Hormones are known to influence various body systems that include skeletal, cardiac, digestive, excretory, and immune systems. Emerging investigations suggest the key role played by secretions of endocrine glands in immune cell differentiation, proliferation, activation, and memory attributes of the immune system. The link between steroid hormones such as glucocorticoids and inflammation is widely known. However, the role of peptide hormones and amino acid derivatives such as growth and thyroid hormones, prolactin, dopamine, and thymopoietin in regulating the functioning of the immune system remains unclear. Here, we reviewed the findings pertinent to the functional role of hormone-immune interactions in health and disease and proposed perspective directions for translational research in the field.

Background:Natural products have continually played an important role in drug discovery because it serves as active principles in drugs as well as templates for synthesis of new drugs. Cayratia trifolia (L.) is a medicinal plant, which has been reported to have antiviral, antibacterial, antiprotozoal, hypoglycemic, anticancer and diuretic activities.Objective:Therefore, the objective of this study is to isolate and identify the natural compound from the ethanolic extract of Cayratia trifolia (L.) and to predict the Absorption, Distribution, Metabolism and Excretion (ADME) properties of isolated natural compound.Materials and Methods:Column chromatography and thin layer chromatography were used to isolate the natural compound and Fourier-transform infrared (FTIR) spectroscopy was used to predict the functional groups present in the isolated natural compound. The structural characterization studies were functionally carried out using 1H, 13C, two-dimensional nuclear magnetic resonance (NMR) and mass spectrometry methods.Results:FTIR showed that, the groups of OH, C-H, C = C may be present in the isolated natural compound. 1H, 13C, two-dimensional NMR and mass spectrometry data suggests that the isolated natural compound probably like linoleic acid. In silico ADME properties, prediction of the compound was under acceptable range.Conclusion:Based on the results, it can be concluded that, the isolated natural compound of linoleic acid that has been exhibited good medicinal properties.

Enhancer of Zeste Homolog 2 (EZH2) is the histone lysine methyltransferase (HKMT) component of the Polycomb Repressive Complex 2 (PRC2). In conjunction with other members of the complex, EZH2 represses gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumor progression and correlates with poor prognosis in several tumor types and enzymatic hyperactivity of EZH2 has been linked to aberrant repression of tumor suppressor genes in diverse cancers. Recently, direct inhibition of EZH2 HKMT activity by small molecules has been shown to be effective in inhibiting the proliferation of EZH2 mutant diffuse large B-cell lymphoma (DLBCL) cell lines and the growth of tumors in EZH2 mutant DLBCL xenografts. We have identified and optimized a series of small molecule EZH2 inhibitors that is structurally distinct from previously published chemotypes. CPI-169, a representative compound from that effort, inhibits the catalytic activity of PRC2 with an IC50 of < 1nM, decreases cellular levels of H3K27me3 with an EC50 of 70 nM, and triggers cell cycle arrest and apoptosis in a variety of cell lines. Importantly, compound treatment triggers a sequence of downstream functional consequences of EZH2 inhibition whereby apoptosis is not induced before ten days of continuous target engagement. Administered subcutaneously at 200 mpk twice daily (BID), CPI-169 is well tolerated in mice with no observed toxic effect or body weight loss. In the present study we show that CPI-169 treatment led to tumor growth inhibition (TGI) of an EZH2 mutant KARPAS-422 DLBCL xenograft. The TGI is proportional to the dose administered and to the reduction of the pharmacodynamic marker H3K27me3. The highest dose, 200 mpk, BID led to complete tumor regression. Since CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) is the standard treatment of advanced DLBCL, we were interested in combining a suboptimal dose of CPI-169 (100 mpk, BID) with a single dose of CHOP in the KARPAS-422 model. After a week of combinatorial treatment the tumors rapidly regressed and became unpalpable. Four weeks after the last dose only a single mouse presented a palpable tumor. The immunohistochemical analysis of tumor samples revealed a strong correlation between the global decrease of H3K27me3, the decrease in the proliferation marker Ki-67 and the increase in cleaved-caspase 3 positive cells. In conclusion, we identified a strong synergistic anti-tumor activity between the standard of care CHOP and CPI-169, a distinct EZH2 inhibitor in an in vivo model of DLBCL. Citation Format: Vidya Balasubramanian, Priya Iyer, Shilpi Arora, Patrick Troyer, Emmanuel Normant. CPI-169, a novel and potent EZH2 inhibitor, synergizes with CHOP in vivo and achieves complete regression in lymphoma xenograft models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1697. doi:10.1158/1538-7445.AM2014-1697

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Histone lysine methylation, which is dynamically regulated by methyltransferases and demethylases, plays an important role in the establishment and maintenance of chromatin structure and thereby contributes to the control of gene expression. The development of small molecule methyltransferase and demethylase inhibitors provides an approach to manipulate transcriptional programs, and thus potentially allow interference with aberrant cellular states as observed in cancer. The histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2) is a component of the Polycomb Repressive Complex 2. It mediates trimethylation of lysine 27 on histone 3 (H3K27me3), which leads to transcriptional repression. EZH2 has been widely implicated in cancer and inhibition of its catalytic activity provides a novel therapeutic approach to treat human cancers. Constellation has identified, characterized and optimized potent, selective and reversible EZH2 small molecule inhibitors as well as studied the biological impact of such inhibition. We have previously shown that pharmacological inhibition of EZH2 causes selective lymphoma cell viability defects with cell lines harboring EZH2 mutations being the most sensitive. The discovery of small molecules that specifically inhibit EZH2 has enabled us to look for other disease indications that might be dependent on EZH2 for survival. We carried out a long term cell viability screen in ∼75 cell lines across several different hematological malignancies using an EZH2 inhibitor. About 30% of all tested Mutliple Myeloma and Plasmacytoma cell lines showed a time-dependent phenotypic response. In these cell lines H3K27me3 levels were effectively reduced in a dose dependent manner within 4 days of compound treatment which was followed by the induction of apoptotsis at later time points. EZH2 inhibitors also achieved tumor growth inhibition in a Multiple Myeloma subcutaneous xenograft model. To understand the underlying molecular mechanism of EZH2 inhibitor sensitivity in Multiple Myeloma, genome-wide mapping of EZH2 and H3K27me3 sites in the absence and presence of the compound have been performed in conjunction with gene expression profiling and the results will be discussed. In conclusion, we identified Multiple Myeloma as a disease modality where EZH2 inhibition leads to cell viability defects both in vitro and in vivo. Citation Format: Shilpi Arora, Vidya Balasubramanian, Kaylyn Williamson, Victor Gehling, Chris Nasveschuk, Rishi Vaswani, Jennifer Busby, Shivani Garapaty, Priya Iyer, Feng Zhao, Robert Campbell, Richard Cummings, Jim Audia, JC Harmange, Brian Albrecht, Andrew Cook, Les Dakin, Emmanuel Normant, Patrick Trojer. Inhibition of the histone methyl transferase EZH2 causes viability defects in multiple myeloma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5526. doi:10.1158/1538-7445.AM2014-5526