Association of Antihypertensives That Stimulate vs Inhibit Types 2 and 4 Angiotensin II Receptors With Cognitive Impairment

JAMA Network Open, Год журнала: 2022, Номер 5(1), С. e2145319 - e2145319

Опубликована: Янв. 28, 2022

Importance

Use of antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, compared with those do not these has been associated a lower risk dementia. However, this association cognitive outcomes in hypertension trials, blood pressure levels the range current guidelines, evaluated.

Objective

To examine between use exclusively medication regimens vs inhibit receptors on mild impairment (MCI) or

Design, Setting, Participants

This cohort study is secondary analysis (April 2011 to July 2018) participants randomized Systolic Blood Pressure Intervention Trial (SPRINT), which recruited individuals 50 years older increased cardiovascular but without history diabetes, stroke, Data was conducted from March 16 6, 2021.

Exposures

Prevalent receptor 4–stimulating –inhibiting at 6-month visit.

Main Outcomes Measures

The primary outcome composite adjudicated amnestic MCI probable

Results

Of 8685 SPRINT who were prevalent users visit (mean [SD] age, 67.7 [11.2] years; 5586 [64.3%] male; 935 [10.8%] Hispanic, 2605 [30.0%] non-Hispanic Black, 4983 [57.4%] White, 162 [1.9%] responded as other race ethnicity), 2644 (30.4%) stimulating, 1536 (17.7%) inhibiting, 4505 (51.9%) mixed regimens. During median 4.8 follow-up (95% CI, 4.7-4.8 years), there 45 59 cases per 1000 person-years dementia among contained stimulating inhibiting (hazard ratio [HR], 0.76; 95% 0.66-0.87). When comparing stimulating-only inhibiting-only users, occurred rates 40 54 (HR, 0.74; 0.64-0.87) 8 10 0.80; 0.57-1.14). Negative control analyses suggested presence residual confounding.

Conclusions Relevance

In SPRINT, contain had incident impairment. Residual confounding cannot be ruled out. If results are replicated clinical certain could prioritized prevent decline.

Язык: Английский

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MEK1/2 inhibition rescues neurodegeneration by TFEB-mediated activation of autophagic lysosomal function in a model of Alzheimer’s Disease

Molecular Psychiatry, Год журнала: 2022, Номер 27(11), С. 4770 - 4780

Опубликована: Авг. 10, 2022

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder, which characterized by cognitive deficit due to synaptic loss and neuronal death. Extracellular amyloid β plaques are one of the pathological hallmarks AD. The autophagic lysosomal pathway essential mechanism maintain cellular homeostasis driving clearance protein aggregates dysfunctional in Here, we showed that inhibiting MEK/ERK signaling using clinically available MEK1/2 inhibitor, trametinib (GSK1120212, SNR1611), induces protection neurons through activation mediated transcription factor EB (TFEB) model Orally administered recovered impaired neural structures, functions, hippocampal long-term potentiation (LTP) 5XFAD mice. Trametinib also reduced Aβ deposition via induction activation. RNA-sequencing analysis revealed upregulation genes administration. In addition, inhibited TFEB phosphorylation at Ser142 promoted its nuclear translocation, turn induced related genes, indicating activates process From these observations, concluded MEK inhibition provides from burden increasing activity. Thus, may be an effective therapeutic strategy for

Язык: Английский

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Angiotensin-converting enzyme 2 (ACE2): Two decades of revelations and re-evaluation

Peptides, Год журнала: 2022, Номер 151, С. 170766 - 170766

Опубликована: Фев. 10, 2022

Язык: Английский

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GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight

Cells, Год журнала: 2022, Номер 11(13), С. 2023 - 2023

Опубликована: Июнь 25, 2022

Defects in brain energy metabolism and proteopathic stress are implicated age-related degenerative neuronopathies, exemplified by Alzheimer’s disease (AD) Parkinson’s (PD). As the currently available drug regimens largely aim to mitigate cognitive decline and/or motor symptoms, there is a dire need for mechanism-based therapies that can be used improve neuronal function potentially slow down underlying processes. In this context, new class of pharmacological agents achieve improved glycaemic control via glucagon-like peptide 1 (GLP-1) receptor has attracted significant attention as putative neuroprotective agents. The experimental evidence supporting their potential therapeutic value, mainly derived from cellular animal models AD PD, been discussed several research reports review opinions recently. article, we discuss pathological relevance derangements neurovascular unit significance neuron–glia metabolic coupling PD. With also some unresolved questions with regard benefits GLP-1 agonists on (NVU), provide examples novel paradigms could useful improving our understanding regarding mode action associated these

Язык: Английский

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ApoE4 associated with severe COVID-19 outcomes via downregulation of ACE2 and imbalanced RAS pathway

Journal of Translational Medicine, Год журнала: 2023, Номер 21(1)

Опубликована: Фев. 9, 2023

Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk severity of coronavirus disease 2019 (COVID-19), yielded inconsistent results. Severe acute respiratory syndrome 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme (ACE2) receptor expressed host cell membranes.A meta-analysis was conducted clarify between COVID-19. Multiple interaction assays were utilized investigate potential molecular link SARS-CoV-2 primary ACE2, protein. Immunoblotting immunofluorescence staining methods used access regulatory effect different isoform ACE2 expression.ApoE gene (ε4 carrier genotypes VS non-ε4 genotypes) is increased (P = 0.0003, OR 1.44, 95% CI 1.18-1.76) progression < 0.00001, 1.85, 1.50-2.28) interacts both but did not show isoform-dependent effects. ApoE4 significantly downregulates expression in vitro vivo subsequently decreases conversion Ang II 1-7.ApoE4 increases infectivity a manner may depend differential interactions or ACE2. Instead, dysregulation renin-angiotensin system (RAS) provide explanation by which exacerbates COVID-19 disease.

Язык: Английский

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