Dataset Information

The Carnosine–HNE Michael Adduct as a Redox-Active Species Associated with Nrf2-Dependent Antioxidant and An-ti-Inflammatory Responses

ABSTRACT: 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 previ-ous studies in both in vitro and in vivo settings, mediates its bioactivity, particularly anti-oxidant and anti-inflammatory responses through Nrf2 activation. 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 trans-fer HNE to thiol nucleophiles at a slow rate under physiologically relevant conditions, consistent with electrophile-mediated Nrf2 activation. This kinetic behavior limits the cy-totoxicity typically associated with free HNE while preserving 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 modu-lating 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 elec-trophilic adducts that transduce anti-inflammatory and antioxidant responses via con-trolled RCS signaling.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Colon

DISEASE(S): Ulcerative Colitis

SUBMITTER: Alessandra Altomare

LAB HEAD: Alessandra Altomare

PROVIDER: PXD075159 | Pride | 2026-04-06

REPOSITORIES: Pride

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The Carnosine-HNE Michael Adduct as a Redox-Active Species Associated with Nrf2-Dependent Antioxidant and Anti-Inflammatory Responses.

Altomare Alessandra A Baron Giovanna G Gado Francesca F Vedova Larissa Della LD Ferrario Giulio G Davani Lara L Gilardoni Ettore E Ferrisi Rebecca R Mocchetti Clara C Singh Lavpreet L Courten Barbora De B Carini Marina M Siracusa Rosalba R D'Amico Ramona R Di Paola Rosanna R Dallanoce Clelia C Impellizzeri Daniela D Aldini Giancarlo G

Antioxidants (Basel, Switzerland) 20260319 3

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. ...[more]

PMID: 41897532

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Project description:RATIONALE: Mechanical ventilation (MV) is an indispensable therapy for critically ill patients with acute lung injury and the adult respiratory distress syndrome. However, the mechanisms by which conventional MV induces lung injury remain unclear. OBJECTIVES: We hypothesized that disruption of the gene encoding Nrf2, a transcription factor which regulates the induction of several antioxidant enzymes, enhances susceptibility to ventilator-induced lung injury (VILI), while antioxidant supplementation attenuates such effect. METHODS: To test our hypothesis and to examine the relevance of oxidative stress in VILI, here we have assessed lung injury and inflammatory responses in Nrf2-deficient (Nrf2(-/-)) mice and wildtype (Nrf2(+/+)) animals following acute (2 h) injurious model of MV with or without administration of antioxidant. MEASUREMENTS AND MAIN RESULTS: Nrf2(-/-) mice displayed greater levels of lung alveolar and vascular permeability and inflammatory responses to MV as compared to Nrf2(+/+) mice. Nrf2-deficieny enhances the levels of several pro-inflammatory cytokines implicated in the pathogenesis of VILI. We found diminished levels of critical antioxidant enzymes and redox imbalance by MV in the lungs of Nrf2(-/-) mice; however antioxidant supplementation to Nrf2(-/-) mice remarkably attenuated VILI. When subjected to clinically relevant prolong period of MV, Nrf2(-/-) mice displayed greater levels of VILI than Nrf2(+/+) mice. Expression profiling revealed lack of induction of several VILI genes, stress response and solute carrier proteins and phosphatases in Nrf2(-/-) mice. CONCLUSIONS: Collectively, our data demonstrate for the first time a critical role for Nrf2 in VILI, which confers protection against cellular responses induced by MV by modulating oxidative stress. Experiment Overall Design: The Nrf2 wildtype (Nrf2+/+) and Nrf2-deficient (Nrf2â/â) CD-1/ICR strains of mice were subjected to mechanical ventilation with high (HVT) amounts of tidal volumes (VT) at 30 ml/kg for 2 hours. The animals subjected to spontaneous ventilation (SpV) for 2 hours were used as controls. Lungs were immediately removed and processed for total RNA isolation using TRIzol reagent (LifeTechnologies, Grand Island, NY). The isolated RNA was applied to Murine Genome 430A GeneChip arrays (Affymetrix, Santa Clara, CA), which contain probes for detecting ~14,500 well-characterized genes and 4371 expressed sequence tags according to standard microarray protocol. Scanned output files were analyzed by using Affymetrix GeneChip Operating Software and were independently normalized to an average intensity of 500.

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