Inflammasome, T Lymphocytes and Innate-Adaptive Immunity Crosstalk: Role in Cardiovascular Disease and Therapeutic Perspectives

AbstractOver the past few decades, lot of evidences have shown atherosclerosis as a chronic progressive disease with an exquisite inflammatory feature. More recently, the role of innate immune response in the onset and progression of coronary artery disease (CAD) and an adaptive immunity imbalance, mostly involving T cell sub-sets, have been documented. Therefore, like in many other inflammatory and autoimmune disorders, an altered innate-adaptive immunity crosstalk could represent the key of the inflammatory burden leading to atherosclerotic plaque formation and progression and to the breakdown of plaque stability. In this review, we will address the role of inflammasome in innate immunity and in the imbalance of adaptive immunity. We will discuss how this altered immune crosstalk is related to CAD onset and progression. We will also discuss how unravelling the key molecular mechanisms is of paramount importance in the development of therapeutic tools to delay the chronic progression and prevent the acute destabilization of atherosclerotic plaque

The VENERE study: EffectiVenEss of a rehabilitation treatment with Nordic walking in obEse or oveRweight diabetic patiEnts with cardiovascular disease

Background. Nordic walking (NW) has several potential benefits for individuals with cardiovascular disease (CV), type 2 diabetes, and obesity/overweight. It improves cardiovascular health, including exercise capacity and blood pressure control. It enhances glycemic control and insulin sensitivity in diabetes. It aids in weight management and body composition improvement. NW offers additional advantages such as improved muscular strength, joint mobility, physical activity levels, and psychological well-being. Methods. This open-label study with three arms will aim to evaluate the efficacy, safety, and adherence to exercise prescription in obese/overweight diabetic patients with CV complications. The primary objective will be to assess the CV performance of participants after a 6- and 12-month follow-up period, following a 3-month NW intervention, compared with standard rehabilitation (SR) and cardiological counseling (control group, CG) training lasting 3 months. Results. The results of the study will provide valuable insights into the comparative effectiveness of a NW intervention versus SR and CG training in improving cardiovascular performance in obese/overweight diabetic patients with CV complications. Additionally, safety and adherence data will help inform the feasibility and sustainability of the exercise prescription over an extended period. Conclusions. These findings may have implications for the development of tailored exercise programs for this specific patient population, with the aim of optimizing cardiovascular health outcomes. This protocol was registered on ClinicalTrials.gov with reference ID: NCT05987410 on 10 August 2023

Analysis of human MDM4 variants in papillary thyroid carcinomas reveals new potential markers of cancer properties

A wild-type (wt) p53 gene characterizes thyroid tumors, except for the rare anaplastic histotype. Because p53 inactivation is a prerequisite for tumor development, alterations of p53 regulators represent an alternative way to impair p53 function. Indeed, murine double minute 2 (MDM2), the main p53 negative regulator, is overexpressed in many tumor histotypes including those of the thyroid. A new p53 regulator, MDM4 (a.k.a. MDMX or HDMX) an analog of MDM2, represents a new oncogene although its impact on tumor properties remains largely unexplored. We estimated levels of MDM2, MDM4, and its variants, MDM4-S (originally HDMX-S) and MDM4-211 (originally HDMX211), in a group of 57 papillary thyroid carcinomas (PTC), characterized by wt tumor protein 53, in comparison to matched contra-lateral lobe normal tissue. Further, we evaluated the association between expression levels of these genes and the histopathological features of tumors. Quantitative real-time polymerase chain reaction revealed a highly significant downregulation of MDM4 mRNA in tumor tissue compared to control tissue (P < 0.0001), a finding confirmed by western blot on a subset of 20 tissue pairs. Moreover, the tumor-to-normal ratio of MDM4 levels for each individual was significantly lower in late tumor stages, suggesting a specific downregulation of MDM4 expression with tumor progression. In comparison, MDM2 messenger RNA (mRNA) and protein levels were frequently upregulated with no correlation with MDM4 levels. Lastly, we frequently detected overexpression of MDM4-S mRNA and presence of the aberrant form, MDM4-211 in this tumor group. These findings indicate that MDM4 alterations are a frequent event in PTC. It is worthy to note that the significant downregulation of full-length MDM4 in PTC reveals a novel status of this factor in human cancer that counsels careful evaluation of its role in human tumorigenesis and of its potential as therapeutic target

Reduced CD31 expression on CD14(+)CD16(+) monocyte subset in acute coronary syndromes

N/

Adaptive immunity, inflammation, and cardiovascular complications in type 1 and type 2 diabetes mellitus

Diabetes mellitus (DM) is a pandemics that affects more than 170 million people worldwide, associated with increased mortality and morbidity due to coronary artery disease (CAD). In type 1 (T1) DM, the main pathogenic mechanism seems to be the destruction of pancreatic \u3b2 -cells mediated by autoreactive T-cells resulting in chronic insulitis, while in type 2 (T2) DM primary insulin resistance, rather than defective insulin production due to \u3b2 -cell destruction, seems to be the triggering alteration. In our study, we investigated the role of systemic inflammation and T-cell subsets in T1- and T2DM and the possible mechanisms underlying the increased cardiovascular risk associated with these diseases

MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic-apoptotic pathway

MDM4 is a key regulator of p53, whose biological activities depend on both transcriptional activity and transcription-independent mitochondrial functions. MDM4 binds to p53 and blocks its transcriptional activity; however, the main cytoplasmic localization of MDM4 might also imply a regulation of p53-mitochondrial function. Here, we show that MDM4 stably localizes at the mitochondria, in which it (i) binds BCL2, (ii) facilitates mitochondrial localization of p53 phosphorylated at Ser46 (p53Ser46P) and (iii) promotes binding between p53Ser46P and BCL2, release of cytochrome C and apoptosis. In agreement with these observations, MDM4 reduction by RNA interference increases resistance to DNA-damage-induced apoptosis in a p53-dependent manner and independently of transcription. Consistent with these findings, a significant downregulation of MDM4 expression associates with cisplatin resistance in human ovarian cancers, and MDM4 modulation affects cisplatin sensitivity of ovarian cancer cells. These data define a new localization and function of MDM4 that, by acting as a docking site for p53Ser46P to BCL2, facilitates the p53-mediated intrinsic-apoptotic pathway. Overall, our results point to MDM4 as a double-faced regulator of p53