Positive Allosteric Modulation of AR Alters Immune Cell Responses and Ameliorates Psoriasis-Like Dermatitis in Mice.

Psoriasis is an immune cell‒mediated inflammatory disease of the skin with a mixed T helper type 1/T helper type17 cytokine environment combined with an innate immune response engaging toll-like receptors. Inflammatory diseases are characterized by dysregulated immune cell responses and elevated levels of adenosine at disease sites. Adenosine, acting through the AR, regulates inflammation, immune response, T-cell homeostasis, and tissue repair.

Positive effects of ferric iron on the systemic efficacy of nephrilin peptide in burn trauma.

Introduction: Nephrilin peptide is a designed inhibitor of Rictor complex (also known as mTORC2), an evolutionarily conserved assembly believed to modulate responses to cellular stress. We previously demonstrated the ability of nephrilin peptide to suppress neuroinflammation, loss of body mass, glycaemic control and kidney function in a rat scald model, as well as sepsis mortality in a mouse model. The present study explores the effect of nephrilin plus iron formulations on clinically relevant outcomes in the rat scald model.

Covalent modification of nephrilin peptide with valproic acid increases its efficacy as a therapeutic in burn trauma.

Introduction: Nephrilin peptide, a designed inhibitor of Rictor complex, modulates systemic responses to trauma, alleviating clinically relevant variables in a rat scald model and sepsis mortality in a mouse model. This study explores the possibility that chemical conjugation of small molecules to the aminoterminus of nephrilin can modify its biological activity in the rat scald model.

Methods: One of four molecules (valproic acid, decanoic acid, fenofibric acid and ibuprofen) was chemically attached to the amino terminus of nephrilin during synthesis.

Differential Effects of Lipid-lowering Drugs in Modulating Morphology of Cholesterol Particles.

Treatment of dyslipidemia patients with lipid-lowering drugs leads to a significant reduction in low-density lipoproteins (LDL) level and a low to moderate level of increase in high-density lipoprotein (HDL) cholesterol in plasma. However, a possible role of these drugs in altering morphology and distribution of cholesterol particles is poorly understood. Here, we describe the in vitro evaluation of lipid-lowering drug effects in modulating morphological features of cholesterol particles using the plaque array method in combination with imaging flow cytometry.

Enhancement of inosine-mediated AR signaling through positive allosteric modulation.

Inosine is an endogenous nucleoside that is produced by metabolic deamination of adenosine. Inosine is metabolically more stable (half-life 15h) than adenosine (half-life <10s). Inosine exerts anti-inflammatory and immunomodulatory effects similar to those observed with adenosine.

Nonenzymatic Mechanism of Statins in Modulating Cholesterol Particles Formation.

Statin drugs are leading medication prescribed for treatment of dyslipidemic patients aimed at preventing both primary and secondary incidences of atherosclerosis-related cardiovascular events. Statin drugs competitively inhibit HMG-CoA reductase enzyme activity, thereby inhibiting cell-mediated cholesterol synthesis and reducing the low-density lipoprotein (LDL) cholesterol concentration of plasma. Conversely, the mechanism by which statins increase high-density lipoprotein (HDL) cholesterol concentration of plasma is not well understood.

The adenosine metabolite inosine is a functional agonist of the adenosine A2A receptor with a unique signaling bias.

Inosine is an endogenous purine nucleoside that is produced by catabolism of adenosine. Adenosine has a short half-life (approximately 10s) and is rapidly deaminated to inosine, a stable metabolite with a half-life of approximately 15h. Resembling adenosine, inosine acting through adenosine receptors (ARs) exerts a wide range of anti-inflammatory and immunomodulatory effects in vivo.

Plaque array method and proteomics-based identification of biomarkers from Alzheimer's disease serum.

Background: Progressive accumulation of amyloid plaques in the regions of brain, carotid and cerebral arteries is the leading cause of Alzheimer's disease (AD) and related dementia in affected patients. The early identification of individuals with AD remains a challenging task relying on symptomatic events and thus the development of a biomarker-based approach will significantly aid in the diagnosis of AD.

Methods: Here we describe a flow cytometer-based serum biomarker identification method using plaque particles, and applying mass spectrometry based proteomic analysis of the isolated plaque particles for the identification of serum proteins present in the plaque particles.

Positive allosteric modulation of the adenosine A2a receptor attenuates inflammation.

Background: Adenosine is produced at high levels at inflamed sites as a by-product of cellular activation and breakdown. Adenosine mediates its anti-inflammatory activity primarily through the adenosine A2a receptor (A2aR), a member of the G-protein coupled receptors. A2aR agonists have demonstrated anti-inflammatory efficacy, however, their therapeutic utility is hindered by a lack of adenosine receptor subtype selectivity upon systemic exposure.

The relaxin gene knockout mouse: a model of progressive scleroderma.

Relaxin is a peptide hormone with anti-fibrotic properties. To investigate the long-term effects of relaxin deficiency on the ageing skin, we compared structural changes in the skin of ageing relaxin-deficient (RLX-/-) and normal (RLX+/+) mice, by biochemical, histological, and magnetic resonance imaging analyses. Skin biopsies from RLX+/+ and RLX-/- mice were obtained at different ages and analyzed for changes in collagen expression and distribution.

The relaxin gene-knockout mouse: a model of progressive fibrosis.

Relaxin is well known for its actions on collagen remodeling. To improve our understanding of the physiologic role(s) of relaxin, the relaxin gene-knockout (RLX-KO) mouse was established by our group and subsequently phenotyped. Pregnant RLX-KO mice underwent inadequate development of the pubic symphysis as well as the mammary glands and nipples compared to wild-type mice, thus preventing lactation.

Relaxin-1-deficient mice develop an age-related progression of renal fibrosis.

Background: Relaxin (RLX) is a peptide hormone that stimulates the breakdown of collagen in preparation for parturition and when administered to various models of induced fibrosis. However, its significance in the aging kidney is yet to be established. In this study, we compared structural and functional changes in the kidney of aging relaxin-1 (RLX-/-) deficient mice and normal (RLX+/+) mice.

Relaxin is a key mediator of prostate growth and male reproductive tract development.

Male mice deficient in relaxin showed retarded growth and marked deficiencies in the reproductive tract within 1 month of age. At 3 months of age, male reproductive organ weight (including the testis, epididymis, prostate, and seminal vesicle) from relaxin null (RLX-/-) mice were significantly (p < 0.05) smaller than those of wild-type (RLX+/+) male mice.

Relaxin regulates fibrillin 2, but not fibrillin 1, mRNA and protein expression by human dermal fibroblasts and murine fetal skin.

Relaxin modulates connective tissue remodeling by altering matrix molecule expression. We have found that relaxin specifically inhibits a microfibril component, fibrillin 2 (FBN2), without affecting fibrillin 1 (FBN1). Human dermal fibroblasts (HDFs) grown or stimulated to overexpress fibrillin expression were used to show that relaxin specifically down-regulated FBN2 mRNA and protein levels.

Relaxin deficiency in mice is associated with an age-related progression of pulmonary fibrosis.

Relaxin (RLX) is a peptide hormone with known antifibrotic properties. However, its significance in the lung and its role as a therapeutic agent against diseases characterized by pulmonary fibrosis are yet to be established. In this study, we examined age-related structural and functional changes in the lung of relaxin-deficient mice.