Identification of new novel scaffold for Aurora A inhibition by pharmacophore modeling and virtual screening.

Aurora kinases belong to family of highly conserved serine/threonine protein kinases that are involved in diverse cell cycle events and play a major role in regulation of cell division. Abnormal expression of Aurora kinases may lead to cancer; hence, these are considered as a potential target in cancer treatment. In this research article, we identified three novel Aurora A inhibitors using modern computational tools. A four-point common 3D pharmacophore hypothesis of Aurora A (AurA) inhibitors was developed using a diverse set of 55 thienopyrimidine derivatives. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was carried out using atom-based alignment of diverse set of 55 molecules to evaluate the structure- activity relationships. Docking and 3D-QSAR studies were performed with the 3D structure of AurA to evaluate the generated pharmacophore. The pharmacophore model and 3D-QSAR results complemented the results of our docking study. The pharmacophore hypothesis, which yields the best results, was used to screen the Zinc 'clean drug-like' database. Various database filters such as 3D-arrangement of pharmacophoric features, predicted activity and binding interaction score were used to retrieve hits having potential AurA inhibition activity.

Protective effects of novel diazepinone derivatives in snake venom induced sterile inflammation in experimental animals.

Snake envenomation leads to the formation of damage-associated molecular patterns (DAMPs), which are mediated by endogenous intracellular molecules. These are recognized by pattern-recognition receptors (PRRs) and can induce sterile inflammation. AIMS: In the present study, we aim at understanding the mechanisms involved in DAMPs induced sterile inflammation to unravel the novel therapeutic strategies for treating snake bites. The potential of benzodiazepinone derivatives to act against snake venom induced inflammation has been explored in the present investigation. MAIN METHODS: Three compounds VA 17, VA 43 and PA 03 were taken from our library of synthetic compounds. Oxidative stress markers such as lipid peroxidation, superoxide and nitric oxide were measured along with the analysis of DAMPs (IL6, HMGB1, vWF, S100b and HSP70). These compounds have been docked using molecular docking against the snake venom PLA2 structure (PDB code: 1OXL). KEY FINDINGS: The compounds have been found to effectively neutralize viper and cobra venoms induced lethal activity both ex vivo and in vivo. The compounds have also neutralized the viper venom induced hemorrhagic, coagulant, anticoagulant reactions as well as inflammation. The fold of protection have always been found to be higher in case of ex vivo than in in vivo. These compounds have neutralized the venom induced DAMPs as exhibited by IL6, HMGB1, vWF, S100b and HSP70. The fold of neutralization is found to be higher in VA 43. SIGNIFICANCE: The identified compounds could be used as potential candidates for developing treatment of snakebites in areas where antiserums are not yet available.

Podophyllum hexandrum-Mediated Survival Protection and Restoration of Other Cellular Injuries in Lethally Irradiated Mice.

This study aims at the development of a safe and effective formulation to counter the effects of lethal irradiation. The sub-fraction (G-001M), prepared from Podophyllum hexandrum has rendered high degree of survival (>90%) at a dose of 6 mg kg(-1) body weight (intramuscular) in lethally irradiated mice. Therapeutic dose of G-001M, at about 20 times lower concentration than its LD(100), has revealed a DRF of 1.62. Comet assay studies in peripheral blood leukocytes have reflected that, treatment of G-001M before irradiation has significantly reduced DNA tail length (P < .001) and DNA damage score (P < .001), as compared to radiation-only group. Spleen cell counts in irradiated animals had declined drastically at the very first day of exposure, and the fall continued till the 5th day (P < .001). In the treated irradiated groups, there was a steep reduction in the counts initially, but this phase did not prolong. More than 60% decline in thymocytes of irradiated group animals was registered at 5 h of irradiation when compared with controls, and the fall progressed further downwards with the similar pace till 5th day of exposure (P < .001). At later intervals, thymus was found fully regressed. In G-001M pre-treated irradiated groups also, thymocytes decreased till the 5th day but thereafter rejuvenated and within 30 days of treatment the values were close to normal. Current studies have explicitly indicated that, G-001M in very small doses has not only rendered high survivability in lethally irradiated mice, but also protected their cellular DNA, besides supporting fast replenishment of the immune system.

Eugenol precludes cutaneous chemical carcinogenesis in mouse by preventing oxidative stress and inflammation and by inducing apoptosis.

The present study was designed to investigate the protective efficacy of eugenol against skin cancer and probe into the mechanistic aspects. Skin tumors were initiated by applying 160 nmol DMBA and promoted by twice weekly applications of 8.5 nmol TPA for 28 wk. All mice developed tumors by 13 wk of promotion. However, in mice pretreated with 30 microL eugenol, no tumors were detected until 8 wk (following anti-initiation protocol) and until 14 wk (following antipromotion protocol) of tumor promotion. PCNA and TUNEL immunohistochemistry of tumors revealed eugenol to ameliorate cell proliferation and elevate apoptosis respectively. The effect of eugenol was assessed on specific stages of carcinogenesis. Initiation with DMBA led to a significant upregulation of p53 expression with a concomitant increase in p21(WAF1) levels in epidermal cells indicating induction of damage to the DNA. However, pretreatment with eugenol led to overexpression of these genes, which probably helped stimulate apoptosis of the initiated cells. To ascertain the molecular mechanisms implicated in the antitumor promoting activity of eugenol, its effect was investigated on markers of tumor promotion and inflammation: ODC activity and iNOS and COX-2 expression, and on levels of proinflammatory cytokines (IL-6, TNF-alpha, and PGE(2)). Eugenol markedly inhibited all. Eugenol also inhibited the upstream signaling molecule: NF-kappaB, which regulates the expression of these genes. TPA-induced depletion of cutaneous GSH and antioxidant enzymes armory was also precluded by eugenol. From these results, it could be concluded that eugenol markedly protects against chemically induced skin cancer and acts possibly by virtue of its antiproliferative, anti-inflammatory, and antioxidant activities.

Dietary supplementation of silymarin protects against chemically induced nephrotoxicity, inflammation and renal tumor promotion response.

Ferric nitrilotriacetate (Fe-NTA) is a potent nephrotoxicant and a renal carcinogen that induces its effect by causing oxidative stress. The present study was undertaken to explore protective effect of silymarin, a flavonolignan from milk thistle (Silybum marianum), against Fe-NTA mediated renal oxidative stress, inflammation and tumor promotion response along with elucidation of the implicated mechanism(s). Administration of Fe-NTA (10 mg/kg bd wt, i.p.) to Swiss albino mice induced marked oxidative stress in kidney, evident from augmentation in renal metallothionein (MT) expression, depletion of glutathione content and activities of antioxidant and phase II metabolizing enzymes, and enhancement in production of aldehyde products such as 4-hydroxy-2-nonenal. Fe-NTA also significantly activated nuclear factor kappa B (NFkappaB) and upregulated the expression of downstream genes: cyclooxygenase 2 and inducible nitric oxide synthase and enhancing the production of proinflammatory cytokines: tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). However, feeding of 0.5% and 1% silymarin diet conferred a significant protection against Fe-NTA induced oxidative stress and inflammation. It further augmented MT expression, restored the antioxidant armory, ameliorated NFkappaB activation and decreased the expression of proinflammatory mediators. Silymarin also suppressed Fe-NTA induced hyperproliferation in kidney, ameliorating renal ornithine decarboxylase activity and DNA synthesis. From these results, it could be concluded that silymarin markedly protects against chemically induced renal cancer and acts plausibly by virtue of its antioxidant, anti-inflammatory and antiproliferative activities.

Inhibition of snake venom induced sterile inflammation and PLA2 activity by Titanium dioxide Nanoparticles in experimental animals.

Sterile inflammation (SI) is an essential process in response to snakebite and injury. The venom induced pathophysiological response to sterile inflammation results into many harmful and deleterious effects that ultimately leads to death. The available treatment for snakebite is antiserum which does not provide enough protection against venom-induced pathophysiological changes like haemorrhage, necrosis, nephrotoxicity and often develop hypersensitive reactions. In order to overcome these hindrances, scientists around the globe are searching for an alternative therapy to provide better treatment to the snake envenomation patients. In the present study TiO2 (Titanium dioxide)-NPs (Nanoparticles) has been assessed for antisnake venom activity and its potential to be used as an antidote. In this study, the synthesis of TiO2-NPs arrays has been demonstrated on p-type Silicon Si < 100 > substrate (∼30 ohm-cm) and the surface topography has been detected by Field-emission scanning electron microscopy (FESEM). The TiO2-NPs successfully neutralized the Daboia russelii venom (DRV) and Naja kaouthia venom (NKV)-induced lethal activity. Viper venom induced haemorrhagic, coagulant and anticoagulant activities were effectively neutralized both in in-vitro and in vivo studies. The cobra and viper venoms-induced sterile inflammatory molecules (IL-6, HMGB1, HSP70, HSP90, S100B and vWF) were effectively neutralised by the TiO2-NPs in experimental animals.

Synthesis of novel steroidal D-ring substituted isoxazoline derivatives of 17-oxoandrostanes.

A facile synthesis of isoxazoline derivatives of 17-oxoandrostane at the side chain of D-ring is reported. The scheme involves the transformation of the starting dehydroepiandrosterone acetate (ketone) to the Knoevenegel product, reduction to the nitrile, and elimination to the carboxaldehyde. Cycloaddition of nitrileoxides across olefinic aldehyde intermediate led to the synthesis of novel side chain isoxazoline derivatives.

Quercus infectoria galls possess antioxidant activity and abrogates oxidative stress-induced functional alterations in murine macrophages.

The present study reports the antioxidant activity of ethanolic extract of Quercus infectoria galls. The antioxidant potency of galls was investigated employing several established in vitro model systems. Their protective efficacy on oxidative modulation of murine macrophages was also explored. Gall extract was found to contain a large amount of polyphenols and possess a potent reducing power. HPTLC analysis of the extract suggested it to contain 19.925% tannic acid (TA) and 8.75% gallic acid (GA). The extract potently scavenged free radicals including DPPH (IC(50)~0.5 microg/ml), ABTS (IC(50)~1 microg/ml), hydrogen peroxide (H(2)O(2)) (IC(50)~2.6 microg/ml) and hydroxyl (*OH) radicals (IC(50)~6 microg/ml). Gall extract also chelated metal ions and inhibited Fe(3+) -ascorbate-induced oxidation of protein and peroxidation of lipids. Exposure of rat peritoneal macrophages to tertiary butyl hydroperoxide (tBOOH) induced oxidative stress in them and altered their phagocytic functions. These macrophages showed elevated secretion of lysosomal hydrolases, and attenuated phagocytosis and respiratory burst. Activity of macrophage mannose receptor (MR) also diminished following oxidant exposure. Pretreatment of macrophages with gall extract preserved antioxidant armory near to control values and significantly protected against all the investigated functional mutilations. MTT assay revealed gall extract to enhance percent survival of tBOOH exposed macrophages. These results indicate that Q. infectoria galls possess potent antioxidant activity, when tested both in chemical as well as biological models.

Protective effect of Didymocarpus pedicellata on ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and hyperproliferative response.

Didymocarpus pedicellata R. Br. (Gesneriaceae) is widely used in traditional Indian medicines against renal afflictions. In the present study, we have revealed ethanolic extract of aerial parts of D. pedicellata to possess significant antioxidant activity and protect against ferric nitrilotriacetate (Fe-NTA) mediated renal oxidative stress, nephrotoxicity and tumor promotion response. D. pedicellata extract was found to possess a high content of total polyphenolics, exhibit potent reducing power and significantly scavenge free radicals including several reactive oxygen species (ROS) and reactive nitrogen species (RNS). The extract also significantly and dose-dependently protected against Fe-NTA plus H(2)O(2)-mediated damage to lipids and DNA. Protective efficacy of the extract was also tested in vivo against Fe-NTA mediated nephrotoxicity and tumor promotion response. Administration of Fe-NTA (9 mg/kg body weight, i.p.) to Swiss albino mice depleted renal glutathione content and activities of antioxidant and phase II metabolizing enzymes with concomitant induction of oxidative damage. Fe-NTA also incited hyperproliferation response elevating ornithine decarboxylase activity and [(3)H]-thymidine incorporation into DNA. Elevation in serum creatinine (SCr) and blood urea nitrogen (BUN), and histopathological changes were also evident and suggested Fe-NTA to afflict damage to kidney. Pretreatment of mice with D. pedicellata extract (100-200 mg/kg body weight) for 7 days not only restored antioxidant armory near normal values but also significantly protected against renal oxidative stress and damage restoring normal renal architecture and levels of renal damage markers, viz., BUN and SCr. The results of the present study indicate D. pedicellata to possess potent antioxidant and free radical scavenging activities and preclude oxidative damage and hyperproliferation in renal tissues.

Protective effect of Rumex patientia (English Spinach) roots on ferric nitrilotriacetate (Fe-NTA) induced hepatic oxidative stress and tumor promotion response.

In this communication, we document the antioxidant potential of ethanolic extract of Rumex patientia L. (Polygonaceae) roots and its chemopreventive effects against Fe-NTA mediated hepatic oxidative stress, hepatotoxicity and tumor promotion response. The extract exhibited high polyphenolic content, potent reducing power and significantly scavenged free radicals (including several reactive oxygen species (ROS) and reactive nitrogen species (RNS)). The extract also significantly and dose dependently protected against oxidative damage to lipids and DNA. These results indicated R. patientia root extract to exert a potent antioxidant activity in vitro. The efficacy of extract was also evaluated in vivo and it was found to exert a potent protective affect in acute oxidative tissue injury animal model: ferric nitrilotriacetate (Fe-NTA) induced hepatotoxicity in mice. Administration of Fe-NTA (9 mg/kg body weight, i.p.) to mice led to a significant oxidative stress and allied damage in liver tissues and induced hyperproliferation. A significant depletion was observed in GSH content and enzymes implicated in its metabolism. Attenuation also occurred in activities of other hepatic antioxidant enzymes including SOD, CAT, and GPX. Fe-NTA also incited hyperproliferation response elevating ornithine decarboxylase activity and [(3)H]-thymidine incorporation into DNA. Histopathological investigations and liver function tests (LFT) indicated Fe-NTA to cause extensive hepatic damage. However, prophylactic treatment with R. patientia root extract at a dose regimen of 100-200mg/kg body weight for a week not only restored hepatic antioxidant armory close to normal, but also significantly precluded oxidative damage restoring normal hepatic architecture and levels of hepatic damage markers. The data obtained in the present study illustrates R. patientia roots to possess potent antioxidant and free radical scavenging activities and thwart oxidative damage and hyperproliferation in hepatic tissues.

Punica granatum (pomegranate) flower extract possesses potent antioxidant activity and abrogates Fe-NTA induced hepatotoxicity in mice.

Most pomegranate (Punica granatum Linn., Punicaceae) fruit parts are known to possess enormous antioxidant activity. The present study evaluated antioxidant and hepatoprotective activity of pomegranate flowers. Alcoholic (ethanolic) extract of flowers was prepared and used in the present study. The extract was found to contain a large amount of polyphenols and exhibit enormous reducing ability, both indicative of potent antioxidant ability. The extract showed 81.6% antioxidant activity in DPPH model system. The ability of extract to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) was tested and it was found to significantly scavenge superoxide (O(2)(.-)) (by up to 53.3%), hydrogen peroxide (H(2)O(2)) (by up to 30%), hydroxyl radicals (()OH) (by up to 37%) and nitric oxide (NO) (by up to 74.5%). The extract also inhibited (.)OH induced oxidation of lipids and proteins in vitro. These results indicated pomegranate flower extract to exert a significant antioxidant activity in vitro. The efficacy of extract was tested in vivo and it was found to exhibit a potent protective activity in acute oxidative tissue injury animal model: ferric nitrilotriacetate (Fe-NTA) induced hepatotoxicity in mice. Intraperitoneal administration of 9 mg/kg body wt. Fe-NTA to mice induced oxidative stress and liver injury. Pretreatment with pomegranate flower extract at a dose regimen of 50-150 mg/kg body wt. for a week significantly and dose dependently protected against Fe-NTA induced oxidative stress as well as hepatic injury. The extract afforded up to 60% protection against hepatic lipid peroxidation and preserved glutathione (GSH) levels and activities of antioxidant enzymes viz., catalase (CAT), glutathione peroxidase (GPX) glutathione reductase (GR) and glutathione-S-transferase (GST) by up to 36%, 28.5%, 28.7%, 40.2% and 42.5% respectively. A protection against Fe-NTA induced liver injury was apparent as inhibition in the modulation of liver markers viz., aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin and albumin in serum. The histopathological changes produced by Fe-NTA, such as ballooning degeneration, fatty changes, necrosis were also alleviated by the extract. These results indicate pomegranate flowers to possess potent antioxidant and hepatoprotective property, the former being probably responsible for the latter.

Evaluation of antioxidant activity of Cassia siamea flowers.

The study was aimed at evaluating the antioxidant activity of alcoholic extract of Cassia siamea Lam. (Fabaceae) flowers. The extract was found to contain a large amount of polyphenols and also exhibited an immense reducing ability. At a concentration of 250 microg/ml, 96% of DPPH radicals and at 500 microg/ml, 42.7, 32.7 and 64.5% of O2-, H2O2 and NO respectively could be scavenged by C. siamea flower extract. The extract also inhibited OH radical induced oxidation of protein (BSA) and LPO in murine hepatic microsomes. The determination of metal chelating capacity of the extract indicated chelating of metal ions (Fe2+) to be a putative mechanism implicated in the inhibition of OH radical-induced BSA oxidation and LPO. C. siamea flower extract also exhibited a significant antioxidant activity in acute oxidative tissue injury animal model constituted by CCl4 induced hepatotoxicity. Oral administration of the extract at a dose of 50-150 mg/kg of body weight significantly protected from CCl4 induced elevation in AST and ALT in the serum, elevation in hepatic LPO, depletion of hepatic GSH and decrease in the activities of hepatic antioxidant enzymes: SOD, CAT and GPX. The extract also protected against histopathological changes produced by CCl4 such as necrosis, fatty changes, ballooning degeneration, etc. The data obtained in the present study suggests that the alcoholic extract of C. siamea flowers have potent antioxidant activity against free radicals, prevent oxidative damage to major biomolecules and afford significant protection against oxidative damage in the liver.

Two New Compounds from the Galls of Quercus infectoria. with Nitric Oxide and Superoxide Inhibiting Ability.

Two compounds isolated from the ethanol extract of the galls of Quercus infectoria. Olivier exhibited nitric oxide (NO) and superoxide [Formula: see text] inhibiting activity. Their structures were established as ellagic acid-4-O.-[ß.-D-glucopyranosyl]-10-O.-[ß.-D-glucopyranosyl]-(4 → 1)-ß.-D-rhamnopyranoside (1) and 2-methyl-3-hydroxymethylene-4,5,6,7,8-pentahydroxynaphthalene (2) on the basis of spectroscopic and chemical evidence.

Antiinflammatory evaluation of alcoholic extract of galls of Quercus infectoria.

Galls of Quercus infectoria Olivier (Fagaceae) possess pleiotropic therapeutic activities, with particular efficacy against inflammatory diseases. The present study was undertaken to evaluate the effect of alcoholic extract of Q. infectoria galls on various in vivo and in vitro experimental models of inflammation. Oral administration of gall extract significantly inhibited carrageenan, histamine, serotonin and prostaglandin E2 (PGE2) induced paw oedemas, while topical application of gall extract inhibited phorbol-12-myristate-13-acetate (PMA) induced ear inflammation. The extract also inhibited various functions of macrophages and neutrophils relevant to the inflammatory response. In vitro exposure of rat peritoneal macrophages to gall extract ameliorated lipopolysaccharide (LPS) stimulated PGE2 and nitric oxide (NO) production and PMA stimulated superoxide (O2*-) production in a dose dependent manner. Gall extract also scavenged NO and O2*-. Probing into mechanism of NO inhibition in macrophages revealed gall extract to ameliorate the induction of inducible NO synthase (iNOS), respectively without any inhibitory effect on its catalytic activities even at higher concentrations. Gall extract also significantly inhibited formyl-Met-Leu-Phe (fMLP) stimulated degranulation in neutrophils. These results suggest that alcoholic extract of galls of Q. infectoria exerts in vivo antiinflammatory activity after oral or topical administration and also has the ability to prevent the production of some inflammatory mediators.

Functionalization of pectin by periodate oxidation.

High methoxy citrus pectin was oxidized by periodic acid to prepare a dialdehyde functionalized material. The effect of various reaction conditions, viz., reaction time, reaction temperature, pH of the medium, periodic acid concentration and solvent composition on the oxidation process was investigated. With an increase in the reaction time, the aldehyde content increased. However, the intrinsic viscosity of the system decreased indicating that degradation takes place simultaneously with oxidation. The amount of aldehyde generated also increased with an increase in reaction temperature and the concentration of periodic acid. Due to the polyanionic behaviour of pectin, greater aldehyde contents were obtained at lower pH. Keeping all other reaction conditions constant, greater aldehyde contents were obtained in water-ethanol system than in pure aqueous medium. Increase in the ethanol content increased the amount of aldehyde generated. FTIR spectra of oxidized pectin systems show a carbonyl peak at 1734 cm(-1). They further reveal that partial ionisation of-COOH groups takes place leading to a peak at 1614 cm(-1).

Synthesis of novel 1,2,3-triazole based benzoxazolinones: their TNF-α based molecular docking with in-vivo anti-inflammatory, antinociceptive activities and ulcerogenic risk evaluation.

A library of novel bis-heterocycles containing benzoxazolinone based 1,2,3-triazoles has been synthesized using click chemistry approach. The compound 3f exhibited potent selective COX-2 inhibition of 59.48% in comparison to standard drug celecoxib (66.36% inhibition). The compound 3i showed significant (p < 0.001, 50.95%), TNF-α inhibitory activity as compared to indomethacin (p < 0.001, 64.01%). The results of the carrageenan induced hind paw oedema showed that compounds 3a, 3f, 3i, 3o, and 3e exhibited potent anti-inflammatory activity in comparison to Indomethacin. The molecular docking studies revealed that 3i exhibits strong inhibitory effect due to the extra stability of the complex because of an extra π-π bond. The histopathology report showed that none of the compounds caused gastric ulceration.

D-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis.

D-Limonene, a common monoterepene has been shown to have antiproliferative, apoptosis-inducing and chemopreventive effects. In the present study, we have investigated the effects of D-limonene on the growth of 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor development. We found that D-limonene (50 and 100 mg/kg body weight) treatments to the mouse skin significantly reduced the TPA-induced (a) edema and hyperplasia (p < 0.001); (b) expression of cyclooxygenase-2; (c) ornithine decarboxylase activity (p < 0.001); and (d) [(3)H] thymidine incorporation into DNA (p < 0.001). In addition, treatment of D-limonene effectively restored the level of reduced glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase, catalase and malondialdehyde production in TPA-treated mouse skin. In a two-stage skin tumorigenesis study, D-limonene significantly reduced the tumor burden (p < 0.005) and tumor incidence as compared to DMBA/TPA-treated mice. D-Limonene treatment also extended the latency period of tumor development from 4 to 9 weeks. D-Limonene treatment decreased the expression level of Ras, Raf and phosphorylation of extracellular signal-regulated protein kinase 1/2 in DMBA/TPA-induced tumors. A decrease in the expression of Bcl-2 and an increase in Bax expression were also observed in tumor tissues of mice treated with D-limonene. Taken together, our findings suggest that D-limonene may exert its chemopreventive activity through the inhibition of inflammation, oxidative stress and Ras-signaling as well as the induction of pro-apoptotic state during TPA-mediated promotion of DMBA-induced skin cancer in mouse model.

Study of the adjuvanticity of lysine lipopeptides; carbamate analogs elicit strong Th1 and Th2 response to ovalbumin in mice.

Bacterial lipoproteins and their synthetic analogs are strong immune modulators of the early host responses. In view of the strong adjuvanticity of bacterial lipopeptide mimics bearing lysine residues, a focused library of lipidated dipeptides and tripeptides has been synthesized with a view to understand the pattern of activity vis a vis the site and extent of lipidation. Compounds 4, 5 and 14 stimulate OVA specific IgG titer, neutralization of antibodies (IgG1 and IgG2a), T lymphocyte sub-sets (CD4/CD8) and its production of soluble mediators for Th1 (IFN-γ)/Th2 (IL-4) cytokines and costimulatory molecules (CD80/CD86) which are ideal traits of immune adjuvants. The results support lipidated lysine dipeptides as potent enhancers of humoral and cell mediated immune responses and thus might become promising immune-adjuvants for self adjuvanted vaccines.

Cumene hydroperoxide debilitates macrophage physiology by inducing oxidative stress: possible protection by alpha-tocopherol.

Macrophages, the major phagocytes of body, are largely dependent on membrane for their apposite functioning. Cum-OOH, a catalyst used in chemical and pharmaceutical industry, is a peroxidative agent, which may induce oxidative stress in macrophages hampering the integrity of their membrane. Alpha-tocopherol is known to protect the membrane from oxidative modulation and preserve its integrity. In the present study, we investigated the effect of Cum-OOH on physiology of macrophages and evaluated the protective effect of alpha-tocopherol against Cum-OOH-induced functional impairment. An in vitro exposure to 10-200 microM Cum-OOH altered redox balance of murine peritoneal macrophages and led to a severe physiological impairment. It markedly augmented the release of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta and prostaglandin E(2)), lipopolysaccharide primed nitric oxide release and inducible nitric oxide synthase expression, and lysosomal hydrolases secretion. It mitigated respiratory burst and phagocytosis and intracellular killing of yeast (Saccharomyces cerevisiae). Mannose receptor, a major macrophage phagocytic receptor (also implicated in S. cerevisiae phagocytosis), exhibited a hampered recycling with its number being reduced to about 54% of the untreated, control cells following Cum-OOH exposure. A 24-h pretreatment of macrophages with 25 microM alpha-tocopherol preserved most of the assessed functions close to their corresponding control values. These data suggest that exposure to Cum-OOH may impair the physiology of immune cells such as macrophages and that supplementation with alpha-tocopherol can safeguard these cells against Cum-OOH toxicity.

Perillyl alcohol attenuates Ras-ERK signaling to inhibit murine skin inflammation and tumorigenesis.

In the present study, the chemopreventive effect of topical application of perillyl alcohol (POH) on 9,10-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumorigenesis and its possible mechanisms of action in Swiss albino mice were investigated. We evaluated the effect of pretreatment of POH (6 and 12 mg/kg body weight) on TPA (2 microg/200 microl of acetone)-induced skin edema, hyperplasia, peroxidase damage and modulation in activities of catalase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione contents. Application of POH 30 min prior to TPA treatment, showed a protective effect in almost all the investigated parameters. Additionally, pretreatment with POH showed a significant inhibition of ornithine decarboxylase (ODC) activity and [(3)H] thymidine incorporation into epidermal DNA. In promotion phase, a significant reduction was found in tumor incidence and tumor burden in mice pretreated with POH (12 mg/kg body weight) with extension of the latency period from 4 to 8 weeks as compared to those treated with TPA alone. POH significantly suppressed the Ras/Raf/ERK pathway and induced apoptosis in Swiss albino mice skin. Our findings suggested that the chemopreventive efficacy of POH is probably due to the inhibition of oxidative stress responses, inhibition of the Ras cell proliferation pathway and induction of apoptosis in murine skin tumor promotion phase.