Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase

We herein disclose a series of compounds with potent inhibitory activities towards histone deacetylases (HDAC) and cyclooxygenases (COX). These compounds potently inhibited the growth of cancer cell lines consistent with their anti-COX and anti-HDAC activities. While compound 2b showed comparable level of COX-2 selectivity as celecoxib, compound 11b outperformed indomethacin in terms of selectivity towards COX-2 relative to COX-1. An important observation with our lead compounds (2b, 8, 11b, and 17b) is their enhanced cytotoxicity towards androgen dependent prostate cancer cell line (LNCaP) relative to androgen independent prostate cancer cell line (DU-145). Interestingly, compounds 2b and 17b arrested the cell cycle progression of LNCaP in the S-phase, while compound 8 showed a G0/G1 arrest, similar to SAHA. Relative to SAHA, these compounds displayed tumor-selective cytotoxicity as they have low anti-proliferative activity towards healthy cells (VERO); an attribute that makes them attractive candidates for drug development

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. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells

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. A combination of PIAA and cilostamide, an inhibitor of β-cell-enriched cAMP hydrolyzing enzyme phosphodiesterase (PDE) 3, enhanced β-cell proliferation, whereas overexpression of PDE3 blunted the mitogenic effect of PIAA in zebrafish. PIAA augmented proliferation of INS-1β-cells and β-cells in mammalian islets including human islets with elevation in cAMP levels and insulin secretion. PIAA improved glycemic control in streptozotocin (STZ)-induced diabetic mice with increases in β-cell proliferation, β-cell area, and insulin content in the pancreas. Collectively, these data reveal an evolutionarily conserved and critical role of TBK1/IKKε suppression in expanding functional β-cell mass

Interaction of anthracyclines with iron responsive element mRNAs

Double-stranded sections of mRNA are often inviting sites of interaction for a wide variety of proteins and small molecules. Interactions at these sites can serve to regulate, or disrupt, the homeostasis of the encoded protein products. Such ligand target sites exist as hairpin–loop structures in the mRNAs of several of the proteins involved in iron homeostasis, including ferritin heavy and light chains, and are known as iron responsive elements (IREs). These IREs serve as the main control mechanism for iron metabolism in the cell via their interaction with the iron regulatory proteins (IRPs). Disruption of the IRE/IRP interaction could greatly affect iron metabolism. Here, we report that anthracyclines, a class of clinically useful chemotherapeutic drugs that includes doxorubicin and daunorubicin, specifically interact with the IREs of ferritin heavy and light chains. We characterized this interaction through UV melting, fluorescence quenching and drug–RNA footprinting. Results from footprinting experiments with wild-type and mutant IREs indicate that anthracyclines preferentially bind within the UG wobble pairs flanking an asymmetrically bulged C-residue, a conserved base that is essential for IRE–IRP interaction. Additionally, drug–RNA affinities (apparent Kds) in the high nanomolar range were calculated from fluorescence quenching experiments, while UV melting studies revealed shifts in melting temperature (ΔTm) as large as 10°C. This anthracycline–IRE interaction may contribute to the aberration of intracellular iron homeostasis that results from anthracycline exposure

REVIEW Gold nanoparticles: From nanomedicine to nanosensing

Abstract: Because of their photo-optical distinctiveness and biocompatibility, gold nanoparticles (AuNPs) have proven to be powerful tools in various nanomedicinal and nanomedical applications. In this review article, we discuss recent advances in the application of AuNPs in diagnostic imaging, biosensing and binary cancer therapeutic techniques. We also provide an eclectic collection of AuNPs delivery strategies, including assorted classes of delivery vehicles, which are showing great promise in specific targeting of AuNPs to diseased tissues. However, successful clinical implementations of the promised applications of AuNPs are still hampered by many barriers. In particular, more still needs to be done regarding our understanding of the pharmacokinetics and toxicological profiles of AuNPs and AuNPs-conjugates

Determination of metal ion contents of two antiemetic clays use in Geophagy

Nausea is usually associated with early to late stages of pregnancy. Geophagy-deliberate consumption of soil is a common method of managing gravidae-induced discomfort. To control nausea, pregnant women in Nigeria commonly eat baked clay called “Eko” and another type of clay that induces buccal constriction called “Omumu”. The metal contents in Eko and Omumu, digested under different pH conditions (acidic, alkaline and neutral), were investigated using Inductively Coupled Plasma Optical Emission Spectroscopy (ICPS-OES). We identified and quantitate the elements present and speculate on their potential impact on maternal and fetal health upon gestational exposure beyond the acceptable exposure levels and the Millennium Contaminant Level Goals (MCLG) set by the United States Environmental Protection Agency (USEPA). Specifically, our result indicates unacceptably high levels of aluminum in Eko and Omumu (>10-fold greater than the highest desirable levels set by the USEPA). The aluminum concentrations were influenced by the pH condition in which the samples were digested. Dietary exposure to aluminum at such high levels may be deleterious to maternal health and fetal development. Therefore consumption of Eko and Omumu as an antidote to reduce nausea during pregnancy should be discouraged. Future studies are planned to investigate specific impacts on fetal and maternal health and likely teratogenicity in rodent models

Inflammation, Fibrosis and Cancer: Mechanisms, Therapeutic Options and Challenges

Uncontrolled inflammation is a salient factor in multiple chronic inflammatory diseases and cancers. In this review, we provided an in-depth analysis of the relationships and distinctions between uncontrolled inflammation, fibrosis and cancers, while emphasizing the challenges and opportunities of developing novel therapies for the treatment and/or management of these diseases. We described how drug delivery systems, combination therapy and the integration of tissue-targeted and/or pathways selective strategies could overcome the challenges of current agents for managing and/or treating chronic inflammatory diseases and cancers. We also recognized the value of the re-evaluation of the disease-specific roles of multiple pathways implicated in the pathophysiology of chronic inflammatory diseases and cancers—as well as the application of data from single-cell RNA sequencing in the success of future drug discovery endeavors