Swayam Prakash Srivastava

Healing potential of Calotropis procera on dermal wounds in Guinea pigs

Calotropis procera (Asclepiadaceae) is a well known plant in the Ayurvedic system of medicine. Based on its traditional use this plant was selected for evaluation of its wound healing potential. For this purpose four full thickness excisional wounds of 8.0 mm diameter were inflicted on the back of guinea pigs. Topical application of 20 microl of 1.0% sterile solution of the latex of C. procera twice daily was followed for 7 days. The latex significantly augmented the healing process by markedly increasing collagen, DNA and protein synthesis and epithelisation leading to reduction in wound area. Thus the present study provides a scientific rationale for the traditional use of this plant in the management of wound healing.

Design and synthesis of 2,4-disubstituted polyhydroquinolines as prospective antihyperglycemic and lipid modulating agents.

A series of 2,4-disubstituted polyhydroquinoline were synthesized and evaluated for their in vivo antihyperglycemic as well as antidyslipidemic activities. Several synthesized compounds have exhibited promising in vivo antihyperglycemic in SLM, STZ-S, and db/db mice model along with significant lipid and TG modulating activity. All these compounds were evaluated in various in vitro models of diabetes to know the possible mechanism of their antihyperglycemic action. Interestingly, compounds 3a-r (diaryl substitution) have exhibited promising protein-tyrosine phosphatase 1B (PTP1B) inhibitory activity whereas, compounds 5a-d (acid substituted) have shown significant glycogen phosphorylase activity.

Flavone-Based Novel Antidiabetic and Antidyslipidemic Agents

The hybrid congeners 62-90 of 6- and 7-hydroxyflavones with aminopropanol have been synthesized and evaluated for their antidiabetic activity in sucrose-challenged low-dosed streptozotocin (STZ)-induced diabetic rats and db/db mice. The optical enantiomers 70a, 70b, 90a, and 90b of two congeners 70 and 90 exhibiting consistent antidiabetic and antidyslipidemic activities were also prepared, and their antidiabetic activity results indicate its association mainly with S isomers. These compounds also lower cholesterol and TG profiles while improving high-density lipoprotein cholesterol to CHOL ratio in db/db mice. The bioavailability of compound 70 and its isomer varies between 27 and 29% whereas that of the more polar compound 90a is poor as determined in rat by oral and intraperitoneal administrations.

Antidiabetic effect of Eclipta alba associated with the inhibition of alpha-glucosidase and aldose reductase

The antidiabetic effect of the ethanolic extract of Eclipta alba (EEA) on hyperglycaemia and diabetic nephropathy was investigated in streptozotocin-induced diabetic rats. Single-dose treatment of EEA to streptozotocin-induced diabetic rats lowered the blood glucose level by 17.6% (p < 0.05) at 250 mg kg−1 dose after 5 h post oral administration. Treatment of animals after 10 weeks of STZ-treatment with EEA (250 mg kg−1) for 21 days significantly reduced the elevated levels of blood glucose, %HbA1C, urea, uric acid and creatinine, and significantly increased the depressed serum insulin level. The extract exerted a significant inhibitory effect on alpha-glucosidase in a noncompetitive manner with an IC50 value of around 54 µg mL−1 and was found inhibitory to eye lens aldose reductase with an IC50 value of around 4.5 µg mL−1. The results suggest that EEA possesses antidiabetic effect associated with alpha-glucosidase and aldose reductase inhibition.

Synthesis and antidyslipidemic activity of chalcone fibrates

A series of chalcone based PPAR-α agonists were synthesized and evaluated for their antidyslipidemic activity in high fructose high fat fed dyslipidemic Syrian golden hamsters. Most of the compounds exhibited antidyslipidemic activity. The compounds 4c and 4f have been identified as most potent antidyslipidemics. A definite structure-activity relationship was observed while varying the nature as well as the position of the substituent.

Inhibition of Alpha-Glucosidase by Acacia nilotica Prevents Hyperglycemia along with Improvement of Diabetic Complications via Aldose Reductase Inhibition

Postprandial hyperglycemia is a prominent and early defect in diabetes and regulating blood glucose elevation may attenuate progression towards diabetes associated secondary complications. Here we investigated the alphaglucosidase inhibitory potential of the ethanolic extract of the stem bark of Acacia nilotica (EEAN). The EEAN showed a remarkable alpha-glucosidase inhibitory effect with IC50 value around 8 μg/ml. Kinetic studies revealed that the extract inhibited alpha-glucosidase in competitive manner and caused conformational changes in secondary structure of the enzyme protein. In vivo analysis showed that EEAN significantly suppresses the sucrose-induced postprandial glucose elevation in normal rats and exerts antihyperglycemic effect in streptozotocin (STZ)-induced diabetic rats in a dose-dependent fashion. Further, treatment of diabetic animals after 10 week of STZ-treatment with EEAN (250 mg/ kg) for 21 days, significantly reduced the elevated levels of blood glucose, %HbA1C, urea, uric acid and creatinine, and significantly increased the depressed plasma insulin level. The EEAN also showed inhibitory potential on aldose reductase activity with an IC50 of 7.5 μg/ml. The results suggest that EEAN possess antihyperglycemic activity through inhibition of alpha-glucosidase along with antidiabetogenic effect on polyol pathway through aldose reductase inhibition.

Identification of novel PTP1B inhibitors by pharmacophore based virtual screening, scaffold hopping and docking.

Design and synthesis of protein tyrosine phosphatases-1B (PTP1B) inhibitors are important for the drugs targeted to treat diabetes and obesity. The pharmacophore modeling, docking and scaffold hopping techniques have been applied to discover the novel PTP1B inhibitors. The ten prioritized compounds (115-119, 120-121, 127, 130-131) from the library of 86 compounds were synthesized and found positive in the micro molar range for PTP1B in-vitro inhibitory assays as compared to Suramin (IC50 9.5 μM). Among these five active compounds (115-119) were tested in STZ-s induced diabetic rat model and the most active compound 115 in this test, was further tested in C57BL/KsJ-db/db mice where it significantly improved OGTT along with the fasting and random blood glucose level. The treatment by the compound 115 significantly improved the insulin resistance and insulin signaling by restoring the insulin level and normalizing the serum lipid profile. Compound 115 also augmented the insulin action by modulating the expression of genes involved in insulin signaling like IRS 1-2, PI3K, PTPN1, Akt2, AMPK and PPAR-α. Western blot analysis of both skeletal muscle and liver demonstrated that proteins and intermediate enzymes of insulin signaling were also increased as compared to control group. The compound 115 was also investigated for anti-adipogenic effect on 3T3L-1 cells. The compound 115 inhibited MDI induced lipid accumulation in a dose-dependent manner. The oral bioavailability of compound 115 was ∼10.29% after 30 mg/kg oral dosing assessed in rat.

Lipid lowering and antioxidant activity of flavones in triton treated hyperlipidemic rats

Flavones are plant derived polyphenolic compounds which are consumed by our diet. Epidemiological studies indicating that high dietary intake of flavones reduces the risk of mortality due to coronary heart disease. The lipid lowering action of flavones—myricetin, rutin, naringenin-7-rhamnoglucosides and naringenin hydrates has been studied in triton treated hyperlipidemic rats (in vivo) and antioxidant activity (in vitro). Among these myricetin and naringenin hydrate showed potent antidyslipidemic and antioxidant activities. The antidyslipidemic and antioxidant activities of these flavones may help in prevention of hyperlipidemia and related cardiovascular diseases.

A transposon insertion mutant of Mycobacterium fortuitum attenuated in virulence and persistence in a murine infection model that is complemented by Rv3291c of Mycobacterium tuberculosis

Mycobacterium fortuitum is a non-tubercular fast growing pathogenic mycobacteria whose virulence factors have not been studied. Infection of M. fortuitum ATCC 6841 in a murine infection model leads to spinning of the head in 8-12 days after infection, 20-25% mortality and a constant bacillary load in the kidney of mice, suggesting persistence. From a TnphoA insertion library, a mutant MT13 was isolated which was attenuated in virulence with lesser bacterial burden, milder and delayed spinning of the head and no mortality of mice. The significant feature of the mutant was its failure to persist in kidney and thus the persistent bacillary load characteristic exhibited by the wild type strain was not observed. The insertion of transposon in MT13 was mapped in a region of the genome, which showed homology to Rv3291c of M. tuberculosis, annotated as a transcriptional regulatory factor and reported to be up regulated in nutrient starvation and anaerobic persistent states. Complementation of MT13 with rv3291c resulted in restoration of wild type characteristics including persistence in kidney suggesting the role of a Rv3291c homolog in the virulence and persistence of M. fortuitum.

Acacia catechu hard wood: potential anti-diabetic cum anti-dyslipidemic

The ethanolic as well as aqueous extracts of the hard wood of Acacia catechu showed improvement on oral glucose tolerance post-sucrose load in normal rats and streptozotocin (STZ)-induced diabetic rats. Around 22 and 27% improvement in glucose tolerance was observed post 7 and 14 days of feeding the ethanolic extracts, respectively, on STZ-induced diabetic rats. Whereas around 17 and 26% improvement on glucose tolerance was observed post 7 and 14 days of feeding the ethanolic extract in the high fructose high fat diet (HFD) fed-low dosed STZ-treated rats. The ethanolic extract of A. catechu hard wood also showed marked anti-dyslipidemic activity on HFD fed Syrian golden hamster as evidenced by around 43 and 26% decline in serum triglycerides and total cholesterol, respectively. The ethanolic and aqueous extracts also showed marked inhibition on eye lens aldose reductase either from normal or STZ-induced diabetic rats. Further studies are warranted to isolate and identify the active ingredients from the ethanolic and aqueous extracts of A. catechu hard wood.