Risultati per: Percorsi personalizzati contro il cancro legati al gene BRCA

Stroke, Volume 55, Issue Suppl_1, Page ATP289-ATP289, February 1, 2024. Introduction:Lactate plays a vital role in various pathophysiological conditions including ischemic stroke. However, an unexplored dimension is the epigenetic modification originating from lactate, lysine lactylation (Kla), and its potential role in cerebral ischemia. Our research sought to elucidate the possible regulation of protein Kla in ischemic stroke, and its underlying mechanisms.Methods:Lactate concentration and pan-Kla levels were assessed in mice subjected to transient middle cerebral artery occlusion (MCAO) . Neurological functions and ischemic infarct volume were investigated through foot fault test and 2,3,5-triphenyltetrazolium chloride staining respectively. Proteomics analysis was used to examine protein Kla and key related proteins in the penumbra after one day of MCAO. Immunofluorescence, western blot, proximity ligation assay, and coimmunoprecipitation were performed to evaluate the cellular localization and modification sites of methyl-CpG-binding protein 2 (MeCP2). Joint CUT&Tag and RNA-sequencing analyses were utilized to identify MeCP2-Kla target genes.Results:We confirmed the accumulation of brain lactate and global protein Kla following cerebral ischemia. MeCP2 was identified as the central protein with Kla modification in ischemic stroke. Furthermore, the potentially beneficial role of neuronal MeCP2 lactylation in ischemic stroke was investigated. Our findings indicated that MeCP2 could protect against stroke-induced neuronal death through transcriptionally inactivating apoptosis-associated genes. It is showing various heterochromatin foci enrichment pattern in neuronal nuclei of different Kla level groups. In addition, it was found that MeCP2 Kla (Lys-210 and Lys-249) suppressed Pdcd4/Pla2g6 mRNA expression, thereby alleviating neurological deficit.Conclusions:MeCP2 lactylation exerts neuroprotection by transcriptionally regulates neuronal apoptosis, indicating it as a potential therapeutic target for ischemic stroke.

New England Journal of Medicine, Volume 390, Issue 5, Page 432-441, February 2024.

Colpa di obesità e alcol. Esperti: “Anticipare lo screening”

Pathogenic variants of the NOD2 (nucleotide-binding oligomerization domain containing protein 2) gene demonstrate the strongest genetic association to Crohn’s inflammatory bowel disease (CD). Mounting evidence links NOD2 deficiency with poor clinical outcome, particularly in pediatric and early onset CD. CD patients with pathogenic NOD2 variants, particularly carriers of more than one risk allele, frequently present an aggressive, fistulizing and fibrostenotic disease, requiring multiple surgical resections.

Interleukin (IL)-1 and its post-translationally modified and released forms, IL-1α and IL-1β, have been identified as key molecules to maintain mucosal homeostasis and to drive inflammatory bowel disease (IBD). Deep cellular phenotypic, transcriptional, and in vitro data highlight the importance of IL-1-associated cytokine networks and IL-1 producing cells in severe and anti-TNF non-responsive IBD. Nevertheless, little is known about the presence of bioactive IL-1 proteins within the cell-free gastrointestinal (GI) mucosal environment and associated function in severe IBD and ulceration.

Annals of Internal Medicine, Ahead of Print.

Annals of Internal Medicine, Ahead of Print.

The US Food and Drug Administration (FDA) recently greenlit 2 cell-based gene treatments for sickle cell anemia, including the first therapy involving the genome editing technology known as CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats–CRISPER-associated protein 9).

Il 31 gennaio un incontro alla Camera per avanzare proposte

Circulation, Volume 149, Issue 3, Page 267-269, January 16, 2024.

Circulation, Ahead of Print. BACKGROUND:The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients with HF progressing to AF. The pathophysiological basis of AF in the context of HF is presumed to result from atrial remodeling. Upregulation of the transcription factor FOG2 (friend of GATA2; encoded byZFPM2) is observed in human ventricles during HF and causes HF in mice.METHODS:FOG2 expression was assessed in human atria. The effect of adult-specific FOG2 overexpression in the mouse heart was evaluated by whole animal electrophysiology, in vivo organ electrophysiology, cellular electrophysiology, calcium flux, mouse genetic interactions, gene expression, and genomic function, including a novel approach for defining functional transcription factor interactions based on overlapping effects on enhancer noncoding transcription.RESULTS:FOG2 is significantly upregulated in the human atria during HF. Adult cardiomyocyte-specific FOG2 overexpression in mice caused primary spontaneous AF before the development of HF or atrial remodeling. FOG2 overexpression generated arrhythmia substrate and trigger in cardiomyocytes, including calcium cycling defects. We found that FOG2 repressed atrial gene expression promoted byTBX5. FOG2 bound a subset ofGATA4andTBX5co-bound genomic locations, defining a shared atrial gene regulatory network. FOG2 repressed TBX5-dependent transcription from a subset of co-bound enhancers, including a conserved enhancer at theAtp2a2locus. Atrial rhythm abnormalities in mice caused byTbx5haploinsufficiency were rescued byFog2haploinsufficiency.CONCLUSIONS:Transcriptional changes in the atria observed in human HF directly antagonize the atrial rhythm gene regulatory network, providing a genomic link between HF and AF risk independent of atrial remodeling.

This retrospective cohort study assesses the cumulative incidence of pregnancy after cancer and disease-free survival in BRCA carriers diagnosed with invasive breast cancer at age 40 years or younger.

Circulation, Ahead of Print. BACKGROUND:Diabetes is associated with cardiovascular complications. microRNAs translocate into subcellular organelles to modify genes involved in diabetic cardiomyopathy. However, functional properties of subcellular Ago2 (Argonaute2), a core member of miRNA machinery, remain elusive.METHODS:We elucidated the function and mechanism of subcellular localized Ago2 on mouse models for diabetes and diabetic cardiomyopathy. Recombinant adeno-associated virus type 9 was used to deliver Ago2 to mice through the tail vein. Cardiac structure and functions were assessed by echocardiography and catheter manometer system.RESULTS:Ago2 was decreased in mitochondria of diabetic cardiomyocytes. Overexpression of mitochondrial Ago2 attenuated diabetes-induced cardiac dysfunction. Ago2 recruitedTUFM, a mitochondria translation elongation factor, to activate translation of electron transport chain subunits and decrease reactive oxygen species. Malonylation, a posttranslational modification of Ago2, reduced the importing of Ago2 into mitochondria in diabetic cardiomyopathy. Ago2 malonylation was regulated by a cytoplasmic-localized short isoform ofSIRT3through a previously unknown demalonylase function.CONCLUSIONS:Our findings reveal that theSIRT3–Ago2–CYTBaxis links glucotoxicity to cardiac electron transport chain imbalance, providing new mechanistic insights and the basis to develop mitochondria targeting therapies for diabetic cardiomyopathy.