Effects of dextromethorphan on dopamine dependent behaviours in rats

Dextromethorphan, a noncompetitive blocker of N-methyl-D- aspartate (NMDA) type of glutamate receptor, at 7.5-75 mg/kg, ip did not induce oral stereotypies or catalepsy and did not antagonize apomorphine stereotypy in rats. These results indicate that dextromethorphan at 7.5-75 mg/kg does not stimulate or block postsynaptic striatal D2 and D1 dopamine (DA) receptors. Pretreatment with 15 and 30 mg/kg dextromethorphan potentiated dexamphetamine stereotypy and antagonised haloperidol catalepsy. Pretreatment with 45, 60 and 75 mg/kg dextromethorphan, which release 5-hydroxytryptamine (5-HT), however, antagonised dexamphetamine stereotypy and potentiated haloperidol catalepsy. Apomorphine stereotypy was not potentiated or antagonised by pretreatment with 7.5-75 mg/kg dextromethorphan. This respectively indicates that at 7.5-75 mg/kg dextromethorphan does not exert facilitatory or inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptors. The results are explained on the basis of dextromethorphan (15-75 mg/kg)-induced blockade of NMDA receptors in striatum and substantia nigra pars compacta. Dextromethorphan at 15 and 30 mg/kg, by blocking NMDA receptors, activates nigrostriatal dopaminergic neurons and thereby potentiates dexampetamine stereotypy and antagonizes haloperidol catalepsy. Dextromethorphan at 45, 60 and 75 mg/kg, by blocking NMDA receptors, releases 5-HT and through the released 5-HT exerts an inhibitory influence on the nigrostriatal dopaminergic neurons with resultant antagonism of dexampetamine stereotypy and potentiation of haloperidol catalepsy.     

A High Throughput Screen Identifies Potent and Selective Inhibitors to Human Epithelial 15-Lipoxygenase-2

Lipoxygenase (LOX) enzymes catalyze the hydroperoxidation of arachidonic acid and other polyunsaturated fatty acids to hydroxyeicosatetraenoic acids with varying positional specificity to yield important biological signaling molecules. Human epithelial 15­lipoxygenase­2 (15-LOX-2) is a highly specific LOX isozyme that is expressed in epithelial tissue and whose activity has been correlated with suppression of tumor growth in prostate and other epithelial derived cancers. Despite the potential utility of an inhibitor to probe the specific role of 15-LOX-2 in tumor progression, no such potent/specific 15­LOX­2 inhibitors have been reported to date. This study employs high throughput screening to identify two novel, specific 15­LOX­2 inhibitors. MLS000545091 is a mixed-type inhibitor of 15-LOX-2 with a K_i of 0.9+/−0.4 µM and has a 20-fold selectivity over 5-LOX, 12-LOX, 15-LOX-1, COX-1, and COX-2. MLS000536924 is a competitive inhibitor with a K_i of 2.5+/−0.5 µM and also possesses 20-fold selectivity toward 15-LOX-2 over the other oxygenases, listed above. Finally, neither compound possesses reductive activity towards the active-site ferrous ion.     

Modulation of Cytochrome P450 Metabolism and Transport across Intestinal Epithelial Barrier by Ginger Biophenolics

Natural and complementary therapies in conjunction with mainstream cancer care are steadily gaining popularity. Ginger extract (GE) confers significant health-promoting benefits owing to complex additive and/or synergistic interactions between its bioactive constituents. Recently, we showed that preservation of natural “milieu” confers superior anticancer activity on GE over its constituent phytochemicals, 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G) and 6-shogaol (6S), through enterohepatic recirculation. Here we further evaluate and compare the effects of GE and its major bioactive constituents on cytochrome P450 (CYP) enzyme activity in human liver microsomes by monitoring metabolites of CYP-specific substrates using LC/MS/MS detection methods. Our data demonstrate that individual gingerols are potent inhibitors of CYP isozymes, whereas GE exhibits a much higher half-maximal inhibition value, indicating no possible herb-drug interactions. However, GE''s inhibition of CYP1A2 and CYP2C8 reflects additive interactions among the constituents. In addition, studies performed to evaluate transporter-mediated intestinal efflux using Caco-2 cells revealed that GE and its phenolics are not substrates of P-glycoprotein (Pgp). Intriguingly, however, 10G and 6S were not detected in the receiver compartment, indicating possible biotransformation across the Caco-2 monolayer. These data strengthen the notion that an interplay of complex interactions among ginger phytochemicals when fed as whole extract dictates its bioactivity highlighting the importance of consuming whole foods over single agents. Our study substantiates the need for an in-depth analysis of hepatic biotransformation events and distribution profiles of GE and its active phenolics for the design of safe regimens.     

A Rare Stinkhorn Fungus Itajahya rosea Attract Drosophila by Producing Chemical Attractants

Itajahya rosea was found growing in association with Leucaena leucocephala plants at Savitribai Phule Pune University campus in India. The species identity was confirmed by phylogenetic analysis based on ITS and LSU regions of rDNA, wherein, our fugus was placed along with I. rosea in phylogenetic tree. It represents first record of I. rosea from India. Frequent visitation by Drosophila species on I. rosea fruiting body particularly on gleba was observed. The Drosophila got attracted to the detached gleba under the laboratory conditions and even sometimes, they prefer to sit over the gleba as compare to their food banana. It suggested that I. rosea gleba or pseudostipe produces some compounds for attraction and feeding behavior of Drosophila species. Therefore, we characterized the volatile attractants produced by gleba and pseudostipe of I. rosea by GC-MS analysis. Nineteen compounds were identified from gleba while nine compounds were recovered from the pseudostipe. Out of them, blends of three abundant odor producing volatile compounds were reported namely, Hexadecane, Pentadecane and Nonadecane, which are responsible for attraction of Drosophila toward the gleba. Three fatty acids namely 9,12-octadecadienoic acid (Z,Z), hexadecanoic acid and benzoic acid ethyl ester produced are served as an appetitive signal through olfactory response of Drosophila, so the flies were feed on the gleba. Two pheromones’ compounds, heneicosane and (+)-(5S,9S)-5,9-dimethylpentadecane, were also reported in pseudostipe and gleba, respectively, which play a role in Drosophila for breeding. Our study highlights an intriguing chemical ecology of fungus–Drosophila interaction.     

<Emphasis Type="Italic">Sesuvium portulacastrum</Emphasis> (L.) L.: a potential halophyte for the degradation of toxic textile dye,Green HE4B

Sesuvium portulacastrum is a common halophyte growing well in adverse surroundings and is exploited mainly for the environmental protection including phytoremediation, desalination and stabilization of contaminated soil. In the present investigation, attempts have been made on the decolorization of a toxic textile dye Green HE4B (GHE4B) using in vitro grown Sesuvium plantlets. The plantlets exhibited significant (70%) decolorization of GHE4B (50 mg l(-1)) that sustain 200 mM sodium chloride (NaCl) within 5 days of incubation. The enzymatic analysis performed on the root and shoot tissues of the in vitro plantlets subjected to GHE4B decolorization in the presence of 200 mM NaCl showed a noteworthy induction of tyrosinase, lignin peroxidase and NADH-DCIP reductase activities, indicating the involvement of these enzymes in the metabolism of the dye GHE4B. The UV-visible spectrophotometer, HPLC and Fourier Transform Infrared Spectroscopy (FTIR) analyses of the samples before and after decolorization of the dye confirmed the efficient phytotransformation of GHE4B in the presence of 200 mM NaCl. Gas Chromatography-Mass Spectroscopy (GC-MS) analysis of the products revealed the formation of three metabolites such as p -amino benzene, p -amino toluene and 1, 2, 7-amino naphthalene after phytotransformation of GHE4B. Based on the FTIR and GC-MS results, the possible pathway for the biodegradation of GHE4B in the presence of 200 mM NaCl has been proposed. The phytotoxicity experiments confirmed the non-toxicity of the degraded products. The present study demonstrates for the first time the potential of Sesuvium for the efficient degradation of textile dyes and its efficacy on saline soils contaminated with toxic compounds.     

Synergistic anti-inflammatory interaction between meloxicam and aminoguanidine hydrochloride in carrageenan-induced acute inflammation in rats

Interaction studies with inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) inhibitor have been conducted to assess the nature of interaction and the possible therapeutic advantage. The interaction between meloxicam--a selective COX-2 inhibitor--and aminoguanidine hydrochloride--a selective iNOS inhibitor-- was examined in carrageenan-induced paw edema in rats. Appropriate statistical method was applied to detect the nature of anti-inflammatory interaction. Different doses of meloxicam (1, 3, 10 and 30 mg/kg) or aminoguanidine hydrochloride (10, 30, 100 and 300 mg/kg) were administered orally to adult male albino rats. Higher doses of meloxicam (3, 10 and 30 mg/kg) showed statistically significant anti-inflammatory effect. However, aminoguanidine hydrochloride did not show any anti-inflammatory activity. Combination of sub-threshold dose of meloxicam (1 mg/kg) with increasing doses of aminoguanidine hydrochloride (30, 100 and 300 mg/kg) resulted in synergistic anti-inflammatory effect. Combined therapy with sub-threshold dose of aminoguanidine hydrochloride (30 mg/kg) with increasing doses of meloxicam (1, 3, 10 and 30 mg/kg) also resulted in synergistic anti-inflammatory effect. The possible mechanism of interaction could be the stimulation of COX-2 activity by nitric oxide (NO) by combining with heme component. These results suggest that co-administration of meloxicam and aminoguanidine hydrochloride may be an alternative in clinical control of inflammation.     

Biodegradation of Methyl red by Galactomyces geotrichum MTCC 1360

Galactomyces geotrichum MTCC 1360 can decolorize triphenylmethane, azo and reactive high exhaust textile dyes. At shaking condition this strain showed 100% decolorization of a toxic azo dye Methyl red (100 m gl⁻¹) within 1 h in deionized water at 30 °C. The degradation of Methyl red was possible through a broad pH (3–12) and temperature (5–50 °C) range. Glucose and mycelium concentration had increased the decolorization rate, but the addition of 1 gl⁻¹ molasses in deionized water made decolorization possible in only 10 min. Induction in the NADH–dichloro phenol indophenol (NADH–DCIP) reductase, Malachite green reductase, laccase and lignin peroxidase (Lip) activities were observed in the cells obtained after complete decolorization, showing that there is direct involvement in the degradation of Methyl red. The absence of N-N′-dimethyl-p-phenylenediamine (DMPD) in 5 °C, 2-aminobenzoic acid (ABA) in 50 °C and both the compounds in 30 °C sample have shown the differences in the metabolic fate of Methyl red at different temperatures. The untreated dye at 300 mg l⁻¹ concentration showed 88% germination inhibition in Sorghum bicolor, whereas it was 72% in Triticum aestivum. There was no germination inhibition for both the plants by Methyl red metabolites at 300 mg l⁻¹ concentration.

The scientific relevance of the paper

The azo dye Methyl red (100 mg l⁻¹) was decolorized by G. geotrichum MTCC 1360 within 1 h at shaking condition in deionized water. This organism could decolorize Methyl red at wide pH and temperature ranges. Decolorization time was reduced to 10 min by the addition of molasses to deionized water. There was induction in laccase and Lip, NADH–DCIP reductase and Malachite green reductase activities. The metabolic fate of Methyl red changes with temperature which can be evidenced by the formation of 2-ABA at 5 °C, N-N′-DMPD at 50 °C and both the compounds were absent at 30 °C. Phytotoxicity showed that metabolites of dye had induced shoot and root length of both the tested plants.