Pranav Kumar Prabhakar

Synergistic effect of phytochemicals in combination with hypoglycemic drugs on glucose uptake in myotubes

The present study analyses the effect of two plant phenolic compounds, namely chlorogenic acid and ferulic acid, and a plant alkaloid, berberine, alone and also in combination with two commercial oral hypoglycemic drugs (OHD), namely metformin and 2,4-thiazolodinedione (THZ), on the uptake of 2-deoxyglucose (2DG) by L6 myotubes. 2-DG uptake is determined using an enzymatic assay. All the three natural products enhance the uptake of 2DG in time- and dose-dependent manner. A combination of different concentrations of chlorogenic acid and metformin or THZ, has a synergistic effect in the uptake of 2DG with a maximum of 5.0- and 5.3-times respectively, with reference to the base value (without the drugs or the natural products). Ferulic acid in combination with metformin or THZ has also shown a synergistic effect and the 2DG uptake increases by 4.98- and 5.11-fold when compared to the control respectively. Whereas, berberine, in combination with either metformin or THZ, has shown an additive effect with maximum 2DG uptake of 4.1- and 4.7-times from the base value, respectively. The synergistic interaction has been explained with the use of combination index and isobologram. Expression of GLUT4 and PPAR-gamma gene were elevated in chlorogenic acid and berberine treated cells, whereas expression of GLUT4 and PI3K transcripts were significantly enhanced in ferulic acid treated cells. The studies indicate that chlorogenic acid enhances glucose uptake by increasing GLUT4 expression via PI3K independent pathway whereas ferulic acid increases glucose uptake by PI3K dependent pathway. The current findings suggest that the phytochemicals can replace the commercial drugs in part, which could lead to a reduction in toxicity and side effects of the later.

A target based therapeutic approach towards diabetes mellitus using medicinal plants.

Diabetes mellitus (DM) is not one disease but is a heterogonous group of syndromes. Contrary to the popular belief DM is a metabolic disorder characterized by increased blood glucose level (hyperglycemia) and this is because of insufficient or inefficient insulin secretary response. Glucose is the main energy source for the body, and in the case of DM, management of glucose becomes irregular. There are around 410 experimentally proven medicinal plants having antidiabetic properties but the complete mechanism of action is available only for about 109. There are several medicinal plants whose extract modulate glycolysis, Krebs cycle, gluconeogenesis, HMP shunt pathway, glycogen synthesis and their degradation, cholesterol synthesis, metabolism and absorption of carbohydrates, and synthesis and release of insulin. This paper provides a comprehensive review of the mode of action of medicinal plants that exhibit anti-diabetic properties.

Biocompatibility studies on polyaniline and polyaniline-silver nanoparticle coated polyurethane composite.

Biocompatibility of medical grade polyurethane coated with polyaniline (PANi) and polyaniline-silver nanoparticle composite (PANi-AgNp) is reported here. These modified films showed 23 and 18% of 3T3 L1 cell death when compared to 41% with virgin polyurethane (PU) after 48h of incubation, respectively. All the surfaces elucidated inflammatory response in the form of enhanced expressions of the proinflammatory cytokines genes, TNF-α and IL-6. But these values were less (by 20%) on modified films than on the bare PU. Attachment of Pseudomonas and Bacillus were markedly less on PANi-AgNp coated surface (by 90.6 and 50.5%, respectively) when compared to the uncoated PU. As the CFU counts decreases on the nanoparticle coated PU, the adsorbed carbohydrate as well as protein content on to the surface of polymer decreases accordingly, indicating less attachment. A 20% reduction in the thickness of biofilm was observed in PANi-AgNp coated PU surface. A very strong positive correlation is observed between the contact angles of the polymers and the various biological parameters (namely colony forming units, protein, carbohydrate, cell death and inflammatory response), indicating hydrophilic surfaces prevent bacterial biofilm as well as are compatible to cells when compared to hydrophobic surfaces. Coating PU with PANi and PANi+AgNp renders the surface conductive, suggesting potential application in electrochemical biosensors. In addition, these modifications make the surface more biocompatible than the original PU.

Mechanism of action of natural products used in the treatment of diabetes mellitus

Diabetes mellitus (DM) is a metabolic disorder caused by insufficient or inefficient insulin secretary response and it is characterized by increased blood glucose levels (hyperglycemia). DM is a heterogonous group of syndromes. Glucose is the main energy source for the body, and in the case of DM, management of glucose becomes irregular. There are three key defects in the onset of hyperglycemia in DM, namely increased hepatic glucose production, diminished insulin secretion, and impaired insulin action. Conventional drugs treat diabetes by improving insulin sensitivity, increasing insulin production and/or decreasing the amount of glucose in blood. This article provides a comprehensive review of the mode of action of most popular hypoglycemic herbs, such as ginseng, bitter melon, fenugreek, banaba, Gymnema sylvestre and Coptis chinensis. The herbs act by increasing insulin secretion, enhancing glucose uptake by adipose and skeletal muscle tissues, inhibiting intestinal glucose absorption and inhibiting hepatic glucose production. Although evidence from animals and humans consistently supports the therapeutic effect of these phytomedicines, multicenter large-scale clinical trials have not been conducted to evaluate the safety and efficacy of these herbal medicines and their interaction with conventional drugs when administered simultaneously.

Synthesis, antioxidant evaluation, and quantitative structure–activity relationship studies of chalcones

Synthesis, antioxidant activity, and quantitative structure–activity relationship (QSAR) of 25 of chalcone derivatives is reported here. They were synthesized by Claisen–Schmidt reaction and were characterized by FTIR, NMR, and mass spectroscopy. Antioxidant activity is evaluated through four different methods namely, superoxide radical-scavenging, hydrogen peroxide scavenging, reducing power, and DPPH radical-scavenging assays. Generally, compounds with –SCH3 and –OCH3 in the para position of the A-ring and –OH in the B-ring were more active than others. In few cases some of the compounds were more active than ascorbic acid or butylated hydroxytoluene. QSAR was developed correlating the antioxidant activity with the structural features of the compounds and the predictive capability of the models was estimated using internal and external validation methods. All the predictions were within the 99% confidence level. Spatial, structural, and lipophilic properties of the compounds determine their antioxidant properties.

Synergistic interaction of ferulic acid with commercial hypoglycemic drugs in streptozotocin induced diabetic rats

Diabetes mellitus is a chronic disorder characterized by increased blood glucose level. The available commercial oral antidiabetic drugs have some serious side effects; hence there is a need for new hypoglycemic agents which will have therapeutic efficacy as well as less side effects. Ferulic acid, a phytochemical, might be a good supplement to manage diabetes. We investigated the antidiabetic and antilipidemic effect of ferulic acid alone and in combination with oral antidiabetic drugs (metformin and Thiazolidinedione (THZ)). Blood glucose, plasma lipid profiles levels, liver function and kidney function markers were measured in control and streptozotocin induced diabetic rats three weeks after administrating ferulic acid and OHDs (oral hypoglycemic drugs) alone and in combinations. The histopathological analysis of the pancreas was also carried out. Ferulic acid and OHDs significantly reduced the blood glucose, lipid profile, urea, creatinine, serum glutamic pyruvic transaminases (SGPT) and serum glutamic oxaloacetate transaminases (SGOT) in diabetic rats. Same level of reduction in blood glucose levels was achieved when ferulic acid was used in combination with even reduced amounts of OHDs. It decreased most of the side effects when used in combination with THZ. Histopathological analysis showed that combinations increased the number of islets. Ferulic acid interacts synergistically with both the drugs. It might be a good supplement with the OHDs to manage diabetic complications as well as reduces the use of the later.

Interaction of phytochemicals with hypoglycemic drugs on glucose uptake in L6 myotubes

The present study analyses the effect of eugenol, arecoline and vanillic acid alone and in combination with two oral hypoglycemic drugs (OHD), namely, metformin and 2,4-thiazolodinedione (THZ), on 2-deoxyglucose (2DG) uptake in L6 myotubes. 2DG uptake in L6 myotubes was determined using an enzymatic assay developed by Yamamoto et al. (2006). Lipid content inside the cells has been estimated with oil red O assay. The absorption, distribution, metabolism, and excretion (ADME) and drug likeness properties of these phytochemicals are estimated using software QikProp(®). All the three phytochemicals enhance 2DG uptake both in time- and dose-dependent manner. Eugenol and arecoline enhances 2DG uptake synergistically with both the OHD; whereas vanillic acid showing partly synergy with THZ and antagonistic activity with metformin on 2DG uptake. Eugenol and arecoline significantly increase the expressions of the glucose transporter type 4 (GLUT4) and phosphoinositide 3-kinase (PI3K) genes, but not the peroxisome proliferator-activated receptor (PPAR) gamma. Whereas vanillic acid does not has any significant effect on the expressions of these genes, the ADME results indicate that these phytochemicals are satisfying all the conditions to have a good oral bioavailability. These findings suggest that these phytochemicals can replace the commercial drugs in part, which could lead to a reduction in toxicity and side effects caused by the later as well as reduce the secondary complications.

Interaction of Cinnamic Acid Derivatives with Commercial Hypoglycemic Drugs on 2-Deoxyglucose Uptake in 3T3-L1 Adipocytes

Hydroxycinnamic acid derivatives are naturally occurring substances found in fruits, vegetables, and flowers and are consumed as dietary phenolic compounds. The effect of cinnamic acid, ferulic acid, p-coumaric acid, eugenol, chlorogenic acid, and caffeic acid, alone and in combination with two commercial oral hypoglycemic drugs (OHD), namely, thiazolidinedione (THZ) and metformin, on the uptake of 2-deoxyglucose (2DG) by 3T3-L1 adipocytes is studied. All of the phytochemicals other than cinnamic acid show synergistic interaction in 2DG uptake with both of the OHDs. THZ (20 μM) in combination with ferulic acid (25 μM) or p-coumaric acid (25 μM) increases 2DG uptake by 7- or 6.34-fold, respectively, with respect to control, whereas metformin (20 μM), along with ferulic acid (25 μM) or cinnamic acid (25 μM), increases 2DG uptake by 6.45- or 5.87-fold, respectively, when compared to control. Chlorogenic and cinnamic acids increased the expression of PPARγ, whereas other hydroxycinnamic acids enhanced the expression of PI3K, indicating different mechanisms of action between these compounds. These phytochemicals were able to reduce the expressions of the fatty acid synthase and HMG CoA reductase genes, indicating that they may be able to reduce the secondary complications caused by the accumulation of lipids. These studies suggest that hydroxycinnamic acid derivatives may be beneficial for the treatment of diabetes mellitus. They may act as a supplement with commercial drugs and may reduce the secondary complications caused by OHDs.

Combination therapy: a new strategy to manage diabetes and its complications.

Diabetes mellitus is the most common metabolic disorder. The major cause of mortality and morbidity here is due to the complications caused by increased glucose concentrations. All the available commercial antidiabetic drugs are associated with side effects. The combination therapy could be a new and highly effective therapeutic strategy to manage hyperglycemia. Combination of commercial drugs with phytochemicals may reduce the side effects caused by these synthetic drugs. Herbal products have been thought to be inherently safe, because of their natural origin and traditional use rather than based on systemic studies. New formulation and cocrystallisation strategies need to be adopted to match the bioavailability of the drug and the phytochemical. This review describes in detail, the observed synergy and mechanism of action between phytochemicals and synthetic drugs in effectively combating. The mode of action of combination differs significantly than that of the drugs alone; hence isolating a single component may lose its importance thereby simplifying the task of pharma industries.

Effect of Natural Products on Commercial Oral Antidiabetic Drugs in Enhancing 2-Deoxyglucose Uptake by 3T3-L1 Adipocytes

Objective: The management of diabetes with insulin and synthetic oral hypoglycemic drugs (OHDs) can produce serious side effects and in addition fails to prevent diabetes-related complications in many patients. A new diabetes management strategy is needed that is more effective and has fewer side effects. Methods: This paper analyzes the dose- and time-dependent effect of three phytochemicals: berberine, arecoline and vanillic acid, and two antidiabetic drugs: 2,4-thiazolidinedione (TZD) and metformin, on the uptake of 2-deoxyglucose (2DG) by 3T3-L1 adipocytes. The interactions of the phytochemicals with the OHDs were analyzed with isobolograms and the combination index. Results: TZD and berberine increased 2DG uptake by 3.3-fold (with respect to control) at 15 µM and 25 µM, respectively. The same concentrations of arecoline and vanillic acid increased 2DG uptake by 3.2-and 2.9-fold, respectively, when compared with the basal level. Berberine and arecoline acted synergistically with both the OHDs, whereas vanillic acid had an additive interaction with TZD and an antagonistic interaction with metformin. Arecoline significantly increased the translocation of GLUT4 via the PPARγ pathway, whereas berberine and vanillic acid did this via the AMPK-dependent pathway. Conclusions: These phytochemicals significantly reduced the expression of the enzymes involved in fatty acid and cholesterol synthesis, indicating that they might help prevent the secondary complications of diabetes. The current study suggests that berberine and arecoline could allow dosage reduction of OHDs, which could also lead to a reduction in the toxicity and side effects caused by OHDs.