a safe and potent agent for diabetes treatment, because it is able to improve carbohydrate metabolism and to reduce overall oxidative stress.

Andrographolide protects liver cells from H2O2 induced cell death by upregulation of Nrf-2/HO-1 mediated via adenosine A2a receptor signalling.

BACKGROUND Andrographolide, principle constituent of Andrographis paniculata Nees is used in traditional medicine in Southeast Asia and is known to exhibit various biological activities. Its antioxidant activity is due to its ability to activate one of the antioxidant enzymes, heme oxygenase-1 (HO-1) which is regulated transcriptionally through Nrf-2. However, molecular mechanism underlying activation of Nrf-2/HO-1 has not yet been clearly understood. METHODS Protective effect of andrographolide against H2O2 induced cell death, reactive oxygen species and lipid peroxidation was observed in HepG2 cells. Ability of andrographolide to modulate G-protein coupled receptor (GPCR) mediated signalling was determined using in silico docking and gene expression was analyzed by qRT-PCR, confocal microscopy and western blot analysis. RESULTS We clearly show that andrographolide via adenosine A2A receptor signalling leads to activation of p38 MAP kinase, resulting in upregulation of Nrf-2, its translocation to nucleus and activation of HO-1. Additionally, it activates adenylate cyclase resulting in cAMP formation which in turn activates protein kinase A leading to inhibition of GSK-3β by phosphorylation. Inactivated GSK-3β leads to retention of Nrf-2 in the nucleus leading to sustained expression of HO-1 by binding to its antioxidant response element (ARE). CONCLUSIONS Thus, andrographolide probably by binding to adenosine A2a receptor activates Nrf-2 transcription and also inhibits its exclusion from the nucleus by inactivating GSK-3β, together resulting in activation of HO-1. GENERAL SIGNIFICANCE We speculate that andrographolide can be used as a therapeutic drug to combat oxidative stress implicated in pathogenesis of various diseases such as diabetes, osteoporosis, neurodegenerative diseases etc.

Treatment of hyperglycaemia in newly diagnosed diabetic patients is associated with a reduction in oxidative stress and improvement in β-cell function

There exist several reports demonstrating enhancement in oxidative stress in diabetic patients; however, serial and comprehensive measurement of oxidative stress parameters in newly diagnosed diabetic patients is not yet reported. We measured the oxidative stress parameters in diabetic patients serially from the time of diagnosis and after starting treatment to study their association with glycaemia, insulin resistance and β‐cell function.