Investigation of selective retinoic acid receptor alpha antagonist ER-50891 and related analogs for male contraception.

Retinoic acid receptor alpha (RARα) antagonist ER-50891 and 15 analogs were prepared and tested in vitro for potency and selectivity at RARα, RARß, and RARγ using transactivation assays. Minor modifications to the parent molecule such as the introduction of a C4 tolyl group in place of the C4 phenyl group on the quinoline moiety slightly increased the RARα selectivity but larger substituents significantly decreased the potency. Replacement of the pyrrole moiety of ER-50891 with triazole, amides, or a double bond produced inactive compounds. ER-50891 was found to be stable in male mouse liver microsomes and was tested in male mice to assess its effects on spermatogenesis. Characteristic, albeit modest and transient, effects on spermatogenesis were observed.

Cytotoxicity of phenylpironetin analogs and the metabolic fate of pironetin and phenylpironetin.

To improve pironetin's metabolic stability we prepared four analogs by replacing its C12-14 segment with an aryl group. The antiproliferative activity of phenyl analog 4 was reduced two-fold and dihydroxy-4-fluorophenyl analog 5 was slightly more effective against OVCAR5 and A2780 ovarian cancer cell lines compared with the parent compound pironetin (1). The activity of 4-fluorophenyl analog 6 was reduced 3-fold in both cell lines. The activity of 7-O-methyl analog 7 was reduced 36-fold in OVCAR5 cells and 47-fold and A2780 cells, compared with pironetin. Phenylpironetin (4) was rapidly metabolized by mouse and human liver microsomes. We identified 17 human metabolites for phenyl analog 4 and 14 human metabolites for pironetin. Metabolism occurred at the C12-13 moiety, the α,ß-unsaturated lactone and the side chains of the molecules (C6-C11 segments). The significant extent of oxidative metabolism suggests that it may not be possible to attain a metabolically stable pironetin analog by structural modifications of the parent compound.

Elucidating genetic diversity and population structure of Pyricularia oryzae isolates causing wheat blast in Bangladesh.

Wheat blast, caused by Pyricularia oryzae pathotype Triticum, is one of the most notorious diseases of wheat. In this study, a total of twenty-four monoconidial isolates representing four major wheat blast affected districts, namely Chuadanga, Meherpur, Kustia and Jhenaidah of Bangladesh were analyzed. Eight RAPD and four ISSR primers being used for genetic diversity assay produced a total of 94 bands of which 85% were polymorphic. UPGMA dendrogram based on combined dataset (RAPD and ISSR) separated all the isolates into two main clusters having similarity ranged from 64 to 93%. Principal coordinate analysis showed congruent result with cluster analysis. However, clustering of the isolates according to their origin and plant part sampled was not apparent in the dendrogram. The genetic diversity indices unveiled that genetic diversity in P. oryzae populations is low. Average Nei's gene diversity (h) and Shannon's Information Index (I) calculated for isolates from each district were found 0.16 and 0.24, respectively. The population structure analysis of the isolates revealed the presence of two sub-populations with admixture of alleles. Analysis of molecular variance indicated that significantly higher level of variation (96%) in the population was present within districts while a relatively low proportion (4%) of the variation was detected among districts. Knowledge generated in this study will give a pace in the development of appropriate wheat blast management strategies to control this disease in Bangladesh.

Curcuma longa L. Prevents the Loss of ß-Tubulin in the Brain and Maintains Healthy Aging in Drosophila melanogaster.

Loss of tubulin is associated with neurodegeneration and brain aging. Turmeric (Curcuma longa L.) has frequently been employed as a spice in curry and traditional medications in the Indian subcontinent to attain longevity and better cognitive performance. We aimed to evaluate the unelucidated mechanism of how turmeric protects the brain to be an anti-aging agent. D. melanogaster was cultured on a regular diet and turmeric-supplemented diet. ß-tubulin level and physiological traits including survivability, locomotor activity, fertility, tolerance to oxidative stress, and eye health were analyzed. Turmeric showed a hormetic effect, and 0.5% turmeric was the optimal dose in preventing aging. ß-tubulin protein level was decreased in the brain of D. melanogaster upon aging, while a 0.5% turmeric-supplemented diet predominantly prevented this aging-induced loss of ß-tubulin and degeneration of physiological traits as well as improved ß-tubulin synthesis in the brain of D. melanogaster early to mid-age. The higher concentration (≥ 1%) of turmeric-supplemented diet decreased the ß-tubulin level and degenerated many of the physiological traits of D. melanogaster. The turmeric concentration-dependent increase and decrease of ß-tubulin level were consistent with the increment and decrement data obtained from the evaluated physiological traits. This correlation demonstrated that turmeric targets ß-tubulin and has both beneficial and detrimental effects that depend on the concentration of turmeric. The findings of this study concluded that an optimal dosage of turmeric could maintain a healthy neuron and thus healthy aging, by preventing the loss and increasing the level of ß-tubulin in the brain.

Reusing greywater for cultivation of Capsicum frutescens and Calendula officinalis.

This study investigated the impact of greywater application for home yard gardening. Greywater was collected and treated using screening, sedimentation and solar disinfection methods. Finally, a field experiment was conducted to investigate the impact of untreated and treated greywater on a selected vegetable, Capsicum frutescens and flowering plant, Calendula officinalis for 2 months. The findings depicted that untreated greywater contains higher macro-nutrients with excessive bacterial population compared with tap water (control), however, the treatment process reduced the concentration of most of the unwanted parameters from greywater samples to bring them into irrigation standards. Overall, treated greywater irrigation showed the species-specific impact on experimental plants with more stimulation in Capsicum frutescens species compared with tap water irrigation. Both treated and untreated greywater irrigation increased the growth parameters of Calendula officinalis in comparison with control. The impact was not significant for most of the parameters of Calendula officinalis while compared between greywater (treated and untreated) and control, and between treated and untreated greywater irrigation. Treated greywater irrigation significantly stimulated most of the parameters of Capsicum frutescens while untreated greywater increased only moisture content, and number of branches compared with control. Most interestingly, treated greywater irrigation had significant impact on Capsicum frutescens particularly for number of branches and leaves compared with untreated greywater irrigation. In fine, the greywater, after treatment was bacterially safe and had positive impact on plant growth. The findings of this study will help to conserve irrigation water and to protect and manage aquatic ecosystem from the adverse impact of wastewater.

Retinoic acid receptor antagonists for male contraception: current status†.

Retinoic acid receptor alpha (RARA), a nuclear receptor protein, has been validated as a target for male contraception by gene knockout studies and also pharmacologically using a pan-retinoic acid receptor antagonist. Retinoic acid receptor alpha activity is indispensable for the spermatogenic process, and therefore its antagonists have potential as male contraceptive agents. This review discusses the effects of systematic dosing regimen modifications of the orally bioavailable and reversible pan-antagonist BMS-189453 as well as studies with the alpha-selective antagonists BMS-189532 and BMS-189614 in a murine model. We also provide an overview of structure-activity studies of retinoic acid receptor alpha antagonists that provide insight for the design of novel alpha-selective ligands.

Crispenes F and G, cis-Clerodane Furanoditerpenoids from Tinospora crispa, Inhibit STAT3 Dimerization.

Two new cis-clerodane-type furanoditerpenes, crispenes F and G (1 and 2), together with seven known compounds, were isolated from the stems of Tinospora crispa. Crispenes F and G (1 and 2) inhibited STAT3 dimerization in a cell-free fluorescent polarization assay and were found to have significant cytotoxicity against a STAT3-dependent MDA-MB 231 breast cancer cell line, while being inactive in a STAT3-null A4 cell line. These two compounds share structural similarities with a previously reported STAT3 inhibitor, crispene E, isolated from the same plant. Molecular docking studies suggested that the molecules inhibit STAT3 by interacting with its SH2 domain.