Small-molecule disruption of androgen receptor-dependent chromatin clusters.

Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models.

A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy.

Hepatocellular carcinoma (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylase (HDAC) activation. However, inhibiting HDACs-an effective treatment for lymphomas-has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells.

Development and validation of a sensitive LC-MS/MS assay of GT-14, a novel Gα2 inhibitor, in rat plasma, and its application in pharmacokinetic study.

A sensitive and selective LC-MS/MS method was developed and validated for the quantitation of a novel Gα2 inhibitor, GT-14, in rat plasma using a SCIEX 6500+ triple QUAD LC-MS system equipped with an ExionLC UHPLC unit. GT-14 (m/z 265.2 → 134.

A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy.

Hepatocellular cancer (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylases (HDACs) activation. However, inhibiting HDACs, an effective treatment for lymphomas, has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells.

Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC).

Background: Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT).

Presence of Bromotyrosine Alkaloids in Marine Sponges Is Independent of Metabolomic and Microbiome Architectures.

Marine sponge holobionts are prolific sources of natural products. One of the most geographically widespread classes of sponge-derived natural products is the bromotyrosine alkaloids. A distinguishing feature of bromotyrosine alkaloids is that they are present in phylogenetically disparate sponges.

TBK1 regulates regeneration of pancreatic β-cells.

Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells.

Liver-Targeting Class I Selective Histone Deacetylase Inhibitors Potently Suppress Hepatocellular Tumor Growth as Standalone Agents.

Dysfunctions in epigenetic regulation play critical roles in tumor development and progression. Histone deacetylases (HDACs) and histone acetyl transferase (HAT) are functionally opposing epigenetic regulators, which control the expression status of tumor suppressor genes. Upregulation of HDAC activities, which results in silencing of tumor suppressor genes and uncontrolled proliferation, predominates in malignant tumors.

Small Molecule Inhibitors Targeting Gα2 Protein Attenuate Migration of Cancer Cells.

Heterotrimeric G-proteins are ubiquitously expressed in several cancers, and they transduce signals from activated G-protein coupled receptors. These proteins have numerous biological functions, and they are becoming interesting target molecules in cancer therapy. Previously, we have shown that heterotrimeric G-protein subunit alphai2 (Gα2) has an essential role in the migration and invasion of prostate cancer cells.

Publisher Correction: Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Deferiprone: Pan-selective Histone Lysine Demethylase Inhibition Activity and Structure Activity Relationship Study.

Deferiprone (DFP) is a hydroxypyridinone-derived iron chelator currently in clinical use for iron chelation therapy. DFP has also been known to elicit antiproliferative activities, yet the mechanism of this effect has remained elusive. We herein report that DFP chelates the Fe ion at the active sites of selected iron-dependent histone lysine demethylases (KDMs), resulting in pan inhibition of a subfamily of KDMs.

Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells.

β-cell proliferation induction is a promising therapeutic strategy to restore β-cell mass. By screening small molecules in a transgenic zebrafish model of type 1 diabetes, we identified inhibitors of non-canonical IκB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε), as enhancers of β-cell regeneration. The most potent β-cell regeneration enhancer was a cinnamic acid derivative (E)-3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA), which, acting through the cAMP-dependent protein kinase A (PKA), stimulated β-cell-specific proliferation by increasing cyclic AMP (cAMP) levels and mechanistic target of rapamycin (mTOR) activity.

Bronchiectasis and Focal Segmental Glomerulosclerosis in Rheumatoid Arthritis.

A 28-year-old male patient who was a nonsmoker presented with bilateral symmetrical polyarthritis and polyarthralgia, suggestive of rheumatoid arthritis (RA), along with shortness of breath, fever and cough, suggestive of chronic renal failure and nephrotic range proteinuria. The chest radiograph was suggestive of panacinar emphysematous changes with bilateral central bronchiectasis. The patient reported that two of his brothers had died in their third decade because of renal failure.

A Case of Good's Syndrome Presenting with Pulmonary Tuberculosis.

Adult onset immunodeficiency associated with thymoma is a rare condition. The combination of hypogammaglobulinemia, reduced number of peripheral B and CD4+ T cells, along with thymoma constitutes Good's syndrome (GS). This immunodeficiency condition is often complicated with opportunistic infection with organisms, like bacteria (Haemophilus influenzae, Streptococcus pneumonia etc), viruses (Cytomegalovirus, Herpes simplex etc), fungi and protozoa.

A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities.

Inhibition of the enzymatic activity of histone deacetylase (HDAC) is a promising therapeutic strategy for cancer treatment and several distinct small molecule histone deacetylase inhibitors (HDACi) have been reported. We have previously identified a new class of non-peptide macrocyclic HDACi derived from 14- and 15-membered macrolide skeletons. In these HDACi, the macrocyclic ring is linked to the zinc chelating hydroxamate moiety through a para-substituted aryl-triazole cap group.

Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease.

Alzheimer's disease, one of the most important brain pathologies associated with neurodegenerative processes, is related to overactivation of calpain-mediated proteolysis. Previous data showed a compelling efficacy of calpain inhibition against abnormal synaptic plasticity and memory produced by the excess of amyloid-β, a distinctive marker of the disease. Moreover, a beneficial effect of calpain inhibitors in Alzheimer's disease is predictable by the occurrence of calpain hyperactivation leading to impairment of memory-related pathways following abnormal calcium influxes that might ensue independently of amyloid-β elevation.

Exploiting translational stalling peptides in an effort to extend azithromycin interaction within the prokaryotic ribosome nascent peptide exit tunnel.

The ribosome is the primary protein synthesis machine in the cell and is a target for treatment of a variety of diseases including bacterial infection and cancer. The ribosomal peptide exit tunnel, the route of egress for the nascent peptide, is an inviting site for drug design. Toward a rational engagement of the nascent peptide components for the design of small molecule inhibitors of ribosome function, we designed and disclosed herein a set of N-10 indole functionalized azithromycin analogs.

Assessment of spontaneous pneumothorax in adults in a tertiary care hospital.

Context: Pneumothorax continues to be a major cause of morbidity and mortality among respiratory patients, but there is a paucity of data regarding etiology, clinical profile, management, and outcome of spontaneous pneumothorax (SP), from this part of the world.

Aims: To assess the patients of spontaneous pneumothorax in adults with special reference to the etiology, clinical presentation, management, and outcome of SP.

Settings And Design: Prospective, observational study conducted in a tertiary care institution over a period of one year.

The Effect of Acebrophylline vs Sustained Release Theophylline in Patients of COPD- A Comparative Study.

Introduction: Over the past several decades, the use of drug therapy in COPD has expanded, and provides an optimistic picture. Methyixanthines are used freely in COPD. Of them, Theophylline is an age old bronchodilator and anti-inflammatory agent while Acebrophylline is a newer one.

Assessment of RV Function in Patients of (COPD).

Introduction: Chronic Obstructive Pulmonary Disease (COPD) has considerable effects on cardiac functions primarily affecting the pulmonary vasculature and then right ventricle along with left ventricle. One of the important causes of increased morbidity and mortality associated with COPD is cor pulmonale. Echocardiography provides a rapid, non-invasive method to evaluate cardiac changes.

Design, synthesis, and optimization of novel epoxide incorporating peptidomimetics as selective calpain inhibitors.

Hyperactivation of the calcium-dependent cysteine protease calpain 1 (Cal1) is implicated as a primary or secondary pathological event in a wide range of illnesses and in neurodegenerative states, including Alzheimer's disease (AD). E-64 is an epoxide-containing natural product identified as a potent nonselective, calpain inhibitor, with demonstrated efficacy in animal models of AD. By use of E-64 as a lead, three successive generations of calpain inhibitors were developed using computationally assisted design to increase selectivity for Cal1.

Unilateral lung hypoplasia: a rare cause of unilateral opaque hemithorax in chest X-ray in a young boy.

Congenital abnormalities of lung are very rare entity, and very often under or misdiagnosed by physicians. The present case, a 12-year boy, who was initially diagnosed as unilateral massive pleural effusion with collapse of lung, and after thorough investigation, including CT scan of thorax, fiber-optic bronchoscopy, and echocardiography, a final diagnosis of unilateral lung hypoplasia was made. So if a teenager present with a unilateral opaque hemithorax in chest X-ray, this entity may be a differential diagnosis.