Fatty-Acid Binding Protein 4 (FABP4) as a Potential Preclinical Biomarker of Drug-Induced Kidney Injury.

Identification of improved translatable biomarkers of nephrotoxicity is an unmet safety biomarker need. Fatty-acid-binding protein 4 (FABP4) was previously found to be associated with clinical renal dysfunction and was proposed as a biomarker of glomerular damage. The aim of this study was to evaluate FABP4 as a potential preclinical biomarker of drug-induced kidney injury (DIKI).

Pramipexole induced place preference after L-dopa therapy and nigral dopaminergic loss: linking behavior to transcriptional modifications.

Rationale: Impulsive-compulsive disorders (ICD) in patients with Parkinson's disease (PD) have been described as behavioral or substance addictions including hypersexuality, gambling, or compulsive medication use of the dopamine replacement therapy (DRT).

Objectives: A remaining challenge is to understand the neuroadaptations leading to reward bias in PD patients under DRT.

Methods: To this end, the appetitive effect of the D2/D3 agonist pramipexole was assessed after chronic exposure to L-dopa in an alpha-synuclein PD rat model.

Paving the Route to Plasma miR-208a-3p as an Acute Cardiac Injury Biomarker: Preclinical Rat Data Supports Its Use in Drug Safety Assessment.

Drug-induced cardiac injury (DICI) detection remains a major safety issue in drug development. While circulating microRNAs (miRs) have emerged as promising translational biomarkers, novel early detection biomarkers of cardiotoxicity are needed. This work aims at evaluating whether a panel of putative cardiac injury plasma miRs could serve as early DICI biomarkers in a 4-day rat preclinical model.

Eosinophils affect functions of in vitro-activated human CD3-CD4+ T cells.

Background: The recent development of eosinophil-targeting agents has raised enthusiasm for management of patients with hypereosinophilic syndromes. Roughly half of anti-IL-5-treated patients with corticosteroid-responsive lymphocytic (L-HES) and idiopathic disease variants can be tapered off corticosteroids. Potential consequences of corticosteroid-withdrawal on clonal expansion of pre-malignant CD3⁻CD4⁺ T-cells associated with L-HES are a subject of concern.

Reviving function in CD4+ T cells adapted to persistent systemic antigen.

In bone marrow-transplanted patients, chronic graft-versus-host disease is a complication that results from the persistent stimulation of recipient minor histocompatibility Ag (mHA)-specific T cells contained within the graft. In this study, we developed a mouse model where persistent stimulation of donor T cells by recipient's mHA led to multiorgan T cell infiltration. Exposure to systemic mHA, however, deeply modified T cell function and chronically stimulated T cells developed a long-lasting state of unresponsiveness, or immune adaptation, characterized by their inability to mediate organ immune damages in vivo.

Unaltered imprinting establishment of key imprinted genes in mouse oocytes after in vitro follicle culture under variable follicle-stimulating hormone exposure.

Imprinted genes are differentially methylated during gametogenesis to allow parental-specific monoallelic expression of genes. During mouse oogenesis, DNA methylation at imprinted genes is established during the transition from primordial to antral follicle stages. Studies in human and mouse suggest aberrant imprinting in oocytes following in vitro maturation and after superovulation with high doses of gonadotrophines.

Cyclic adenosine 3',5'-monophosphate (cAMP)-dependent protein kinases, but not exchange proteins directly activated by cAMP (Epac), mediate thyrotropin/cAMP-dependent regulation of thyroid cells.

TSH, mainly acting through cAMP, is the principal physiological regulator of thyroid gland function, differentiation expression, and cell proliferation. Both cAMP-dependent protein kinases [protein kinase A (PKA)] and the guanine-nucleotide-exchange factors for Rap proteins, exchange proteins directly activated by cAMP (Epac) 1 and Epac2, are known to mediate a broad range of effects of cAMP in various cell systems. In the present study, we found a high expression of Epac1 in dog thyrocytes, which was further increased in response to TSH stimulation.

Differential involvement of the actin cytoskeleton in differentiation and mitogenesis of thyroid cells: inactivation of Rho proteins contributes to cyclic adenosine monophosphate-dependent gene expression but prevents mitogenesis.

In thyroid epithelial cells, TSH via cAMP induces a rounding up of the cells associated with actin stress fiber disruption, expression of differentiation genes and cell cycle progression. Here we have evaluated the role of small G proteins of the Rho family and their impact on the actin cytoskeleton in these different processes in primary cultures of canine thyrocytes. TSH and forskolin, but not growth factors, rapidly inactivated RhoA, Rac1, and Cdc42, as assayed by detection of GTP-bound forms.

cAMP analog mapping of Epac1 and cAMP kinase. Discriminating analogs demonstrate that Epac and cAMP kinase act synergistically to promote PC-12 cell neurite extension.

Little is known about the relative role of cAMP-dependent protein kinase (cAPK) and guanine exchange factor directly activated by cAMP (Epac) as mediators of cAMP action. We tested cAMP analogs for ability to selectively activate Epac1 or cAPK and discriminate between the binding sites of Epac and of cAPKI and cAPKII. We found that commonly used cAMP analogs, like 8-Br-cAMP and 8-pCPT-cAMP, activate Epac and cAPK equally as well as cAMP, i.