Iron accumulation is a key mediator of several cytotoxic mechanisms leading to the impairment of redox homeostasis and cellular death. Iron overload is often associated with haematological diseases which require regular blood transfusion/phlebotomy, and it represents a common complication in thalassaemic patients. Major damages predominantly occur in the liver and the heart, leading to a specific form of cell death recently named ferroptosis. Different from apoptosis, necrosis, and autophagy, ferroptosis is strictly dependent on iron and reactive oxygen species, with a dysregulation of mitochondrial structure/function. Susceptibility to ferroptosis is dependent on intracellular antioxidant capacity and varies according to the different cell types. Chemotherapy-induced cardiotoxicity has been proven to be mediated predominantly by iron accumulation and ferroptosis, whereas there is evidence about the role of ferritin in protecting cardiomyocytes from ferroptosis and consequent heart failure. Another paradigmatic organ for transfusion-associated complication due to iron overload is the liver, in which the role of ferroptosis is yet to be elucidated. Some studies report a role of ferroptosis in the initiation of hepatic inflammation processes while others provide evidence about an involvement in several pathologies including immune-related hepatitis and acute liver failure. In this manuscript, we aim to review the literature to address putative common features between the response to ferroptosis in the heart and liver. A better comprehension of (dys)similarities is pivotal for the development of future therapeutic strategies that can be designed to specifically target this type of cell death in an attempt to minimize iron-overload effects in specific organs.

Asthma is a heterogeneous and complex condition characterized by chronic airway inflammation, which may be clinically stratified into three main phenotypes: type 2 (T2) low, T2-high allergic, and T2-high non-allergic asthma. This real-world study investigated whether phenotyping patients with asthma using non-invasive parameters could be feasible to characterize the T2-low and T2-high asthma phenotypes in clinical practice. This cross-sectional observational study involved asthmatic outpatients (n = 503) referring to the Severe Asthma Centre of the San Luigi Gonzaga University Hospital. Participants were stratified according to the patterns of T2 inflammation and atopic sensitization. Among outpatients, 98 (19.5%) patients had T2-low asthma, 127 (25.2%) T2-high non-allergic, and 278 (55.3%) had T2-high allergic phenotype. In comparison to T2-low, allergic patients were younger (OR 0.945, p < 0.001) and thinner (OR 0.913, p < 0.001), had lower smoke exposure (OR 0.975, p < 0.001) and RV/TLC% (OR 0.950, p < 0.001), higher prevalence of asthma severity grade 5 (OR 2.236, p < 0.05), more frequent rhinitis (OR 3.491, p < 0.001) and chronic rhinosinusitis with (OR 2.650, p < 0.001) or without (OR 1.919, p < 0.05) nasal polyps, but less common arterial hypertension (OR 0.331, p < 0.001). T2-high non-allergic patients had intermediate characteristics. Non-invasive phenotyping of asthmatic patients is possible in clinical practice. Identifying characteristics in the three main asthma phenotypes could pave the way for further investigations on useful biomarkers for precision medicine.

Endothelial cell injury and vascular function strongly correlate with cardiac function following ischemia/reperfusion injury. Several studies indicate that endothelial cells are more sensitive to ischemia/reperfusion compared to cardiomyocytes and are critical mediators of cardiac ischemia/reperfusion injury. H2S is involved in the regulation of cardiovascular system homeostasis and can act as a cytoprotectant during ischemia/reperfusion. Activation of ERK1/2 in endothelial cells after H2S stimulation exerts an enhancement of angiogenesis while its inhibition significantly decreases H2S cardioprotective effects. In this work, we investigated how H2S pretreatment for 24 hours prevents the ischemia/reperfusion injury and promotes angiogenesis on microvascular endothelial cells following an ischemia/reperfusion protocol in vitro, using a hypoxic chamber and ischemic buffer to simulate the ischemic event. H2S preconditioning positively affected cell viability and significantly increased endothelial cell migration when treated with 1 μM H2S. Furthermore, mitochondrial function was preserved when cells were preconditioned. Since ERK1/2 phosphorylation was extremely enhanced in ischemia/reperfusion condition, we inhibited ERK both directly and indirectly to verify how H2S triggers this pathway in endothelial cells. Taken together, our data suggest that H2S treatment 24 hours before the ischemic insult protects endothelial cells from ischemia/reperfusion injury and eventually decreases myocardial injury.

In systemic lupus erythematosus (SLE) patients, most of the clinical manifestation share a vascular component triggered by endothelial dysfunction. Endothelial cells (ECs) activation occurs both on the arterial and venous side, and the high vascular density of kidneys accounts for the detrimental outcomes of SLE through lupus nephritis (LN). Kidney damage, in turn, exerts a negative feedback on the cardiovascular (CV) system aggravating risk factors for CV diseases such as hypertension, stroke and coronary syndrome among others. Despite the intensive investigation on SLE and LN, the role of endothelial dysfunction, as well as the underlying mechanisms, remains to be fully understood, with no specifically targeted pharmacological treatment. It is not known, in fact, if the activation pathway(s) in venous ECs are similar to the one in arterial ECs and doubts persist on the shared manifestation of microcirculation compared to macrocirculation. In this work, we aim to review the recent literature about the role of endothelial activation and dysfunction in the development of CV complications in SLE and LN patients. We, therefore, focus on arteriovenous similarities and differences and on specific pathways of great vessels compared to capillaries. Critically summarising the available data is of pivotal importance for both basic researchers and clinicians in order to develop and test new pharmacological approaches in the treatment of basic components of SLE and LN.

<b><i>Background:</i></b> In asthma, exhaled nitric oxide (F_ENO) is a clinically established biomarker of airway T2 inflammation and an indicator for anti-inflammatory therapy. <b><i>Objectives:</i></b> The aim of the study was to identify, in an observational real-world cross-sectional study, the main characteristics of patients with asthma as classified by their F_ENO level. <b><i>Method:</i></b> We stratified 398 patients with stable mild-to-severe asthma according to F_ENO level as low (≤25 ppb) versus elevated (&#x3e;25 ppb), subdividing the latter into two subgroups: moderately elevated (26–50 ppb) versus very high F_ENO (&#x3e;50 ppb). Clinical, functional, and blood parameters were extrapolated from patients’ chart data and compared with the F_ENO stratification. Predictors of low and elevated F_ENO asthma were detected by logistic regression model. <b><i>Results:</i></b> Low BMI, higher blood eosinophilia, allergen poly-sensitization, the severest airflow obstruction (FEV₁/FVC), and anti-leukotriene use are predictors of elevated F_ENO values in asthma, as well as persistent rhinitis and chronic rhinosinusitis with or without nasal polyps. Beyond these, younger age, more than 2 asthma exacerbations/year, higher airflow reversibility (post-bronchodilator ∆FEV₁), and oral corticosteroid dependence are predictors of very high F_ENO values. In contrast, obesity, obstructive sleep apnoea syndrome, gastroesophageal reflux disease, arterial hypertension, and myocardial infarction are predictors of low F_ENO asthma. In our population, F_ENO correlated with blood eosinophils, airflow obstruction, and reversibility and negatively correlated with age and BMI. <b><i>Conclusions:</i></b> Stratifying patients by F_ENO level can identify specific asthma phenotypes with distinct clinical features and predictors useful in clinical practice to tailor treatment and improve asthmatic patients’ outcomes.