Syntheses of lipophilic chalcones and their conformationally restricted analogues as antitubercular agents

Lipophilic chalcones and their conformationally restricted analogues were synthesized and evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv strain. Compounds 16, 24, 25a and 25c were found to be active MIC at 60, 30, 3.5 and 7.5 μg-mL^?1. In vitro cytotoxicity of compounds 16, 24, 25a, 25c and 26 in non-cancerous human epithelial kidney cell line (HEK-293) showed that most active compound 25a was approximately 2.85 times selective towards tubercular versus healthy cells whereas compound 24 was found to be 16 times selective.     

Effects of interleukin-18 on natural killer cells: costimulation of activation through Fc receptors for immunoglobulin

The antitumor activity of monoclonal antibodies is mediated by effector cells, such as natural killer (NK) cells, that express Fc receptors for immunoglobulin. Efficacy of monoclonal antibodies, including the CD20 antibody rituximab, could be improved by agents that augment the function of NK cells. Interleukin (IL)-18 is an immunostimulatory cytokine that has antitumor activity in preclinical models. The effects of IL-18 on NK cell function mediated through Fcγ receptors were examined. Human NK cells stimulated with immobilized IgG in vitro secreted IFN-γ as expected; such IFN-γ production was partially inhibited by blocking CD16 with monoclonal antibodies. IL-18 augmented IFN-γ production by NK cells stimulated with immobilized IgG or CD16 antibodies. NK cell IFN-γ production in response to immobilized IgG and/or IL-18 was inhibited by chemical inhibitors of Syk and several other kinases involved in CD16 signaling pathways. IL-18 augmented antibody-dependent cellular cytotoxicity (ADCC) of human NK cells against rituximab-coated Raji cells in vitro. IL-18 and rituximab acted synergistically to promote regression of human lymphoma xenografts in SCID mice. Inasmuch as IL-18 costimulates IFN-γ production and ADCC of NK cells activated through Fc receptors in vitro and augments antitumor activity of rituximab in vivo, it is an attractive cytokine to combine with monoclonal antibodies for treatment of human cancer.     

Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells

Background

Metabolic syndrome (MetS) is a constellation of factors including abdominal obesity, hyperglycemia, dyslipidemias, and hypertension that increase morbidity and mortality from diabetes and cardiovascular diseases and affects more than a third of the population in the US. Clozapine, an atypical antipsychotic used for the treatment of schizophrenia, has been found to cause drug-induced metabolic syndrome (DIMS) and may be a useful tool for studying cellular and molecular changes associated with MetS and DIMS. Mitochondria dysfunction, oxidative stress and inflammation are mechanisms proposed for the development of clozapine-related DIMS. In this study, the effects of clozapine on mitochondrial function and inflammation in insulin responsive and obesity-associated cultured cell lines were examined.

Methodology/Principal Findings

Cultured mouse myoblasts (C2C12), adipocytes (3T3-L1), hepatocytes (FL-83B), and monocytes (RAW 264.7) were treated with 0, 25, 50 and 75 µM clozapine for 24 hours. The mitochondrial selective probe TMRM was used to assess membrane potential and morphology. ATP levels from cell lysates were determined by bioluminescence assay. Cytokine levels in cell supernatants were assessed using a multiplex array. Clozapine was found to alter mitochondria morphology, membrane potential, and volume, and reduce ATP levels in all cell lines. Clozapine also significantly induced the production of proinflammatory cytokines IL-6, GM-CSF and IL12-p70, and this response was particularly robust in the monocyte cell line.

Conclusions/Significance

Clozapine damages mitochondria and promotes inflammation in insulin responsive cells and obesity-associated cell types. These phenomena are closely associated with changes observed in human and animal studies of MetS, obesity, insulin resistance, and diabetes. Therefore, the use of clozapine in DIMS may be an important and relevant tool for investigating cellular and molecular changes associated with the development of these diseases in the general population.     

Cinnamic acid induced changes in reactive oxygen species scavenging enzymes and protein profile in maize (Zea mays L.) plants grown under salt stress

Plant growth and development are greatly affected due to changes in environmental conditions and become a serious challenge to scientific people. Therefore, present study was conducted to determine the role of secondary metabolites on the growth and development of maize under abiotic stress conditions. Cinnamic acid (CA) is one of the basic phenylpropanoid with antioxidant activity, produced by plants in response to stressful conditions. Response of maize seeds to the presoaking treatment with 0.5 mM CA was studied under different concentrations of NaCl stress. Exogenous CA increased growth characteristics in saline and non-saline conditions, while effects of CA were more significant under saline conditions in comparison to non-saline conditions in maize plants. CA also reduced oxidative damage through the induction of ROS scavenging enzymes such as supperoxide dismutase (SOD) (EC 1.15.1.1), peroxidase (POD) (EC 1.11.1.7), while the activity of enzyme catalase (CAT) (EC 1.11.1.6) was decreased. The content of malondialdehyde (MDA) was reduced significantly in maize leaf under CA treatment. Changes in protein banding patterns in the maize leaves showed a wide variation in response to NaCl-stress, while in the presence of CA salt-induced expression of polypeptides was reduced significantly. Present study clearly reports the alleviative effects of CA in response to salinity stress on growth, metabolic activity and changes in protein profile of 21 days old maize plants.     

Association of peroxisome proliferator activated receptor-γ gene with non-alcoholic fatty liver disease in Asian Indians residing in north India

Background

Genetics of non-alcoholic fatty liver (NAFLD) in Asian Indians has been inadequately studied. We investigated the association of polymorphisms C161T and Pro12Ala of peroxisome proliferator-activated receptor gamma (PPARγ) with clinical and biochemical parameters in Asian Indians with NAFLD.

Methods

In this case–control study, 162 NAFLD cases and 173 controls were recruited. Abdominal ultrasound, clinical and biochemical profiles, fasting insulin levels and value of homeostasis model assessment of insulin resistance were determined. Polymerase chain reaction–restriction fragment length polymorphisms of two polymorphisms were performed. The association of these polymorphisms with clinical and biochemical parameters was analysed.

Results

Higher frequency of Ala and T alleles of PPARγ was obtained in cases. Ala/Ala genotype of PPARγ (Pro12Ala) was associated with significantly higher serum triglycerides (TG), alkaline phosphatase (ALK) and waist–hip ratio in cases as compared to controls. In C161T polymorphism, TT genotype was significantly increased TG (p = 0.04), total cholesterol (p = 0.01), ALK (p = 0.04) and gamma-glutamyl transpeptidase (p = 0.007) in cases. The linkage disequilibrium for these two single-nucleotide polymorphisms of PPARγ was differed in cases (D1 = 0.1; p = 0.006) and controls (D1 = 0.07; p = 0.1). Using a multivariate analysis after adjusting for age, sex and body mass index, the presence of NAFLD was linked to these two polymorphisms (odds ratio 1.64 (95% CI: 1.09–2.45, p = 0.05)].

Conclusion

Asian Indians in north India carrying the alleles Ala and T of PPARγ (Pro12Ala and C161T) polymorphisms are predisposed to develop NAFLD.     

Substituent control of DNA binding modes in a series of chalcogenoxanthylium photosensitizers as determined by isothermal titration calorimetry and topoisomerase I DNA unwinding assay

The DNA binding efficacy and preferred mode of binding of a series of rhodamine-related chalcogenoxanthylium dyes was investigated by isothermal titration calorimetry (ITC) using ctDNA, [poly(dCdG)](2) and [poly(dAdT)](2), and by a topoisomerase I DNA unwinding (Topo I) assay. The dyes of this study showed tight binding to ctDNA with binding constants, K(b), on the order of 10(6)-10(7)M(-1). The ITC and Topo I assay studies suggested that the 9-substituent has a strong impact on binding modes ranging from an apparent preference for intercalation with a 9-2-thienyl substituent (similar binding to [poly(dCdG)](2) and [poly(dAdT)](2), re-supercoiling of DNA in the Topo I assay at <10(-5)M dye), to mixed binding modes with 9-phenyl derivatives (2- to 3-fold preference for binding to [poly(dAdT)](2), re-supercoiling of DNA in the Topo I assay at approximately 2 x 10(-5)M dye), to minor groove binding in a 9-(2-thienyl-5-diethylcarboxamide) derivative (strong preference for binding to [poly(dAdT)](2), did not show complete re-supercoiling in the Topo I assay). No binding to ctDNA was observed in one derivative with a 9-(3-thienyl-2-diethylcarboxamide) substituent, which cannot be co-planar with the xanthylium core. In series of dyes where the chalcogen atom was varied, the selenoxanthylium derivatives had 2- to 3-fold higher values of K(b) than the corresponding xanthylium, thioxanthylium, or telluroxanthylium derivatives, which all showed comparable values of K(b). The chalcogen atom appeared to have little influence on binding mode.     

Speed Breeding Opportunities and Challenges for Crop Improvement

Journal of Plant Growth Regulation - Crop improvement in light of the rapidly changing climate and the increasing human population continues to be one of the primary concerns for researchers across...     

A robust genetic transformation protocol to obtain transgenic shoots of Solanum tuberosum L. cultivar ‘Kufri Chipsona 1’

The genetic transformation of plants is an important biotechnological tool used for crop improvement for many decades. The present study was focussed to investigate various factors affecting genetic transformation of potato cultivar ‘Kufri Chipsona 1’. It was observed that explants pre-cultured for 2 days on MS2 medium (MS medium containing 10 µM silver nitrate, 10 µM BA, 15 µM GA3), injured with a surgical blade and co-cultivated with Agrobacterium tumefaciens strain EHA105 [O.D600 (0.6)] for 2 days results in maximum transient β-glucuronidase (GUS) expression. The addition of 100 µM acetosyringone in MS2 medium also increased rate of transient GUS expression in both the explants. Clumps of putative transgenic shoots were regenerated using the optimised culture conditions from leaf and internodal explants. The stable integration of T-DNA was established using histochemical staining for GUS and amplification of DNA fragment specific to nptII and uidA genes. Within the clumps, around 67.85% of shoots showed uniform GUS expression in all the tissues and about 32.15% shoots show intermittent GUS expression establishing chimeric nature. Uniform GUS staining of the tissue was used as initial marker of non-chimeric transgenic shoots. Quantitative expression of nptII transgene was found to be directly proportional to uniformity of GUS staining in transgenic shoots. The present investigation indicated that manipulation of culture conditions and the medium composition may help to get transgenic shoots with uniform expression of transgene in all the tissues of potato cultivar ‘Kufri Chipsona 1’.     

Fractal dimension in aspiration cytology smears of breast and cervical lesions

OBJECTIVE: To standardize the automated measurement of fractal dimension on cytologic smears and compare the fractal dimension of benign and malignant breast cells and cervical lesions on cytologic material to evaluate its role in the discrimination of benign from malignant cells. STUDY DESIGN: We randomly selected fine needle aspiration cytology smears of 42 cases of infiltrating duct carcinoma and 38 cases of fibroadenoma of the breast. Similarly, 16 cervical carcinoma and 20 normal cervical smears were selected for study. Ten cells were selected randomly from each case. Box counting of fractal dimension of malignant and benign cells was achieved with an image cytometer (Leica, Cambridge, England) using Quantimet 600 software (Leica). Then a well-spaced grid with multiple small boxes of a particular pixel length was superimposed on the cell. The dimension of the box was selected as 4, 8 and 16 pixels. With the help of a logical "AND" operation, we counted the number of boxes touching the peripheral margin of the cell nuclei. For each cell, the log-log graph of 1 per box size was plotted against the number of boxes touching the peripheral rim of the cell. The slope of each graph was identified using the least-squares method of regression analysis. RESULTS: The mean fractal dimension of malignant cells was 0.8536 +/- 0.1120 as compared to 0.8403 +/- 0.1115 in benign cell groups. The Mann-Whitney U test showed a significant difference in fractal dimension in these 2 groups (P = .05). The mean fractal dimension of malignant cells from the cervix was 0.8656 +/- 0.1499 as compared to 0.8315 +/- 0.1312 in benign cells. The Mann-Whitney U test showed a significant difference in fractal dimension in these 2 groups (P < .02). CONCLUSION: Fractal dimension may be a helpful adjunctive technique to discriminate between benign and malignant cells.