The Dendritic Cell Receptor DNGR-1 Promotes the Development of Atherosclerosis in Mice.

RATIONALE: Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. However, the molecular links between necrosis and the development of atherosclerosis are not completely understood. Clec9a (C-type lectin receptor) or DNGR-1 (dendritic cell NK lectin group receptor-1) is preferentially expressed by the CD8α+ subset of dendritic cells (CD8α+ DCs) and is involved in sensing necrotic cells. We hypothesized that sensing of necrotic cells by DNGR-1 plays a determinant role in the inflammatory response of atherosclerosis. OBJECTIVE: We sought to address the impact of total, bone marrow-restricted, or CD8α+ DC-restricted deletion of DNGR-1 on atherosclerosis development. METHODS AND RESULTS: We show that total absence of DNGR-1 in Apoe (apolipoprotein e)-deficient mice (Apoe-/-) and bone marrow-restricted deletion of DNGR-1 in Ldlr (low-density lipoprotein receptor)-deficient mice (Ldlr-/-) significantly reduce inflammatory cell content within arterial plaques and limit atherosclerosis development in a context of moderate hypercholesterolemia. This is associated with a significant increase of the expression of interleukin-10 (IL-10). The atheroprotective effect of DNGR-1 deletion is completely abrogated in the absence of bone marrow-derived IL-10. Furthermore, a specific deletion of DNGR-1 in CD8α+ DCs significantly increases IL-10 expression, reduces macrophage and T-cell contents within the lesions, and limits the development of atherosclerosis. CONCLUSIONS: Our results unravel a new role of DNGR-1 in regulating vascular inflammation and atherosclerosis and potentially identify a new target for disease modulation

Building the process-drug–side effect network to discover the relationship between biological Processes and side effects

<p>Abstract</p> <p>Background</p> <p>Side effects are unwanted responses to drug treatment and are important resources for human phenotype information. The recent development of a database on side effects, the side effect resource (SIDER), is a first step in documenting the relationship between drugs and their side effects. It is, however, insufficient to simply find the association of drugs with biological processes; that relationship is crucial because drugs that influence biological processes can have an impact on phenotype. Therefore, knowing which processes respond to drugs that influence the phenotype will enable more effective and systematic study of the effect of drugs on phenotype. To the best of our knowledge, the relationship between biological processes and side effects of drugs has not yet been systematically researched.</p> <p>Methods</p> <p>We propose 3 steps for systematically searching relationships between drugs and biological processes: enrichment scores (ES) calculations, t-score calculation, and threshold-based filtering. Subsequently, the side effect-related biological processes are found by merging the drug-biological process network and the drug-side effect network. Evaluation is conducted in 2 ways: first, by discerning the number of biological processes discovered by our method that co-occur with Gene Ontology (GO) terms in relation to effects extracted from PubMed records using a text-mining technique and second, determining whether there is improvement in performance by limiting response processes by drugs sharing the same side effect to frequent ones alone.</p> <p>Results</p> <p>The multi-level network (the process-drug-side effect network) was built by merging the drug-biological process network and the drug-side effect network. We generated a network of 74 drugs-168 side effects-2209 biological process relation resources. The preliminary results showed that the process-drug-side effect network was able to find meaningful relationships between biological processes and side effects in an efficient manner.</p> <p>Conclusions</p> <p>We propose a novel process-drug-side effect network for discovering the relationship between biological processes and side effects. By exploring the relationship between drugs and phenotypes through a multi-level network, the mechanisms underlying the effect of specific drugs on the human body may be understood.</p

Striated muscle activator of Rho signalling (STARS) is reduced in ageing human skeletal muscle and targeted by miR-628-5p

Aim: The striated muscle activator of Rho signalling (STARS) is a muscle-specific actin-binding protein. The STARS signalling pathway is activated by resistance exercise and is anticipated to play a role in signal mechan-otransduction. Animal studies have reported a negative regulation of STARS signalling with age, but such regulation has not been investigated in humans. Methods: Ten young (18–30 years) and 10 older (60–75 years) subjects completed an acute bout of resistance exercise. Gene and protein expres-sion of members of the STARS signalling pathway and miRNA expression of a subset of miRNAs, predicted or known to target members of STARS signalling pathway, were measured in muscle biopsies collected pre-exer-cise and 2 h post-exercise. Results: For the first time, we report a significant downregulation of the STARS protein in older subjects. However, there was no effect of age on the magnitude of STARS activation in response to an acute bout of exer-cise. Finally, we established that miR-628-5p, a miRNA regulated by age and exercise, binds to the STARS 3’UTR to directly downregulate its tran-scription. Conclusion: This study describes for the first time the resistance exercise-induced regulation of STARS signalling in skeletal muscle from older humans and identifies a new miRNA involved in the transcriptional con-trol of STARS

The TWEAK–Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice

The TNF-related cytokine TWEAK promotes skeletal muscle atrophy that is associated with classical disuse syndromes

Blunted hypertrophic response in old mouse muscle is associated with a lower satellite cell density and is not alleviated by resveratrol

Background Sarcopenia contributes to the decreased quality of life in the older person. While resistance exercise is an effective measure to increase muscle mass and strength, the hypertrophic response may be blunted in old age. Objectives To determine 1) whether hypertrophy in the m. plantaris of old mice was blunted compared to adult and 2) whether this was related to a reduced satellite cell (SC) density and 3) how resveratrol affects hypertrophy in old mice. Methods In adult (7.5 months, n = 11), old (23.5 months, n = 10) and old-resveratrol-treated (n = 10) male C57BL/6J mice, hypertrophy of the left m. plantaris was induced by denervation of its synergists. The contralateral leg served as control. Results After six weeks, overload-induced myofiber hypertrophy and IIB–IIA shift in myofiber type composition were less pronounced in old than adult mice (P = 0.03), irrespective of resveratrol treatment. Muscles from old mice had a lower SC density than adult muscles (P = 0.002). Overload-induced SC proliferation (P < 0.05) resulted in an increased SC density in old, but not adult muscles (P = 0.02), while a decrease occurred after resveratrol supplementation (P = 0.044). Id2 and myogenin protein expression levels were higher in old than adult muscles (P < 0.05). Caspase-3 was expressed more in hypertrophied than control muscles and was reduced with resveratrol (P < 0.05). Conclusion The blunted hypertrophic response in old mice was associated with a lower SC density, but there was no evidence for a lower capacity for proliferation. Resveratrol did not rescue the hypertrophic response and even reduced, rather than increased, the number of SCs in hypertrophied muscles

SRF, un facteur de transcription crucial dans la physiologie des muscles squelettiques (Contribution au vieillissement et à l'hypertrophie)

Afin de déterminer le rôle de SRF dans la physiologie du muscle adulte, nous avons créé un modèle murin d'invalidation inductible de SRF dans les muscles squelettiques. Après induction de la perte de SRF, les muscles mutants présentent des altérations similaires à celles observées lors du vieillissement musculaire. L'expression de SRF diminuant de façon drastique avec le temps dans des muscles contrôles, cette perte de SRF avec l'âge pourrait contribuer au processus naturel du vieillissement. Afin d'évaluer le rôle de SRF dans l'hypertrophie, j'ai soumis les muscles de souris contrôles et mutantes à une surcharge et montré que seuls les muscles contrôles présentent une réponse hypertrophique. Ce défaut d'hypertrophie dans les muscles mutants est due à une altération de la prolifération et de la fusion des cellules satellites, SRF contrôlant de façon paracrine l'expression de IL6 et IL4. Nos résultats montrent que SRF est impliqué dans le maintien et l'hypertrophie musculaire.To investigate SRF function in adult skeletal muscle physiology, we developed a myofiber-specific and tamoxifen-inducibie SRF Knockout mice model. After induction of SRF loss, mutant muscles exhibits similar alterations to those observed during muscle aging. We also observed an important age-associated decrease in SRF expression in control muscles. Thus SRF loss with age could contribute to the natural muscle aging process. To assess the role of SRF during hypertrophy, I submitted muscles of mutant and control mice to an overload-induced hypertrophy and showed that only controls muscles show a hypertrophic response. The lack of hypertrophy in mutant muscles is due to an impairment of satellite cells proliferation and fusion. In fact, SRF enhance hypertrophy through the control of IL6 and IL4 expression in a paracrine fashion. Our results show that SRF is involved in skeletal muscle maintenance and hypertrophy.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Mortalités et géographie de la santé dans le Nord et le Pas-de-Calais

All causes mortality of the Region Nord -Pas-de-Calais is well higher that the french average but this excess of mortality varies with causes of death. This excess is especially high for mortality due to some cancers (oesophagus and upper aerodigestives tracts), respiratory diseases and alcohol -related diseases in men and alcohol -related diseases in women. At the infraregional scale, the «Bassin minier» can be lesly distinguished by high alcohol related and respiratory mortality in men. This spatial pattern could be due to specific local human and socioeconomic factors.La mortalité régionale du Nord -Pas-de-Calais est nettement supérieure à la moyenne française mais cette surmortalité varie selon les causes de décès. Elle est particulièrement nette pour les cancers de l'œsophage et des voies aérodigestives supérieures, les maladies respiratoires et les maladies attribuées à l'alcool. A l'échelle infrarégionale, le Bassin minier se distingue nettement du reste de la région par une importante mortalité, d'origine respiratoire ou alcoolique. Les spécificités humaines, économiques et sociales locales semblent jouer un rôle non négligeable dans cette focalisation géographique.Lacoste Olivier, Lahoute C., Declercq C. Mortalités et géographie de la santé dans le Nord et le Pas-de-Calais. In: Hommes et Terres du Nord, 1990/2. Géographie de la scolarité et de la santé. pp. 117-126