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.

Ischemia is the underlying mechanism in a wide variety of acute and persistent pathologies. As such, understanding the fine intracellular events occurring during (and after) the restriction of blood supply is pivotal to improving the outcomes in clinical settings. Among others, gaseous signaling molecules constitutively produced by mammalian cells (gasotransmitters) have been shown to be of potential interest for clinical treatment of ischemia/reperfusion injury. Nitric oxide (NO and its sibling, HNO), hydrogen sulfide (H₂S), and carbon monoxide (CO) have long been proven to be cytoprotective in basic science experiments, and they are now awaiting confirmation with clinical trials. The aim of this work is to review the literature and the clinical trials database to address the state of development of potential therapeutic applications for NO, H₂S, and CO and the clinical scenarios where they are more promising.

Background: High total IgE levels are weak predictors of T2_High and have been reported in nonallergic asthma. Therefore, the role of total serum IgE (IgE) in the T2_High phenotype is still debated. Objective: This study investigated the reliability of stratifying asthmatics into IgE_High and IgE_Low within the T2_High and T2_Low phenotypes. Methods: This cross-sectional single-center study investigated the association of clinical, functional, and bio-humoral parameters in a large asthmatic population stratified by IgE ≥ 100 kU/L, allergen sensitization, B-EOS ≥ 300/µL, and F_ENO ≥ 30 ppb. Results: Combining T2 biomarkers and IgE identifies (1) T2_Low-IgE_Low (15.5%); (2) T2_Low-IgE_High (5.1%); (3) T2_High-IgE_Low (33.6%); and T2_High-IgE_High (45.7%). T2_Low-IgE_Low patients have more frequent cardiovascular and metabolic comorbidities, a higher prevalence of emphysema, and higher LAMA use than the two T2_High subgroups. Higher exacerbation rates, rhinitis, and anxiety/depression syndrome characterize the T2_Low-IgE_High phenotype vs. the T2_Low-IgE_Low phenotype. Within the T2_High, low IgE was associated with female sex, obesity, and anxiety/depression. Conclusions: High IgE in T2_Low patients is associated with a peculiar clinical phenotype, similar to T2_High in terms of disease severity and nasal comorbidities, while retaining the T2_Low features. IgE may represent an additional biomarker for clustering asthma in both T2_High and T2_Low phenotypes rather than a predictor of T2_High asthma “per se”.

Introduction: Glyphosate is the active compound of different non-selective herbicides, being the most used agriculture pesticide worldwide. Glyphosate and AMPA (one of its main metabolites) are common pollutants of water, soil, and food sources such as crops. They can be detected in biological samples from both exposed workers and general population. Despite glyphosate acts as inhibitor of the shikimate pathway, present only in plants and some microorganisms, its safety in mammals is still debated. Acute glyphosate intoxications are correlated to cardiovascular/neuronal damages, but little is known about the effects of the chronic exposure.Methods: We evaluated the direct biological effects of different concentrations of pure glyphosate/AMPA on a rat-derived cell line of cardiomyoblasts (H9c2) in acute (1–2 h) or sub-chronic (24–48 h) settings. We analyzed cell viability/morphology, ROS production and mitochondrial dynamics.Results: Acute exposure to high doses (above 10 mM) of glyphosate and AMPA triggers immediate cytotoxic effects: reduction in cell viability, increased ROS production, morphological alterations and mitochondrial function. When exposed to lower glyphosate concentrations (1 μM—1 mM), H9c2 cells showed only a slight variation in cell viability and ROS production, while mitochondrial dynamic was unvaried. Moreover, the phenotype was completely restored after 48 h of treatment. Surprisingly, the sub-chronic (48 h) treatment with low concentrations (1 μM—1 mM) of AMPA led to a late cytotoxic response, reflected in a reduction in H9c2 viability.Conclusion: The comprehension of the extent of human exposure to these molecules remains pivotal to have a better critical view of the available data.

Background: Indirect comparison among biologics in severe asthma (SA) is a challenging but desirable goal for clinicians in real life. The aim of the study is to define characteristics of a biologic-treated T2-driven-SA population and to evaluate the effectiveness of biologic treatments in a real-world setting by variation in intra/inter-biologic parameters in an up to 4-year follow-up. Methods: Demographic, clinical, functional, and biological characteristics were evaluated retrospectively in 104 patients recruited until July 2022 at baseline (T0) and over a maximum of 4 years (T4) of biologic therapy (omalizumab/OmaG = 41, from T0 to T4, mepolizumab/MepoG = 26, from T0 to T4, benralizumab/BenraG = 18, from T0 to T2, and dupilumab/DupiG = 19, from T0 to T1). Variations of parameters using means of paired Delta were assessed. Results: At baseline, patients had high prevalence of T2-driven comorbidities, low asthma control test (ACT mean 17.65 ± 4.41), impaired pulmonary function (FEV₁ 65 ± 18 %pred), frequent exacerbations/year (AEs 3.5 ± 3), and OCS dependence (60%). DupiG had lower T2 biomarkers/comorbidities and AEs, and worse FEV₁ (57 ± 19 %pred) compared to other biologics (p < 0.05). All biologics improved ACT, FEV₁%, FVC%, AEs rate, and OCS use. FEV₁% improved in MepoG and BenraG over the minimal clinically important difference and was sustained over 4 years in OmaG and MepoG. A significant RV reduction in OmaG (T4) and DupiG (T1), and BenraG normalization (T2) of airflow limitation were found. We observed through inter-biologic parameters pair delta variation comparison a significant nocturnal awakenings reduction in BenraG vs. OmaG/MepoG, and neutrophils reduction in BenraG/DupiG vs. OmaG. Conclusions: Indirect comparison among biologics unveils clinical and functional improvements that may mark a different effectiveness. These results may highlight the preference of a single biologic compared to another with regard to specific treatable traits.