Mitochondria-derived H2O2 triggers liver regeneration via FoxO3a signaling pathway after partial hepatectomy in mice.

Reactive oxygen species (ROS) can induce oxidative injury and are generally regarded as toxic byproducts, although they are increasingly recognized for their signaling functions. Increased ROS often accompanies liver regeneration (LR) after liver injuries, however, their role in LR and the underlying mechanism remains unclear. Here, by employing a mouse LR model of partial hepatectomy (PHx), we found that PHx induced rapid increases of mitochondrial hydrogen peroxide (H2O2) and intracellular H2O2 at an early stage, using a mitochondria-specific probe. Scavenging mitochondrial H2O2 in mice with liver-specific overexpression of mitochondria-targeted catalase (mCAT) decreased intracellular H2O2 and compromised LR, while NADPH oxidases (NOXs) inhibition did not affect intracellular H2O2 or LR, indicating that mitochondria-derived H2O2 played an essential role in LR after PHx. Furthermore, pharmacological activation of FoxO3a impaired the H2O2-triggered LR, while liver-specific knockdown of FoxO3a by CRISPR-Cas9 technology almost abolished the inhibition of LR by overexpression of mCAT, demonstrating that FoxO3a signaling pathway mediated mitochondria-derived H2O2 triggered LR after PHx. Our findings uncover the beneficial roles of mitochondrial H2O2 and the redox-regulated underlying mechanisms during LR, which shed light on potential therapeutic interventions for LR-related liver injury. Importantly, these findings also indicate that improper antioxidative intervention might impair LR and delay the recovery of LR-related diseases in clinics.

Vitamin K2 Alleviates Insulin Resistance in Skeletal Muscle by Improving Mitochondrial Function Via SIRT1 Signaling.

Aims: High-fat diet (HFD)-induced insulin resistance (IR) impairs skeletal muscle mitochondrial biogenesis and functions, adversely affecting human health and lifespan. Vitamin K2 (VK2) has a beneficial role in improving insulin sensitivity and glucose metabolism. However, the underlying molecular mechanisms of VK2 on insulin sensitivity have not been well established. We investigated VK2's modulation of mitochondrial function to protect against IR in mice and cell models. Results: VK2 supplementation could effectively ameliorate the development of IR by improving mitochondrial function in both HFD-fed mice and palmitate acid-exposed cells. We revealed for the first time that HFD-caused mitochondrial dysfunction could be reversed by VK2 treatment. VK2 enhanced the mitochondrial function by improving mitochondrial respiratory capacity, increasing mitochondrial biogenesis and the enzymatic activities of mitochondrial complexes through SIRT1 signaling. The benefits of VK2 were abrogated in C2C12 transfected with SIRT1 siRNA but not in C2C12 transfected with AMPK siRNA. VK2 and SRT1720, a specific agonist of SIRT1, had the same effect on improving mitochondrial function via SIRT1 signaling. Thus, SIRT1 is required for VK2 improvement in skeletal muscle. Further, the beneficial effects of both VK2 and geranylgeraniol contribute to inhibited IR in skeletal muscle via SIRT1. Innovation and Conclusion: These studies demonstrated a previously undiscovered mechanism by which VK2 alleviates IR in skeletal muscle by improving mitochondrial function via SIRT1. Naturally occurring VK2 prevents IR by improving mitochondrial function through SIRT1 signaling. These results could provide a foundation to identify new VK2-based preventive and therapeutic strategies for IR.

Exercise and dietary intervention ameliorate high-fat diet-induced NAFLD and liver aging by inducing lipophagy.

Exercise and dietary intervention are currently available strategies to treat nonalcoholic fatty liver disease (NAFLD), while the underlying mechanism remains controversial. Emerging evidence shows that lipophagy is involved in the inhibition of the lipid droplets accumulation. However, it is still unclear if exercise and dietary intervention improve NAFLD through regulating lipophagy, and how exercise of skeletal muscle can modulate lipid metabolism in liver. Moreover, NAFLD is associated with aging, and little is known about the effect of lipid accumulation on aging process. Here in vivo and in vitro models, we found that exercise and dietary intervention reduced lipid droplets formation, decreased hepatic triglyceride in the liver induced by high-fat diet. Exercise and dietary intervention enhanced the lipophagy by activating AMPK/ULK1 and inhibiting Akt/mTOR/ULK1 pathways respectively. Furthermore, exercise stimulated FGF21 production in the muscle, followed by secretion to the circulation to promote the lipophagy in the liver via an AMPK-dependent pathway. Importantly, for the first time, we demonstrated that lipid accumulation exacerbated liver aging, which was ameliorated by exercise and dietary intervention through inducing lipophagy. Our findings suggested a new mechanism of exercise and dietary intervention to improve NAFLD through promoting lipophagy. The study also provided evidence to support that muscle exercise is beneficial to other metabolic organs such as liver. The FGF21-mediated AMPK dependent lipophagy might be a potential drug target for NAFLD and aging caused by lipid metabolic dysfunction.

Osteosarcoma cell proliferation and migration are partly regulated by redox-activated NHE-1.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. OS is associated with locally aggressive growth and high metastatic potential. The mechanisms that underlie these processes are currently elusive. Reactive oxygen species (ROS) and Na+/H+ exchanger 1 (NHE1) have been suggested to regulate proliferation and migration of tumor cells. However, the relationship between NHE1 and ROS in OS proliferation and migration has not been investigated before. AIM: To investigate the role of NHE1 and ROS in the proliferation and migration of OS. METHODS: ROS levels and NHE1 expression were studied in cultured human OS cells and human OS xenografts in nude mice. In vitro, OS cells were treated with different doses of tert-butyl hydroperoxide (tBHP), a ROS inducer, and cariporide, an NHE1 inhibitor, to study the effect on cell proliferation and migration. In vivo, nude mice bearing OS cells were administrated with NHE1 inhibitor or antioxidant and the tumor weights were measured. RESULTS: This study reported for the first time that the expression of NHE1 and intracellular ROS level were both increased in OS tissues and cells. Exposure of OS cell to ROS derived from tBHP was able to accelerate cell proliferation and migration and also up-regulate NHE1 protein expression. Moreover, tBHP significantly increased intracellular pH (pHi), decreased extracellular pH (pHe) and induced upregulation of ERK, MMP2, and MMP9. Lowering of ROS levels with the anti-oxidant DMTU or inhibiting NHE1 activity via cariporide abolished the stimulatory effect of tBHP. However, there cariporide did not affect intracellular ROS levels. In vivo study we further confirmed that cariporide could inhibit tumor growth in the nude mouse xenografts of OS cells. CONCLUSIONS: The data demonstrate that up-regulation of NHE1 was induced by low concentrations of ROS contributes to the regulation of tumor proliferation and invasion of OS. RELEVANCE FOR PATIENTS: There is potential application for cariporide as an effective antitumor agent during the development of human osteosarcoma. In addition, redox modulation on proton transport may represent a novel target of osteosarcoma prevention, and open a new avenues for future research.