Cardiovascular disease (CVD) represents a major threat for human health. The available preventive and treatment interventions are insufficient to revert the underlying pathological processes, which underscores the urgency of alternative approaches. Mitochondria dysfunction plays a key role in the etiopathogenesis of CVD and is regarded as an intriguing target for the development of innovative therapies. Oxidative stress, mitochondrial permeability transition pore opening, and excessive fission are major noxious pathways amenable to drug therapy. Thanks to the advancements of nanotechnology research, several mitochondria-targeted drug delivery systems (DDS) have been optimized with improved pharmacokinetic and biocompatibility, and lower toxicity and antigenicity for application in the cardiovascular field. This review summarizes the recent progress and remaining obstacles in targeting mitochondria as a novel therapeutic option for CVD. The advantages of nanoparticle delivery over un-targeted strategies are also discussed.
The available evidence indicates a close connection between gut microbiota (GM) disturbance and increased risk of cardiometabolic (CM) disorders and cardiovascular (CV) disease. One major objective of this narrative review is to discuss the key contribution of dietary regimen in determining the GM biodiversity and the implications of GM dysbiosis for the overall health of the CV system. In particular, emerging molecular pathways are presented, linking microbiota-derived signals to the local activation of the immune system as the driver of a systemic proinflammatory state and permissive condition for the onset and progression of CM and CV disease. We further outline how the cross-talk between sex hormones and GM impacts disease susceptibility, thereby offering a mechanistic insight into sexual dimorphism observed in CVD. A better understanding of these relationships could help unravel novel disease targets and pave the way to the development of innovative, low-risk therapeutic strategies based on diet interventions, GM manipulation, and sex hormone analogues.
The opening of the ATP-sensitive mitochondrial potassium channel (mitok-ATP) is a common goal of cardioprotective strategies in the setting of acute and chronic myocardial disease. The biologically active thyroid hormone (TH), 3-5-3-triiodothyronine (T3), has been indicated as a potential activator of mitoK-ATP but the underlying mechanisms are still elusive. Here we describe a novel role of T3 in the transcriptional regulation of mitoK and mitoSur, the recently identified molecular constituents of the channel. To mimic human ischemic heart damage, we used a rat model of a low T3 state as the outcome of a myocardial ischemia/reperfusion event, and neonatal rat cardiomyocytes (NRCM) challenged with hypoxia or H2O2. Either in the in vivo or in vitro models, T3 administration to recover the physiological concentrations was able to restore the expression level of both the channel subunits, which were found to be downregulated under the stress conditions. Furthermore, the T3-mediated transcriptional activation of mitoK-ATP in the myocardium and NRCM was associated with the repression of the TH-inactivating enzyme, deiodinase 3 (Dio3), and an up-regulation of the T3-responsive miR-133a-3p. Mechanistically, the loss and gain of function experiments and reporter gene assays performed in NRCM, have revealed a new regulatory axis whereby the silencing of Dio3 under the control of miR-133a-3p drives the T3-dependent modulation of cardiac mitoK and mitoSur transcription.
Alzheimer’s disease (AD) is the leading cause of dementia, but the pathogenetic factors are not yet well known, and the relationships between brain and systemic biochemical derangements and disease onset and progression are unclear. We aim to focus on blood biomarkers for an accurate prognosis of the disease. We used a dataset characterized by longitudinal findings collected over the past 10 years from 90 AD patients. The dataset included 277 observations (both clinical and biochemical ones, encompassing blood analytes encompassing routine profiles for different organs, together with immunoinflammatory and oxidative markers). Subjects were grouped into four severity classes according to the Clinical Dementia Rating (CDR) Scale: mild (CDR = 0.5 and CDR = 1), moderate (CDR = 2), severe (CDR = 3) and very severe (CDR = 4 and CDR = 5). Statistical models were used for the identification of potential blood markers of AD progression. Moreover, we employed the Pathfinder tool of the Reactome database to investigate the biological pathways in which the analytes of interest could be involved. Statistical results reveal an inverse significant relation between four analytes (high-density cholesterol, total cholesterol, iron and ferritin) with AD severity. In addition, the Reactome database suggests that such analytes could be involved in pathways that are altered in AD progression. Indeed, the identified blood markers include molecules that reflect the heterogeneous pathogenetic mechanisms of AD. The combination of such blood analytes might be an early indicator of AD progression and constitute useful therapeutic targets.
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