Search Results for: L'automisurazione della pressione arteriosa: I target pressori

Uno studio pubblicato recentemente su “JAMA Network Open” ha dimostrato che la somministrazione serale dell’associazione olmesartan-amlodipina garantisce un controllo superiore della pressione arteriosa sistolica notturna rispetto al dosaggio mattutino, con una riduzione media significativamente maggiore e senza incremento del rischio di ipotensione.

Circulation, Ahead of Print. BACKGROUND:β-Adrenergic receptors (βARs) are prototypical G protein–coupled receptors that regulate contractility in the normal heart and pathological remodeling in disease. Canonical βAR signaling originates at the plasma membrane, but functional βARs have been localized to intracellular membranes such as the endosome, sarcoplasmic reticulum, Golgi, and nuclear envelope. The functional significance of these intracellular receptors remains unclear, including whether they regulate cellular processes distinct from those regulated by plasma membrane receptors and whether they can be independently targeted for therapeutic benefit.METHODS:Live cell imaging of rat and human cardiomyocytes expressing novel compartment-specific modulators of βAR activity and fluorescent biosensors was used to study the compartment-specific βAR regulation of second messengers and to target enzyme activity. Compartmentalized signaling was compared with myocyte gene expression and hypertrophy. Adeno-associated virus gene delivery conferring gain and loss of perinuclear βAR activity was studied in wild-type mice and a mouse model of familial dilated cardiomyopathy.RESULTS:We demonstrate here that intracellular β1ARs present on Golgi membrane facing the outer nuclear membrane regulate a perinuclear cAMP compartment containing the A-kinase anchoring protein 6β signalosome, conferring selective regulation of perinuclear cAMP-dependent protein kinase activity independently of βARs at the plasma membrane or endosome. The A-kinase anchoring protein 6β compartment is shown to be of nanometer scale and dependent on local restriction of cAMP diffusion. In addition, perinuclear βARs are shown to be sufficient and necessary for activation of the Ca2+-dependent calcineurin–nuclear factor of activated T cells pathway and myocyte hypertrophy in vitro. Accordingly, adeno-associated virus 9–based delivery of an outer nuclear membrane–localized pepducin, which selectively activated perinuclear βARs in vitro, induced dilated cardiomyopathy in wild-type mice. Conversely, in vivo delivery of an outer nuclear membrane–localized nanobody, which selectively inhibited perinuclear βARs in vitro, improved cardiac function and inhibited pathological remodeling in a mouse model of familial dilated cardiomyopathy with established disease.CONCLUSIONS:These results demonstrate that β1ARs localized to Golgi membranes facing the outer nuclear membrane regulate A-kinase anchoring protein 6β signalosomes required for the induction of pathological cardiac remodeling, defining an intracellular nanocompartment. Proof of concept is provided for a novel therapeutic approach for familial dilated cardiomyopathy, with potential application to other forms of cardiovascular disease.

I pazienti con BPCO e diabete di tipo 2 presentano un rischio ridotto di ricovero per BPCO, di necessità di ricorrere alla ventilazione non invasiva a pressione positiva e di mortalità per tutte le cause se assumono un inibitore del co-trasportatore sodio-glucosio 2 (SGLT2i). Queste le conclusioni di uno studio retrospettivo, condotto a Taiwan, i cui risultati sono stati pubblicati negli Annals of the American Thoracic Society.

Anaao: “Chi resta fa salti mortali, ma i reparti restano aperti”

Un nuovo inibitore selettivo dell’aldosterone, baxdrostat, ha mostrato in uno studio di Fase III un’efficace riduzione della pressione arteriosa sistolica a 12 settimane, aprendo nuovi scenari terapeutici per pazienti con ipertensione non controllata o resistente.

Background
The gut microbiome and diet are important factors in the pathogenesis and management of Crohn’s disease (CD). However, the role of the gut phageome under dietary influences is unknown.

Objective
We aim to explore the effect of diet on the gut phageome-bacteriome interaction linking to CD protection.

Design
We recruited CD patients and healthy subjects (n=140) and conducted a multiomics investigation, including paired ileal mucosa phageome and bacteriome profiling, dietary survey and phenome interrogation. We screened for the effect of diet on the gut phageome and bacteriome, as well as its epidemiological association with CD risks. The underlying mechanisms were explored in target phage-bacteria monocultures and cocultures in vitro and in two mouse models in vivo.

Results
On dietary screening in humans, whey protein (WP) consumption was found to profoundly impact the gut phageome and bacteriome (more pronounced on the phageome) and was associated with a lower CD risk. Indeed, the WP reshaped gut phageome can causally attenuate intestinal inflammation, as shown by faecal phageome versus bacteriome transplantation from WP-consuming versus WP-non-consuming mice to recipient mice. Mechanistically, WP induced phage (a newly isolated phage AkkZT003P herein) lysis of the mucin-foraging bacterium Akkermansia muciniphila, which unleashed the symbiotic bacterium Streptococcus thermophilus to counteract intestinal inflammation.

Conclusion
Our study charted the importance of cross-kingdom interaction between gut phage and bacteria in mediating the dietary effect on CD protection. Importantly, we uncovered a beneficial dietary WP, a keystone phage AkkZT003P, and a probiotic S. thermophilus that can be used in CD management in the future.

Background
GPR171 suppresses T cell immune responses involved in antitumour immunity, while its role in inflammatory bowel disease (IBD) pathogenesis remains unclear.

Objective
We aimed to investigate the role of GPR171 in modulating CD4+ T cell effector functions in IBD and evaluate its therapeutic potential.

Design
We analysed GPR171 expression in colon biopsies and peripheral blood samples from patients with IBD and assessed the impact of GPR171 on CD4+ T cell differentiation through administration of its endogenous ligand (BigLEN). We further determined the role of GPR171 in dextran sulfate sodium (DSS)-induced colitis and CD45RBhighCD4+ T-cell transfer colitis model and deciphered the underlying mechanisms using RNA sequencing (RNA-seq) and lipidomics. We developed a novel BigLEN-based Fc fusion protein (BigLEN-Fc) and evaluated its potential in preventing and treating colitis.

Results
GPR171 was markedly increased in inflamed mucosa and CD4+ T cells of patients with IBD compared with controls. BigLEN-triggered GPR171 activation inhibited Th17 cell differentiation in vitro. GPR171 deficiency exacerbated DSS- and CD45RBhighCD4+ T cell-induced colitis in mice, characterised by increased Th17 cell responses in intestinal mucosa. Mechanistically, GPR171 deficiency promoted Th17 cell differentiation and altered lipidome profile in Th17 cells via the cAMP-pCREB-FABP5 axis. Blockage of FABP5 reduced Th17 cell differentiation in vitro and ameliorated DSS-induced colitis in Gpr171 –/– mice. Furthermore, BigLEN-mutFc administration potently mitigated colitis in mice.

Conclusions
GPR171 deficiency promotes Th17 cell differentiation and causes lipid metabolism perturbation, contributing to intestinal inflammation in a FABP5-dependent manner. Target therapy (eg, BigLEN-Fc) represents a novel therapeutic approach for IBD treatment.

Background
The resistance of pancreatic ductal adenocarcinoma (PDAC) to trametinib therapy limits its clinical use. However, the molecular mechanisms underlying trametinib resistance in PDAC remain unclear.

Objective
We aimed to illustrate the mechanisms of resistance to trametinib in PDAC and identify trametinib resistance-associated druggable targets, thus improving the treatment efficacy of trametinib-resistant PDAC.

Design
We established patient-derived xenograft (PDX) models and primary cell lines to conduct functional experiments. We also applied single-cell RNA sequencing, Assay for Transposase-accessible Chromatin with sequencing and Cleavage Under Targets and Tagmentation sequencing to explore the relevant molecular mechanism.

Results
We have identified a cancer cell subpopulation featured by hyperactivated viral mimicry response in trametinib-resistant PDXs. We have demonstrated that trametinib treatment of PDAC PDXs induces expression of transcription factor MAX dimerisation protein 1 (MXD1), which acts as a cofactor of histone methyltransferase mixed lineage leukaemia 1 to increased H3K4 trimethylation in transposable element (TE) loci, enhancing chromatin accessibility and thus the transcription of TEs. Mechanistically, enhanced transcription of TEs produces excessive double-stranded RNAs, leading to the activation of viral mimicry response and downstream oncogenic interferon-stimulated genes. Inhibiting MXD1 expression can recover the drug vulnerability of trametinib-resistant PDAC cells to trametinib.

Conclusions
Our study has discovered an important mechanism for trametinib resistance and identified MXD1 as a druggable target in treatment of trametinib-resistant PDAC.

Introduction
There is a need for early, non-invasive and inexpensive biomarkers for Alzheimer’s disease (AD), which could serve as a proxy measure in prevention and intervention trials that might eventually be suitable for mass screening. People with Down syndrome (DS) are the largest patient group whose condition is associated with a genetically determined increased risk of AD. The REVEAL study aims to examine changes in the structure and function of the eye in individuals with DS compared with those with mild cognitive impairment (MCI) and cognitively healthy control (HC) individuals. REVEAL will also explore whether these changes are connected to inflammatory markers previously associated with AD.

Methods and analysis
The protocol describes a cross-sectional, non-interventional, single-centre study recruiting three cohorts, including (1) participants with DS (target n=50; age range, 6–60 years), (2) participants with MCI (target n=50; age range, 50–80 years) and (3) HC participants (target n=50; age range, 50–80 years). The primary research objective is to profile retinal, choroidal and lenticular status using a variety of eye imaging modalities and retinal functional testing to determine potential associations with cognitive status. The REVEAL study will also measure and compare established blood markers for AD and proteomic and transcriptomic marker profiles between DS, MCI and HC groups. Between-group differences will be assessed with an independent sample t-test and 2 tests for normally distributed or binary measures, respectively. Multivariate regression analysis will be used to analyse parameters across all three cohorts. Data collection began in October 2023 and is expected to end in October 2025.

Ethics and dissemination
The study gained a favourable opinion from Health and Social Care Research Ethics Committee A (REC reference 22/NI/0158; approved on 2 December 2022; Amendment 22/0064 Amend 1, 5 April 2023; Amendment 22/0064 Amend 2; 23 May 2024; Amendment 22/0064 Amend 3; 25 June 2024; Amendment 22/0064 Amend 4; 16 January 2025; Amendment 22.0064 Amend 5; 9 May 2025; Amendment 22.0064 Amend 6; 9 June 2025). The study has also been reviewed and approved by the School of Biomedical Sciences Research Ethics Filter Committee within Ulster University. Findings from the REVEAL study will be presented to academic audiences at international conferences and peer-reviewed publications in targeted high-impact journals after data collection and analysis are complete. Dissemination activities will also include presentations at public events.

This study highlights the urgent need for comprehensive, context-sensitive NCD monitoring frameworks. The proposed set of indicators offers a validated foundation for improving NCD care delivery and aligns with efforts to achieve SDG target 3.4. Ongoing updates and local adaptations will be essential to ensure continued relevance and effectiveness.

This Viewpoint describes the target trial emulation approach and the importance of it being used thoughtfully and correctly.

This cohort study examines membrane target expression in RET fusion–positive non–small cell lung cancer.

In Reply In response to our recent Viewpoint, Ms Wilson and colleagues raise important points about potential POC testing conducted among American Indian and Alaska Native individuals and on tribal lands. More broadly, they highlight the importance of ensuring inclusive and transparent public health services that meet the needs of the target populations they are designed to serve.

To the Editor We read with interest the study by Canales et al, which used target trial emulation to examine the adverse outcomes of as-needed blood pressure (BP) medications in hospitalized veterans. As hospital-based internists, we understand the uncertainties surrounding the treatment of asymptomatic BP elevations among inpatients and welcome further research on this issue. However, this study has methodological limitations that require acknowledgment.

Starace (Cnel), Pronto soccorso sono già sotto pressione. Si sposta l’assistenza a casa del paziente riducendo i rischi

Circulation, Ahead of Print. BACKGROUND:Pathological cardiac remodeling after myocardial infarction (MI) is a leading cause of heart failure and sudden death. The detailed mechanisms underlying the transition to heart failure after MI are not fully understood. Disruptions in the endoplasmic reticulum (ER)–mitochondria connectivity, along with mitochondrial dysfunction, are substantial contributors to this remodeling process. In this study, we aimed to explore the impact of mitochondrial tumor suppressor 1A (Mtus1A) on cardiac remodeling subsequent to MI and elucidate its regulatory role in ER-mitochondria interactions.METHODS:Single-nucleus RNA sequencing analysis was performed to delineate the expression patterns of Mtus1 in human cardiomyocytes under ischemic stress. MI models were induced in mice by left coronary artery ligation and replicated in vitro using primary neonatal rat ventricular myocytes exposed to oxygen glucose deprivation. Cardiac-specific deletion of Mtus1 was achieved by crossing floxed Mtus1 mice with the Myh6-MerCreMer mice. The impact of Mtus1A, a mitochondrial isoform of Mtus1, on cardiac function and the molecular mechanisms were investigated in both in vivo and in vitro settings. Mitochondria-associated ER membranes coupling levels were evaluated by transmission electron microscopy and live-cell imaging. Protein interactions involving Mtus1A were explored through immunoprecipitation–mass spectrometry, coimmunoprecipitation, and proximity ligation assay. The roles of Mtus1A and Fbxo7 (F-box protein 7) were validated in a murine MI model using adeno-associated virus serotype 9 (AAV9).RESULTS:Bioinformatics analysis revealed a significant downregulation of Mtus1 expression in human cardiomyocytes under ischemic conditions, indicating its potential role in stress response. The predominant isoform in murine cardiomyocytes, Mtus1A, showed reduced expression in the left ventricle of mice after MI, which is consistent with the decreased levels of its orthologs in heart tissues from patients with MI. Cardiac-specific knockout of Mtus1 in mice exacerbated cardiac dysfunction after MI. Both in vitro and in vivo studies demonstrated the vital role of Mtus1A in modulating mitochondria-associated ER membranes coupling and preserving mitochondrial function. Mechanistically, Mtus1A functions as a scaffold protein that maintains the formation of inositol 1,4,5-trisphosphate receptor 1 (IP3R1)–glucose-regulated protein 75 (Grp75)–voltage-dependent anion channel 1 (VDAC1) complex through its amino acid sequence 189-219. In addition, Mtus1A protein is stabilized by K6-linked ubiquitination through the E3 ubiquitin ligase Fbxo7. Mtus1A overexpression in mice mitigated MI-induced cardiac dysfunction and remodeling by maintaining ER-mitochondria connectivity.CONCLUSIONS:Our study demonstrates that Mtus1A is crucial for modulating MI-induced cardiac remodeling by preserving ER-mitochondria communication and ameliorating mitochondrial function in cardiomyocytes. Mtus1A may serve as a potential therapeutic target for treating heart failure after MI.