Notes

Multifaceted function regarding β-arrestins throughout inflammation and illness.
Herein, two new series of N-substituted indole-based analogues were rationally designed, synthesized via microwave heating technology, and evaluated as noteworthy MAO-B potential inhibitors. Compared to the reported indazole-based hits VI and VII, compounds 4b and 4e exhibited higher inhibitory activities over MAO-B with IC50 values of 1.65 and 0.78 µM, respectively. When compared to the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), both 4b and 4e also showed better selectivity indices (SI > 60 and 120, respectively). A further kinetic evaluation of the most potent derivative (4e) displayed a competitive mode of inhibition (inhibition constant (Ki)/MAO-B = 94.52 nM). Reasonable explanations of the elicited biological activities were presented via SAR study and molecular docking simulation. Accordingly, the remarkable MAO-B inhibitory activity of 4e (N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)pyrazine-2-carboxamide), with its selectivity and competitive inhibition, advocates its potential role as a promising lead worthy of further optimization.Phthalate esters are produced widely for their use as plasticizer in consumer products such as cosmetics, PVC, deodorants etc. Their use is considered harmless but they are known to induce cancer and work as endocrine disruptors. In this review, we try to emphasize the ubiquitous presence of phthalate esters and the pathways they affect to induce, metastasizes cancer or to prompt drug resistance in cancer cells. We reviewed the literature from the last one decade on PubMed. The keywords used were 'Phthalates' 'Breast cancer' 'endocrine disruptors' 'environmental carcinogens' 'Phthalates and reproductive health' etc. In conclusion, the phthalates are able to mimic estrogen, to prompt proliferation, metastasis and drug resistance in breast cancer cells. The data for its dosage exposure to induce ill-effects remains largely inconsistent. The only well researched molecular target of phthalate is Aryl hydrocarbon receptor (AhR) which is a ligand activated transcription factor. Being an interesting and important problem of research this aspect had not been touched in the way as it has to be.The overexpression of P21-activated kinase 1 (PAK1) is associated with poor prognosis in several cancers, which has emerged as a promising drug targets. Based on high-throughput virtual screening strategy, tetrahydrothieno [2,3-c]pyridine scaffold was identified as an initial lead for targeting PAK1. Herein we reported our structure-based optimisation strategy to discover a potent PAK1 inhibitor (7j) which displayed potent PAK1 inhibition and antiproliferatory activity in MDA-MB-231 cells. 7j induced obviously G2/M cell cycle arrest via PAK1-cdc25c-cdc2 pathway, and also inhibited MAPK-ERK and MAPK-JNK cascade to induce MDA-MB-231 cell death. Together, these results provided a novel chemical scaffold as PAK1 inhibitor for breast cancer treatment.The study was designed to evaluate antigenotoxic effect of methanol Teucrium arduini and Teucrium flavum extracts against mitomycin C (MMC)-induced chromosome and DNA damage in vitro. Cytokinesis-block micronucleus (CBMN) and comet assays were used to investigate effect of plant extracts in different concentrations (125, 250, 500 and 1000 µg/mL) on human peripheral blood lymphocytes (PBLs). The obtained results showed that the all tested concentrations of T. arduini and the highest concentration of T. flavum significantly reduced the MMC-induced micronucleus (MN) frequency in comparison to positive control (only MMC). There were significantly negative correlations between the extracts concentrations and MN frequencies (Pearson, r = -0.905, p = 0.0001 for T. arduini; r = -0.861, p = 0.0001 for T. flavum). The extracts of both plants further lowered the MMC-decreased nuclear division index (NDI) in a dose dependent-manner (Pearson, r = -0.837, p = 0.001 for T. arduini; r = -0.598, p = 0.040 for T. flavum), but significantly only in the highest concentration (1000 µg/mL). Comet assay showed that extracts reduced MMC-increased genetic damage index (GDI), significantly in the concentrations of 500 and 1000 μg/mL, in comparison with positive control. Based on our results, it can be concluded that methanol T. arduini and T. flavum extracts possess protective proapoptotic and antigenotoxic effect which is indication of their medicinal relevance and use in treatment.Survival in chronic obstructive pulmonary disease (COPD) is enhanced in obese patients, which is called the obesity paradox. Despite some theories, the precise mechanism remains unclear. Since COPD exacerbations play a major role in COPD survival, this study aimed to stratify patients into BMI classes and investigate exacerbation frequency, time to readmission and survival in patients hospitalized with a COPD exacerbation. Therefore, patients hospitalized with an exacerbation of COPD were categorized into BMI groups using cut-offs less then 18.5, 25, 30 and ≥35 kg/m2 for underweight, normal, overweight, moderately obese and severely obese groups and followed for five years. A total of 604 COPD patients was included. In comparison to normal weight patients, the 5-year exacerbation frequency was significantly decreased by 34-40% in obese patients depending on the BMI group (1.83 ± 1.60 per year in the normal weight group; overweight 1.60 ± 1.41; moderately obese 1.20 ± 1.18; severely obese 1.09 ± 1.13 per year; and 1.59 ± 1.30 in the underweight group). The time to readmission was up to 1.7 times longer for moderately obese patients compared to normal weight patients (954 ± 734 versus 564 ± 660 days). The data were supported by enhanced survival in obese patients and a regression analysis showing that both time to readmission and survival were associated with BMI independent of other possible confounders. DAPK inhibitor In conclusion, this study shows a 'dose dependent' reduced exacerbation frequency and an increased time to readmission in obese patients admitted to the hospital with an exacerbation of COPD.Diet containing watermelon coloring (5, 20, 35 and 50 mg lycopene/100g) was fed to albino rats to study in-vivo bioavailability of lycopene. The rats were fed with lycopene enriched test diets for seven days of treatment period along with control diet during pre and post treatment periods of seven days each. The body weight of each group of albino rats significantly increased during feeding trial which showed that rats were in healthy condition during the treatment. The daily lycopene intake from test diets varied from 0.03 to 0.51 mg during treatment period of seven days which decreased to 0.02-0.07 mg during post-treatment period with control diet. The lycopene absorbed by different groups of rats varied from 0.22 to 3.74 mg/kg body weight of rat during treatment period and 0.15-0.67 mg/kg body weight of rat during post-treatment periods. Lycopene bioavailability increased proportionately with the lycopene content of test diet.
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