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

Synthesis and characterisation of a new benzamide-containing nitrobenzoxadiazole as a GSTP1-1 inhibitor endowed with high stability to metabolic hydrolysis

The antitumor agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (1) is a potent inhibitor of GSTP1-1, a glutathione S-transferase capable of inhibiting apoptosis by binding to JNK1 and TRAF2. We recently demonstrated that, unlike its parent compound, the benzoyl ester of 1 (compound 3) exhibits negligible reactivity towards GSH, and has a different mode of interaction with GSTP1-1. Unfortunately, 3 is susceptible to rapid metabolic hydrolysis. In an effort to improve the metabolic stability of 3, its ester group has been replaced by an amide, leading to N-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexyl)benzamide (4). Unlike 3, compound 4 was stable to human liver microsomal carboxylesterases, but retained the ability to disrupt the interaction between GSTP1-1 and TRAF2 regardless of GSH levels. Moreover, 4 exhibited both a higher stability in the presence of GSH and a greater cytotoxicity towards cultured A375 melanoma cells, in comparison with 1 and its analog 2. These findings suggest that 4 deserves further preclinical testing

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

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

“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

Interplay between Nox2 activity and platelet activation in patients with sepsis and septic shock. a prospective study

Background. Although preclinical studies highlighted the potential role of NADPH oxidase (NOX) in sepsis, only few studies evaluated the oxidative stress in patients with sepsis and septic shock. The objective of the study is to appraise the oxidative stress status and platelet function in patients with sepsis and septic shock compared to healthy controls. Methods and Results. Patients with sepsis or septic shock admitted to the hospital Policlinico Umberto I (Sapienza University, Rome) underwent a blood sample collection within 1 hour from admission. Platelet aggregation, serum thromboxane B2 (TxB2), soluble NOX2-derived peptides (sNox2-dp), and hydrogen peroxide breakdown activity (HBA) were measured and compared to those of healthy volunteers. Overall, 33 patients were enrolled; of these, 20 (60.6%) had sepsis and 13 (39.4%) septic shock. Compared to healthy controls (n=10, age 67.8±3.2, male 50%), patients with sepsis and septic shock had higher platelet aggregation (49% (IQR 45-55), 60% (55.75-67.25), and 73% (IQR 69-80), respectively, p<0.001), higher serum TxB2 (77.5 (56.5-86.25), 122.5 (114-131.5), and 210 (195-230) pmol/L, respectively, p<0.001), higher sNox2-dp (10 (7.75-12), 19.5 (17.25-21), and 33 (29.5-39) pg/mL, respectively, p<0.001), and lower HBA (75% (67.25-81.5), 50% (45-54.75), and 27% (21.5-32.5), respectively, p<0.001). Although not statistically significant, a trend in higher levels of serum TxB2 and sNox2-dp in patients who died was observed. Conclusions. Patients with septic shock exhibit higher Nox2 activity and platelet activation than patients with sepsis. These insights joined to better knowledge of these mechanisms could guide the identification of future prognostic biomarkers and new therapeutic strategies in the scenario of septic shock

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

A dynamic folded hairpin conformation is associated with α-globin activation in erythroid cells

We investigate the three-dimensional (3D) conformations of the α-globin locus at the single-allele level in murine embryonic stem cells (ESCs) and erythroid cells, combining polymer physics models and high-resolution Capture-C data. Model predictions are validated against independent fluorescence in situ hybridization (FISH) data measuring pairwise distances, and Tri-C data identifying three-way contacts. The architecture is rearranged during the transition from ESCs to erythroid cells, associated with the activation of the globin genes. We find that in ESCs, the spatial organization conforms to a highly intermingled 3D structure involving non-specific contacts, whereas in erythroid cells the α-globin genes and their enhancers form a self-contained domain, arranged in a folded hairpin conformation, separated from intermingling flanking regions by a thermodynamic mechanism of micro-phase separation. The flanking regions are rich in convergent CTCF sites, which only marginally participate in the erythroid-specific gene-enhancer contacts, suggesting that beyond the interaction of CTCF sites, multiple molecular mechanisms cooperate to form an interacting domain

Impact of environmental pollution and weather changes on the incidence of ST-elevation myocardial infarction

Background: Environmental pollution and weather changes unfavorably impact on cardiovascular disease. However, limited research has focused on ST-elevation myocardial infarction (STEMI), the most severe yet distinctive form of acute coronary syndrome. Methods and results: We appraised the impact of environmental and weather changes on the incidence of STEMI, analysing the bivariate and multivariable association between several environmental and atmospheric parameters and the daily incidence of STEMI in two large Italian urban areas. Specifically, we appraised: carbon monoxide (CO), nitrogen dioxide (NO2), nitric oxide (NOX), ozone, particulate matter smaller than 10 μm (PM10) and than 2.5 μm (PM2.5), temperature, atmospheric pressure, humidity and rainfall. A total of 4285 days at risk were appraised, with 3473 cases of STEMI. Specifically, no STEMI occurred in 1920 (44.8%) days, whereas one or more occurred in the remaining 2365 (55.2%) days. Multilevel modelling identified several pollution and weather predictors of STEMI. In particular, concentrations of CO (p=0.024), NOX (p=0.039), ozone (p=0.003), PM10 (p=0.033) and PM2.5 (p=0.042) predicted STEMI as early as three days before the event, as well as subsequently, and NO predicted STEMI one day before (p = 0.010), as well as on the same day. A similar predictive role was evident for temperature and atmospheric pressure (all p < 0.05). Conclusions: The risk of STEMI is strongly associated with pollution and weather features. While causation cannot yet be proven, environmental and weather changes could be exploited to predict STEMI risk in the following days