Cells

The earliest effect of spaceflight is an alteration in vestibular function due to microgravity. Hypergravity exposure induced by centrifugation is also able to provoke motion sickness. The blood-brain barrier (BBB) is the crucial interface between the vascular system and the brain to ensure efficient neuronal activity. We developed experimental protocols of hypergravity on C57Bl/6JRJ mice to induce motion sickness and reveal its effects on the BBB. Mice were centrifuged at 2× for 24 h. Fluorescent dextrans with different sizes (40, 70 and 150 kDa) and fluorescent antisense oligonucleotides (AS) were injected into mice retro-orbitally. The presence of fluorescent molecules was revealed by epifluorescence and confocal microscopies in brain slices. Gene expression was evaluated by RT-qPCR from brain extracts. Only the 70 kDa dextran and AS were detected in the parenchyma of several brain regions, suggesting an alteration in the BBB. Moreover, Ctnnd1, Gja4 and Actn1 were upregulated, whereas Jup, Tjp2, Gja1, Actn2, Actn4, Cdh2 and Ocln genes were downregulated, specifically suggesting a dysregulation in the tight junctions of endothelial cells forming the BBB. Our results confirm the alteration in the BBB after a short period of hypergravity exposure

Endocytosis of Activated Muscarinic m2 Receptor (m2R) in Live Mouse Hippocampal Neurons Occurs via a Clathrin-Dependent Pathway

Our aim was to examine the dynamics of the muscarinic m2 receptor (m2R), a G-protein coupled receptor (GPCR), after agonist activation in living hippocampal neurons, and especially clathrin dependency endocytosis. We have previously shown that the m2R undergoes agonist-induced internalization in vivo. However, the nature of the endocytotic pathway used by m2R after activation is still unknown in living neurons. Using live cell imaging and quantitative analyses, we have monitored the effect of stimulation on the fate of the membrane-bound m2R and on its redistribution in intraneuronal compartments. Shortly (6 min) after activation, m2R is internalized into clathrin immunopositive structures. Furthermore, after clathrin-dependent endocytosis, m2R associates with early and late endosomes and with subcellular organelles involved in degradation. Together, these results provide, for the first time, a description of m2R trafficking in living neurons and prove that m2R undergoes clathrin-dependent endocytosis before being degraded

Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease

From the inoculation of Plasmodium sporozoites via Anopheles mosquito bites to the development of blood-stage parasites, a hallmark of the host response is an inflammatory reaction characterized by elevated histamine levels in the serum and tissues. Given the proinflammatory and immunosuppressive activities associated with histamine, we postulated that this vasoactive amine participates in malaria pathogenesis. Combined genetic and pharmacologic approaches demonstrated that histamine binding to H1R and H2R but not H3R and H4R increases the susceptibility of mice to infection with Plasmodium. To further understand the role of histamine in malaria pathogenesis, we used histidine decarboxylase–deficient (HDC−/−) mice, which are free of histamine. HDC−/− mice were highly resistant to severe malaria whether infected by mosquito bites or via injection of infected erythrocytes. HDC−/− mice displayed resistance to two lethal strains: Plasmodium berghei (Pb) ANKA, which triggers cerebral malaria (CM), and Pb NK65, which causes death without neurological symptoms. The resistance of HDC−/− mice to CM was associated with preserved blood–brain barrier integrity, the absence of infected erythrocyte aggregation in the brain vessels, and a lack of sequestration of CD4 and CD8 T cells. We demonstrate that histamine-mediated signaling contributes to malaria pathogenesis. Understanding the basis for these biological effects of histamine during infection may lead to novel therapeutic strategies to alleviate the severity of malaria

A focus on mast cells and pain

International audienceMast cells (MCs) are immunocytes with secretory functions that act locally in peripheral tissues to modulate local hemodynamics, nociceptor activation and pain. They are also able to infiltrate the central nervous system (CNS), especially the spinal cord and the thalamus, but their cerebral function remains an enigma. A role in regulating the opening of the blood–brain barrier has been proposed. Paracrine-like action of MCs on synaptic transmission might also signal a modulation of the nervous system by the immune system. In this review, we examine the link between MCs and nociceptive process, at the periphery as well as in the CNS

Use of placebo in French hospitals: data from polyvalent medicine units: Regard sur son utilisation dans les services de médecine polyvalente

International audienceA placebo drug is defined as a treatment without any specific pharmacological efficacy, that works when the patient thinks to receive an active treatment, through a psychological and physiological mechanism. This study aimed to evaluate the use of placebo in French hospitals, in Polyvalent Medicine units. A questionnaire comprising 15 items was sent to 372 units. The analysis of 153 responses was conducted from dynamic crosstabs in Excel and using the R software available online. The survey confirmed that the use of placebos in hospital is frequent, with nearly 2/3 of professionals answering the questionnaire declared to use it. The oral capsule is the most commonly used form. Placebo is mainly administered at night, in case of pain, insomnia or anxiety, to so-called “difficult” patients. Placebo is not always given after medical prescription. In most cases, patients are not informed that they receive a placebo. The majority of professionals believed in the placebo effect but considered to be insufficiently informed and trained in the use of placebo in current practice. Although the placebo effect is now demonstrated, ethical and legal considerations recommend placebo treatment only on medical prescription, with the prior information of the patient. The placebo could be used as complementary therapy to conventional treatment in the cases of this therapeutic effectiveness has been demonstrated. Professionals should be trained in the use of placebo in order to avoid nocebo effect and potentiate beneficial effects of placebo

Blood brain barrier precludes the cerebral arteries to intravenously-injected antisense oligonucleotide

International audienceAlternative splicing of the ryanodine receptor subtype 3 (RyR3) produces a short isoform (RyR3S) able to negatively regulate the ryanodine receptor subtype 2 (RyR2), as shown in cultured smooth muscle cells from mice. The RyR2 subtype has a crucial role in the control of vascular reactivity via the fine tuning of Ca(2+) signaling to regulate cerebral vascular tone. In this study, we have shown that the inhibition of RyR3S expression by a specific antisense oligonucleotide (asRyR3S) was able to increase the Ca(2+) signals implicating RyR2 in cerebral arteries ex vivo. Moreover, we tried to inhibit the expression of RyR3S in vivo. The asRyR3S was complexed with JetPEI and injected intravenously coupled with several methods known to induce a blood brain barrier disruption. We tested solutions to induce osmotic choc (mannitol), inflammation (bacteria lipopolysaccharide and pertussis toxin), vasoconstriction or dilatation (sumatriptan, phenylephrine, histamine), CD73 activation (NECA) and lipid instability (Tween80). All tested technics failed to target asRyR3 in the cerebral arteries wall, whereas the molecule was included in hepatocytes or cardiomyocytes. Our results showed that the RyR3 alternative splicing could have a function in cerebral arteries ex vivo; however, the disruption of the blood brain barrier could not induce the internalization of antisense oligonucleotides in the cerebral arteries, in order to prove the function of RYR3 short isoform in vivo

Murine splenic B cells express corticotropin-releasing hormone receptor 2 that affect their viability during a stress response

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Maillard Reaction Products from highly heated food prevent mast cell number increase and inflammation in a mouse model of colitis

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Effects of centrifugation and whole-body vibrations on blood–brain barrier permeability in mice

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Blood brain barrier precludes the cerebral arteries to intravenously-injected antisense oligonucleotide

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