Aims: The manner in which hydrogen sulfide (H 2 S) suppresses neuroinflammation is poorly understood. We investigated whether H 2 S polarized microglia to an anti-inflammatory (M2) phenotype by activating AMPactivated protein kinase (AMPK). Results: Three structurally unrelated H 2 S donors (5-(4-hydroxyphenyl)-3H-1,2-dithiocyclopentene-3-thione [ADT-OH], (p-methoxyphenyl) morpholino-phosphinodithioic acid [GYY4137], and sodium hydrosulfide [NaHS]) enhanced AMPK activation in BV2 microglial cells in the presence and absence of lipopolysaccharide (LPS). The overexpression of the H 2 S synthase cystathionine bsynthase (CBS) in BV2 cells enhanced endogenous H 2 S production and AMPK activation regardless of LPS stimulation. On LPS stimulation, overexpression of both ADT-OH and CBS promoted M2 polarization of BV2 cells, as evidenced by suppressed M1 and elevated M2 signature gene expression. The promoting effects of ADT-OH on M2 polarization were attenuated by an AMPK inhibitor or AMPK knockdown. Liver kinase B1 (LKB1) and calmodulin-dependent protein kinase kinase b (CaMKKb) are upstream kinases that activate AMPK. ADT-OH activated AMPK in Hela cells lacking LKB1. In contrast, both the CaMKKb inhibitor and siRNA abolished ADT-OH activation of AMPK in LPS-stimulated BV2 cells. Moreover, the CaMKKb inhibitor and siRNA blunted ADT-OH suppression on M1 gene expression and enhancement of M2 gene expression in LPS-stimulated BV2 cells. Moreover, ADT-OH promoted M2 polarization of primary microglia in an AMPK activation-and CaMKKb-dependent manner. Finally, in an LPS-induced in vivo neuroinflammation model, both ADT-OH and NaHS enhanced AMPK activation in the brain area where microglia were overactivated on LPS stimulation. Furthermore, ADT-OH suppressed M1 and promoted M2 gene expression in this in vivo model. Innovation and Conclusion: CaMKKb-dependent AMPK activation is an unrecognized mechanism underlying H 2 S suppression on neuroinflammation.
Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis and other cardiovascular diseases. Unfortunately, Hcy-lowering strategies were found to have limited effects in reducing cardiovascular events. The underlying mechanisms remain unclear. Increasing evidence reveals a role of inflammation in the pathogenesis of HHcy. Homocysteine (Hcy) is a precursor of hydrogen sulfide (H2S), which is formed via the transsulfuration pathway catalyzed by cystathionine β-synthase and cystathionine γ-lyase (CSE) and serves as a novel modulator of inflammation. In the present study, we showed that methionine supplementation induced mild HHcy in mice, associated with the elevations of TNF-α and IL-1β in the plasma and reductions of plasma H2S level and CSE expression in the peritoneal macrophages. H2S-releasing compound GYY4137 attenuated the increases of TNF-α and IL-1β in the plasma of HHcy mice and Hcy-treated raw264.7 cells while CSE inhibitor PAG exacerbated it. Moreover, the in vitro study showed that Hcy inhibited CSE expression and H2S production in macrophages, accompanied by the increases of DNA methyltransferase (DNMT) expression and DNA hypermethylation in cse promoter region. DNMT inhibition or knockdown reversed the decrease of CSE transcription induced by Hcy in macrophages. In sum, our findings demonstrate that Hcy may trigger inflammation through inhibiting CSE-H2S signaling, associated with increased promoter DNA methylation and transcriptional repression of cse in macrophages.
Bow hunter's syndrome (BHS), also known as rotational vertebral artery (VA) occlusion syndrome, is a rare yet treatable type of symptomatic vertebrobasilar insufficiency resulting from mechanical occlusion or stenosis of the VA during head and neck rotation or extension. The symptoms of BHS range from transient vertigo to posterior circulation stroke. The underlying pathology is dynamic stenosis or compression of the VA by abnormal bony structures with neck rotation or extension in many cases, such as osteophyte, disc herniation, cervical spondylosis, tendinous bands or tumors. Imaging approaches, such as Doppler sonography, computed tomography and angiography, as well as magnetic resonance imaging and angiography, are widely used in the diagnosis and evaluation of this syndrome. Digital subtraction angiography with head rotation remains the gold standard diagnostic method. Conservative management, surgery and endovascular procedures are the three major treatment methods for BHS, whereas some symptomatic patients may need operative treatment including surgery and endovascular procedures when conservative management is not adequate.
A dynamic increase in neutrophils after stroke significantly predicts 3-month death or major disability in acute ischaemic stroke patients receiving r-tPA treatment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.