Endogenous CSE/H2S directly sulfhydrated SIRT1, enhanced SIRT1 binding to zinc ion, then promoted its deacetylation activity, and increased SIRT1 stability, thus reducing atherosclerotic plaque formation. Antioxid. Redox Signal. 00, 000-000.

Aims: Hydrogen sulfide (H2S) plays an essential role in bone formation, in part, by inhibiting osteoclast differentiation, maintaining mesenchymal stem cell osteogenesis ability, or reducing osteoblast injury. We aimed to investigate the role of H2S in osteoblast function and its possible molecular target. Results: In this study, we found that cystathionine c-lyase (CSE) majorly contributed to endogenous H2S production in the primary osteoblast. Overexpressed CSE increased osteoblast differentiation and maturation with higher bone morphogenetic protein 2 and osteopontin expression, alkaline phosphatase activity, and calcium nodule formation; in contrast, knockdown of CSE had opposite effects. Runt-related transcript factor 2 (RUNX2) is required for osteoblast biologic function. CSE-H2S increased nuclear RUNX2 accumulation, DNA binding activity, and target gene transcription. Protein sulfhydration is a common signal by H2S. We confirmed that RUNX2 was also sulfhydrated by H2S. This chemical modification enhanced RUNX2 transactivation, which was blocked by dithiothreitol (DTT, sulfhydration remover). Mutation of two cysteine sites in the runt domain of RUNX2 abolished H2S-induced RUNX2 sulfhydration and transactivation. In a bone -fracture rat model, overexpressed CSE promoted bone healing, which confirmed the effect of CSE-H2S on osteoblasts. Innovation: CSE-H2S is a dominant H2S generation system in osteoblasts and promotes osteoblast activity by the RUNX2 pathway, with RUNX2 sulfhydration as a novel transactivation regulation. Conclusion: CSE-H2S sulfhydrated RUNX2 enhanced its transactivation and increased osteoblast differentiation and maturation, thereby promoting bone healing. Antioxid. Redox Signal. 27, 742-753.

Hydrogen sulfide (H2S) is an essential neuromodulator, generates by cystathionine β synthase (CBS) or 3-mecaptopyruvate sulfurtransferase (3MST) in the brain. H2S can mediate paraventricular nucleus (PVN) neuron activity, and regulate neuroendocrine hormones secretion. On the other hand, CBS deficiency caused metabolic disorder and body weight reduction. However, whether CBS/H2S of PVN regulates neuroendocrine hormones to mediate energy metabolism is unknown. Here, we first identified the CBS co-localization with thyrotropin-releasing hormone (TRH) and corticotropin releasing hormone (CRH) positive neurons. In HFD induced obese rats, CBS protein of hypothalamus decreased. By contrast, overexpression CBS in PVN via lentivirus, lowered food uptake, body weight and fat mass, and reduced blood glucose, lipid disorders and insulin resistance. Intriguingly, CBS overexpression increased the pre-TRH expression, slightly elevated plasma thyroxine and thyrotropin level, but decreased the plasma ACTH and corticosterone level. Then, we found that mTOR activation contributed to pre-TRH up-regulation by CBS/H2S system. In db/db obese mice, hypothalamus CBS/H2S system also down-regulated association with reduction pre-TRH expression; in contrast, CBS overexpression in PVN slightly elevated plasma leptin. Next, leptin stimulated FOXO3a nuclear translocation, increased FOXO3a binding activity to two binding sites of CBS promoter, and then enhanced CBS protein expression. In conclusion, leptin activates neuron CBS-H2S system by FOXO3a, regulates neuroendocrine hormones to modulate the energy homeostasis, thus highlights a new brain-adipose feedback axis in energy metabolism.

Background and Purpose Hydrogen sulfide donors can block the cardiovascular injury of hyperhomocysteinemia. H 2 S also lowers serum homocysteine in rats with mild hyperhomocysteinemia, but the pharmacological mechanism is unknown. The present study investigated the mechanism(s) involved. Experimental Approach ApoE‐knockout mice were fed a Paigen diet and L‐methionine in drinking water for 16 weeks to create a mouse model of atherosclerosis with hyperhomocysteinemia. H 2 S donors (NaHS and GYY4137) were administered by intraperitoneal injection. We also assayed the H 2 S produced (by methylene blue assay and mito‐HS [H 2 S fluorescence probe]), cystathionine γ lyase (CSE) mRNA and protein expression, and CSE sulfhydration and nitrosylation and its activity. Key Results H 2 S donor treatment significantly lowered atherosclerotic plaque area, macrophage infiltration, and serum homocysteine level in the mouse model of atherosclerosis with co‐existing hyperhomocysteinemia. mRNA and protein levels of CSE, a key enzyme catalyzing homocysteine trans‐sulfuration, were down‐regulated with hyperhomocysteinemia, and CSE catalytic activity was inhibited. All these effects were reversed with H 2 S donor treatment. Hyperhomocysteinemia induced CSE nitrosylation, whereas H 2 S sulfhydrated CSE at the same cysteine residues. Nitrosylated CSE decreased and sulfhydrated CSE increased its catalytic and binding activities towards L‐homocysteine. Mutation of C252, C255, C307, and C310 residues in CSE abolished CSE nitrosylation or sulfhydration and prevented its binding to L‐homocysteine. Conclusions and Implications Sulfhydration or nitrosylation of CSE represents a yin/yang regulation of catalysis or binding to L‐homocysteine. H 2 S donor treatment enhanced CSE sulfhydration, thus lowering serum L‐homocysteine, which contributed in part to the anti‐atherosclerosis effects in ApoE‐knockout mice with hyperhomocysteinemia.

Metal phenolic coordination frameworks (MPCFs) exhibiting relatively large surface area tend to serve as excellent fillers to stabilize electroactive beta phase of PVDF by enhancing electrical dipole moment via large...