Estrogen receptor activation in response to Azadirachtin A stimulates osteoblast differentiation and bone formation in mice.

The positive effects of the sex hormone in sustaining bone homeostasis are exercised by maintaining the equilibrium between cell activity and apoptosis. In this regard, the importance of estrogen receptors in maintaining the bone is that it is an attractive drug target, if devoid of known side effects. In this study, we show that a natural pure compound Azadirachtin A (Aza A) isolated from Azadirachta indica binds selectively to a site in the estrogen receptor, identifying itself to be a selective tissue modifier. Using computational and medicinal chemistry, we show that Aza A binds potentially and selectively to estrogen receptor-α (ERα) as compared with ERß. This preferential binding of Aza A to ERα with good pharmacokinetic distribution in the body forms metabolites, showing that it is well absorbed. In in vivo estrogen deficiency models for osteoporosis, Aza A at a much lower dose enhances new bone formation at both sites of the trabecular and cortical bone with increased bone strength and presents with no hyperplastic effect in the uterus.

Genome-wide identification and interactome analysis of members of two-component system in Banana.

BACKGROUND: Ethylene signal transduction in plants is conducted by the two-component system (TCS) which consists of histidine kinase (HK), histidine phosphotransferase (HPT) and response regulators (RRs). This system plays an important role in signal transduction during various cellular processes, including fruit ripening and response to multiple environmental cues. Though members of TCS have been identified in a few plants, no detailed analysis has been carried out in banana. RESULTS: Through genome-wide analysis, we identified a total of 80 (25 HK, 10 HPT and 45 RR) and 72 (25 HK, 5 HPT and 42 RR) TCS genes in Musa acuminata and Musa balbisiana respectively. The analysis of identified genes revealed that most of the genes are highly conserved however; there are subtle divergences among various members. Comparative expression analysis revealed an involvement of a set of TCS members during banana fruit ripening. Co-expression network analysis identified a working TCS module with direct interactions of HK-HPT and RR members. The molecular dynamics analysis of TCS module showed a significant change in structural trajectories of TCS proteins in the presence of ethylene. Analysis suggests possible interactions between the HK-HPTs and RRs as well as other members leading to banana fruit ripening. CONCLUSIONS: In this study, we identified and compared the members of TCS gene family in two banana species and showed their diversity, within groups on the basis of whole-genome duplication events. Our analysis showed that during banana fruit ripening TCS module plays a crucial role. We also demonstrated a possible interaction mechanism of TCS proteins in the presence and absence of ethylene by molecular dynamics simulations. These findings will help in understanding the functional mechanism of TCS proteins in plants in different conditions.

Genome and transcriptome-wide study of carbamoyltransferase genes in major fleshy fruits: A multi-omics study of evolution and functional significance.

The carbamoyltransferase or aspartate carbamoyltransferase (ATCase)/ornithine carbamoyltransferase (OTCase) is an evolutionary conserved protein family, which contains two genes, ATCase and OTCase. The ATCase catalyzes the committed step in the synthesis of UMP from which all pyrimidine molecules are synthesized. The second member, OTCase, catalytically regulates the conversion of ornithine to citrulline. This study traces the evolution of the carbomoyltransferase genes in the plant kingdom and their role during fruit ripening in fleshy fruits. These genes are highly conserved throughout the plant kingdom and, except for melon and watermelon, do not show gene expansion in major fleshy fruits. In this study, 393 carbamoyltransferase genes were identified in the plant kingdom, including 30 fleshy fruit representatives. Their detailed phylogeny, evolutionary patterns with their expression during the process of fruit ripening, was analyzed. The ATcase and OTcase genes were conserved throughout the plant kingdom and exhibited lineage-specific signatures. The expression analysis of the ATcase and OTcase genes during fruit development and ripening in climacteric and non-climacteric fruits showed their involvement in fruit ripening irrespective of the type of fruits. No direct role in relation to ethylene-dependent or -independent ripening was identified; however, the co-expression network suggests their involvement in the various ripening processes.