Guiding Documents for Engaging with Remote Chronic Disease Management Programs as a Healthcare Provider: A Scoping Review.

Introduction: Chronic disease management programs (CDMP) that include education and exercise enhance outcomes and reduce healthcare costs. Remote CDMP have the potential to provide convenient, cost-effective, and accessible options for individuals, but it is unclear how to best implement programs that include education and exercise. This review identified and synthesized resources for implementing remote CDMP programs that incorporate education and exercise.

The cAMP-signaling cancers: Clinically-divergent disorders with a common central pathway.

The cAMP-signaling cancers, which are defined by functionally-significant somatic mutations in one or more elements of the cAMP signaling pathway, have an unexpectedly wide range of cell origins, clinical manifestations, and potential therapeutic options. Mutations in at least 9 cAMP signaling pathway genes (, and ) have been identified as driver mutations in human cancer. Although all cAMP-signaling pathway cancers are driven by mutation(s) that impinge on a single signaling pathway, the ultimate tumor phenotype reflects interactions between five critical variables: (1) the precise gene(s) that undergo mutation in each specific tumor type; (2) the effects of specific allele(s) in any given gene; (3) mutations in modifier genes (mutational "context"); (4) the tissue-specific expression of various cAMP signaling pathway elements in the tumor stem cell; and (5) and the precise biochemical regulation of the pathway components in tumor cells.

Relationship between the in vitro efficacy, pharmacokinetics and in vivo efficacy of curcumin.

Considerable interest continues to be focused on the development of curcumin either as an effective stand-alone therapeutic or as an adjunct therapy to established therapies. Curcumin (1, 7-bis (4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3, 5- dione; also called diferuloylmethane) is a polyphenolic phytochemical extracted from the root of curcuma longa, commonly called turmeric. Despite evidence from in vitro (cell culture) and preclinical studies in animals, clinical studies have not provided strong evidence for a therapeutic effect of curcumin.

Ketotifen is a Prodrug. Norketotifen is the active metabolite.

Evaluation of the in vitro human liver microsome and hepatocyte metabolism of ketotifen demonstrated that norketotifen (NK) is the major demethylated hepatic metabolite of ketotifen. It is here reported that NK is completely devoid of the severe and dose-limiting sedative effects of ketotifen. Thus, while ketotifen is clinically dose-limited to 1 mg, bid, there are no dose-limiting sedative effects elicited by NK, even after the highest single-dose (16 mg) or after repeat-doses (8 mg × 7 days) in humans or after the highest doses given to dogs in repeat-dose toxicological studies (40 mg/kg × 14 days).

The PDE-Opathies: Diverse Phenotypes Produced by a Functionally Related Multigene Family.

The phosphodiesterase (PDE)-opathies, an expanding set of disorders caused by germline mutations in cyclic nucleotide PDEs, present an intriguing paradox. The enzymes encoded by the PDE family all hydrolyze cAMP and/or cGMP, but mutations in different family members produce very divergent phenotypes. Three interacting factors have been shown recently to contribute to this phenotypic diversity: (i) the 21 genes encode over 80 different isoforms, using alternative mRNA splicing and related mechanisms; (ii) the various isoforms have different regulatory mechanisms, mediated by their unique amino-terminal regulatory domains; (iii) the isoforms differ widely in their pattern of tissue expression.

Dominant-Negative Attenuation of cAMP-Selective Phosphodiesterase PDE4D Action Affects Learning and Behavior.

PDE4 cyclic nucleotide phosphodiesterases reduce 3', 5' cAMP levels in the CNS and thereby regulate PKA activity and the phosphorylation of CREB, fundamental to depression, cognition, and learning and memory. The PDE4 isoform PDE4D5 interacts with the signaling proteins β-arrestin2 and RACK1, regulators of β-adrenergic and other signal transduction pathways. Mutations in in humans predispose to acrodysostosis, associated with cognitive and behavioral deficits.

Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases.

Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased with unchanged ), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms.

Towards an exposure narrative for metals and arsenic in historically contaminated Ni refinery soils: Relationships between speciation, bioavailability, and bioaccessibility.

Archived soils contaminated with Ni, Cu, Co, and As from legacy operations of a nickel refinery at Port Colborne, Ontario, Canada were speciated using mineral liberation analysis. Four Ni minerals were identified as fingerprint compounds of the historical refinery emissions. Cu and Co were present in solid solution in these minerals due to their presence in the refinery's feed.

Phosphodiesterases and cAMP Pathway in Pituitary Diseases.

Human phosphodiesterases (PDEs) comprise a complex superfamily of enzymes derived from 24 genes separated into 11 PDE gene families (PDEs 1-11), expressed in different tissues and cells, including heart and brain. The isoforms PDE4, PDE7, and PDE8 are specific for the second messenger cAMP, which is responsible for mediating diverse physiological actions involving different hormones and neurotransmitters. The cAMP pathway plays an important role in the development and function of endocrine tissues while phosphodiesterases are responsible for ensuring the appropriate intensity of the actions of this pathway by hydrolyzing cAMP to its inactive form 5'-AMP.

Intense Uptake of Liposomal Curcumin by Multiple Myeloma Cell Lines: Comparison to Normal Lymphocytes, Red Blood Cells and Chronic Lymphocytic Leukemia Cells.

Background/aim: Curcumin is being widely investigated for its anticancer properties and several studies in the literature suggest that curcumin is distributed to a higher degree in cancer cells compared to normal cells. The goal of this study was to investigate the disposition of curcumin in the form of Lipocurc™ in multiple myeloma (MM)-causing plasma cell lines and B-lymphocytes from healthy individuals and compare the uptake to previously published data for red blood cells (RBCs), peripheral blood mononuclear cells (PBMCs) from healthy individuals and PBMCs from patients with chronic lymphocytic leukemia (CLL-cells).

Materials And Methods: Two MM-producing cell lines were studied: RPMI-8266, an IgG lambda cell line, and NCL-H929, an IgA kappa line.

Reduced protein expression of the phosphodiesterases PDE4A4 and PDE4A8 in AIP mutation positive somatotroph adenomas.

Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs).

Altered phosphorylation, electrophysiology, and behavior on attenuation of PDE4B action in hippocampus.

Background: PDE4 cyclic nucleotide phosphodiesterases regulate 3', 5' cAMP abundance in the CNS and thereby regulate PKA activity and phosphorylation of CREB, which has been implicated in learning and memory, depression and other functions. The PDE4 isoform PDE4B1 also interacts with the DISC1 protein, implicated in neural development and behavioral disorders. The cellular functions of PDE4B1 have been investigated extensively, but its function(s) in the intact organism remained unexplored.

Improving the selectivity and sensitivity for quantifying 8-α-hydroxy-mutilin in rabbit tissues by using basic mobile phases and negative ionization.

Previously reported LC-MS methods for quantifying 8-α-hydroxy-mutilin (a marker residue of tiamulin) in tissues all used a pseudo MRM transition (from protonated molecular ion to protonated molecular ion, m/z 337→337) due to difficulties in finding a product ion, leading to suboptimal selectivity and sensitivity for detection. By using electrospray negative ionization in a basic medium, we, for the first time, found a highly selective and sensitive true MRM transition for 8-α-hydroxy-mutilin, m/z 335→179. With this newly found MRM transition and the use of pleuromutilin as the internal standard, a very sensitive, selective, and robust LC-MS/MS method has been developed and validated for quantifying 8-α-hydroxy-mutilin in rabbit tissues (muscle, liver, kidney, and fat).

The PDE4 cAMP-Specific Phosphodiesterases: Targets for Drugs with Antidepressant and Memory-Enhancing Action.

The PDE4 cyclic nucleotide phosphodiesterases are essential regulators of cAMP abundance in the CNS through their ability to regulate PKA activity, the phosphorylation of CREB, and other important elements of signal transduction. In pre-clinical models and in early-stage clinical trials, PDE4 inhibitors have been shown to have antidepressant and memory-enhancing activity. However, the development of clinically-useful PDE4 inhibitors for CNS disorders has been limited by variable efficacy and significant side effects.

Distribution and Metabolism of Lipocurc™ (Liposomal Curcumin) in Dog and Human Blood Cells: Species Selectivity and Pharmacokinetic Relevance.

Background/aim: The aim of this study was to investigate the distribution of curcumin (in the form of Lipocurc™) and its major metabolite tetrahydrocurcumin (THC) in Beagle dog and human red blood cells, peripheral blood mononuclear cells (PBMC) and hepatocytes.

Materials And Methods: Lipocurc™ was used as the source of curcumin for the cell distribution assays. In vitro findings with red blood cells were also compared to in vivo pharmacokinetic data available from preclinical studies in dogs and phase I clinical studies in humans.

The RNA-binding protein SERBP1 interacts selectively with the signaling protein RACK1.

The RACK1 protein interacts with numerous proteins involved in signal transduction, the cytoskeleton, and mRNA splicing and translation. We used the 2-hybrid system to identify additional proteins interacting with RACK1 and isolated the RNA-binding protein SERBP1. SERPB1 shares amino acid sequence homology with HABP4 (also known as Ki-1/57), a component of the RNA spicing machinery that has been shown previously to interact with RACK1.

Safety and Biosimilarity of iorLeukoCIM Compared to Neupogen Based on Toxicity, Pharmacodynamic, and Pharmacokinetic Studies in the Sprague-Dawley Rat.

This study examined the safety, pharmacodynamic and pharmacokinetic similarity of the human recombinant filgrastim products iorLeukoCIM and Neupogen following a 28-day repeated subcutaneous dose administration in male and female Sprague-Dawley rats with a 14-day recovery period. Safety profiling was based on clinical observations, clinical pathology, and pathology findings for control rats dosed with vehicle and rats dosed either with 15, 75, and 150 μg/kg of iorLeukoCIM or with 150 μg/kg of Neupogen. The major adverse treatment-related clinical finding was mild to severe swelling of the hock-joint (tarsal joint) and hind limb, alone or accompanied with lameness which was more prominent in males and which had a similar frequency of occurrence for both iorLeukoCIM and Neupogen.

Use of basic mobile phase to improve chromatography and boost sensitivity for quantifying tetrahydrocurcumin in human plasma by LC-MS/MS.

Tetrahydrocurcumin (THC), a major metabolite of curcumin, is often quantified by LC-MS or LC-MS/MS using acidic mobile phases due to the concern of its instability in a basic medium. However, acidic mobile phases often lead to poor chromatography (e.g.

cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors.

PDE4 cyclic nucleotide phosphodiesterases regulate cAMP abundance in cells and therefore regulate numerous processes, including cell growth and differentiation. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein (also called XAP2 or ARA-9). Germline mutations in AIP occur in approximately 20% of patients with Familial Isolated Pituitary Adenoma (FIPA) and 20% of childhood-onset simplex somatotroph adenomas.

RACK1 and β-arrestin2 attenuate dimerization of PDE4 cAMP phosphodiesterase PDE4D5.

PDE4 family cAMP-selective cyclic nucleotide phosphodiesterases are important in the regulation of cAMP abundance in numerous systems, and thereby play an important role in the regulation of PKA and EPAC activity and the phosphorylation of CREB. We have used the yeast 2-hybrid system to demonstrate recently that long PDE4 isoforms form homodimers, consistent with data obtained recently by structural studies. The long PDE4 isoform PDE4D5 interacts selectively with β-arrestin2, implicated in the regulation of G-protein-coupled receptors and other cell signaling components, and also with the β-propeller protein RACK1.