Heterogeneity in oligodendrocyte precursor cell proliferation is dynamic and driven by passive bioelectrical properties.

Oligodendrocyte precursor cells (OPCs) generate myelinating oligodendrocytes and are the main proliferative cells in the adult central nervous system. OPCs are a heterogeneous population, with proliferation and differentiation capacity varying with brain region and age. We demonstrate that during early postnatal maturation, cortical, but not callosal, OPCs begin to show altered passive bioelectrical properties, particularly increased inward potassium (K) conductance, which correlates with G1 cell cycle stage and affects their proliferation potential.

Pharmacological Gq inhibition induces strong pulmonary vasorelaxation and reverses pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease with limited survival. Herein, we propose the pharmacological inhibition of Gq proteins as a novel concept to counteract pulmonary vasoconstriction and proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in PAH. We demonstrate that the specific pan-Gq inhibitor FR900359 (FR) induced a strong vasorelaxation in large and small pulmonary arteries in mouse, pig, and human subjects ex vivo.

Site-specific genetic and functional signatures of aortic endothelial cells at aneurysm predilection sites in healthy and AngII ApoE mice.

Aortic aneurysm is characterized by a pathological dilation at specific predilection sites of the vessel and potentially results in life-threatening vascular rupture. Herein, we established a modified "Häutchen method" for the local isolation of endothelial cells (ECs) from mouse aorta to analyze their spatial heterogeneity and potential role in site-specific disease development. When we compared ECs from aneurysm predilection sites of healthy mice with adjacent control segments we found regulation of genes related to extracellular matrix remodeling, angiogenesis and inflammation, all pathways playing a critical role in aneurysm development.

Pull me - push you? The disparate financing mechanisms of drug research in global health.

Background: There is an inconsistency in the way pharmaceutical research is financed. While pull mechanisms are predominantly used to incentivize later-stage pharmaceutical research for products with demand in the Global North, so-called neglected diseases are chiefly financed by push funding. This discrepancy has so far been ignored in the academic debate, and any compelling explanation for why we draw the line between push and pull at poor people is lacking.

The endocannabinoid anandamide is an airway relaxant in health and disease.

Chronic obstructive airway diseases are a global medical burden that is expected to increase in the near future. However, the underlying mechanistic processes are poorly understood so far. Herein, we show that the endocannabinoid anandamide (AEA) induces prominent airway relaxation in vitro and in vivo.

A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases.

Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents, such as β-adrenergic receptor (β-AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by β-ARs in airway structural and inflammatory cells.

Inhibition of Vascular Growth by Modulation of the Anandamide/Fatty Acid Amide Hydrolase Axis.

Objective: Pathological angiogenesis is a hallmark of various diseases characterized by local hypoxia and inflammation. These disorders can be treated with inhibitors of angiogenesis, but current compounds display a variety of side effects and lose efficacy over time. This makes the identification of novel signaling pathways and pharmacological targets involved in angiogenesis a top priority.

Macrocyclic Gq Protein Inhibitors FR900359 and/or YM-254890-Fit for Translation?

Guanine nucleotide-binding proteins (G proteins) transduce extracellular signals received by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. While GPCRs represent the largest class of drug targets, G protein inhibition has only recently been recognized as a novel strategy for treating complex diseases such as asthma, inflammation, and cancer. The structurally similar macrocyclic depsipeptides FR900359 (FR) and YM-254890 (YM) are potent selective inhibitors of the Gq subfamily of G proteins.

Heterotrimeric G Protein Subunit Gαq Is a Master Switch for Gβγ-Mediated Calcium Mobilization by Gi-Coupled GPCRs.

Mechanisms that control mobilization of cytosolic calcium [Ca] are key for regulation of numerous eukaryotic cell functions. One such paradigmatic mechanism involves activation of phospholipase Cβ (PLCβ) enzymes by G protein βγ subunits from activated Gα-Gβγ heterotrimers. Here, we report identification of a master switch to enable this control for PLCβ enzymes in living cells.

Sensitive LC-MS/MS Method for the Quantification of Macrocyclic Gα Protein Inhibitors in Biological Samples.

The cyclic depsipeptide FR900359 (FR) isolated from the plant and produced by endosymbiotic bacteria acts as a selective Gq protein inhibitor. It is a powerful tool to study G protein-coupled receptor signaling, and has potential as a novel drug for the treatment of pulmonary diseases and cancer. For pharmacokinetic studies, sensitive quantitative measurements of drug levels are required.

Cell-permeable high-affinity tracers for G proteins provide structural insights, reveal distinct binding kinetics and identify small molecule inhibitors.

Background And Purpose: G proteins are intracellular switches that transduce and amplify extracellular signals from GPCRs. The G protein subtypes, which are coupled to PLC activation, can act as oncogenes, and their expression was reported to be up-regulated in cancer and inflammatory diseases. G inhibition may be an efficient therapeutic strategy constituting a new level of intervention.

Targeted inhibition of G signaling induces airway relaxation in mouse models of asthma.

Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of G protein-dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) are used to reduce airway tone.

Surpassing light-induced cell damage in vitro with novel cell culture media.

Light is extensively used to study cells in real time (live cell imaging), separate cells using fluorescence activated cell sorting (FACS) and control cellular functions with light sensitive proteins (Optogenetics). However, photo-sensitive molecules inside cells and in standard cell culture media generate toxic by-products that interfere with cellular functions and cell viability when exposed to light. Here we show that primary cells from the rat central nervous system respond differently to photo-toxicity, in that astrocytes and microglia undergo morphological changes, while in developing neurons and oligodendrocyte progenitor cells (OPCs) it induces cellular death.

Endogenous GABA controls oligodendrocyte lineage cell number, myelination, and CNS internode length.

Adjusting the thickness and internodal length of the myelin sheath is a mechanism for tuning the conduction velocity of axons to match computational needs. Interactions between oligodendrocyte precursor cells (OPCs) and developing axons regulate the formation of myelin around axons. We now show, using organotypic cerebral cortex slices from mice expressing eGFP in Sox10-positive oligodendrocytes, that endogenously released GABA, acting on GABA receptors, greatly reduces the number of oligodendrocyte lineage cells.

The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy.

Ischemic heart disease is associated with inflammation, interstitial fibrosis and ventricular dysfunction prior to the development of heart failure. Endocannabinoids and the cannabinoid receptor CB2 have been claimed to be involved, but their potential role in cardioprotection is not well understood. We therefore explored the role of the cannabinoid receptor CB2 during the initial phase of ischemic cardiomyopathy development prior to the onset of ventricular dysfunction or infarction.

RGD peptides induce relaxation of pulmonary arteries and airways via β3-integrins.

Novel relaxants of pulmonary arteries and airways are of special interest to obtain insights into pulmonary signaling pathways and to develop treatment strategies for lung diseases. Herein, we demonstrate that Arg-Gly-Asp (RGD) peptides induce a dose-dependent relaxation of pulmonary arteries and airways in mouse. The relaxing effect was specific because it was strongly reduced using the control peptides RGE or RAD (P<0.

Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction.

Endocannabinoids are important regulators of organ homeostasis. Although their role in systemic vasculature has been extensively studied, their impact on pulmonary vessels remains less clear. Herein, we show that the endocannabinoid anandamide (AEA) is a key mediator of hypoxic pulmonary vasoconstriction (HPV) via fatty acid amide hydrolase (FAAH)-dependent metabolites.

Identification of a novel vasoconstrictor peptide specific for the systemic circulation.

Some small molecular weight peptides possess potent vasoactive properties. Herein we have identified the laminin nonapeptide (LNP) CDPGYIGSR as a novel vasoconstrictive agent. Isometric force measurements revealed that LNP induced vasoconstriction in small and large murine arteries in a dose-dependent fashion; LNP also increased vascular tone in human mammary arteries.

O-glycosylation regulates ubiquitination and degradation of the anti-inflammatory protein A20 to accelerate atherosclerosis in diabetic ApoE-null mice.

Background: Accelerated atherosclerosis is the leading cause of morbidity and mortality in diabetic patients. Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete.

beta(2)-adrenoceptor antagonist ICI 118,551 decreases pulmonary vascular tone in mice via a G(i/o) protein/nitric oxide-coupled pathway.

beta(2)-adrenoceptors are important modulators of vascular tone, particularly in the pulmonary circulation. Because neurohormonal activation occurs in pulmonary arterial hypertension, we have investigated the effect of different adrenergic vasoactive substances on tone regulation in large and small pulmonary arteries, as well as in systemic vessels of mice. We found that the beta(2)-adrenoceptor antagonist ICI 118,551 (ICI) evoked a decrease of vascular tone in large pulmonary arteries and reduced the sensitivity of pulmonary arteries toward different contracting agents, eg, norepinephrine, serotonin, or endothelin.

Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene.

Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder. Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex. The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study.

Diagnostic interview for genetic studies (DIGS): inter-rater and test-retest reliability of alcohol and drug diagnoses.

The semi-structured diagnostic interview for genetic studies (DIGS) was developed to assess major mood and psychotic disorders and their spectrum manifestations in genetic studies. Our research group developed a French version of the DIGS and tested its inter-rater and test-retest reliability in psychiatric patients. In this article, we present estimates of the reliability of substance use and antisocial personality disorders.