Hydrogen sulfide (H₂S) plays a crucial role in the regulation of blood pressure and oxidative stress. In the present study, we tested the hypothesis that H₂S exerts its cardiovascular effects by reducing oxidative stress via inhibition of NADPH oxidase activity in the rostral ventrolateral medulla (RVLM). We examined cell distributions of cystathionine-β-synthase (CBS) and effects of H₂S on reactive oxygen species (ROS) and mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHRs). We found that CBS was expressed in neurons of the RVLM, and the expression was lower in SHRs than in Wistar-Kyoto rats. Microinjection of NaHS (H₂S donor), S-adenosyl-l-methionine (SAM, a CBS agonist), or Apocynin (NADPH oxidase inhibitor) into the RVLM reduced the ROS level, NADPH oxidase activity, and MAP, whereas microinjection of hydroxylamine hydrochloride (HA, a CBS inhibitor) increased MAP. Furthermore, intracerebroventricular infusion of NaHS inhibited phosphorylation ofp47phox, a key step of NADPH oxidase activation. Since decreasing ROS level in the RVLM reduces MAP and heart rate and increasing H₂S reduces ROS production, we conclude that H₂S exerts an antihypertensive effect via suppressing ROS production. H₂S, as an antioxidant, may be a potential target for cardiovascular diseases.

Oxidative stress in adipose tissue is a crucial pathogenic mechanism of obesity-associated cardiovascular diseases. Chronic low-grade inflammation caused by obesity increases ROS production and dysregulation of adipocytokines. Leonurine (LEO) is an active alkaloid extracted from Herba Leonuri and plays a protective role in the cardiovascular system. The present study tested whether LEO alleviates inflammation and oxidative stress, and improves vascular function in an obese mouse model. Here, we found that obesity leads to inflammation and oxidative stress in epididymal white adipose tissue (EWAT), as well as vascular dysfunction. LEO significantly improved inflammation and oxidative stress both in vivo and in vitro. Obesity-induced vascular dysfunction was also improved by LEO as evidenced by the ameliorated vascular tone and decreased mesenteric artery fibrosis. Using mass spectrometry, we identified YTHDF1 as the direct target of LEO. Taken together, we demonstrated that LEO improves oxidative stress and vascular remodeling induced by obesity and targets YTHDF1, raising the possibility of LEO treating other obesity-related metabolic syndromes.

In the present study, we attempted to elucidate mechanisms for the regulation of intracellular calcium levels by H₂S in primary rat medullary neurons. Our results showed that NaHS significantly increased the level of in rat medullary neurons in a concentration‐dependent manner. L‐Cysteine and SAM significantly raised the level of in the medullary neurons while HA and/or AOAA produced a reversal effect. In addition, L‐cysteine and SAM significantly increased but HA and/or AOAA decreased the production of H₂S in the cultured neurons. The elevation induced by H₂S was significantly diminished by EGTA‐Ca²⁺‐free solutions, and this elevation was also reduced by nifedipine or nimodipine and mibefradil, suggesting the role of L‐type and/or T‐type Ca²⁺ channels. Moreover, the effect of H₂S on level in neurons was significantly attenuated by BAPTA‐AM and thapsigargin, suggesting the source of Ca²⁺. Therefore, we concluded that both exogenous and endogenous H₂S elevates level in primarily cultured rat medullary neurons via both increasing calcium influx and mobilizing intracellular Ca²⁺ stores from ER.

Background and Purpose As the only ionotropic receptor in 5-HT receptor family, 5-HT3 receptor (5-HT3R) involves in psychiatric disorders and its modulators have potential therapeutic effects for cognitive impairment in these disorders. However, it remains unclear how 5-HT3Rs shape synaptic plasticity for memory function. Experimental Approach Extracellular as well as whole-cell recordings were used to monitor hippocampal long-term potentiation (LTP) and synaptic transmission in hippocampal slices from 5-HT3AR knock-out or 5-HT3AR-GFP mice. Immunocytochemistry, qRT-PCR and Western blot were used to measure receptor expression. We also assessed hippocampal dependent cognition and memory using the Morris water maze (MWM) and novel object recognition. Key Results We found that 5-HT3R dysfunction impaired hippocampal LTP in Schaffer collateral (SC)-CA1 pathway in hippocampal slices by facilitating GABAergic inputs in pyramidal cells. This effect was dependent on 5-HT3Rs on axon-terminals. It resulted from reduced expression and function of cannabinoid receptor 1 (CB1R) co-localized with 5-HT3Rs on axon terminals, which led to diminishment of tonic inhibition of GABA release by CB1Rs. Inhibition of CB1Rs mimicked the facilitation of GABAergic transmission by 5-HT3R disruption. Consequently, mice with hippocampal 5-HT3R disruption exhibited impaired spatial memory in Morris water maze tasks. Conclusion and Implications These results suggest that 5-HT3Rs are crucial in enabling hippocampal synaptic plasticity via a novel CB1R-GABA_A-dependent pathway to regulate spatial memory.

Urotensin II (UII) could increase blood pressure and heart rate via increased central reactive oxygen species (ROS) levels. We reported previously that hydrogen sulfide (H₂S) exerts an antihypertensive effect by suppressing ROS production. The aim of the current study is to further examine the effects of endogenous and exogenous H₂S on UII-induced cardiovascular effects by using an integrated physiology approach. We also use cell culture and molecular biological techniques to explore the inhibitory role of H₂S on UII-induced cardiovascular effects. In this study, we found that cystathionine-β-synthase (CBS), the main H₂S synthesizing enzyme in CNS, was expressed in neuronal cells of the rostral ventrolateral medulla (RVLM) area. Cellular distribution of CBS and urotensin II receptor (UT) in SH-SY5Y cells that are confirmed as glutamatergic were identified by immunofluorescent and Western blots assay. In Sprague–Dawley rats, administration of UII into the RVLM resulted in an increase in mean arterial pressure (MAP), heart rate (HR), ROS production, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and phosphorylation of p47^phox, extracellular signal-regulated protein kinase (ERK)1/2 and p38MAPK, but not stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK). These effects of UII were attenuated by application into the RVLM of endogenous (L-cysteine, SAM) or exogenous (NaHS) H₂S. These results were confirmed in SH-SY5Y cells. UII-induced cardiovascular effects were also significantly abolished by pretreatment with microinjection of Tempol, Apocynin, SB203580, or PD98059 into the RVLM. Preincubated SH-SY5Y cells with Apocynin before administration of UII followed by Western blots assay showed that ROS is in the upstream of p38MAPK/ERK1/2. Ga_o activation assay in SH-SY5Y cells suggested that H₂S may exert an inhibitory role on UII-induced cardiovascular effects by inhibiting the activity of Gα_o. These results suggest that both endogenous and exogenous H₂S attenuate UII-induced cardiovascular effects via Gα_o-ROS-p38MAPK/ERK1/2 pathway.