Studies from our laboratory indicate that Sch B treatment protects multiple tissues in rodents from damage or cell death caused by oxidants by improving mitochondrial glutathione redox status [12] - [15] . This is achieved by promoting a cellular glutathione antioxidant response, which helps maintain mitochondrial GSH levels, especially during oxidative stress [7] [15] [16] . Sch B helps maintain mitochondrial glutathione levels, suppressing mitochondrial permeability transition and protecting cells from death [17] - [19] . The molecular mechanism behind the enhancing effect of Sch B on the cellular glutathione antioxidant response involves activating nuclear factor erythroid 2-related factor 2 (Nrf2, a transcription activator) in both hepatocytes and cardiomyocytes [20] [21] . Accordingly, Nrf2 activators have been suggested to provide health benefits by slowing the aging process [22] . A study from our laboratory on male and female mice revealed that long-term Sch B treatment delayed the decline in mitochondrial glutathione levels and ATP production as the mice aged, resulting in an increase in average lifespan [12] . Maintaining optimal levels of mitochondrial GSH is important for preventing age-related diseases and slowing the aging process due to its role in maintaining mitochondrial redox status [23] .

Reactive oxygen species (ROS), such as superoxide anion and hydrogen peroxide (H₂O₂), are produced by complexes I and III during mitochondrial electron transport [24] . These molecules can attack mitochondrial membranes and proteins or reach the cytoplasm and nucleus, triggering gene-regulatory processes that respond to changes in redox levels [24] . Mitochondrial glutathione (mtGSH) emerges as a key antioxidant in mitochondria, protecting against oxidative damage from reactive oxygen species (ROS). It plays a crucial role in maintaining the proper redox environment within the mitochondria by directly scavenging ROS and supporting other mitochondrial enzymes such as glutathione peroxidase (GPx) 1 and GPx4, glutathione transferases, and glutaredoxin-2, which catalyzes the reversible oxidation and glutathionylation of mitochondrial membrane thiol proteins [23] [25] . The pool of mtGSH is maintained in a reduced state by glutathione reductase, which uses NADPH to reduce oxidized glutathione. Along with the thioredoxin system, specifically mitochondrial thioredoxin 2/thioredoxin reductase 2 (Trx2/TrxR2), mtGSH aids in preserving the redox status of thiols in mitochondria [23] [25] . Depletion of mtGSH can disrupt the GSH system or the Trx2 system, leading to the oxidation of the dithiol on the active site of Trx2 and making cells more susceptible to ROS-induced cell death [23] [25] . In addition, mtGSH regulates mitochondrial ATP production by influencing the protein sulfhydryl redox states of complexes I and II, which in turn affects electron flow in the electron transport chain [23] .

Experimental and clinical research suggests that reactive oxygen species (ROS) play a role in causing insulin resistance [26] , which is causally related to the development of metabolic syndrome [27] - [29] . Specifically, mitochondrial ROS may contribute to insulin resistance in adipose tissue and skeletal muscle [26] . A preliminary study in our laboratory found that treating mice fed a high-fat diet with Sch B improved glucose intolerance, suggesting an improvement in insulin resistance (unpublished data). Further investigation is needed to determine if Sch B’s effect on mice fed a high-fat diet is due to an enhancement of mitochondrial glutathione redox status. Previous research in our laboratory demonstrated that a lignan-enriched SF extract protected rat skeletal muscle from exercise-induced damage. This muscle protection was linked to the enhancement of tissue glutathione status in the liver, but not in skeletal muscle [30] . This finding suggests that the efflux of GSH from the liver to skeletal muscle in SF extract-treated rats may occur during running exercise. Enhancing liver glutathione status with Sch B treatment could improve insulin resistance in skeletal muscle in mice fed a high-fat diet through GSH-mediated reduction in mitochondrial ROS production.