ACBP/DBI protein neutralization confers autophagy-dependent organ protection through inhibition of cell loss, inflammation, and fibrosis

Acyl-coenzyme A (CoA)–binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular feedback regulator of autophagy. Here, we report that injection of a monoclonal antibody neutralizing ACBP/DBI (α-DBI) protects the murine liver against ischemia/reperfusion damage, intoxication by acetaminophen and concanavalin A, and nonalcoholic steatohepatitis caused by methionine/choline-deficient diet as well as against liver fibrosis induced by bile duct ligation or carbon tetrachloride. α-DBI downregulated proinflammatory and profibrotic genes and upregulated antioxidant defenses and fatty acid oxidation in the liver. The hepatoprotective effects of α-DBI were mimicked by the induction of ACBP/DBI-specific autoantibodies, an inducible Acbp/Dbi knockout or a constitutive Gabrg2F77I mutation that abolishes ACBP/DBI binding to the GABAA receptor. Liver-protective α-DBI effects were lost when autophagy was pharmacologically blocked or genetically inhibited by knockout of Atg4b. Of note, α-DBI also reduced myocardium infarction and lung fibrosis, supporting the contention that it mediates broad organ-protective effects against multiple insults.We thank the core facilities of Centre de Recherche des Cordeliers and Gustave Roussy for technical support. G.K. is supported by the Ligue contre le Cancer (equipe labellisee); Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la Recherche sur le Cancer; Association “Ruban Rose”; Cancerop^ole Ile-de-France; Fondation pour la Recherche Medicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases; Gustave Roussy Odyssea, the European Union Horizon 2020 Projects Oncobiome and Crimson (No. 101016923); Fondation Carrefour; Institut National du Cancer; Inserm (Heterogeneite des tumeurs dans leur microenvironnement); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18- IDEX-0001); the Leducq Foundation; a Cancer Research Accelerating Scientific Platforms and Innovative Research Award from the Mark Foundation;, the Recherche Hospitalo-Universitaire Torino Lumiere; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination; and SIRIC Cancer Research and Personalized Medicine. This study contributes to the IdEx Universite de Paris ANR-18-IDEX-0001. G.A. is supported by the FRM. L.S. is supported by Beatriz Galindo senior program of the Spanish Ministry of Universities; Strategic Program “Instituto de Biologıa y Genetica Molecular (IBGM), Junta de Castilla y Leon” (Ref. CCVC8485); and Internationalisation Project of the “Unidad de Excelencia IBGM of Valladolid” (Ref. CL-EI-2021)

An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABAA receptor

Acyl-coenzyme-A-binding protein (ACBP), also known as a diazepam-binding inhibitor (DBI), is a potent stimulator of appetite and lipogenesis. Bioinformatic analyses combined with systematic screens revealed that peroxisome proliferator-activated receptor gamma (PPARγ) is the transcription factor that best explains the ACBP/DBI upregulation in metabolically active organs including the liver and adipose tissue. The PPARγ agonist rosiglitazone-induced ACBP/DBI upregulation, as well as weight gain, that could be prevented by knockout of Acbp/Dbi in mice. Moreover, liver-specific knockdown of Pparg prevented the high-fat diet (HFD)-induced upregulation of circulating ACBP/DBI levels and reduced body weight gain. Conversely, knockout of Acbp/Dbi prevented the HFD-induced upregulation of PPARγ. Notably, a single amino acid substitution (F77I) in the γ2 subunit of gamma-aminobutyric acid A receptor (GABAAR), which abolishes ACBP/DBI binding to this receptor, prevented the HFD-induced weight gain, as well as the HFD-induced upregulation of ACBP/DBI, GABAAR γ2, and PPARγ. Based on these results, we postulate the existence of an obesogenic feedforward loop relying on ACBP/DBI, GABAAR, and PPARγ. Interruption of this vicious cycle, at any level, indistinguishably mitigates HFD-induced weight gain, hepatosteatosis, and hyperglycemia

Versatile functionalization platform of biporous poly(2-hydroxyethylmethacrylate)-based materials: Application in heterogeneous supportedcatalysis

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Rs867228 in FPR1 accelerates the manifestation of luminal B breast cancer

ABSTRACTFormyl peptide receptor-1 (FPR1) is a pathogen recognition receptor involved in the detection of bacteria, in the control of inflammation, as well as in cancer immunosurveillance. A single nucleotide polymorphism in FPR1, rs867228, provokes a loss-of-function phenotype. In a bioinformatic study performed on The Cancer Genome Atlas (TCGA), we observed that homo-or heterozygosity for rs867228 in FPR1 (which affects approximately one-third of the population across continents) accelerates age at diagnosis of specific carcinomas including luminal B breast cancer by 4.9 years. To validate this finding, we genotyped 215 patients with metastatic luminal B mammary carcinomas from the SNPs To Risk of Metastasis (SToRM) cohort. The first diagnosis of luminal B breast cancer occurred at an age of 49.2 years for individuals bearing the dysfunctional TT or TG alleles (n = 73) and 55.5 years for patients the functional GG alleles (n = 141), meaning that rs867228 accelerated the age of diagnosis by 6.3 years (p=0.0077, Mann & Whitney). These results confirm our original observation in an independent validation cohort. We speculate that it may be useful to include the detection of rs867228 in breast cancer screening campaigns for selectively increasing the frequency and stringency of examinations starting at a relatively young age

Conception de matériaux polymères fonctionnalisés à double porosité

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Conception de matériaux polymères fonctionnalisés à double porosité

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Systematic Investigation of the Diagnostic and Prognostic Impact of LINC01087 in Human Cancers

: (1) Background: Long non-coding RNAs may constitute epigenetic biomarkers for the diagnosis, prognosis, and therapeutic response of a variety of tumors. In this context, we aimed at assessing the diagnostic and prognostic value of the recently described long intergenic non-coding RNA 01087 (LINC01087) in human cancers. (2) Methods: We studied the expression of LINC01087 across 30 oncological indications by interrogating public resources. Data extracted from the TCGA and GTEx databases were exploited to plot receiver operating characteristic curves (ROC) and determine the diagnostic performance of LINC01087. Survival data from TCGA and KM-Plotter directories allowed us to graph Kaplan-Meier curves and evaluate the prognostic value of LINC01087. To investigate the function of LINC01087, gene ontology (GO) annotation and Kyoto Encyclopedia of Gene and Genomes (KEGG) enrichment analyses were performed. Furthermore, interactions between LINC01087 and both miRNA and mRNA were studied by means of bioinformatics tools. (3) Results: LINC01087 was significantly deregulated in 7 out of 30 cancers, showing a predominant upregulation. Notably, it was overexpressed in breast (BC), esophageal (ESCA), and ovarian (OV) cancers, as well as lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD), and uterine carcinosarcoma (UCS). By contrast, LINC01087 displayed downregulation in testicular germ cell tumors (TGCT). ROC curve analyses identified LINC01087 as a potential diagnostic indicator in BC, ESCA, OV, STAD, and TGCT. Moreover, high and low expression of LINC01087 predicted a favorable prognosis in BC and papillary cell carcinoma, respectively. In silico analyses indicated that deregulation of LINC01087 in cancer was associated with a modulation of genes related to ion channel, transporter, and peptide receptor activity. (4) Conclusions: the quantification of an altered abundance of LINC01087 in tissue specimens might be clinically useful for the diagnosis and prognosis of some hormone-related tumors, including BC, OV, and TGCT, as well as other cancer types such as ESCA and STAD. Moreover, our study revealed the potential of LINC01087 (and perhaps other lncRNAs) to regulate neuroactive molecules in cancer

Kidney–Targeted drug delivery systems based on tailor-made nanocapsules

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Détection et suivi de petites molécules polluantes dans l’air ambiant

International audienceDans le cadre de l'évaluation des risques encourus dans les atmosphères confinées, l'étude du transport de molécules polluantes dans l'air et leur détection via des capteurs est d'autant plus performante qu'elle repose sur des méthodologies de modélisation et d'expérimentation à des échelles d'espace différentes. La mise au point d'un dispositif de détection sélectif et sensible fait ainsi intervenir l'interaction molécule-capteur à l'échelle atomique, tandis que le transport des particules dans l'air est analysé à des échelles plus grandes. Mots-clés Capteurs, qualité de l'air, transport, nanotubes de carbone fonctionnalisés, CNTFET, fonctionnalisation de surface, imidazole, porphyrines, phtalocyanines, gaz polluants, simulation numérique multi-échelle, caractérisation. Abstract Detecting and monitoring of small pollutants in ambient air In the context of the assessment of the risks incurred in confined atmospheres, the study of the transport of polluting molecules in the air and their detection via sensors is all the more effective as it is based on modeling and experimentation methodologies at different space scales. The development of a selective and sensitive detection device thus involves molecule-sensor interaction at the atomic scale, while the transport of particles in the air is analyzed on larger scales