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Homocysteine (Hcy) is detrimental to bone health in a mouse model of diet‐induced hyperhomocysteinemia (HHcy). However, little is known about Hcy‐mediated osteoblast dysfunction via mitochondrial oxidative damage. Hydrogen sulfide (H2S) has potent antioxidant, anti‐inflammatory, and antiapoptotic effects. In this study, we hypothesized that the H2S mediated recovery of osteoblast dysfunction by maintaining mitochondrial biogenesis in Hcy‐treated osteoblast cultures in vitro. MC3T3‐E1 osteoblastic cells were exposed to Hcy treatment in the presence or absence of an H2S donor (NaHS). Cell viability, osteogenic differentiation, reactive oxygen species (ROS) production were determined. Mitochondrial DNA copy number, adenosine triphosphate (ATP) production, and oxygen consumption were also measured. Our results demonstrated that administration of Hcy increases the intracellular Hcy level and decreases intracellular H2S level and expression of the cystathionine β‐synthase/Cystathionine γ‐lyase system, thereby inhibiting osteogenic differentiation. Pretreatment with NaHS attenuated Hcy‐induced mitochondrial toxicity (production of total ROS and mito‐ROS, ratio of mitochondrial fission (DRP‐1)/fusion (Mfn‐2)) and restored ATP production and mitochondrial DNA copy numbers as well as oxygen consumption in the osteoblast as compared with the control, indicating its protective effects against Hcy‐induced mitochondrial toxicity. In addition, NaHS also decreased the release of cytochrome c from the mitochondria to the cytosol, which induces cell apoptosis. Finally, flow cytometry confirmed that NaHS can rescue cells from apoptosis induced by Hcy. Our studies strongly suggest that NaHS has beneficial effects on mitochondrial toxicity, and could be developed as a potential therapeutic agent against HHcy‐induced mitochondrial dysfunction in cultured osteoblasts in vitro. [ABSTRACT FROM AUTHOR]

Bone homeostasis requires a balance between the bone formation of osteoblasts and bone resorption of osteoclasts to maintain ideal bone mass and bone quality. An imbalance in bone remodeling processes results in bone metabolic disorders such as osteoporosis. Hydrogen sulfide (H 2 S), a gasotransmitter, has attracted the focus of many researchers due to its multiple physiological functions. It has been implicated in anti-inflammatory, vasodilatory, angiogenic, cytoprotective, anti-oxidative and anti-apoptotic mechanisms. H 2 S has also been shown to exert osteoprotective activity through its anti-inflammatory and anti-oxidative effects. However, the underlying molecular mechanisms by which H 2 S mitigates bone diseases are not completely understood. Experimental evidence suggests that H 2 S may regulate signaling pathways by directly influencing a gene in the cascade or interacting with some other gasotransmitter (carbon monoxide or nitric oxide) or both. MicroRNAs (miRNAs) are short non-coding RNAs which regulate gene expression by targeting, binding and suppressing mRNAs; thus controlling cell fate. Certainly, bone remodeling is also regulated by miRNAs expression and has been reported in many studies. MicroRNAs also regulate H 2 S biosynthesis. The inter-regulation of microRNAs and H 2 S opens a new possibility for exploring the H 2 S-microRNA crosstalk in bone diseases. However, the relationship between miRNAs, bone development, and H 2 S is still not well explained. This review focuses on miRNAs and their roles in regulating bone remodeling and possible mechanisms behind H 2 S mediated bone loss inhibition, H 2 S-miRNAs crosstalk in relation to the pathophysiology of bone remodeling, and future perspectives for miRNA-H 2 S as a therapeutic agent for bone diseases. [ABSTRACT FROM AUTHOR]

Alcohol is one of the most socially accepted addictive drugs in modern society. Its abuse affects virtually all organ systems with the central nervous system (CNS) being particularly vulnerable to excessive alcohol exposure. Alcohol exposure also causes profound damage to both the adult and developing brain. Excessive alcohol consumption induces numerous pathophysiological stress responses, one of which is the endoplasmic reticulum (ER) stress response. Potential mechanisms that trigger the alcohol induced ER stress response are either directly or indirectly related to alcohol metabolism, which include toxic levels of acetaldehyde and homocysteine, oxidative stress and abnormal epigenetic modifications. Growing evidence suggests that H 2 S is the most recently recognized gasotransmitter with tremendous physiological protective functions against oxidative stress induced neurotoxicity. In this review we address the alcohol induced oxidative stress mediated ER stress and the role of H 2 S in its mitigation in the context of alcohol neurotoxicity. Interruption of ER stress triggers is anticipated to have therapeutic benefits for alcohol mediated diseases and disorders. [ABSTRACT FROM AUTHOR]