Chem‐bioinformatics: QSTR studies on TIBO derivatives

In the present study, effort has been made to develop a mathematical model for the set of 19 (tetrahydromidazo [4,5,1‐jk][1,4] benzodizepin‐2(1H)‐one) (TIBO) derivatives. The biological activity modeled in the present investigation is cytotoxic concentration (log 1/C). To investigate the cytotoxic behavior of TIBO derivatives, classical and nonconventional physicochemical properties are tested separately. Out of the two categories, the classical physicochemical properties play a dominating role in the modeling of cytotoxicity. On the basis of the results obtained and with the help of molecular modeling parameters, we discovered that the molecular property is most responsible for the cytotoxicity of TIBO derivatives. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:166–171, 2009; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20270     

QSAR study of flavonoid derivatives as p56lck tyrosinkinase inhibitors

QSAR studies on 104 flavonoid derivatives as p56lck protein tyrosine kinase inhibitors were performed using hydration energy and logP as predictor parameters. The results obtained demonstrate in detail, which specify that hydration energy and hydrophobic parameters of the compounds play a significant role in developing QSAR models. The significance of presence and absence of substituents on particular position is successfully explored with the help of indicator parameters. The results are critically discussed on the basis of multiple linear regression parameters.     

QSAR study on benzenesulphonamide carbonic anhydrase inhibitors: topological approach using Balaban index

QSAR study on benzenesulphonamide carbonic anhydrase inhibitors has been made using the most discriminatory Balaban index (J). The regression analysis has shown that even in monoparametric regression this index gave excellent results. Furthermore, using the combination of the Balaban Index (J) with the first-order Randic connectivity index ((1)chi) and indicator parameters, tremendous improvement in the statistics has been observed. The results are critically discussed on the basis of regression data and cross-validation parameters.     

Development and validation of candidate gene-specific markers for the major fertility restorer genes, <Emphasis Type="Italic">Rf4</Emphasis> and <Emphasis Type="Italic">Rf3</Emphasis> in rice

Two major nuclear genes, Rf3 and Rf4, are known to be associated with fertility restoration of wild-abortive cytoplasmic male sterility (WA-CMS) in rice. In the present study, through a comparative sequence analysis of the reported putative candidate genes, viz. PPR9-782-(M,I) and PPR762 (for Rf4) and SF21 (for Rf3), among restorer and maintainer lines of rice, we identified significant polymorphism between the two lines and developed a set of PCR-based codominant markers, which could distinguish maintainers from restorers. Among the five markers developed targeting the polymorphisms in PPR9-782-(M,I), the marker RMS-PPR9-1 was observed to show clear polymorphism between the restorer (n = 120) and maintainer lines (n = 44) analyzed. Another codominant marker, named RMS-PPR762 targeting PPR762, displayed a lower efficiency in identification of restorers and maintainers, indicating that PPR9-782-(M,I) is indeed the candidate gene for Rf4. With respect to Rf3, a codominant marker, named RMS-SF21-5 developed targeting SF21, displayed significantly lower efficiency in identification of restorers and non-restorers as compared to the Rf4-specific markers. Validation of these markers in a F₂ mapping population segregating for fertility restoration indicated that Rf4 has a major influence on fertility restoration and Rf3 is a minor gene. Further, the functional marker RMS-PPR9-1 was observed to be very useful in identification of impurities in a seed lot of the popular hybrid, DRRH3. Interestingly, when RMS-PPR9-1 and RMS-SF21-5 were considered in conjunction with analysis, near-complete, marker–trait co-segregation was observed, indicating that deployment of the candidate gene-specific markers both Rf4 and Rf3, together, can be helpful in accurate identification of fertility restorer lines and can facilitate targeted transfer of the two restorer genes into elite varieties through marker-assisted breeding.     

Attenuation of arsenic trioxide induced cardiotoxicity through flaxseed oil in experimental rats

Objectives: Arsenic trioxide (As₂O₃) is a potent drug for acute promyelocytic leukaemia, but its clinical trials are allied with some serious adverse events mainly cardiac functional abnormalities. So the objective of our investigation is to identify the cardioprotective action of flaxseed oil (FSO), a natural compound against As₂O₃ induced cardiotoxicity.

Methods: Male wistar rats were treated with As₂O₃ (4?mg/kg) to induce cardiotoxicity. FSO (250 and 500?mg/kg) was given in combination with As₂O₃ for evaluating its cardioprotective efficacy.

Results: Treatment with As₂O₃ resulted in deposition of arsenic in heart tissue, increased cardiac marker enzymes release, lipid peroxidation (LPO), oxidative insults and pathological damages in the heart. Co-treatment with FSO (500?mg/kg) significantly reduced the arsenic accumulation, cardiac marker enzymes, LPO and cardiac structural alterations. FSO treatment significantly improved cardiac glutathione content, antioxidant enzymes and reduced the pathological damages in cardiac tissue. Gas chromatographic–mass spectrometry analysis revealed that the major fatty acid content in the FSO is alpha-linolenic acid, which has a strong milieu in cardiac health.

Conclusion: The results of the current investigation suggested that FSO is an effective agent in reducing arsenic-induced cardiac toxicity and can be used as an adjunct/dietary supplement for the cancer patients on As₂O₃ therapy.     

Marker-assisted pyramiding of bacterial blight and gall midge resistance genes into RPHR-1005, the restorer line of the popular rice hybrid DRRH-3

Bacterial blight (BB) of rice caused by the pathogen Xanthomonas oryzae pv. oryzae and the insect gall midge (GM) (Orseolia oryzae) are two major constraints of rice production. The present study was carried out to improve RPHR-1005, a stable restorer line of the fine-grain-type rice hybrid DRRH-3, for BB and GM resistance through marker-assisted backcross breeding (MABB). Two major GM resistance genes, Gm4 and Gm8, and a major BB resistance gene, Xa21, were selected as target genes for transfer to RPHR-1005. Two sets of backcrosses were carried out to combine either Xa21 + Gm4 or Xa21+ Gm8 into RPHR-1005 using breeding lines in the genetic background of ISM possessing either Gm4 or Gm8 along with Xa21. Foreground selection was performed for Xa21, Gm4, Gm8, and the major fertility restorer genes Rf3 and Rf4 using gene-specific markers, while 61 polymorphic simple sequence repeat (SSR) markers were used for background selection and marker-assisted backcrossing was continued until BC₂ generation. A promising homozygous backcross-derived plant at the BC₂F₂ generation possessing Xa21 + Gm4, and another possessing Xa21 + Gm8, were intercrossed to stack the target resistance genes. At ICF ₄ (inter-crossed F₄) , three promising lines possessing the three target resistance genes in a homozygous condition along with fine-grain type, complete fertility restoration, and better panicle exsertion than RPHR-1005 have been identified. Among these, a single line, # RPIC-16-65-125, showed better yield, was highly resistant to BB and GM, was of medium–slender grain type, and had complete fertility restoration along with better panicle exsertion and taller plant type than RPHR-1005. This is the first report of combining resistance against BB and GM in the genetic background of a hybrid rice parental line.     

The adult-specific ubiquinone Q(8) functions as an antioxidant in the filarial parasite, Setaria digitata.

The filarial parasite Setaria digitata is unique in having two ubiquinones, Q(6) and Q(8), in the adult stage, in place of one, namely Q(10), in the host. However, the microfilariae (mf) as well as the electron transfer complexes from adult mitochondria have been recently shown to contain only Q(6). The second ubiquinone Q(8) is present only in the adult and absent in the mf. Though both Q(6) and Q(8) are present in the adult stage in the ratio 65:35, there is an enrichment of Q(8) in the excretory and secretory (ES) materials released into the incubation medium. The Q(6) level in the ES materials decreased further when the adult parasite was incubated in presence of diethylcarbamazine, a drug which inhibits the release of mf, indicating that the Q(6) detected in ES may be of mf origin. The preferential release of Q(8) into the external medium and its presence in the adult stage without any apparent role in the electron transport process strongly indicate an antioxidant role for the molecule. The inhibitory effect of Q(8) on lipid peroxidation and the presence of other components such as catalase and superoxide dismutase shown to be present in ES materials in earlier studies help the filarial parasite survive for longer periods by overcoming the oxidative reactions of the host generated against it.     

Osteopontin-targeted probe detects orthotopic breast cancers using optoacoustic imaging

Improved detection of breast cancer using highly sensitive, tumor-specific imaging would facilitate diagnosis, surveillance and assessment of response to treatment. We conjugated osteopontin peptide to an infrared fluorescent dye to serve as a contrast agent for detection of breast cancer by multispectral optoacoustic tomography (MSOT). Selective binding of the osteopontin-based probe was identified using flow cytometry and near infrared fluorescent imaging in triple negative and HER2 positive breast cancer cell lines in vitro. Osteopontin-750 accumulation was evaluated in vivo using MSOT with secondary confirmation of signal accumulation using near infrared fluorescent imaging. The osteopontin-based probe demonstrated binding to breast cancer cells in vitro. Similarly, after intravenous administration of the osteopontin-750 probe, it accumulated preferentially in the subcutaneous breast tumor in nude mice (557 MSOT a.u. compared to untargeted organs such as kidney (53.7 MSOT a.u.) and liver (32.1 MSOT a.u.). At 2.5 h post-injection, signal intensity within the tumor was 9.7 and 17 times greater in the tumor bed than in the kidney or liver, respectively. Fluorescence imaging ex vivo comparing tumor signal to that of nontarget organs confirmed the results in vivo. MSOT imaging demonstrated selective accumulation of the fluorescent osteopontin targeting probe to tumor sites both in vitro and in vivo, and provided high-resolution images. Further development of this tool is promising for advanced diagnostic imaging, disease surveillance and therapeutic models that limit nontarget toxicity.