Modulation of Ferroptosis Biomarkers by Thinned Apple Polyphenols Extract in Acute and Chronic Lung Injuries Rosalba Siracusa, Alessia Arangia, Marika Cordaro, Roberta Fusco, Salvatore Cuzzocrea, et al. Efood, 2026 Acute and chronic lung injuries are characterized by a large amount of ROS, pro‐inflammatory leukocytes and ferroptosis, resulting in alveolar injury. Nowadays, there is great interest in the bioactive compounds obtained from the waste products deriving from agriculture and the food industry. Thinned young apples are particularly rich in polyphenols, more than 10‐fold with respect to harvested apples, and have antioxidant and anti‐inflammatory activities. Therefore, the aim of this study is to investigate whether modulation of ferroptosis biomarkers by thinned apple polyphenols (TAP) extract was able to reduce lung injuries in two experimental model: acute lung injury (ALI) and bleomycin‐induced idiopathic pulmonary fibrosis (IPF). Our results demonstrated that TAP extract was able to inhibit the ferroptosis, modulating the main biomarkers: malondialdehyde, NADPH oxidase‐4, glutathione peroxidase 4 and ferritin heavy chain 1. This modulation is probably due to Nrf2 activation, negative regulator of ferroptosis, by TAP extract and consequently activating the production of antioxidant enzymes. This induced histological alteration, cytokines release and fibrosis in the alveoli and lung parenchyma. Collectively, these results demonstrated that TAP extract was able to reduce ferroptosis in acute and chronic lung injury models, suggesting it as a potential biomarker for early diagnosis and intervention timely.
The Effect of Carnosine Supplementation on Depressive Symptoms and Health-Related Quality of Life in Individuals With Prediabetes and Well-Controlled Type 2 Diabetes: A Randomized Controlled Trial Robel Hussen Kabthymer, Jack Feehan, Aya Mousa, Giancarlo Aldini, Maximilian de Courten, et al. Food Science and Nutrition, 2026 Type 2 diabetes mellitus (T2DM) is commonly associated with mental health disorders such as depression and anxiety. Carnosine, an over‐the‐counter food supplement, may improve depressive symptoms through its anti‐inflammatory properties; however, its effects on depressive symptoms and quality of life in prediabetes or T2DM remain unexplored. This randomized controlled trial aimed to examine whether carnosine supplementation may improve depressive symptoms and quality of life among individuals with prediabetes and well‐controlled T2DM. A total of 38 participants (73.6% male) with a median (IQR) age of 54.8 years (46.2, 59.4) and mean ± SD body mass index (BMI) of 29.0 ± 4.2 kg/m 2 were randomized to carnosine ( n = 18) or placebo ( n = 20) for 14 weeks. None of the patients were diagnosed with depression or anxiety or any other chronic disease other than prediabetes ( n = 20, 52.6%) and T2DM ( n = 18, 47.4%), the latter being well‐controlled with diet or metformin only. Depressive symptoms were measured using the patient health questionnaire (PHQ‐8) and health‐related quality of life was measured with five‐dimension EuroQoL three level (EQ‐5D‐3L) scale. Paired t ‐tests were employed for within‐group comparisons. Analysis of covariance (ANCOVA) was used for between group comparisons adjusted for age, BMI, and baseline values. Carnosine supplementation resulted in improvement of depressive symptoms assessed by total PHQ‐8 score (mean difference = −2.0; 95% CI: −3.9, −0.2; p = 0.03), compared with placebo. However, the eight subcomponents of the PHQ‐8 scale did not show significant changes ( p > 0.05). There were no significant changes both in between‐group and within‐group comparisons in health‐related quality of life scores ( p > 0.05). We demonstrated for the first time that carnosine supplementation resulted in a modest improvement in depressive symptoms in individuals with prediabetes or T2DM. Further studies are needed to corroborate these findings in larger cohorts with more diverse baseline risk profiles. Trial Registration: NCT02917928
The Carnosine–HNE Michael Adduct as a Redox-Active Species Associated with Nrf2-Dependent Antioxidant and Anti-Inflammatory Responses Alessandra Altomare, Giovanna Baron, Francesca Gado, Larissa Della Vedova, Giulio Ferrario, et al. Antioxidants, 2026 Carnosine (CAR), an endogenous histidine-containing dipeptide, exhibits antioxidant and anti-inflammatory activity in various experimental models; however, its molecular mechanism of action remains poorly understood. Here, we demonstrate that the Michael adduct between CAR and 4-hydroxy-2-nonenal (HNE), which has been detected in previous studies in both in vitro and in vivo settings, mediates its bioactivity, particularly its antioxidant and anti-inflammatory responses, through Nrf2 activation. The CAR–HNE adduct was synthesized and its physicochemical, metabolic, and biological properties were evaluated. CAR–HNE exhibited high stability in biological matrices and retained the ability to transfer HNE to thiol nucleophiles at a slow rate under physiologically relevant conditions, consistent with electrophile-mediated Nrf2 activation. This kinetic behavior limits the cytotoxicity typically associated with free HNE while preserving the redox signaling capacity. CAR–HNE induced dose-dependent Nrf2 activation and NF-κB inhibition in cell-based assays without the hormetic toxicity observed for free HNE. Mechanistically, CAR–HNE may act as a redox-tunable electrophilic reservoir, restoring nucleophilic tone and modulating redox-sensitive transcription factors. In vivo, CAR–HNE attenuated DSS-induced colitis more effectively than equimolar doses of either carnosine or HNE alone. Proteomic analyses revealed modulation of canonical Nrf2-dependent antioxidant pathways. Our findings suggest a conceptual shift in carnosine biology: rather than acting as a classical antioxidant or carbonyl quencher, carnosine functions as a precursor of redox-active electrophilic adducts that transduce anti-inflammatory and antioxidant responses via controlled RCS signaling.
Histidine-Containing Dipeptides in Obesity and Cardiometabolic Health: A Systematic Scoping Review Saeede Saadati, Robel Hussen Kabthymer, Giancarlo Aldini, Thilini R. Thrimawithana, Julie E. Stevens, et al. Obesity Reviews, 2025 BackgroundHistidine‐containing dipeptides (HCDs) have been reported to have anti‐inflammatory and antidiabetic properties. Yet, no previous reviews have examined the impact of HCDs on Type 2 diabetes (T2D) risk factors (e.g., obesity) and progression (e.g., microvascular and macrovascular complications). In this scoping review, we aimed to thoroughly examine the evidence on the effects of HCDs, particularly carnosine, which is the most studied HCD, on T2D risk factors and complications and the underlying mechanisms of action.MethodsWe systematically searched Ovid‐Medline, Embase, CINAHL, Scopus, Web of Science, and Cochrane Library from inception to December 2023. We included experimental studies (animal models and cell studies), observational studies, and randomized controlled trials (RCTs) investigating the mechanism of action of HCDs and the effects of supplementation in individuals with obesity and/or T2D.ResultsThe primary literature search yielded 10,973 articles and 121 studies were eligible for inclusion. HCDs have been shown to mitigate inflammation and improve lipid profile and glycemic control in obesity and T2D with or without microvascular and macrovascular complications. However, most studies are experimental, focusing on elucidating the potential mechanisms of action of HCDs, with limited observational data or RCTs of individuals with obesity and/or T2D. No RCTs have investigated the effects of HCDs in individuals with neuropathy, retinopathy, cerebrovascular disease, and cardiovascular disease within a diabetic context.ConclusionsAlthough the existing evidence, predominantly from preclinical studies, generally supports the use of HCDs for improving cardiometabolic health, further human studies, especially RCTs with adequately powered sample sizes, are needed.
