Design, Synthesis, Characterization, and Crystal Structure Studies of Nrf2 Modulators for Inhibiting Cancer Cell Growth In Vitro and In Vivo.

Nrf2 is one of the important therapeutic targets studied extensively in several cancers including the carcinomas of the colon and rectum. However, to date, not many Nrf2 inhibitors showed promising results for retarding the growth of colorectal cancers (CRCs). Therefore, in this study, first, we have demonstrated the therapeutic effect of siRNA-mediated downmodulation of Nrf2 on the proliferation rate of CRC cell lines. Next, we have designed, synthesized, characterized, and determined the crystal structures for a series of tetrahydrocarbazoles (THCs) and assessed their potential to modulate the activity of Nrf2 target gene NAD(P)H:quinone oxidoreductase (NQO1) activity by treating colorectal carcinoma cell line HCT-116. Later, the cytotoxic potential of compounds was assessed against cell lines expressing varying amounts of Nrf2, viz., breast cancer cell lines MDA-MB-231 and T47D (low functionally active Nrf2), HCT-116 (moderately active Nrf2), and lung cancer cell line A549 (highly active Nrf2), and the lead compound 5b was tested for its effect on cell cycle progression in vitro and for retarding the growth of Ehrlich ascites carcinomas (EACs) in mice. Data from our study demonstrated that among various compounds 5b exhibited better therapeutic index and retarded the growth of EAC cells in mice. Therefore, compound 5b is recommended for further development to target cancers.

Impact of weather and climate change with indoor and outdoor air quality in asthma: A Work Group Report of the AAAAI Environmental Exposure and Respiratory Health Committee.

Weather and climate change are constant and ever-changing processes that affect allergy and asthma. The purpose of this report is to provide information since the last climate change review with a focus on asthmatic disease. PubMed and Internet searches for topics included climate and weather change, air pollution, particulates, greenhouse gasses, traffic, insect habitat, and mitigation in addition to references contributed by the individual authors. Changes in patterns of outdoor aeroallergens caused by increasing temperatures and amounts of carbon dioxide in the atmosphere are major factors linked to increased duration of pollen seasons, increased pollen production, and possibly increased allergenicity of pollen. Indoor air pollution threats anticipated from climate changes include microbial and mold growth secondary to flooding, resulting in displacement of persons and need for respiratory protection of exposed workers. Air pollution from indoor burning of mosquito repellants is a potential anticipatory result of an increase in habitat regions. Air pollution from fossil fuel burning and traffic-related emissions can alter respiratory defense mechanisms and work synergistically with specific allergens to enhance immunogenicity to worsen asthma in susceptible subjects. Community efforts can significantly reduce air pollution, thereby reducing greenhouse gas emission and improving air quality. The allergist's approach to weather pattern changes should be integrated and anticipatory to protect at-risk patients.

Induction of colon and cervical cancer cell death by cinnamic acid derivatives is mediated through the inhibition of Histone Deacetylases (HDAC).

Recent studies from our group and many others have shown the ability of histone deacetylase (HDAC) inhibitors for retarding the growth of carcinomas of cervix, colon and rectum in vitro. A search for naturally occurring HDAC inhibitors continues due to the adverse effects associated with known HDAC inhibitors like SAHA and TSA. Therefore in the current study, naturally occurring cinnamic acids derivatives were screened for HDAC inhibitory effect using in silico docking method which identified cinnamic acids as potential candidates. Cinnamic acids (CA) are naturally occurring phenolic compounds known to exhibit anticancer properties. However, it is not clearly known whether the anticancer properties of CA derivatives are due to the inhibition of oncogenic HDACs, if so how the efficacy varies among various CA derivatives. Hence, the HDAC inhibitory potential of CA derivatives containing increasing number of hydroxylic groups or methoxy moieties was determined using Discovery Studio software and the most potent CA derivatives tested ex vivo (biochemical assay) as well as in vitro (using cell based assay). Among CA derivatives tested, dihydroxy cinnamic acid (DHCA, commonly known as caffeic acid) exhibited better interactions with HDAC2 (compared to other isoforms) in silico and inhibited its activity ex vivo as well as in vitro. Targeted reduction of HDAC activity using DHCA induced death of cancer cells by (a) generating reactive oxygen species, (b) arresting cells in S and G2/M phases; and (c) induction of caspase-3 mediated apoptosis. In conclusion, we demonstrated that DHCA inhibited cancer cell growth by binding to HDAC followed by the induction of apoptosis.

Naturally occurring benzoic acid derivatives retard cancer cell growth by inhibiting histone deacetylases (HDAC).

Histone deacetylases (HDACs), which modulate the expression of genes, are potential therapeutic targets in several cancers. Targeted inhibition of HDAC prevents the expression of oncogenes thereby help in the treatment of cancers. Hence, several pharmaceutical companies developed inhibitors of HDAC and tested them in preclinical models and in clinical trials. SAHA (suberanilohydroxamic acid) is one such HDAC inhibitor developed for treating breast and colorectal carcinomas. However, due to poor efficacy in clinical trials the utility of SAHA for treating cancers was discouraged. Similarly another HDAC inhibitor Trichostatin-A (TSA) also showed promising results in clinical trials but exhibited severe adverse effects, which dampened the interest of using this molecule for cancer treatment. Therefore, search for developing a potent HDAC inhibitor with minimal side effects still continues. Hence, in this study we have screened benzoic acid and benzoic acid derivatives with hydroxylic (-OH) groups and methoxy (-OCH3) groups for their efficacy to bind to the TSA binding site of HDAC using molecular docking studies. Molecules that showed much stronger affinity (than TSA) to HDAC were tested for inhibiting HDAC expressing cultured cancer cells. DHBA but not Dimethoxy Benzoic Acid (DMBA) inhibited HDAC activity, leading to cancer cell growth inhibition through the induction of ROS and cellular apoptosis mediated by Caspase-3. In addition, DHBA arrested cells in G2/M phase of the cell cycle and elevated the levels of sub-G0-G1 cell population. In summary, results of this study report that DHBA could be a strong HDAC inhibitor and inhibit cancer cell growth more effectively.

Health-related quality of life assessment using St. George's respiratory questionnaire in asthmatics on inhaled corticosteroids.

CONTEXT: Chronic diseases like asthma have significant effects on patients' health-related quality of life (HRQoL). HRQoL measures additional indices as compared to objective measurements like spirometry. AIMS: To assess and compare disease-specific quality of life in asthma patients using St. George's Respiratory Questionnaire (SGRQ) receiving fluticasone, beclomethasone, and budesonide (BUD). SETTINGS AND DESIGN: A prospective, open label, randomized, parallel group study conducted at a tertiary care teaching hospital in South India. MATERIALS AND METHODS: A 6-month follow-up of 277 patients with mild, moderate, and severe persistent asthma was randomized to receive fluticasone propionate (FP), BUD, or beclomethasone dipropionate (BDP) in equipotent doses according to their global initiative on asthma (GINA) severity. STATISTICAL ANALYSIS USED: Data analyzed using SPSS version: 13.0. General linear-repeated measures using the post-hoc bonferroni method assessed significance between treatment groups. RESULTS: Significant decrease (P < 0.05) in each SGRQ domains and total scores as well as improvement in FEV(1) (P < 0.05) was observed in all study subjects. A significant early response (P < 0.05) was noted after 15 days treatment in patients receiving FP with respect to SGRQ (activity, impact and total) scores and dyspnea indices, but not FEV(1). This improvement with FP was due to its greater effect in patients with moderate and severe persistent asthma. No difference was noted subsequently in all outcome measures studied until 6 months. CONCLUSIONS: There was evidence for an early QoL improvement to FP as compared to BUD or BDP in moderate and severe persistent asthma. Subsequently, the three ICS showed similar improvements in lung functions and dyspnea indices throughout the study.