A novel signalling mechanism regulating telomere length in cardiomyocytes

Clinical management and treatment of human diseases are continuously improving, with a progressive elongation of life expectancy in Western countries. As a consequence of the elevation of the average age of the population, the incidence of ageing-related diseases will progressively in- crease in the next years. Among ageing-related diseases, cardiovascular diseases still represent the first of cause of death in the Western world

Editorial: Mitochondrial dysfunction and cardiovascular diseases

A deeper understanding of the molecular mechanisms underlying the development and progression of cardiovascular diseases represents a major goal in cardiovascular medicine. Mitochondrial dysfunction has emerged as major player in the development of cardiovascular diseases, with potential therapeutic implications. Mitochondrial dysfunction encompasses mitochondrial complex disruption, mitochondrial uncoupling, and cristae remodeling and swelling, which in turn cause ROS accumulation, energy stress, and cell death

SARS-CoV-2 and COVID-19. Facing the pandemic together as citizens and cardiovascular practitioners

Despite their highbrow name, coronarvirus have proved eminently disruptive in recent years. Since the epidemic of severe respiratory distress syndrome (SARS) due to the SARS-related coronavirus (SARS-CoV) infection and the Middle East respiratory syndrome (MER S) due to the MER S-related coronavirus (MER S-CoV), several experts could expect the advent of additional epidemics due to coronaviruses. Yet, the ongoing pandemic of coronavirus-associated disease 2019 (COVID -2019) due to the infection from SARS-CoV-2 (also known as 2019-nCoV) has wreaked havoc worldwide (Figure 1). As Italian citizens and cardiovascular practitioners, we are now facing this storm, with a mix of incredulity, fear, boldness, and sense of duty

Lats2 promotes heart failure by stimulating p53-mediated apoptosis during pressure overload

The Hippo pathway plays a wide variety of roles in response to stress in the heart. Lats2, a component of the Hippo pathway, is phosphorylated by Mst1/2 and, in turn, phosphorylates YAP, causing inactivation of YAP. Lats2 stimulates apoptosis and negatively affects hypertrophy in cardiomyocytes. However, the role of Lats2 during cardiac stress is poorly understood in vivo. Lats2 is activated in the mouse heart in response to transverse aortic constriction (TAC). We used systemic Lats2 +/- mice to elucidate the role of endogenous Lats2. Cardiac hypertrophy and dysfunction induced by 4 weeks of TAC were attenuated in Lats2 +/- mice, and interstitial fibrosis and apoptosis were suppressed. Although TAC upregulated the Bcl-2 family proapoptotic (Bax and Bak) and anti-apoptotic (Bcl-2 and Bcl-xL) molecules in non-transgenic mice, TAC-induced upregulation of Bax and Bak was alleviated and that of Bcl-2 was enhanced in Lats2 +/- mice. TAC upregulated p53, but this upregulation was abolished in Lats2 +/- mice. Lats2-induced increases in apoptosis and decreases in survival in cardiomyocytes were inhibited by Pifithrin-α, a p53 inhibitor, suggesting that Lats2 stimulates apoptosis via a p53-dependent mechanism. In summary, Lats2 is activated by pressure overload, thereby promoting heart failure by stimulating p53-dependent mechanisms of cell death

Cell clearing systems as targets of polyphenols in viral infections: Potential implications for COVID-19 pathogenesis

The novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has generated the ongoing coronavirus disease-2019 (COVID-19) pandemic, still with an uncertain outcome. Besides pneumonia and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), other features became evident in the context of COVID-19. These includes endothelial and coagulation dysfunction with disseminated intravascular coagulation (DIC), and multiple organ dysfunction syndrome (MODS), along with the occurrence of neurological alterations. The multi-system nature of such viral infection is a witness to the exploitation and impairment of ubiquitous subcellular and metabolic pathways for the sake of its life-cycle, ranging from host cell invasion, replication, transmission, up to a cytopathic effect and overt systemic inflammation. In this frame, alterations in cell-clearing systems of the host are emerging as a hallmark in the pathogenesis of various respiratory viruses, including SARS-CoV-2. Indeed, exploitation of the autophagy and proteasome pathways might contribute not only to the replication of the virus at the site of infection but also to the spreading of either mature virions or inflammatory mediators at both cellular and multisystem levels. In this frame, besides a pharmacological therapy, many researchers are wondering if some non-pharmacological substances might counteract or positively modulate the course of the infection. The pharmacological properties of natural compounds have gained increasing attention in the field of alternative and adjunct therapeutic approaches to several diseases. In particular, several naturally-occurring herbal compounds (mostly polyphenols) are reported to produce widespread antiviral, anti-inflammatory, and anti-oxidant effects while acting as autophagy and (immuno)-proteasome modulators. This article attempts to bridge the perturbation of autophagy and proteasome pathways with the potentially beneficial effects of specific phytochemicals and flavonoids in viral infections, with a focus on the multisystem SARS-CoV-2 infection

“Discovery of promising 1,2,4-oxadiazoles hits for the development of new anti-inflammatory agents interfering with eicosanoid biosynthesis pathways”

Prostaglandin E2 (PGE2) is an inflammatory mediator that plays a pivotal role in the evolvement and progression of inflammatory and tumor diseases.1The identification of novel inhibitors of eicosanoids biosynthesis with unexplored scaffolds is of great demand to develop a next generation of anti-inflammatory or anti-cancer drugs. Following a multidisciplinary protocol that involves virtual combinatorial screening, chemical synthesis, and validation of the biological activities we afforded to the identification of 1,2,4-oxadiazole-based hits, as a novel class of anti-inflammatory agents able to inhibit several enzymes involved in the progression of inflammation. 1,2,4-oxadiazoles represent a versatile “privileged scaffold” in drug discovery, due to the possibility of modifying and opportunely decorating the nucleus,2 and are never explored for their inhibitory activity on eicosanoid biosynthesis. This multidisciplinary scientific approach led to the identification of a multi-target inhibitor of cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1). Moreover, in vivo studies on the disclosed hit demonstrate that it attenuates leukocytes migration in a model of zymosan-induced peritonitis and modulates the production of IL-1β and TNF-α. These promising outcomes pave the way toward a medicinal chemistry optimization campaign of the disclosed hit characterized by a promising and safer pharmacological profile

The role of antioxidants supplementation in clinical practice. focus on cardiovascular risk factors

Oxidative stress may be defined as an imbalance between reactive oxygen species (ROS) and the antioxidant system to counteract or detoxify these potentially damaging molecules. This phenomenon is a common feature of many human disorders, such as cardiovascular disease. Many of the risk factors, including smoking, hypertension, hypercholesterolemia, diabetes, and obesity, are associated with an increased risk of developing cardiovascular disease, involving an elevated oxidative stress burden (either due to enhanced ROS production or decreased antioxidant protec-tion). There are many therapeutic options to treat oxidative stress-associated cardiovascular dis-eases. Numerous studies have focused on the utility of antioxidant supplementation. However, whether antioxidant supplementation has any preventive and/or therapeutic value in cardiovascular pathology is still a matter of debate. In this review, we provide a detailed description of oxidative stress biomarkers in several cardiovascular risk factors. We also discuss the clinical implications of the supplementation with several classes of antioxidants, and their potential role for protecting against cardiovascular risk factors

Comparative indoor pollution from Glo, Iqos, and Juul, using traditional combustion cigarettes as benchmark. Evidence from the randomized sur-vapes air trial

Modified risk products (MRP) such as electronic vaping cigarettes (EVC) and heat-not-burn cigarettes (HNBC) are appealing alternatives to combustion cigarettes. Limited between-and within-device comparative data are available on MRP. We aimed at comparing indoor particulate matter (PM) emissions measured in a randomized trial enforcing standardized smoking sessions, testing different devices and flavors of MRP, using traditional combustion cigarettes (TCC) as benchmark. Overall, MRP yielded significantly lower levels of indoor PM in comparison to TCC (with median PM levels during smoking for MRP < 100 µg/m3, and for TCC > 1000 µg/m3). Despite this, significant differences among MRP were found, with Iqos appearing associated with a significantly lower burden of emissions for all the monitored fractions of PM, including total PM (all p < 0.05). Precisely, during use, PM ≤ 1 µm (PM1) emissions were 28 (16; 28) µg/m3 for Glo, 25 (15; 57) µg/m3 for Iqos, and 73 (15; 559) µg/m3 for Juul (p < 0.001 for Glo vs. Iqos, p <0.001 for Glo vs. Juul, and p = 0.045 for Iqos vs. Juul). Exploratory within-MRP analyses suggested significant differences between flavors, favoring, for instance, Ultramarine for Glo, Bronze for Iqos, and Mango for Juul, even if results varied substantially according to individual smoker. In conclusion, leading MRP have significantly less intense and persistent effects on indoor pollution in comparison to TCC. Yet, when focusing solely on MRP, between-product and between-flavor differences appear, with quantitative estimates suggesting lower polluting effects with Iqos. These results, if confirmed externally, could be used to individualize product and flavor choice to minimize the untoward effects of EVC and HNBC on indoor pollution

Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model

Friedreich's ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNAseq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management