Effect of Grewia asiatica fruit on glycemic index and phagocytosis tested in healthy human subjects.

The Grewia asiatica (commonly known as Phalsa or Fasla) is a shrub or small tree found in southern Asia. It produces purple to black color fruit when ripe. In folk medicine the edible Grewia asiatica fruit is used in a number of pathological conditions. The current study described the effects of Grewia asiatica fruit on glycemic index (GI) and phagocytosis in healthy non-diabetic human subjects. The results showed that Grewia asiatica fruit has low GI value of 5.34 with modest hypoglycemic activity. Luminol-enhanced chemiluminescence assay was carried out to determine the production of reactive oxygen species (ROS) in the oxidative burst activity of whole blood. ROS production was found to be significantly affected, having the 78.3, 58.6 and 30.8% when the subjects were fed with D-glucose, mixture of D-glucose and Grewia asiatica fruit and Grewia asiatica fruit alone respectively as compared to the control. The aqueous, methanolic and butanolic extracts of Grewia asiatica fruits were found to produce a stimulatory effect on ROS production however; the chloroform, hexane and ethanol-acetate extracted exerted significant inhibitory effect. These results demonstrated that Grewia asiatica fruit has desirable effects on blood glucose metabolism manifested as low glycemic response and modulation of ROS production.

In-vitro immunomodulatory and anti-cancerous activities of biotransformed products of Dianabol through Azadirachta indica and its molecular docking studies.

BACKGROUND: Plant Biotransformation is one of the tools for structural modifications of the organic substrate of low, moderate or high biological value utilizing plant cultured cells, these modifications of organic structures may lead to biologically augmented products and which may be ultimately substantial in cure or improvement of various morbidities and diseases. RESULTS: Azadirachta indica A. Juss. suspension culture was employed for the biotransformation of dianabol (1) for the first time, and two metabolites, 17ß-hydroxy-17α-methyl-5α-androst-1-en-3-one (2), and 17ß-hydroxy-17α-methyl-5α-androstan-3-one (3) were obtained. CONCLUSIONS: Most important aspect of this work was the evaluation of metabolite 2, which strongly and differentially suppressed [not affecting whole blood and human polymorphonuclear cells (PMN)] the phytohemagglutinin (PHA)-activated T-cell proliferation (IC50: <10.33 µM), and also found to inhibit IL-2 production (IC50: 16.89 ± 1.32) unlike metabolite 3 and compound 1. Compound 2 also exhibited anticancer activity against lung cancer cell line; NCI-H460, it moderately inhibited the growth of cancer cells (22.5 ± 4.15 µM). Furthermore, a good correlation between the predicted binding energies of the compounds acquired by the FlexX program and the experimental affinities were speculated upon interacting with IL-2 protein during molecular docking studies.

Synthesis of some potent immunomodulatory and anti-inflammatory metabolites by fungal transformation of anabolic steroid oxymetholone.

BACKGROUND: Biotransformation of organic compounds by using microbial whole cells provides an efficient approach to obtain novel analogues which are often difficult to synthesize chemically. In this manuscript, we report for the first time the microbial transformation of a synthetic anabolic steroidal drug, oxymetholone, by fungal cell cultures. RESULTS: Incubation of oxymetholone (1) with Macrophomina phaseolina, Aspergillus niger, Rhizopus stolonifer, and Fusarium lini produced 17ß-hydroxy-2-(hydroxy-methyl)-17α-methyl-5α-androstan-1-en-3-one (2), 2α,17α-di(hydroxyl-methyl)-5α-androstan-3ß,17ß-diol (3), 17α-methyl-5α-androstan-2α,3ß,17ß-triol (4), 17ß-hydroxy-2-(hydroxymethyl)-17α-methyl-androst-1,4-dien-3-one (5), 17ß-hydroxy-2α-(hydroxy-methyl)-17α-methyl-5α-androstan-3-one (6), and 2α-(hydroxymethyl)-17α-methyl-5α-androstan-3ß-17ß-diol (7). Their structures were deduced by spectral analyses, as well as single-crystal X-ray diffraction studies. Compounds 2-5 were identified as the new metabolites of 1. The immunomodulatory, and anti-inflammatory activities and cytotoxicity of compounds 1-7 were evaluated by observing their effects on T-cell proliferation, reactive oxygen species (ROS) production, and normal cell growth in MTT assays, respectively. These compounds showed immunosuppressant effect in the T-cell proliferation assay with IC50 values between 31.2 to 2.7 µg/mL, while the IC50 values for ROS inhibition, representing anti-inflammatory effect, were in the range of 25.6 to 2.0 µg/mL. All the compounds were found to be non-toxic in a cell-based cytotoxicity assay. CONCLUSION: Microbial transformation of oxymetholone (1) provides an efficient method for structural transformation of 1. The transformed products were obtained as a result of de novo stereoselective reduction of the enone system, isomerization of double bond, insertion of double bond and hydroxylation. The transformed products, which showed significant immunosuppressant and anti-inflammatory activities, can be further studied for their potential as novel drugs.

Synthesis of novel inhibitors of ß-glucuronidase based on benzothiazole skeleton and study of their binding affinity by molecular docking.

Benzothiazole derivatives 1-26 have been synthesized and their in vitro ß-glucuronidase potential has been evaluated. Compounds 4 (IC(50)=8.9 ± 0.25 µM), 5 (IC(50)=36.1 ± 1.80 µM), 8 (IC(50)=8.9 ± 0.38 µM), 13 (IC(50)=19.4 ± 1.00 µM), 16 (IC(50)=4.23 ± 0.054 µM), and 18 (IC(50)=2.26 ± 0.06 µM) showed ß-glucuronidase activity potent than the standard (d-saccharic acid 1,4-lactone, IC(50)=48.4 ± 1.25 µM). Compound 9 (IC(50)=94.0 ± 4.16 µM) is found to be the least active among the series. All active analogs were also evaluated for cytotoxicity and none of the compounds showed any cytotoxic effect. Furthermore, molecular docking studies were performed using the gold 3.0 program to investigate the binding mode of benzothiazole derivatives. This study identifies a novel class of ß-glucuronidase inhibitors.

Oxidative burst inhibitory and cytotoxic amides and lignans from the stem bark of Fagara heitzii (Rutaceae).

Two amides, heitziamide A and heitziamide B and two phenylethanoids, heitziethanoid A and heitziethanoid B together with thirteen known compounds were isolated from F. heitzii (Letouzey). The structures of all compounds were established by spectroscopic analysis. Nine compounds were evaluated for oxidative burst inhibitory activity in a chemoluminescence assay and for cytotoxicity against PC-3 prostate cancer cells. All compounds exhibited a clear suppressive effect on phagocytosis response upon activation with serum opsonized zymosan at the range of IC(50)=2.0-6.5 microM, but no cytotoxic effect was observed (IC(50)>100 microM).

Inhibitors of phosphatidylinositide 3-kinase: effects on reactive oxygen species and platelet aggregation.

Phosphoinositide 3-kinase (PI 3-kinase) exists in cells as a family of isoforms. The enzymes are important regulators of fundamental metabolic processes, such as energy utilization, growth, cell proliferation and survival. They are activated by cell surface receptors for hormones, and by G-protein coupled receptors. Enzyme p110 gamma, in particular, catalyzes production of second messengers from inositol phospholipids, including phosphoinositide (3,4,5) triphosphate or PtdIns (3,4,5) P3, PtdIns (3,4) P2 and Ptdins (3) P. The objective of this study was to corroborate the role of PI 3 kinase in ROS generation and in platelet aggregation through the use of four chemically unrelated inhibitors of PI 3 kinase: wortmannin, LY-294002, resveratrol and quercetin. In this study, we describe the effects of four PI 3-kinase inhibitors on the production of reactive oxygen species (ROS) and platelet aggregation induced by a diversity of agonists. Neutrophils and platelets were obtained from human blood and macrophages from mouse peritoneal cavity. ROS production was measured by a luminol-enhanced chemiluminescence assay; aggregation was measured in platelet-rich plasma (PRP) with a Chronolog Dual Channel Lumi-Aggregometer. Effects of graded concentrations of four enzyme inhibitors (wortmannin, LY-294002, resveratrol and quercetin) were evaluated. All inhibitors caused concentration-dependent depression of ROS generation and human platelet aggregation. They differed only in their potencies as revealed by concentration-response data. Moreover, inhibitors blocked activity of three chemically unrelated stimulants of aggregation: ADP, collagen and epinephrine. We conclude that inhibition of PI 3-kinase would appear to be a useful therapeutic goal in those conditions where the activities of platelets and/or phagocytes become aberrant.