DETERMINATION OF IN VITRO EFFICACY OF AQUEOUS AND CHLOROFORM EXTRACTS OF ADHATODA VASICA AGAINST RHIPICEPHALUS MICROPLUS TICKS

: The aqueous and chloroform extracts obtained from leaves of Adhatoda vasica were evaluated for acaricidal activity against engorged females of Rhipicephalus microplus and their larvae. No significant mortality of adult ticks was observed in the tested concentration of aqueous extract except at 80%. Whereas, chloroform extract showed a dosedependent increase in adult mortality, and LC50 and LC90 values were determined as 10.47% and 11.74%, respectively. A significant difference in egg hatching of laid eggs was observed at all concentrations tested and 98.55% inhibition of hatching was observed at 12.5% concentration. Dose-dependent larval mortality was observed in larval immersion test with various concentrations of chloroform extract with LC 50 and LC 90 values of 0.51%, and 1.09%, respectively. The results indicate that the chloroform extract of Adhatoda vasica could have very good in vitro acaricidal activities on adult and larval stages of Rhipicephalus microplus ticks

GBS-based SNP map pinpoints the QTL associated with sorghum downy mildew resistance in maize (Zea mays L.)

Sorghum downy mildew (SDM), caused by the biotrophic fungi Peronosclerospora sorghi, threatens maize production worldwide, including India. To identify quantitative trait loci (QTL) associated with resistance to SDM, we used a recombinant inbred line (RIL) population derived from a cross between resistant inbred line UMI936 (w) and susceptible inbred line UMI79. The RIL population was phenotyped for SDM resistance in three environments [E1-field (Coimbatore), E2-greenhouse (Coimbatore), and E3-field (Mandya)] and also utilized to construct the genetic linkage map by genotyping by sequencing (GBS) approach. The map comprises 1516 SNP markers in 10 linkage groups (LGs) with a total length of 6924.7 cM and an average marker distance of 4.57 cM. The QTL analysis with the phenotype and marker data detected nine QTL on chromosome 1, 2, 3, 5, 6, and 7 across three environments. Of these, QTL namely qDMR1.2, qDMR3.1, qDMR5.1, and qDMR6.1 were notable due to their high phenotypic variance. qDMR3.1 from chromosome 3 was detected in more than one environment (E1 and E2), explaining the 10.3% and 13.1% phenotypic variance. Three QTL, qDMR1.2, qDMR5.1, and qDMR6.1 from chromosomes 1, 5, and 6 were identified in either E1 or E3, explaining 15.2%–18% phenotypic variance. Moreover, genome mining on three QTL (qDMR3.1, qDMR5.1, and qDMR6.1) reveals the putative candidate genes related to SDM resistance. The information generated in this study will be helpful for map-based cloning and marker-assisted selection in maize breeding programs

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 CYPspecific 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 indepth analysis of hepatic biotransformation events and distribution profiles of GE and its active phenolics for the design of safe regimens

Effects of GE and its active constituents on the activity of CYP3A4 with substrates, (A) midazolam and (B) testosterone upon incubation with human liver microsomes.

<p>The corresponding positive control, (Ai and Bi) ketoconazole's inhibitory activity was tested followed by (Aii, Bii) 6G, 8G, 10G, 6S and (Aiii, Biii) GE. Data shown are averages of duplicate experiments for GE and positive controls.</p

Effects of GE and its active constituents on the activity of (A) CYP2D6 with substrate, dextromethorphan and (B) CYP2E1 with substrate, chlorzoxazone upon incubation with human liver microsomes.

<p>The corresponding positive controls (Ai) sulfapenazole and (Bi) tranylcypromine activities were tested followed by (Aii, Bii) 6G, 8G, 10G, 6S and (Aiii, Biii) GE. Data shown are averages of duplicate experiments for GE and positive controls.</p

Effects of GE and its active constituents on the activity of (A) CYP2C9 with substrate, diclofenac and (B) CYP2C19 with substrate, (s)-mephenytoin upon incubation with human liver microsomes.

<p>The corresponding positive controls (Ai) sulfapenazole and (Bi) benzylnirvanol activities were tested followed by (Aii, Bii) 6G, 8G, 10G, 6S and (Aiii, Biii) GE. Data shown are averages of duplicate experiments for GE and positive controls.</p

An amide to thioamide substitution improves the permeability and bioavailability of macrocyclic peptides

Abstract Solvent shielding of the amide hydrogen bond donor (NH groups) through chemical modification or conformational control has been successfully utilized to impart membrane permeability to macrocyclic peptides. We demonstrate that passive membrane permeability can also be conferred by masking the amide hydrogen bond acceptor (>C = O) through a thioamide substitution (>C = S). The membrane permeability is a consequence of the lower desolvation penalty of the macrocycle resulting from a concerted effect of conformational restriction, local desolvation of the thioamide bond, and solvent shielding of the amide NH groups. The enhanced permeability and metabolic stability on thioamidation improve the bioavailability of a macrocyclic peptide composed of hydrophobic amino acids when administered through the oral route in rats. Thioamidation of a bioactive macrocyclic peptide composed of polar amino acids results in analogs with longer duration of action in rats when delivered subcutaneously. These results highlight the potential of O to S substitution as a stable backbone modification in improving the pharmacological properties of peptide macrocycles