Publications by authors named "Yaqian Huang"

60 Publications

Compensatory role of endogenous sulfur dioxide in nitric oxide deficiency-induced hypertension.

Redox Biol 2021 Nov 18;48:102192. Epub 2021 Nov 18.

Department of Pediatrics, Peking University First Hospital, Beijing, China. Electronic address:

Objective: This study aimed to determine the communicational pattern of gaseous signaling molecules sulfur dioxide (SO) and nitric oxide (NO) between vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), and elucidate the compensatory role and significance of endogenous SO in the development of hypertension due to NO deficiency.

Approach And Results: Blood pressure was monitored by the tail-cuff and implantable physiological signal telemetry in L-nitro-arginine methyl ester (l-NAME)-induced hypertensive mice, and structural alterations of mouse aortic vessels were detected by the elastic fiber staining method. l-NAME-treated mice showed decreased plasma NO levels, increased SO levels, vascular remodeling, and increased blood pressure, and application of l-aspartate-β-hydroxamate, which inhibits SO production, further aggravated vascular structural remodeling and increased blood pressure. Moreover, in a co-culture system of HAECs and HASMCs, NO from HAECs did not influence aspartate aminotransferase (AAT)1 protein expression but decreased AAT1 activity in HASMCs, thereby resulting in the inhibition of endogenous SO production. Furthermore, NO promoted S-nitrosylation of AAT1 protein in HASMCs and purified AAT1 protein. Liquid chromatography with tandem mass spectrometry showed that the Cys192 site of AAT1 purified protein was modified by S-nitrosylation. In contrast, dithiothreitol or C192S mutations in HASMCs blocked NO-induced AAT1 S-nitrosylation and restored AAT1 enzyme activity.

Conclusion: Endothelium-derived NO inhibits AAT activity by nitrosylating AAT1 at the Cys192 site and reduces SO production in HASMCs. Our findings suggest that SO acts as a compensatory defense system to antagonize vascular structural remodeling and hypertension when the endogenous NO pathway is disturbed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2021.102192DOI Listing
November 2021

Endogenous SO Controls Cell Apoptosis: The State-of-the-Art.

Front Cell Dev Biol 2021 7;9:729728. Epub 2021 Oct 7.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

SO, previously known as the product of industrial waste, has recently been proven to be a novel gasotransmitter in the cardiovascular system. It is endogenously produced from the metabolism pathway of sulfur-containing amino acids in mammalians. Endogenous SO acts as an important controller in the regulation of many biological processes including cardiovascular physiological and pathophysiological events. Recently, the studies on the regulatory effect of endogenous SO on cell apoptosis and its pathophysiological significance have attracted great attention. Endogenous SO can regulate the apoptosis of vascular smooth muscle cells, endothelial cells, cardiomyocytes, neuron, alveolar macrophages, polymorphonuclear neutrophils and retinal photoreceptor cells, which might be involved in the pathogenesis of hypertension, pulmonary hypertension, myocardial injury, brain injury, acute lung injury, and retinal disease. Therefore, in the present study, we described the current findings on how endogenous SO is generated and metabolized, and we summarized its regulatory effects on cell apoptosis, underlying mechanisms, and pathophysiological relevance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.729728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529009PMC
October 2021

Sulfur Dioxide: Endogenous Generation, Biological Effects, Detection, and Therapeutic Potential.

Antioxid Redox Signal 2021 Sep 20. Epub 2021 Sep 20.

Peking University First Hospital, 26447, Beijing, China;

Significance: Previously, sulfur dioxide (SO) was recognized as an air pollutant. However, it is found to be endogenously produced in mammalian tissues. As a new gasotransmitter, SO is involved in regulating the structure and function of blood vessels, heart, lung, gastrointestinal tract, and nervous system, etc. Recent Advances: Increasing evidence showed that endogenous SO regulates cardiovascular physiological processes, such as blood pressure control, vasodilation, maintenance of the normal vascular structure, and cardiac negative inotropy. Under pathological conditions including hypertension, atherosclerosis, vascular calcification, aging endothelial dysfunction, myocardial injury, myocardial hypertrophy, diabetic myocardial fibrosis, sepsis-induced cardiac dysfunction, pulmonary hypertension, acute lung injury, colitis, epilepsy-related brain injury, depression and anxiety, and addictive drug reward memory consolidation, endogenous SO protects against the pathological changes via different molecular mechanisms and the disturbed SO/aspartate aminotransferase pathway is likely involved in the mechanisms for the abovementioned pathologic processes.

Critical Issues: A comprehensive understanding of the biological effects of endogenous SO is extremely important for the development of novel SO therapy. In this review, we summarized the biological effects, mechanism of action, SO detection methods, and its related prodrugs.

Future Directions: Further studies should be conducted to understand the effects of endogenous SO in various physiological and pathophysiological processes and clarify its underlying mechanisms. More efficient and accurate SO detection methods, as well as specific and effective SO-releasing systems should be designed for the treatment and prevention of clinical related diseases. The translation from SO basic medical research to its clinical application is also worthy of further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2021.0213DOI Listing
September 2021

Endogenous Taurine Downregulation Is Required for Renal Injury in Salt-Sensitive Hypertensive Rats via CBS/HS Inhibition.

Oxid Med Cell Longev 2021 25;2021:5530907. Epub 2021 Aug 25.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Although taurine is known to exert an antihypertensive effect, it is unclear whether it is involved in the mechanism for hypertension-related target organ injury. To reveal the role of endogenous taurine in renal injury formation during salt-sensitive hypertension and clarify its mechanisms, both salt-sensitive Dahl rats and salt-resistant SS-13BN rats were fed a high-salt diet (8% NaCl) and given 2% taurine for 6 weeks. Rat systolic blood pressure (SBP) was measured by the tail-cuff method and artery catheterization. Kidney ultrastructure was observed under an electron microscope. Taurine content and mRNA and protein levels of taurine synthases, cysteine dioxygenase type 1 (CDO1) and cysteine sulfinic acid decarboxylase (CSAD), were decreased in Dahl rats fed a high-salt diet. However, taurine supplementation and the resulting increase in renal taurine content reduced the increased SBP and improved renal function and structural damage in high-salt diet-fed Dahl rats. In contrast, taurine did not affect SS-13BN SBP and renal function and structure. Taurine intervention increased the renal HS content and enhanced cystathionine--synthase (CBS) expression and activity in Dahl rats fed a high-salt diet. Taurine reduced the renin, angiotensin II, and aldosterone contents and the levels of oxidative stress indices in Dahl rat renal tissues but increased antioxidant capacity, antioxidant enzyme activity, and protein expression. However, taurine failed to achieve this effect in the renal tissue of SS-13BN rats fed a high-salt diet. Pretreatment with the CBS inhibitor HA or renal CBS knockdown inhibited HS generation and subsequently blocked the effect of taurine on renin, superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2) levels in high-salt-stimulated Dahl renal slices. In conclusion, the downregulation of endogenous taurine production resulted in a decrease in the renal CBS/HS pathway. This decrease subsequently promoted renin-angiotensin-aldosterone system (RAAS) activation and oxidative stress in the kidney, ultimately contributing to renal injury in salt-sensitive Dahl rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/5530907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413057PMC
August 2021

Endothelial Cell-Derived SO Controls Endothelial Cell Inflammation, Smooth Muscle Cell Proliferation, and Collagen Synthesis to Inhibit Hypoxic Pulmonary Vascular Remodelling.

Oxid Med Cell Longev 2021 17;2021:5577634. Epub 2021 Apr 17.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Hypoxic pulmonary vascular remodelling (PVR) is the major pathological basis of aging-related chronic obstructive pulmonary disease and obstructive sleep apnea syndrome. The pulmonary artery endothelial cell (PAEC) inflammation, and pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy and collagen remodelling are the important pathophysiological components of PVR. Endogenous sulfur dioxide (SO) was found to be a novel gasotransmitter in the cardiovascular system with its unique biological properties. The study was aimed to investigate the role of endothelial cell- (EC-) derived SO in the progression of PAEC inflammation, PASMC proliferation, hypertrophy and collagen remodelling in PVR and the possible mechanisms. EC-specific aspartic aminotransferase 1 transgenic (EC-AAT1-Tg) mice were constructed . Pulmonary hypertension was induced by hypoxia. Right heart catheterization and echocardiography were used to detect mouse hemodynamic changes. Pathologic analysis was performed in the pulmonary arteries. High-performance liquid chromatography was employed to detect the SO content. Human PAECs (HPAECs) with lentiviruses containing AAT1 cDNA or shRNA and cocultured human PASMCs (HPASMCs) were applied . SO probe and enzyme-linked immunosorbent assay were used to detect the SO content and determine p50 activity, respectively. Hypoxia caused a significant reduction in SO content in the mouse lung and HPAECs and increases in right ventricular systolic pressure, pulmonary artery wall thickness, muscularization, and the expression of PAEC ICAM-1 and MCP-1 and of PASMC Ki-67, collagen I, and -SMA ( < 0.05). However, EC-AAT1-Tg with sufficient SO content prevented the above increases induced by hypoxia ( < 0.05). Mechanistically, EC-derived SO deficiency promoted HPAEC ICAM-1 and MCP-1 and the cocultured HPASMC Ki-67 and collagen I expression, which was abolished by andrographolide, an inhibitor of p50 ( < 0.05). Meanwhile, EC-derived SO deficiency increased the expression of cocultured HPASMC -SMA ( < 0.05). Taken together, these findings revealed that EC-derived SO inhibited p50 activation to control PAEC inflammation in an autocrine manner and PASMC proliferation, hypertrophy, and collagen synthesis in a paracrine manner, thereby inhibiting hypoxic PVR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/5577634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068783PMC
May 2021

Shensu IV prevents glomerular podocyte injury in nephrotic rats via promoting lncRNA H19/DIRAS3-mediated autophagy.

Biosci Rep 2021 05;41(5)

Department of Nephrology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China.

Shensu IV is a Chinese prescription well-known for its function in treating chronic kidney diseases. However, the potential mechanisms underlying how Shensu IV exerts its effects remain unclear. In the present study, we investigated the effects of Shensu IV on glomerular podocyte injury in nephrotic rats and puromycin-induced injury in cultured podocytes, and assessed the associated molecular mechanisms. Liquid chromatography-mass spectrometry (LC-MS) results showed that the main components of Shensu IV were l-Carnitine, P-lysoPC (LPC) 16:0, Coumaroyl tyramine, Tetramethylpyrazine, LPC 18:1, Choline, (S,S)-Butane-2,3-diol, and Scopoletin. We further found that nephrotic rats displayed pathological alterations in kidney tissues and ultrastructural changes in glomerular podocytes; however, these effects were reversed with Shensu IV treatment. Compared with the control, the numbers of autophagosomes were markedly reduced in the model group, but not in the Shensu IV treatment group. Furthermore, the expression of p62 was significantly higher in the model group than in the controls, whereas the LC3-II/I ratio was significantly lower; however, these changes were not observed when Shensu IV was administered. The protective effects of Shensu IV were further confirmed in podocytes displaying puromycin-induced injury. Compared with control group, the expression of long non-coding RNA (lncRNA) H19, mTOR, p-mTOR, and p62 was significantly increased in the puromycin group, whereas that of distinct subgroup of the RAS family member 3 (DIRAS3) was significantly decreased, as was the LC3-II/I ratio. The opposite results were obtained for both shH19- and Shensu IV-treated cells. Collectively, our data demonstrated that Shensu IV can prevent glomerular podocyte injury in nephrotic rats and puromycin-treated podocytes, likely via promoting lncRNA H19/DIRAS3-regulated autophagy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BSR20203362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112846PMC
May 2021

Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation.

J Adv Res 2021 03 8;29:55-65. Epub 2020 Sep 8.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Introduction: Mast cell (MC) degranulation is an important step in the pathogenesis of inflammatory reactions and allergies; however, the mechanism of stabilizing MC membranes to reduce their degranulation is unclear.

Methods: SO content in MC culture supernatant was measured by HPLC-FD. The protein and mRNA expressions of the key enzymes aspartate aminotransferase 1 (AAT1) and AAT2 and intracellular AAT activity were detected. The cAMP level in MCs was detected by immunofluorescence and ELISA. The release rate of MC degranulation marker β-hexosaminidase was measured. The expression of AAT1 and cAMP, the MC accumulation and degranulation in lung tissues were detected.

Objectives: To exam whether an endogenous sulfur dioxide (SO) pathway exists in MCs and if it serves as a novel endogenous MC stabilizer.

Results: We firstly show the existence of the endogenous SO/AAT pathway in MCs. Moreover, when AAT1 was knocked down in MCs, MC degranulation was significantly increased, and could be rescued by a SO donor. Mechanistically, AAT1 knockdown decreased the cyclic adenosine monophosphate (cAMP) content in MCs, while SO prevented this reduction in a dose-independent manner. Pretreatment with the cAMP-synthesizing agonist forskolin or the cAMP degradation inhibitor IBMX significantly blocked the increase in AAT1 knockdown-induced MC degranulation. Furthermore, in hypoxia-stimulated MCs, AAT1 protein expression and SO production were markedly down regulated, and MC degranulation was activated, which were blunted by AAT1 overexpression. The cAMP synthesis inhibitor SQ22536 disrupted the suppressive effect of AAT1 overexpression on hypoxia-induced MC degranulation. In a hypoxic environment, mRNA and protein expression of AAT1 was significantly reduced in lung tissues of rats. Supplementation of SO elevated the cAMP level and reduced perivascular MC accumulation and degranulation in lung tissues of rats exposed to a hypoxic environment .

Conclusion: SO serves as an endogenous MC stabilizer via upregulating the cAMP pathway under hypoxic circumstance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jare.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020161PMC
March 2021

Metabolic Reprogramming of Vascular Endothelial Cells: Basic Research and Clinical Applications.

Front Cell Dev Biol 2021 18;9:626047. Epub 2021 Feb 18.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Vascular endothelial cells (VECs) build a barrier separating the blood from the vascular wall. The vascular endothelium is the largest endocrine organ, and is well-known for its crucial role in the regulation of vascular function. The initial response to endothelial cell injury can lead to the activation of VECs. However, excessive activation leads to metabolic pathway disruption, VEC dysfunction, and angiogenesis. The pathways related to VEC metabolic reprogramming recently have been considered as key modulators of VEC function in processes such as angiogenesis, inflammation, and barrier maintenance. In this review, we focus on the changes of VEC metabolism under physiological and pathophysiological conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.626047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930387PMC
February 2021

Endogenous SO-dependent Smad3 redox modification controls vascular remodeling.

Redox Biol 2021 05 18;41:101898. Epub 2021 Feb 18.

Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China; Key Laboratory of Cardiovascular Sciences, Ministry of Education, China. Electronic address:

Sulfur dioxide (SO) has emerged as a physiological relevant signaling molecule that plays a prominent role in regulating vascular functions. However, molecular mechanisms whereby SO influences its upper-stream targets have been elusive. Here we show that SO may mediate conversion of hydrogen peroxide (HO) to a more potent oxidant, peroxymonosulfite, providing a pathway for activation of HO to convert the thiol group of protein cysteine residues to a sulfenic acid group, aka cysteine sulfenylation. By using site-centric chemoproteomics, we quantified >1000 sulfenylation events in vascular smooth muscle cells in response to exogenous SO. Notably, ~42% of these sulfenylated cysteines are dynamically regulated by SO, among which is cysteine-64 of Smad3 (Mothers against decapentaplegic homolog 3), a key transcriptional modulator of transforming growth factor β signaling. Sulfenylation of Smad3 at cysteine-64 inhibits its DNA binding activity, while mutation of this site attenuates the protective effects of SO on angiotensin II-induced vascular remodeling and hypertension. Taken together, our findings highlight the important role of SO in vascular pathophysiology through a redox-dependent mechanism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2021.101898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933484PMC
May 2021

Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury.

Cell Res 2021 Jul 28;31(7):773-790. Epub 2021 Jan 28.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China.

Compelling evidence has revealed that biased activation of G protein-coupled receptor (GPCR) signaling, including angiotensin II (AngII) receptor type 1 (AT1) signaling, plays pivotal roles in vascular homeostasis and injury, but whether a clinically relevant endogenous biased antagonism of AT1 signaling exists under physiological and pathophysiological conditions has not been clearly elucidated. Here, we show that an extracellular matrix protein, cartilage oligomeric matrix protein (COMP), acts as an endogenous allosteric biased modulator of the AT1 receptor and its deficiency is clinically associated with abdominal aortic aneurysm (AAA) development. COMP directly interacts with the extracellular N-terminus of the AT1 via its EGF domain and inhibits AT1-β-arrestin-2 signaling, but not Gq or Gi signaling, in a selective manner through allosteric regulation of AT1 intracellular conformational states. COMP deficiency results in activation of AT1a-β-arrestin-2 signaling and subsequent exclusive AAA formation in response to AngII infusion. AAAs in COMP or ApoE mice are rescued by AT1a or β-arrestin-2 deficiency, or the application of a peptidomimetic mimicking the AT1-binding motif of COMP. Explorations of the endogenous biased antagonism of AT1 receptor or other GPCRs may reveal novel therapeutic strategies for cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41422-020-00464-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249609PMC
July 2021

Persulfidation of transcription factor FOXO1 at cysteine 457: A novel mechanism by which HS inhibits vascular smooth muscle cell proliferation.

J Adv Res 2021 Jan 1;27:155-164. Epub 2020 Jul 1.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Introduction: The proliferation of vascular smooth muscle cells (VSMCs) is an important physiological and pathological basis for many cardiovascular diseases. Endogenous hydrogen sulfide (HS), the third gasotransmitter, is found to preserve vascular structure by inhibiting VSMC proliferation. However, the mechanism by which HS suppresses VSMC proliferation has not been fully clear.

Objectives: This study aimed to explore whether HS persulfidates the transcription factor FOXO1 to inhibit VSMC proliferation.

Methods: After the proliferation of VSMC A7r5 cells was induced by endothelin-1 (ET-1), FOXO1 phosphorylation and proliferating cell nuclear antigen (PCNA) expression were detected by Western blotting, the degree of FOXO1 nuclear exclusion and PCNA fluorescent signals in the nucleus were detected by immunofluorescence, and the persulfidation of FOXO1 was measured through a biotin switch assay.

Results: The results showed that ET-1 stimulation increased cell proliferation, FOXO1 phosphorylation and FOXO1 nuclear exclusion to the cytoplasm in the cells. However, pretreatment with NaHS, an HS donor, successfully abolished the ET-1-induced increases in the VSMC proliferation, FOXO1 phosphorylation, and FOXO1 nuclear exclusion to the cytoplasm. Mechanistically, HS persulfidated the FOXO1 protein in A7r5 and 293T cells, and the thiol reductant DTT reversed this effect. Furthermore, the C457S mutation of FOXO1 abolished the HS-induced persulfidation of FOXO1 in the cells and the subsequent inhibitory effects on FOXO1 phosphorylation at Ser256, FOXO1 nuclear exclusion to the cytoplasm and cell proliferation.

Conclusion: Thus, our findings demonstrated that HS might inhibit VSMC proliferation by persulfidating FOXO1 at Cys457 and subsequently preventing FOXO1 phosphorylation at Ser256.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jare.2020.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728583PMC
January 2021

Hydrogen sulfide and vascular regulation - An update.

J Adv Res 2021 Jan 16;27:85-97. Epub 2020 May 16.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Background: Hydrogen sulfide (HS) is considered to be the third gasotransmitter after carbon monoxide (CO) and nitric oxide (NO). It plays an important role in the regulation of vascular homeostasis. Vascular remodeling have has proved to be related to the impaired HS generation.

Aim Of Review: This study aimed to summarize and discuss current data about the function of HS in vascular physiology and pathophysiology as well as the underlying mechanisms.

Key Scientific Concepts Of Review: Endogenous hydrogen sulfide (HS) as a third gasotransmitter is primarily generated by the enzymatic pathways and regulated by several metabolic pathways. HS as a physiologic vascular regulator, inhibits proliferation, regulates its apoptosis and autophagy of vascular cells and controls the vascular tone. Accumulating evidence shows that the downregulation of HS pathway is involved in the pathogenesis of a variety of vascular diseases, such as hypertension, atherosclerosis and pulmonary hypertension. Alternatively, HS supplementation may greatly help to prevent the progression of the vascular diseases by regulating vascular tone, inhibiting vascular inflammation, protecting against oxidative stress and proliferation, and modulating vascular cell apoptosis, which has been verified in animal and cell experiments and even in the clinical investigation. Besides, HS system and angiotensin-converting enzyme (ACE) inhibitors play a vital role in alleviating ischemic heart disease and left ventricular dysfunction. Notably, sulfhydryl-containing ACEI inhibitor zofenopril is superior to other ACE inhibitors due to its capability of HS releasing, in addition to ACE inhibition. The design and application of novel HS donors have significant clinical implications in the treatment of vascular-related diseases. However, further research regarding the role of HS in vascular physiology and pathophysiology is required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jare.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728588PMC
January 2021

Hydrogen sulfide regulates insulin secretion and insulin resistance in diabetes mellitus, a new promising target for diabetes mellitus treatment? A review.

J Adv Res 2021 Jan 26;27:19-30. Epub 2020 Feb 26.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Background: Insulin resistance and impaired insulin secretion lead to disorders of glucose metabolism, which contributes to the development of diabetes. Hydrogen sulfide (H2S), a novel gasotransmitter, is found to play important roles in regulation of glucose metabolism homeostasis.

Aim Of Review: This study aimed to summarize and discuss current data about the function of H2S in insulin secretion and insulin resistance regulation as well as the underlying mechanisms.

Key Scientific Concepts Of Review: HS could be endogenously produced in islet β cells, liver, adipose, skeletal muscles, and the hypothalamus, and regulates local and systemic glucose metabolism. It is reported that HS suppresses insulin secretion, promotes or reduces the apoptosis of islet β cells. It plays important roles in the regulation of insulin sensitivity in insulin responsive tissues. HS inhibits glucose uptake and glycogen storage, and promotes or inhibits gluconeogenesis, mitochondrial biogenesis and mitochondrial bioenergetics in the liver. In adipose tissue, several investigators indicated that H2S promoted glucose uptake in adipocytes, while other studies reported that HS inhibits this process. HS has also been shown to promote adipogenesis, inhibit lipolysis, and regulate adiponectin and MCP-1 secretion from adipocytes. In skeletal muscle, HS increases glucose uptake and improves insulin sensitivity. It is also observed that HS modulates circadian-clock genes in muscle. Hypothalamic CBS/HS pathway reduces obesity and improves insulin sensitivity via the brain-adipose interaction. Most studies indicated plasma HS levels decreased in diabetic patients. However, the mechanisms by which HS regulates systemic glucose metabolism remain unclear. Whether HS acts as a new promising target for diabetes mellitus treatment merits further studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jare.2020.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728586PMC
January 2021

Post-translational Modifications of IκBα: The State of the Art.

Front Cell Dev Biol 2020 5;8:574706. Epub 2020 Nov 5.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

The nuclear factor-kappa B (NF-κB) signaling pathway regulates a variety of biological functions in the body, and its abnormal activation contributes to the pathogenesis of many diseases, such as cardiovascular and respiratory diseases and cancers. Therefore, to ensure physiological homeostasis of body systems, this pathway is strictly regulated by IκBα transcription, IκBα synthesis, and the IκBα-dependent nuclear transport of NF-κB. Particularly, the post-translational modifications of IκBα including phosphorylation, ubiquitination, SUMOylation, glutathionylation and hydroxylation are crucial in the abovementioned regulatory process. Because of the importance of the NF-κB pathway in maintaining body homeostasis, understanding the post-translational modifications of IκBα can not only provide deeper insights into the regulation of NF-κB pathway but also contribute to the development of new drug targets and biomarkers for the diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2020.574706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674170PMC
November 2020

Postural Tachycardia Syndrome in Children and Adolescents: Pathophysiology and Clinical Management.

Front Pediatr 2020 20;8:474. Epub 2020 Aug 20.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Postural tachycardia syndrome (POTS), characterized by chronic (≥6 months) orthostatic intolerance symptoms with a sustained and excessive heart rate increase while standing without postural hypotension, is common in children and adolescents. Despite the unclear pathogenesis of POTS, the present opinion is that POTS is a heterogeneous and multifactorial disorder that includes altered central blood volume, abnormal autonomic reflexes, "hyperadrenergic" status, damaged skeletal muscle pump activity, abnormal local vascular tension and vasoactive factor release, mast cell activation, iron insufficiency, and autoimmune dysfunction. A number of pediatric POTS patients are affected by more than one of these pathophysiological mechanisms. Therefore, individualized treatment strategies are initiated in the management of POTS, including basal non-pharmacological approaches (e.g., health education, the avoidance of triggers, exercise, or supplementation with water and salt) and special pharmacological therapies (e.g., oral rehydration salts, midodrine hydrochloride, and metoprolol). As such, the recent progress in the pathogenesis, management strategies, and therapeutic response predictors of pediatric POTS are reviewed here.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2020.00474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468430PMC
August 2020

Sulfur Dioxide: An Endogenous Protector Against Myocardial Injury.

J Cardiovasc Pharmacol 2020 10;76(4):389-396

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Sulfur dioxide (SO2) was previously known as a harmful gas in air pollution. Recently, it was reported that SO2 can be endogenously generated in cardiovascular tissues. Many studies have revealed that endogenous SO2 has important physiological and pathophysiological significance and pharmacological potential. As a novel gasotransmitter, SO2 has important regulatory effects on the heart. It has a dose-dependent negative inotropic effect on cardiac function, in which L-type calcium channels are involved. SO2 can also attenuate myocardial injury caused by various harmful stimuli and play an important role in myocardial ischemia-reperfusion injury and myocardial hypertrophy. These effects are thought to be linked to its ability to reduce inflammation and as an antioxidant. In addition, SO2 regulates cardiomyocyte apoptosis and autophagy. Therefore, endogenous SO2 plays an important role in maintaining cardiovascular system homeostasis. In the present review, the literature concerning the metabolism of endogenous SO2, its cardiac toxicological effects and physiological regulatory effects, mechanisms for SO2-mediated myocardial protection and its pharmacological applications are summarized and discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FJC.0000000000000882DOI Listing
October 2020

Different attributes of creaky voice distinctly affect Mandarin tonal perception.

Authors:
Yaqian Huang

J Acoust Soc Am 2020 03;147(3):1441

Department of Linguistics, University of California San Diego, 9500 Gilman Drive #0108, La Jolla, California 92093-0108, USA.

Previous work has shown mixed findings concerning the role of voice quality cues in Mandarin tones, with some studies showing that creak improves identification. This study tests the linguistic importance of acoustic properties of creak for Mandarin tone perception. Mandarin speakers identified tones with four resynthesized creak manipulations: low spectral tilt, irregular F0, period doubling, and extra-low F0. Two experiments with three conditions were conducted. In Experiment 1, the manipulations were confined to a portion of the stimuli's duration; in Experiment 2 the creak manipulations were modified and lengthened throughout the stimuli, and in a second condition, noise was incorporated to weaken F0 cues. Listeners remained most sensitive to extra-low F0, which affected identification of the four tones differently: it improved the identification accuracy of Tone 3 and hindered that of Tones 1 and 4. Irregular F0 consistently hindered T1 identification. The effects of irregular F0, period doubling, and low spectral tilt emerged in Experiment 2, where F0 cues were less robust and creak cues were stronger. Thus, low F0 is the most prominent cue used in Mandarin tone identification, but other voice quality cues become more salient to listeners when the F0 cues are less retrievable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1121/10.0000721DOI Listing
March 2020

Reduced 24-h Sodium Excretion Is Associated With a Disturbed Plasma Acylcarnitine Profile in Vasovagal Syncope Children: A Pilot Study.

Front Pediatr 2020 11;8:98. Epub 2020 Mar 11.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

To investigate if the low sodium intake is associated with the plasma carnitine and acylcarnitine profile in children with vasovagal syncope (VVS). Twenty-six children suffering from VVS were recruited in the present study and divided into a group of low urinary sodium excretion or a group of normal urinary sodium excretion according to the excretion of 24-h urinary sodium <3 or 3-6 g, respectively. The excretion of 24-h urinary sodium was detected with ion-selective electrode approach. Plasma carnitine and acylcarnitine concentrations were measured with tandem mass spectrometry. Each participant completed the head-up tilt test. The demographics, clinical characteristics, hemodynamic parameters and plasma carnitine and acylcarnitine concentrations were compared between the two groups. A bivariate correlation between plasma acylcarnitine profiles and the excretion of 24-h urinary sodium was conducted with Spearman's correlation coefficients. Of the enrolled VVS patients, 14 patients were assigned to the group of low urinary sodium excretion and the remaining 12 patients were assigned to the group of normal urinary sodium excretion. Symptoms of fatigue were more prevalent in the group of low urinary sodium excretion than in the group of normal urinary sodium excretion ( = 0.009). Aside from fatigue, no other differences in the demographics, clinical characteristics or hemodynamic parameters during the head-up tilt test were found between the two groups ( > 0.05). Concentrations of plasma tiglylcarnitine (C5:1), hydroxyhexadecanoylcarnitine (C16OH), hydroxyoctadecanoylcarnitine (C18OH), and carnitine C22 were significantly higher in the group of low urinary sodium excretion than in the group of normal urinary sodium excretion (all values = 0.048); moreover, they were all negatively correlated with 24-h urinary sodium levels (all -values = 0.016). There were no differences between the two groups in other acylcarnitines or free carnitine. Reduced excretion of 24-h urinary sodium is associated with a disturbed plasma acylcarnitine profile in children with VVS. The findings suggest that restricted sodium intake-induced disturbance of plasma acylcarnitines and related cellular energy metabolism might be involved in the pathogenesis of VVS in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2020.00098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078237PMC
March 2020

Endothelin-1 Downregulates Sulfur Dioxide/Aspartate Aminotransferase Pathway via Reactive Oxygen Species to Promote the Proliferation and Migration of Vascular Smooth Muscle Cells.

Oxid Med Cell Longev 2020 28;2020:9367673. Epub 2020 Jan 28.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

The regulatory mechanisms for proliferation and migration of vascular smooth muscle cells have not yet been clear. The present study was designed to investigate whether and how endothelin-1 (ET-1) impacted the generation of endogenous sulfur dioxide (SO) in rat vascular smooth muscle cell (VSMC) proliferation and migration. Primary VSMCs and purified aspartate aminotransferase (AAT) protein were used in this study. We found that in the presence of ET-1, the expression of PCNA and Ki-67 was upregulated and the migration of VSMCs was promoted, while the AAT activity and SO levels in VSMCs were reduced without any changes in AAT1 and AAT2 expression. SO supplementation successfully prevented the ET-1-facilitated expression of PCNA and Ki-67 and the migration of VSMCs. Interestingly, ET-1 significantly increased reactive oxygen species (ROS) production in association with SO/AAT pathway downregulation in VSMCs compared with controls, while the ROS scavenger N-acetyl-L-cysteine (NAC) and the antioxidant glutathione (GSH) significantly abolished the ET-1-stimulated downregulation of the SO/AAT pathway. Moreover, the AAT activity was reduced in purified protein after the treatment for 2 h. However, NAC and GSH blocked the hydrogen peroxide-induced AAT activity reduction. In conclusion, our results suggest that ET-1 results in the downregulation of the endogenous SO/AAT pathway via ROS generation to enhance the proliferation and migration of VSMCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/9367673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008293PMC
September 2020

Negative auto-regulation of sulfur dioxide generation in vascular endothelial cells: AAT1 S-sulfenylation.

Biochem Biophys Res Commun 2020 Feb 19. Epub 2020 Feb 19.

Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China. Electronic address:

Recently, endogenous sulfur dioxide (SO) has been found to exert an important function in the cardiovascular system. However, the regulatory mechanism for SO generation has not been entirely clarified. Hence, we aimed to explore the possible auto-regulation of endogenous SO generation and its mechanisms in vascular endothelial cells. We showed that SO did not affect the protein expression of aspartate aminotransferase 1 (AAT1), a major SO synthesis enzyme, but significantly inhibited AAT activity in primary human umbilical vein endothelial cells (HUVECs) and porcine purified AAT1 protein. An AAT1 enzymatic kinetic study showed that SO reduced the Vmax (1.89 ± 0.10 vs 2.55 ± 0.12, μmol/mg/min, P < 0.05) and increased the Km (35.97 ± 9.54 vs 19.33 ± 1.76 μmol/L, P < 0.05) values. Furthermore, SO induced S-sulfenylation of AAT1 in primary HUVECs and purified AAT1 protein. LC-MS/MS analysis indicated that SO sulfenylated AAT1 at Cys192. Mechanistically, thiol reductant DTT treatment or C192S mutation prevented SO-induced AAT1 sulfenylation and the subsequent inhibition of AAT activity in purified AAT1 protein and primary HUVECs. Our findings reveal, for the first time, a mechanism of auto-regulation of SO generation through sulfenylation of AAT1 at Cys192 to suppress AAT activity in vascular endothelial cells. These findings will greatly deepen the understanding of regulatory mechanisms in the cardiovascular homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.02.040DOI Listing
February 2020

Macrophage-derived sulfur dioxide is a novel inflammation regulator.

Biochem Biophys Res Commun 2020 04 10;524(4):916-922. Epub 2020 Feb 10.

Department of Pediatrics, Peking University First Hospital, Beijing, China. Electronic address:

Macrophage-mediated inflammation is a key pathophysiological component of cardiovascular diseases, but the underlying mechanisms by which the macrophage regulates inflammation have been unclear. In our study, we, for the first time, showed an endogenous sulfur dioxide (SO) production in RAW267.4 macrophages by using HPLC and SO-specific fluorescent probe assays. Moreover, the endogenous SO generating enzyme aspartate aminotransferase (AAT) was found to be expressed by the macrophages. Furthermore, we showed that AAT2 knockdown triggered spontaneous macrophage-mediated inflammation, as represented by the increased TNF-α and IL-6 levels and the enhanced macrophage chemotaxis; these effects could be reversed by the treatment with a SO donor. Mechanistically, AAT2 knockdown activated the NF-κB signaling pathway in macrophages, while SO successfully rescued NF-κB activation. In contrast, forced AAT2 expression reversed AngII-induced NF-κB activation and subsequent macrophage inflammation. Moreover, treatment with a SO donor also alleviated macrophage infiltration in AngII-treated mouse hearts. Collectively, our data suggest that macrophage-derived SO is an important regulator of macrophage activation and it acts as an endogenous "on-off switch" in the control of macrophage activation. This knowledge might enable a new therapeutic strategy for cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.02.013DOI Listing
April 2020

A New Scoring System for Prediction of Intravenous Immunoglobulin Resistance of Kawasaki Disease in Infants Under 1-Year Old.

Front Pediatr 2019 11;7:514. Epub 2019 Dec 11.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Children with Kawasaki disease (KD) under 1-year old are at high risk for intravenous immunoglobulin (IVIG) resistance. The study was designed to explore the predictive measure of IVIG resistance in infants under 1-year old with KD. This study enrolled children under 1-year old suffering from KD in Peking University First Hospital and Wuhan Children's Hospital. All infants were divided into IVIG-responsive and IVIG-resistant groups. The differences in demographic characteristics, clinical features, and laboratory examinations were compared and the risk factors of IVIG resistant KD were analyzed. Furthermore, a scoring system was developed for predicting IVIG resistance in KD infants and an external validation was performed. A total of 282 infants (194 boys, median age of 7.0 months) were enrolled in this study, of whom 23 children were IVIG-resistant. Compared with IVIG-responsive infants, those in the IVIG-resistant group had a high neutrophil-to-lymphocyte ratio (NLR), high platelet-to-lymphocyte ratio (PLR), high mean platelet volume-to-lymphocyte ratio (MPVLR) in peripheral blood, and low serum albumin, and low serum sodium before IVIG therapy (all < 0.01). Multiple regression analysis indicated that high levels of peripheral NLR and MPVLR, and low levels of serum albumin and serum sodium were independent risk factors for IVIG resistant KD infants. A scoring system, which included peripheral NLR ≥ 2.69 (1 point), MPVLR ≥ 2.78 (1 point), serum albumin ≤ 30.7 g/L (1 point), and serum sodium ≤ 135.2 mmol/L (1 point), was established. A cut-off value of a total score of 2 points or higher yielded a sensitivity of 87.0% and a specificity of 78.4%, with an area under the curve of 0.891. External validation with clinical diagnostic standard showed that a cut-off value of total score of 2 points or higher for predicting the IVIG-resistance yielded a sensitivity of 70.0% and a specificity of 75.1%. For the first time, we proposed a predictive model of IVIG resistance in KD infants under 1-year old. The scoring system, which accounts for baseline peripheral NLR, MPVLR, and serum albumin and sodium, predicts with relatively high sensitivity and specificity for IVIG-resistant infants with KD under 1-year old.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2019.00514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917618PMC
December 2019

L-Cystathionine Protects against Homocysteine-Induced Mitochondria-Dependent Apoptosis of Vascular Endothelial Cells.

Oxid Med Cell Longev 2019 25;2019:1253289. Epub 2019 Nov 25.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

The study was aimed at investigating the effects of L-cystathionine on vascular endothelial cell apoptosis and its mechanisms. Cultured human umbilical vein endothelial cells (HUVECs) were used in the study. Apoptosis of vascular endothelial cells was induced by homocysteine. Apoptosis, mitochondrial superoxide anion, mitochondrial membrane potential, mitochondrial permeability transition pore (MPTP) opening, and caspase-9 and caspase-3 activities were examined. Expression of Bax, Bcl-2, and cleaved caspase-3 was tested and BTSA1, a Bax agonist, and HUVEC Bax overexpression was used in the study. Results showed that homocysteine obviously induced the apoptosis of HUVECs, and this effect was significantly attenuated by the pretreatment with L-cystathionine. Furthermore, L-cystathionine decreased the production of mitochondrial superoxide anion and the expression of Bax and restrained its translocation to mitochondria, increased mitochondrial membrane potential, inhibited mitochondrial permeability transition pore (MPTP) opening, suppressed the leakage of cytochrome c from mitochondria into the cytoplasm, and downregulated activities of caspase-9 and caspase-3. However, BTSA1, a Bax agonist, or Bax overexpression successfully abolished the inhibitory effect of L-cystathionine on Hcy-induced MPTP opening, caspase-9 and caspase-3 activation, and HUVEC apoptosis. Taken together, our results indicated that L-cystathionine could protect against homocysteine-induced mitochondria-dependent apoptosis of HUVECs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/1253289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899331PMC
May 2020

Endogenous hydrogen sulfide sulfhydrates IKKβ at cysteine 179 to control pulmonary artery endothelial cell inflammation.

Clin Sci (Lond) 2019 10;133(20):2045-2059

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Background: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear.

Methods: Purified recombinant human inhibitor of κB kinase subunit β (IKKβ) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein.

Results: We showed that hydrogen sulfide (H2S) inhibited IKKβ activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKβ activity directly via sulfhydrating IKKβ at cysteinyl residue 179 (C179) in purified recombinant IKKβ protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKβ inactivation. Furthermore, to demonstrate the significance of IKKβ sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKβ. In purified IKKβ protein, C179S mutation of IKKβ abolished H2S-induced IKKβ sulfhydration and the subsequent IKKβ inactivation. In human PAECs, C179S mutation of IKKβ blocked H2S-inhibited IKKβ activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKβ abolished the inhibitory effect of H2S on IKKβ activation and pulmonary vascular inflammation and remodeling.

Conclusion: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKβ via sulfhydrating IKKβ at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/CS20190514DOI Listing
October 2019

Angiotensin II downregulates vascular endothelial cell hydrogen sulfide production by enhancing cystathionine γ-lyase degradation through ROS-activated ubiquitination pathway.

Biochem Biophys Res Commun 2019 06 10;514(3):907-912. Epub 2019 May 10.

Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China. Electronic address:

The interactions between vasoactive peptides and gasotransmitters have attracted considerable attention from scientists. However, the impact of angiotensin II (AngII) on the endogenous hydrogen sulfide/cystathionine γ-lyase (HS/CSE) pathway in vascular endothelial cells remains unclear. In this study, we found, for the first time, that AngII downregulated the endogenous HS/CSE pathway in a time-dependent manner. Mechanistically, AngII accelerated the degradation of the CSE protein and shortened its half-life in endothelial cells. AngII significantly induced Lys48 (K48)-linked CSE ubiquitination and subsequent CSE degradation but did not affect Lys63 (K63)-linked CSE ubiquitination in vascular endothelial cells. Treatment with the proteasome inhibitor MG132 and mutation of Lys48 to Arg in ubiquitin successfully blunted the inhibitory effects of AngII on the endogenous HS/CSE pathway in vascular endothelial cells. Furthermore, we found that superoxide anion levels were significantly increased in AngII-treated endothelial cells compared with controls and that the ROS scavenger N-acetyl-l-cysteine (NAC) significantly abolished CSE ubiquitination. Taken together, our data suggested that AngII inhibited endogenous HS generation through ubiquitination-mediated CSE degradation via the ROS pathway in vascular endothelial cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2019.05.021DOI Listing
June 2019

Sulfur Dioxide Activates Cl/HCO Exchanger via Sulphenylating AE2 to Reduce Intracellular pH in Vascular Smooth Muscle Cells.

Front Pharmacol 2019 27;10:313. Epub 2019 Mar 27.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Sulfur dioxide (SO) is a colorless and irritating gas. Recent studies indicate that SO acts as the gas signal molecule and inhibits vascular smooth muscle cell (VSMC) proliferation. Cell proliferation depends on intracellular pH (pH). Transmembrane cystein mutation of Na- independent Cl/HCO exchanger (anion exchanger, AE) affects pH. However, whether SO inhibits VSMC proliferation by reducing pH is still unknown. Here, we investigated whether SO reduced pH to inhibit the proliferation of VSMCs and explore its molecular mechanisms. Within a range of 50-200 μM, SO was found to lower the pH in VSMCs. Concurrently, NHCl pre-perfusion showed that SO significantly activated AE, whereas the AE inhibitor 4,4'-diisothiocyanatostilbene- 2,20-disulfonic acid (DIDS) significantly attenuated the effect of SO on pH in VSMCs. While 200 μM SO sulphenylated AE2, while dithiothreitol (DTT) blocked the sulphenylation of AE2 and subsequent AE activation by SO, thereby restoring the pH in VSMCs. Furthermore, DIDS pretreatment eliminated SO-induced inhibition of PDGF-BB-stimulated VSMC proliferation. We report for the first time that SO inhibits VSMC proliferation in part by direct activation of the AE via posttranslational sulphenylation and induction of intracellular acidification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2019.00313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446831PMC
March 2019

Perceptual features predict word frequency asymmetry across modalities.

Atten Percept Psychophys 2019 May;81(4):1076-1087

Department of Psychology, University of California, San Diego, La Jolla, CA, USA.

The relationships between word frequency and various perceptual features have been used to study the cognitive processes involved in word production and recognition, as well as patterns in language use over time. However, little work has been done comparing spoken and written frequencies against each other, which leaves open the question of whether there are modality-specific relationships between perceptual features and frequency. Words have different frequencies in speech and written texts, with some words occurring disproportionately more often in one modality than the other. In the present study, we investigated whether perceptual features predict this frequency asymmetry across modalities. Our results suggest that perceptual features such as length, neighborhood density, and positional probability differentially affect speech and writing, which reveals different online processing constraints and considerations for communicative efficiency across the two modalities. These modality-specific effects exist above and beyond formality differences. This work provides arguments against theories that assume that words differing in frequency are perceptually equivalent, as well as models that predict little to no influence of perceptual features on top-down processes of word selection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3758/s13414-019-01682-yDOI Listing
May 2019

The Increased Endogenous Sulfur Dioxide Acts as a Compensatory Mechanism for the Downregulated Endogenous Hydrogen Sulfide Pathway in the Endothelial Cell Inflammation.

Front Immunol 2018 30;9:882. Epub 2018 Apr 30.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Endogenous hydrogen sulfide (HS) and sulfur dioxide (SO) are regarded as important regulators to control endothelial cell function and protect endothelial cell against various injuries. In our present study, we aimed to investigate the effect of endogenous HS on the SO generation in the endothelial cells and explore its significance in the endothelial inflammation and . The human umbilical vein endothelial cell (HUVEC) line (EA.hy926), primary HUVECs, primary rat pulmonary artery endothelial cells (RPAECs), and purified aspartate aminotransferase (AAT) protein from pig heart were used for experiments. A rat model of monocrotaline (MCT)-induced pulmonary vascular inflammation was used for experiments. We found that endogenous HS deficiency caused by cystathionine-γ-lyase (CSE) knockdown increased endogenous SO level in endothelial cells and enhanced the enzymatic activity of AAT, a major SO synthesis enzyme, without affecting the expressions of AAT1 and AAT2. While HS donor could reverse the CSE knockdown-induced increase in the endogenous SO level and AAT activity. Moreover, HS donor directly inhibited the activity of purified AAT protein, which was reversed by a thiol reductant DTT. Mechanistically, HS donor sulfhydrated the purified AAT1/2 protein and rescued the decrease in the sulfhydration of AAT1/2 protein in the CSE knockdown endothelial cells. Furthermore, an AAT inhibitor l-aspartate-β-hydroxamate (HDX), which blocked the upregulation of endogenous SO/AAT generation induced by CSE knockdown, aggravated CSE knockdown-activated nuclear factor-κB pathway in the endothelial cells and its downstream inflammatory factors including ICAM-1, TNF-α, and IL-6. In experiment, HS donor restored the deficiency of endogenous HS production induced by MCT, and reversed the upregulation of endogenous SO/AAT pathway sulfhydrating AAT1 and AAT2. In accordance with the results of the experiment, HDX exacerbated the pulmonary vascular inflammation induced by the broken endogenous HS production in MCT-treated rat. In conclusion, for the first time, the present study showed that HS inhibited endogenous SO generation by inactivating AAT the sulfhydration of AAT1/2; and the increased endogenous SO generation might play a compensatory role when HS/CSE pathway was downregulated, thereby exerting protective effects in endothelial inflammatory responses and .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.00882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936987PMC
June 2019
-->