Selective pks+ Escherichia coli strains induce cell cycle arrest and apoptosis in colon cancer cell line.

pks+ Escherichia coli (E. coli) triggers genomic instability in normal colon cells which leads to colorectal cancer (CRC) tumorigenesis. Previously, we reported a significant presentation of pks+ E. coli strains in CRC patients' biopsies as compared to healthy cohorts. In this work, using an in vitro infection model, we further explored the ability of these strains in modulating cell cycle arrest and activation of apoptotic mediators in both primary colon epithelial cells (PCE) and CRC cells (HCT-116). Sixteen strains, of which eight tumours and the matching non-malignant tissues, respectively, from eight pks+ E. coli CRC patients were subjected to BrDU staining and cell cycle analysis via flow cytometry, while a subset of these strains underwent analysis of apoptotic mediators including caspase proteins, cellular reactive oxygen species (cROS) and mitochondrial membrane potential (MMP) via spectrophotometry as well as proinflammatory cytokines via flow cytometry. Data revealed that all strains exerted S-phase cell cycle blockade in both cells and G2/M phase in PCE cells only. Moreover, more significant upregulation of Caspase 9, cROS, proinflammatory cytokines and prominent downregulation of MMP were detected in HCT-116 cells indicating the potential role of pks related bacterial toxin as anticancer agent as compared to PCE cells which undergo cellular senescence leading to cell death without apparent upregulation of apoptotic mediators. These findings suggest the existence of discrepancies underlying the mechanism of action of pks+ E. coli on both cancer and normal cell lines. This work propounds the rationale to further understand the mechanism underlying pks+ E. coli-mediated CRC tumorigenesis and cancer killing.

A waste to energy technology for Enrichment of biomethane generation: A review on operating parameters, types of biodigesters, solar assisted heating systems, socio economic benefits and challenges.

Anaerobic Digestion (AD) is one of the promising wastestoenergy (WtE) technologies that convert organic wastes to useful gaseous fuel (biogas). In this process methane is produced in the presence of methanogens (bacteria). The survival and activities of methanogens are based on several parameters such as pH, temperature, organic loading rate, types of biodigester. Moreover, these parameters influence the production of biogas in terms of yield and composition. Maintaining an appropriate temperaturefor AD is highly critical and energy intensive. This study reviews the various hybrid technologies assistedbio gas production schemes particularly from renewable energy sources. Also discuss the direct and indirect solar assisted bio-digester impacts and recommendation to improve its performance. In addition, the performance analysis Solar Photovoltaic (PV) and thermal collector assisted bio gas plants; besides their impact on the performance of anaerobic digesters. Since opportunities of solar energy are attractive, the effective utilization of the same is selected for the discussion. Besides, the various constraints that affect the yield and composition of biogas are also evaluated along with the current biogas technologies and the biodigesters. The environmental benefits, challenges and socio-economic factors are also discussed for the successful implementation of various technologies.

Determining pulmonary function and the associated risk factors among stone quarry workers in a suburban area of Chennai, Tamil Nadu, India.

BACKGROUND: Stone quarrying activities generate dust and fine particulate matters of silica and heavy metals. The prolonged exposure to suspended particulates leads to fatal respiratory complications. Occupational pulmonary complications are poorly characterized among quarry workers in Tamil Nadu. OBJECTIVES: This study aims to assess pulmonary function and determine the associated risk factors among quarry workers. MATERIALS AND METHODS: A comparative, cross-sectional study was conducted from April 2014 to January 2015 among workers at seven stone quarries in Chennai and residents within a 5 Km radius. Pulmonary function tests (PFT) and sputum analysis were done. RESULTS: Overall, 670 participants were enrolled in the study, with a median age of 37 years. Comparatively, the mean PFT measures were significantly lower in quarry workers with a higher proportion of airflow obstruction and tuberculosis infection. CONCLUSION: The risk of airflow obstruction among quarry workers increased with smoking and longer duration of work years in quarry.

Discovery of hydroxy pyrimidine Factor IXa inhibitors.

The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.

Design, Synthesis, and Evaluation of Novel and Selective G-protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists.

Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist 14. Furthermore, compound 14 was evaluated in vivo and demonstrated acute glucose lowering in an oral glucose tolerance test (oGTT), as well as improvements in homeostatic measurement assessment of insulin resistance (HOMA-IR; a surrogate marker for insulin sensitization) and an increase in glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp in diet-induced obese (DIO) mice.

Himbacine-derived thrombin receptor antagonists: c7-aminomethyl and c9a-hydroxy analogues of vorapaxar.

We have synthesized several C7-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound 6a from this series showed excellent PAR-1 activity (K i = 5 nM). We have also synthesized a C9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (K i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey.

Himbacine-derived thrombin receptor antagonists: c7-spirocyclic analogues of vorapaxar.

We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (K i = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure-activity relationships in this series.

Hypericin-photodynamic therapy leads to interleukin-6 secretion by HepG2 cells and their apoptosis via recruitment of BH3 interacting-domain death agonist and caspases.

Photodynamic therapy (PDT) has emerged as a capable therapeutic modality for the treatment of cancer. PDT is a targeted cancer therapy that reportedly leads to tumor cell apoptosis and/or necrosis by facilitating the secretion of certain pro-inflammatory cytokines and expression of multiple apoptotic mediators in the tumor microenvironment. In addition, PDT also triggers oxidative stress that directs tumor cell killing and activation of inflammatory responses. However, the cellular and molecular mechanisms underlying the role of PDT in facilitating tumor cell apoptosis remain ambiguous. Here, we investigated the ability of PDT in association with hypericin (HY) to induce tumor cell apoptosis by facilitating the induction of reactive oxygen species (ROS) and secretion of Th1/Th2/Th17 cytokines in human hepatocellular liver carcinoma cell line (HepG2) cells. To discover if any apoptotic mediators were implicated in the enhancement of cell death of HY-PDT-treated tumor cells, selected gene profiling in response to HY-PDT treatment was implemented. Experimental results showed that interleukin (IL)-6 was significantly increased in all HY-PDT-treated cells, especially in 1 µg/ml HY-PDT, resulting in cell death. In addition, quantitative real-time PCR analysis revealed that the expression of apoptotic genes, such as BH3-interacting-domain death agonist (BID), cytochrome complex (CYT-C) and caspases (CASP3, 6, 7, 8 and 9) was remarkably higher in HY-PDT-treated HepG2 cells than the untreated HepG2 cells, entailing that tumor destruction of immune-mediated cell death occurs only in PDT-treated tumor cells. Hence, we showed that HY-PDT treatment induces apoptosis in HepG2 cells by facilitating cytotoxic ROS, and potentially recruits IL-6 and apoptosis mediators, providing additional hints for the existence of alternative mechanisms of anti-tumor immunity in hepatocellular carcinoma, which contribute to long-term suppression of tumor growth following PDT.

Assessment of compost as a bio-fertilizer for the growth of paddy.

The vegetable wastes were converted into compost by a stepwise degradation and its characteristics were studied and analysed at each stage. The temperature increased from 290C to 60 degrees C on 60th day and reached 33 degrees C on 90th day. Shift of pH from 7.6 to 7.3 on 60th day caused a shift of microflora from 12.01 x 10(7) to 11.13 x 10(8) CFU ml(-1) on 30th day and 63.2 x 10(6) on 60th day and 36.75 x 10(6) on 90th day. Shift of microflora caused high decomposition of the waste into compost which were used for enriching the soil as manures. The other characteristics such as moisture, ash content and C:N ratio established the short period required for preparing a complete compost of good quality. The study showed the efficiency of these organisms as plant growth promoting rhizobacteria. Combinations of microorganisms with compost act as a good biofertilizer which improves the fertility of soil and increases plant growth. Better results were produced by organisms in combinations like Azospirillum, Rhizobium and Azotobacter. The least growth in shoot length (64 cm) total fresh weight (151g) and total dry weight (3.994 g) were observed in paddy grown in soil and Bacillus combination, but microbial mixture of compost and soil gave high paddy growth efficiency. The present study concludes that the rhizospheric organisms play well as plant growth promoting agents and gave a better yield and growth of plants in combination with the compost.

Discovery of nor-seco himbacine analogs as thrombin receptor antagonists.

Discovery of a novel nor-seco himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey.

Heterotricyclic himbacine analogs as potent, orally active thrombin receptor (protease activated receptor-1) antagonists.

Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4.3 nM, is presented.