The gas molecules O₂, NO, H₂S, CO, and CH₄, have been increasingly used for medical purposes. Other than these gas molecules, H₂ is the smallest diatomic molecule in nature and has become a rising star in gas medicine in the past few decades. As a non-toxic and easily accessible gas, H₂ has shown preventive and therapeutic effects on various diseases of the respiratory, cardiovascular, central nervous system, and other systems, but the mechanisms are still unclear and even controversial, especially the mechanism of H₂ as a selective radical scavenger. Mitochondria are the main organelles regulating energy metabolism in living organisms as well as the main organelle of reactive oxygen species’ generation and targeting. We propose that the protective role of H₂ may be mainly dependent on its unique ability to penetrate every aspect of cells to regulate mitochondrial homeostasis by activating the Keap1-Nrf2 phase II antioxidant system rather than its direct free radical scavenging activity. In this review, we summarize the protective effects and focus on the mechanism of H₂ as a mitochondria-targeting nutrient by activating the Keap1-Nrf2 system in different disease models. In addition, we wish to provide a more rational theoretical support for the medical applications of hydrogen.

Aims: α-Ketoglutarate (AKG) is an intermediate of the tricarboxylic acid cycle and a key hub linking amino acid metabolism and glucose oxidation. Previous studies have shown that AKG improved cardiovascular diseases such as myocardial infarction and myocardial hypertrophy through antioxidant and lipid-lowering characteristics. However, its protective effect and mechanism on endothelial injury caused by hyperlipidemia have not been elucidated yet. In this study, we tested whether AKG possesses protective effects on hyperlipidemia-induced endothelial injury and studied the mechanism. Results: AKG administration both in vivo , and in vitro significantly suppressed the hyperlipidemia-induced endothelial damage, regulated ET-1 and nitric oxide levels, and reduced the inflammatory factor interleukin-6 and matrix metallopeptidase-1 by inhibiting oxidative stress and mitochondrial dysfunction. The protective effects were achieved by the mechanism of activating the Nrf2 phase II system through the ERK signaling pathway. Innovation: These results reveal the role of the AKG-ERK-Nrf2 signaling pathway in the prevention of hyperlipidemia-induced endothelial damage, and suggest that AKG, as a mitochondria-targeting nutrient, is a potential drug for the treatment of endothelial damage in hyperlipidemia. Conclusion: AKG ameliorated the hyperlipidemia-induced endothelial damage and inflammatory response by inhibiting oxidative stress and mitochondrial dysfunction. Antioxid. Redox Signal . 39, 777–793. Color images are available online.

The gas molecules O2, NO, H2S, CO, CH4 , have been increasingly used for medical purposes. Beside these gas molecules, H2, the smallest diatomic molecule in nature, has become a rising star in gas medicine in the past few decades. As a non-toxic and easily accessible gas, H2 has shown preventive and therapeutic effects on various diseases of the respiratory, cardiovascular, central nervous and other systems, but the mechanisms are still unclear and even controversial, especially the mechanism of H2 as a selective radical scavenger. Mitochondria are the main organelles regulating energy metabolism in living organisms, as well as the main organelle of reactive oxygen species generation and target. We propose that the protective role of H2 may be mainly dependent on its unique penetrating ability to everywhere of the cells to regulate mitochondrial homeostasis by activating the Keap1-Nrf2 phase II antioxidant system, rather than its direct free radical scavenging activity. In this review, we summarize the protective effects and focus on the mechanism of H2 as a mitochondria-targeting nutrient by activating the Keap1-Nrf2 system in different disease models, and wish to provide a more rational theoretical support for the medical applications of hydrogen.

Background: Cardiovascular diseases (CVDs), particularly coronary heart disease (CHD), impose a global health burden with unpredictable major adverse cardiovascular events (MACE) despite optimal treatment. Systemic inflammation and malnutrition are key pathogenic drivers, yet integrated biomarkers capturing this duality are lacking. The Neutrophil-to-Albumin Ratio (NPAR) emerges as a cost-effective indicator reflecting both pathways, but its prognostic value for post-discharge MACE in hospitalized CHD patients remains unestablished. Our study aimed at investigating the prognostic value of NPAR for MACE in CHD patients. Methods: This prospective cohort study enrolled CHD patients (2013–2020) from the First Affiliated Hospital of Xi’an Jiaotong University. NPAR was calculated from admission blood samples. Participants were stratified into NPAR tertiles (T1: 5.21–16.00; T2: 16.01–18.50; T3: 18.51–42.38). Multivariable Cox models (adjusting for demographics, comorbidities, and laboratory parameters) assessed NPAR-MACE associations. Restricted cubic splines (RCS) and subgroup analyses explored nonlinearity and effect modifiers. Results: A total of 2,990 patients with CHD were eligible for analysis. With a median follow-up of 70 months, Kaplan–Meier survival curves demonstrated that participants in the highest NPAR tertile (T3) exhibited significantly lower cumulative survival rates free from MACE compared to those in the lowest tertile (T1). The highest NPAR tertile (T3) exhibited a 72% increased MACE risk (adjusted hazard ratio (HR) = 1.72, 95% confidence interval (CI): 1.36–2.20) versus T1. A J-shaped relationship emerged, with risk escalating above NPAR = 17 (P nonlinear = 0.01). Sex-specific heterogeneity was observed: males in T3 had markedly elevated risk (HR = 2.03, 95% CI: 1.50–2.75; P interaction = 0.03). Conclusion: Elevated admission NPAR independently predicts long-term MACE in CHD patients, particularly among males. This supports NPAR’s utility for post-discharge risk stratification.