Deferoxamine preconditioning of canine stem cell derived extracellular vesicles alleviates inflammation in an EAE mouse model through STAT3 regulation.

Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs), specifically those preconditioned with deferoxamine (DFO) in canine adipose tissue-derived MSCs (cAT-MSCs), were explored for treating autoimmune diseases. This study assessed the effects of DFO-preconditioned EVs (EV) in an experimental autoimmune encephalomyelitis (EAE) mouse model. cAT-MSCs were treated with DFO for 48 h, after which EVs were isolated.

Carfilzomib-Loaded Ternary Polypeptide Nanoparticles Stabilized by Polycationic Complexation.

Carfilzomib (CFZ) is a second-generation proteasome inhibitor showing great efficacy in multiple myeloma treatment, yet its clinical applications for other diseases such as solid cancers are limited due to low aqueous solubility and poor biostability. Ternary polypeptide nanoparticles (tPNPs) are drug carriers that we previously reported to overcome these pharmaceutical limitations by entrapping CFZ in the core of the nanoparticles and protecting the drugs from degradation in biological media. However, preclinical studies revealed that tPNPs would require further improvement in particle stability to suppress initial burst drug release and thus achieve prolonged inhibition of proteasome activity with CFZ against tumor cells in vivo.

Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism.

It is particularly challenging to develop a truly effective pharmacotherapy for cocaine use disorder (CUD) treatment. Accelerating cocaine metabolism hydrolysis at cocaine benzoyl ester using an efficient cocaine hydrolase (CocH) is known as a promising pharmacotherapeutic approach to CUD treatment. Preclinical and clinical studies on our first CocH (CocH1), in its human serum albumin-fused form known as TV-1380, have demonstrated the promise of a general concept of CocH-based pharmacotherapy for CUD treatment.

Gene expression of adipokines and inflammatory cytokines in peripheral blood mononuclear cells of obese dogs.

Background: Peripheral blood mononuclear cells (PBMCs) have been identified as a possible marker of inflammation in obesity. Understanding the expression of pro- and anti-inflammatory cytokines in PBMCs in obese dogs will help control obesity-related inflammatory diseases.

Objectives: The aim of this study was to evaluate the role of PBMCs in obesity-associated chronic inflammation by analyzing the expression of adipokines and inflammatory cytokines.

Effects of Organic Acids on Drug Release From Ternary Polypeptide Nanoparticles Entrapping Carfilzomib.

Carfilzomib (CFZ) is an FDA-approved proteasome inhibitor with antineoplastic properties against various cancers, yet its short blood retention time after intravenous injection (< 30 min) makes clinical applications limited to multiple myeloma. We previously developed ternary polypeptide nanoparticles (tPNPs) as a new nanoparticle formulation of CFZ to overcome these limitations. The formulation was prepared by polyion complexation between poly(ethylene glycol)-poly(L-glutamate) block copolymers (PEG-PLE) and CFZ-cyclodextrin (CD) inclusion complexes, where CDs were positively charged with 7 primary amines attached while PEG-PLE carried 100 carboxyl groups per polymer chain.

Autoimmune polyendocrine syndrome with hypoadrenocorticism and diabetes mellitus in a dog: A rare case.

Background: Autoimmune polyendocrine syndrome, also called polyglandular autoimmune syndrome, is a rare immune-mediated disorder that involves various endocrine glands.

Purpose: To report autoimmune polyendocrine syndrome in a dog.

Methods: A 9-year-old spayed female miniature poodle diagnosed with insulin-dependent diabetes mellitus emergently visited our clinic for anorexia, severe depression, and vomiting.

Coleopteran-specific StaufenC functions like Loquacious-PD in dsRNA processing.

In , PD isoform of the double-stranded RNA binding protein (dsRBP) Loquacious (Loqs-PD) facilitates dsRNA cleavage to siRNA by Dicer-2. StaufenC (StauC) was discovered as a coleopteran-specific dsRBP required for dsRNA processing in coleopteran insects. Here, we show that StauC is essential for the high RNAi efficiency observed in coleopterans.

Cocaine hydrolase blocks cocaine-induced dopamine transporter trafficking to the plasma membrane.

Cocaine blocks dopamine uptake via dopamine transporter (DAT) on plasma membrane of neuron cells and, as a result, produces the high and induces DAT trafficking to plasma membrane which contributes to the drug seeking or craving. In this study, we first examined the dose dependence of cocaine-induced DAT trafficking and hyperactivity in rats, demonstrating that cocaine at an intraperitoneal dose of 10 mg/kg or higher led to redistribution of most DAT to the plasma membrane while inducing significant hyperactivity in rats. However, administration of 5-mg/kg cocaine (ip) did not significantly induce DAT trafficking or hyperactivity in rats.

Extracellular vesicles derived from DFO-preconditioned canine AT-MSCs reprogram macrophages into M2 phase.

Background: Mesenchymal stem/stromal cells (MSCs) are effective therapeutic agents that ameliorate inflammation through paracrine effect; in this regard, extracellular vesicles (EVs) have been frequently studied. To improve the secretion of anti-inflammatory factors from MSCs, preconditioning with hypoxia or hypoxia-mimetic agents has been attempted and the molecular changes in preconditioned MSC-derived EVs explored. In this study, we aimed to investigate the increase of hypoxia-inducible factor 1-alpha (HIF-1α)/cyclooxygenase-2 (COX-2) in deferoxamine (DFO)-preconditioned canine MSC (MSCDFO) and whether these molecular changes were reflected on EVs.

Identification of juvenile hormone-induced posttranslational modifications of methoprene tolerant and Krüppel homolog 1 in the yellow fever mosquito, Aedes aegypti.

Recent studies reported that JH-regulated phosphorylation status of the JH-receptor complex contributes to its transcription activity in Aedes aegypti. However, phosphorylation sites of these proteins have not yet been identified. In this study, we found that the fusion of an EGFP tag to Ae.

Ternary Polypeptide Nanoparticles with Improved Encapsulation, Sustained Release, and Enhanced In Vitro Efficacy of Carfilzomib.

Purpose: To develop a new nanoparticle formulation for a proteasome inhibitor Carfilzomib (CFZ) to improve its stability and efficacy for future in vivo applications.

Methods: CFZ-loaded ternary polypeptide nanoparticles (CFZ/tPNPs) were prepared by using heptakis(6-amino-6-deoxy)-β-cyclodextrin(hepta-hydrochloride) (HaβCD) and azido-poly(ethylene glycol)-block-poly(L-glutamic acid sodium salt) (N-PEG-PLE). The process involved ternary (hydrophobic/ionic/supramolecular) interactions in three steps: 1) CFZ was entrapped in the cavity of HaβCD by hydrophobic interaction, 2) the drug-cyclodextrin inclusion complexes were mixed with N-PEG-PLE to form polyion complex nanoparticles, and 3) the nanoparticles were modified with fluorescent dyes (AFDye 647) for imaging and/or epithelial cell adhesion molecule (EpCAM) antibodies for cancer cell targeting.

Structure-Based Design and Discovery of a Long-Acting Cocaine Hydrolase Mutant with Improved Binding Affinity to Neonatal Fc Receptor for Treatment of Cocaine Abuse.

Despite decades of efforts to develop a pharmacotherapy for cocaine abuse treatment, there is still no FDA-approved treatment of diseases associated with this commonly abused drug. Our previously designed highly efficient cocaine hydrolases (CocHs) and the corresponding Fc-fusion proteins (e.g.

Development of a novel prostate apoptosis response-4 (Par-4) protein entity with an extended duration of action for therapeutic treatment of cancer.

Prostate apoptosis response-4 (Par-4) is a tumor suppressor which protects against neoplastic transformation. Remarkably, Par-4 is capable of inducing apoptosis selectively in cancer cells without affecting the normal cells. In this study, we found that recombinant Par-4 protein had limited serum persistence in mice that may diminish its anti-tumor activity in vivo.

PEGylation but Not Fc-Fusion Improves in Vivo Residence Time of a Thermostable Mutant of Bacterial Cocaine Esterase.

It is very popular to fuse a protein drug or drug candidate to the Fc domain of immunoglobulin G (IgG) in order to prolong the in vivo half-life. In this study, we have designed, prepared, and tested an Fc-fused thermostable cocaine esterase (CocE) mutant (known as E196-301, with the T172R/G173Q/L196C/I301C substitutions on CocE) expressed in . As expected, Fc-fusion does not affect the in vitro enzyme activity and thermal stability of the enzyme and that Fc-E196-301 can favorably bind FcRn with = 386 ± 35 nM.

Prevalence, Predictors, and Psychosocial Mechanism of Cancer Information Avoidance: Findings from a National Survey of U.S. Adults.

The current study examined the prevalence, predictors, and psychosocial mechanism of cancer information avoidance (CIA). With a nationally representative sample, we sought to confirm the prevalence of CIA among Americans. Studies, based on crisis decision theory, have shown that a lack of personal or interpersonal resources to manage threat-related information leads to information avoidance.

Blocking drug activation as a therapeutic strategy to attenuate acute toxicity and physiological effects of heroin.

Heroin is a growing national crisis in America. There is an increasing frequency of heroin overdoses. All of the currently used therapeutic approaches to treatment of heroin abuse and other opioid drugs of abuse focus on antagonizing a brain receptor (particularly µ-opiate receptors).

Oligomerization and Catalytic Parameters of Human UDP-Glucuronosyltransferase 1A10: Expression and Characterization of the Recombinant Protein.

UDP-glucuronosyltransferase (UGT), as an integral membrane protein localized in the endoplasmic reticulum, has the ability to detoxify potentially hazardous xenobiotic substances. Most UGTs are expressed in liver, but UGT1A10 has proven to be an extrahepatic enzyme considerably expressed throughout the gastrointestinal tract. Earlier studies indicated that different UGT isoforms could exist in higher-order homo-oligomers or at least dimers within the membrane, but the formation of intermolecular disulfide bridges between UGT molecules was not often observed.

Kinetic characterization of cholinesterases and a therapeutically valuable cocaine hydrolase for their catalytic activities against heroin and its metabolite 6-monoacetylmorphine.

As the most popularly abused one of opioids, heroin is actually a prodrug. In the body, heroin is hydrolyzed/activated to 6-monoacetylmorphine (6-MAM) first and then to morphine to produce its toxic and physiological effects. It has been known that heroin hydrolysis to 6-MAM and morphine is accelerated by cholinesterases, including acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE).

Development of Fc-Fused Cocaine Hydrolase for Cocaine Addiction Treatment: Catalytic and Pharmacokinetic Properties.

Cocaine abuse is a worldwide public health and social problem without a US Food and Drug Administration (FDA)-approved medication. Accelerating cocaine metabolism that produces biologically inactive metabolites by administration of an efficient cocaine hydrolase (CocH) has been recognized as a promising strategy for cocaine abuse treatment. However, the therapeutic effects of CocH are limited by its short biological half-life (e.

Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1.

Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of induced PGE without blocking the normal biosynthesis of other prostanoids including homeostatic PGE. Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). Identified from structure-based virtue screening, the compound with (Z)-5-benzylidene-2-iminothiazolidin-4-one scaffold was used as lead in rational design of novel inhibitors.

Elucidating the catalytic subunit composition of distinct proteasome subtypes: a crosslinking approach employing bifunctional activity-based probes.

In addition to two well-recognized proteasome subtypes-constitutive proteasomes and immunoproteasomes-mounting evidence also suggests the existence of intermediate proteasome subtypes containing unconventional mixtures of catalytic subunits. Although they appear to play unique biological roles, the lack of practical methods for detecting distinct proteasome subtypes has limited functional investigations. Here, we report the development of activity-based probes that crosslink two catalytic subunits within intact proteasome complexes.

Structure-based design of β1i or β5i specific inhibitors of human immunoproteasomes.

Mammalian genomes encode seven catalytic proteasome subunits, namely, β1c, β2c, β5c (assembled into constitutive 20S proteasome core particles), β1i, β2i, β5i (incorporated into immunoproteasomes), and the thymoproteasome-specific subunit β5t. Extensive research in the past decades has yielded numerous potent proteasome inhibitors including compounds currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. Proteasome inhibitors that selectively target combinations of β1c/β1i, β2c/β2i, or β5c/β5i are available, yet ligands truly selective for a single proteasome activity are scarce.

Selective immunoproteasome inhibitors with non-peptide scaffolds identified from structure-based virtual screening.

As a major component of the crucial nonlysosomal protein degradation pathway in the cells, the proteasome has been implicated in many diseases such as Alzheimer's disease, Huntington's disease, inflammatory bowel diseases, autoimmune diseases, multiple myeloma (MM) and other cancers. There are two main proteasome subtypes: the constitutive proteasome which is expressed in all eukaryotic cells and the immunoproteasome which is expressed in immune cells and can be induced in other cell types. Majority of currently available proteasome inhibitors are peptide backbone-based, having short half-lives in the body.

Understanding the effects of MTV's 16 and Pregnant on adolescent girls' beliefs, attitudes, and behavioral intentions toward teen pregnancy.

This article examines the impact of a popular documentary series about teen pregnancy, MTV's 16 and Pregnant, on adolescent girls' pregnancy-related attitudes, beliefs, and behavioral intentions. The results suggest that girls who watched 16 and Pregnant, compared with a control group, reported a lower perception of their own risk for pregnancy and a greater perception that the benefits of teen pregnancy outweigh the risks. The authors also examined the relationships between homophily and parasocial interaction with the teen moms featured in 16 and Pregnant and attitudes, beliefs, and behavioral intentions, finding that homophily predicted lower risk perceptions, greater acceptance of myths about teen pregnancy, and more favorable attitudes about teen pregnancy.