Introgression of Shoot Fly (Atherigona soccata L. Moench) Resistance QTLs into Elite Post-rainy Season Sorghum Varieties Using Marker Assisted Backcrossing (MABC).

Shoot fly (Atherigona soccata L. Moench) is a serious pest in sorghum production. Management of shoot fly using insecticides is expensive and environmentally un-safe. Developing host-plant resistance is the best method to manage shoot fly infestation. Number of component traits contribute for imparting shoot fly resistance in sorghum and molecular markers have been reported which were closely linked to QTLs controlling these component traits. In this study, three QTLs associated with shoot fly resistance were introgressed into elite cultivars Parbhani Moti (= SPV1411) and ICSB29004 using marker assisted backcrossing (MABC). Crosses were made between recurrent parents and the QTL donors viz., J2658, J2614, and J2714. The F1s after confirmation for QTL presence were backcrossed to recurrent parents and the resultant lines after two backcrosses were selfed thrice for advancement. The foreground selection was carried out in F1 and BCnF1 generations with 22 polymorphic markers. Forty-three evenly distributed simple sequence repeat markers in the sorghum genome were used in background selection to identify plants with higher recurrent parent genome recovery. By using two backcrosses and four rounds of selfing, six BC2F4 progenies were selected for ICSB29004 × J2658, five BC2F4 progenies were selected for ICSB29004 × J2714 and six BC2F4 progenies were selected for Parbhani Moti × J2614 crosses. Phenotyping of these lines led to the identification of two resistant lines for each QTL region present on chromosome SBI-01, SBI-07 and SBI-10 in ICSB 29004 and Parbhani Moti. All the introgression lines (ILs) showed better shoot fly resistance than the recurrent parents and their agronomic performance was the same or better than the recurrent parents. Further, the ILs had medium plant height, desirable maturity with high yield potential which makes them better candidates for commercialization. In the present study, MABC has successfully improved the shoot fly resistance in sorghum without a yield penalty. This is the first report on the use of MABC for improving shoot fly resistance in post-rainy season sorghum.

A review on PARP1 inhibitors: Pharmacophore modeling, virtual and biological screening studies to identify novel PARP1 inhibitors.

A tremendous research on Poly (ADP-ribose) polymerase (PARP) pertaining to cancer and ischemia is in very rapid progress. PARP's are a specific class of enzymes that repairs the damaged DNA. Recent findings suggest also that PARP-1 is the most abundantly expressed nuclear enzyme which involves in various therapeutic areas like inflammation, stroke, cardiac ischemia, cancer and diabetes. The current review describes the overview on clinical candidates of PARP1 and its current status in clinical trials. This paper also covers identification of potent PARP1 inhibitors using structure and ligand based pharmacophore models. Finally 36 potential hits were identified from the virtual screening of pharmacophore models and screened for PARP1 activity. 15 actives were identified as potent PARP1 inhibitors and further optimization of these analogues are in progress.

Fibroblast growth factor receptor inhibitors.

Fibroblast growth factor receptors (FGFRs) play an important role in embryonic development, angiogenesis, wound healing, cell proliferation and differentiation. The fibroblast growth factor receptor (FGFR) isoforms have been under intense scrutiny for effective anticancer drug candidates. The fibroblast growth factor (FGF) and its receptor (FGFR) provide another pathway that seems critical to monitoring angiogenesis. Recent findings suggest that FGFR mediates signaling, regulates the PKM2 activity, and plays a crucial role in cancer metabolism. The current review also covers the recent findings on the role of FGFR1 in cancer metabolism. This paper reviews the progress, mechanism, and binding modes of recently known kinase inhibitors such as PD173074, SU series and other inhibitors still under clinical development. Some of the structural classes that will be highlighted in this review include Pyrido[2,3-d]pyrimidines, Indolin- 2-one, Pyrrolo[2,1-f][1,2,4]triazine, Pyrido[2,3-d]pyrimidin-7(8H)-one, and 1,6- Naphthyridin-2(1H)-ones.

Constitutive and inducible resistance to Atherigona soccata (Diptera: Muscidae) in Sorghum bicolor.

Host plant resistance is one of the important components for minimizing the losses because of sorghum shoot fly, Atherigona soccata (Diptera: Muscidae) attack. Therefore, we studied the constitutive and inducible biochemical mechanisms of resistance to A. soccata in a diverse array of sorghum genotypes to identify lines with diverse mechanisms of resistance to this insect. Fifteen sorghum genotypes with different levels of resistance to A. soccata were evaluated. Methanol extracts of 10-d old damaged and undamaged sorghum seedlings were subjected to high-performance liquid chromatography analysis. Association between peak areas of the identified and unidentified compounds with parameters measuring A. soccata resistance was determined through correlation analysis. Amounts of p-hydroxy benzaldehyde and the unidentified compounds at RTs 24.38 and 3.70 min were associated with susceptibility to A. soccata. Genotypes exhibiting resistance to A. soccata were placed in four groups, and the lines showing constitutive and/or induced resistance to A. soccata with different combinations of biochemical factors potentially could be used for increasing the levels of resistance to A. soccata in sorghum.

Antibacterial activity of Alpinia galanga (L) Willd crude extracts.

Methanol, acetone and diethyl ether extracts of Alpinia galanga have been evaluated against pathogens viz. Bacillus subtilis MTCC 2391, Enterobacter aerogene, Enterobacter cloacae, Enterococcus faecalis, Escherichia coli MTCC 1563, Klebsiella pneumoniae, Pseudomonas aeruginosa MTCC 6642, Salmonella typhimurium, Staphylococcus aureus and Streptococcus epidermis using Agar well diffusion method. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of all the extracts were determined using the macrodilution method. Methanol extracts have shown excellent activity towards all the pathogens with MIC and MBC values ranging from 0.04-1.28 mg/ml and 0.08-2.56 mg/ml, respectively. The GC-MS analysis of methanol extracts have yielded compounds like 5-hydroxymethyl furfural (59.9%), benzyl alcohol (57.6%), 1,8 cineole (15.65%), methylcinnamate (9.4%), 3-phenyl-2-butanone (8.5%) and 1,2 benzenedicarboxylic acid (8.9%), which could be responsible for its broad spectrum activity. So, A. galanga can be quite resourceful for the development of new generation drugs.

Combined pharmacophore and structure-guided studies to identify diverse HSP90 inhibitors.

Heat Shock Protein 90 (HSP90), an ATP-dependent molecular chaperone, has emerged as a promising target in the treatment of cancer. Inhibition of HSP90 represents a new target of antitumor therapy, since it may influence many specific signaling pathways. Many HSP90 inhibitors bind to the ATP-binding pocket, inhibit chaperone function, resulting in cell death. Recent clinical trials for treatment of cancer have put HSP90's importance into focus and have highlighted the need for full scale research into HSP90 related pathways. Here we report five novel HSP90 inhibitors which were identified by using pharmacophore models and docking studies. We used highly discriminative pharmacophore model as a 3D query to search against database of approximately 1 M compounds and cluster analysis results yielded 455 compounds which were further subjected for docking. Glide docking studies suggested 122 compounds as in silico hits and these compounds were further selected for the cytotoxicity assay in the HSP90-over expressing SKBr3 cell line. Of the 122 compounds tested, 5 compounds inhibited cell growth with an IC(50) value less than 50 microM.

Discovery of potential ZAP-70 kinase inhibitors: pharmacophore design, database screening and docking studies.

The best ZAP-70 inhibitor model consists of four-pharmacophore features, (1) one hydrogen bond acceptor, (2) one hydrogen bond donor (3) one hydrophobic aliphatic and (4) one hydrophobic aromatic features. This model was validated against 110 known ZAP-70 inhibitors with a correlation of 0.902 as well as enrichment factor of 1.61 against a maximum value of 2. This model picked 4094 hits from a database of 238,819 molecules while 358 molecules were indicated as highly active. Subsequently, docking studies were performed on the hits and novel series of potent leads were suggested based on the interactions energy between ZAP-70 and the putative inhibitors which validated not only the virtual screening potential of the model but also identified the possible new Chemotypes.

Development and validation of a HPLC method for simultaneous quantitation of gatifloxacin, sparfloxacin and moxifloxacin using levofloxacin as internal standard in human plasma: application to a clinical pharmacokinetic study.

A highly selective, sensitive and accurate HPLC method has been developed and validated for the estimation of three fluoroquinolones (FQs) viz., gatifloxacin (GFC), sparfloxacin (SFC) and moxifloxacin (MFC) with 500 microL human plasma using levofloxacin (LFC) as an internal standard (IS). The sample preparation involved simple liquid-liquid extraction of GFC, SFC, MFC and IS from human plasma with ethyl acetate. The resolution of peaks was achieved with phosphate buffer (pH 2.5)-acetonitrile (80:20, v/v) at a flow rate of 1 mL/min on a Kromasil C(18) column. The total chromatographic run time was 18.0 min and the simultaneous elution of GFC, SFC, MFC and IS occurred at approximately 10.8, 12.8, 17.0 and 6.0 min, respectively. The method proved to be accurate and precise at linearity range of 100-10,000 ng/mL with a correlation coefficient (r) of > or =0.999. The limit of quantitation for each of the FQs studied was 100 ng/mL. The intra- and inter-day precision and accuracy values found to be within the assay variability limits as per the FDA guidelines. The developed assay method was applied to a pharmacokinetic study in human volunteers following oral administration of 400 mg GFC tablet.

Effect of ciprofloxacin and ibuprofen on the in vitro metabolism of rosiglitazone and oral pharmacokinetics of rosiglitazone in healthy human volunteers.

The aim of this study was to study the effect of ciprofloxacin (CFX) and ibuprofen (IBF) on the in vitro metabolism of rosiglitazone (RGZ) in human liver microsomes and on the pharmacokinetics of RGZ in healthy human volunteers. A randomized, placebo controlled, 3-way crossover design oral pharmacokinetic study was done in healthy human male volunteers and in vitro metabolism studies were done in human liver microsomes to study the effect of CFX and IBF on RGZ metabolism. Each subject received orally either 8 mg of RGZ with a placebo or co-administration with either 500 mg of CFX or 400 mg of IBF. Plasma concentrations of RGZ were estimated using a validated LC-MS/MS method and the metabolism studies samples were analyzed by a reported HPLC method. There was no statistically significant difference observed in the pharmacokinetic parameters viz., AUC(0-t), AUC(O-infinity), Cmax, Tmax, Kel and t1/2 of RGZ following co-administration of either CFX or IBF. Both CFX and IBF did not affect the in vitro metabolism of RGZ in human liver microsomes.

Genotyping of Hepatitis C virus (HCV) in infected patients from South India.

Hepatitis C virus shows substantial nucleotide sequence diversity distributed throughout the viral genome. In the present study genotyping for Hepatitis C virus (HCV) infected patients was based on RFLP analysis of 5' UTR and using type specific primers of NS5B regions. It was observed that 60% of the patients (30 patients with chronic hepatitis) were infected with variants of genotype 1 and 40% of the patients (4 chronic hepatitis patients, 12 patients with chronic renal failure and 4 cirrhosis) were infected with variants of type 3 of HCV. None of the cirrhotic patients and patients with chronic renal failure, in the present study, were infected with type 1 of HCV. While PCR-RFLP, typing was rapid in conjunction with the primers used for RT-PCR, NS5 typing was helpful in determining the subtype. There was good correlation between the two typing methods and this method can be used as a cost-effective method for studying large number of samples. The study shows that predominant genotypes of HCV in South India include type 1 and 3. Type 3 seems to be transmitted nosocomially as suggested by the results in patients with chronic renal failure, as these patients are exposed to multiple medical interventions.