Mechanisms Underlying the Hydrogen Sulfide Actions: Target Molecules and Downstream Signaling Pathways.

Significance: As a new important gas signaling molecule like nitric oxide (NO) and carbon dioxide (CO), hydrogen sulfide (H2S), which can be produced by endogenous H2S-producing enzymes through l-cysteine metabolism in mammalian cells, has attracted wide attention for long. H2S has been proved to play an important regulatory role in numerous physiological and pathophysiological processes. However, the deep mechanisms of those different functions of H2S still remain uncertain. A better understanding of the mechanisms can help us develop novel therapeutic strategies. Recent Advances: H2S can play a regulating role through various mechanisms, such as regulating epigenetic modification, protein expression levels, protein activity, protein localization, redox microenvironment, and interaction with other gas signaling molecules such as NO and CO. In addition to discussing the molecular mechanisms of H2S from the above perspectives, this article will review the regulation of H2S on common signaling pathways in the cells, including the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK), Janus kinase (JAK)/signal transducer, and activator of transcription (STAT) signaling pathway. Critical Issues: Although there are many studies on the mechanism of H2S, little is known about its direct target molecules. This article will also review the existing reports about them. Furthermore, the interaction between direct target molecules of H2S and the downstream signaling pathways involved also needs to be clarified. Future Directions: An in-depth discussion of the mechanism of H2S and the direct target molecules will help us achieving a deeper understanding of the physiological and pathophysiological processes regulated by H2S, and lay a foundation for developing new clinical therapeutic drugs in the future. Innovation: This review focuses on the regulation of H2S on signaling pathways and the direct target molecules of H2S. We also provide details on the underlying mechanisms of H2S functions from the following aspects: epigenetic modification, regulation of protein expression levels, protein activity, protein localization, redox microenvironment, and interaction with other gas signaling molecules such as NO and CO. Further study of the mechanisms underlying H2S will help us better understand the physiological and pathophysiological processes it regulates, and help develop new clinical therapeutic drugs in the future. Antioxid. Redox Signal. 40, 86-109.

Enhancement of volatile fatty acids production through anaerobic co-digestion of navel orange residue and waste activated sludge: Effect of pre-treatment and substrate proportions.

In this study, the co-digestion system with Navel orange residues (NOR) and Waste activated sludge (WAS) was established, by pre-treating the NOR and setting different volatile solids (VS) ratios of NOR to WAS to motivate the production of volatile fatty acids (VFA). The pre-treatment method (pH 7 and temperature 70 °C) promoted the release of dissolved organic matter, and the concentration of soluble chemical oxygen demand (SCOD) increased by 45.56% compared with the untreated group (pH 3 and temperature 20 °C). In the co-digestion system, the highest VFA yield (5716.69 mg/L) was obtained at VS ratio of 2. When the VS ratio was increased to 4, the imbalance in proportions of carbon and nitrogen affected VFA production, and the high concentration of essential oils (EO) present in the NOR inhibited the methane production; the cumulative yield of methane gas decreased by 24.10% compared with the yield obtained when the VS ratio was 2. Analysis of microbial community revealed that an increase in the number of VFA-producing microbial populations and the abundance of Methanobacteria resulted in the accumulation of acetic acid. This study demonstrated that co-digestion of NOR with WAS improve VFA production, thus realizing the utilization of solid wastes and reducing environmental pollution.

Skeletal muscle-derived FSTL1 starting up angiogenesis by regulating endothelial junction via activating Src pathway can be upregulated by hydrogen sulfide.

Hydrogen sulfide (H2S) promotes microangiogenesis and revascularization after ischemia. Neovascularization starts with the destruction of intercellular junctions and is accompanied by various endothelial cell angiogenic behaviors. Follistatin-like 1 (FSTL1) is a cardiovascular-protective myokine that works against ischemic injury. The present study examined whether FSTL1 was involved in H2S-induced angiogenesis and explored the underlying molecular mechanism. We observed that H2S accelerated blood perfusion after ischemia in the mouse hindlimb ischemia model. Western blot analysis showed that H2S stabilized FSTL1 transcript and increased FSTL1 and Human antigen R (HuR) levels in skeletal muscle. RNA-interference HuR significantly inhibited the H2S-promoted increase in FSTL1 levels. Exogenous FSTL1 promoted the wound-healing migration of human umbilical vein endothelial cells (HUVECs) and increased monolayer endothelial barrier permeability. Immunostaining showed that FSTL1 increased interendothelial gap formation and decreased VE-Cadherin, Occludin, Connexin-43, and Claudin-5 expression. In addition, FSTL1 significantly increased the phosphorylation of Src and VEGFR2. However, the Src inhibitor, not the VEGFR2 inhibitor, could block FSTL1-induced effects in angiogenesis. In conclusion, we demonstrated that H2S could upregulate the expression of FSTL1 by increasing the HuR levels in skeletal muscle, and paracrine FSTL1 could initiate angiogenesis by opening intercellular junctions via the Src signaling pathway.NEW & NOTEWORTHY The myocyte-derived paracrine protein FSTL1 acts on vascular endothelial cells and initiates the process of angiogenesis by opening the intercellular junction via activating Src kinase. H2S can significantly upregulate FSTL1 protein levels in skeletal muscles by increasing HuR expression.

Hydrogen sulfide functions as a micro-modulator bound at the copper active site of Cu/Zn-SOD to regulate the catalytic activity of the enzyme.

The present study examines whether there is a mechanism beyond the current concept of post-translational modifications to regulate the function of a protein. A small gas molecule, hydrogen sulfide (H2S), was found to bind at active-site copper of Cu/Zn-SOD using a series of methods including radiolabeled binding assay, X-ray absorption near-edge structure (XANES), and crystallography. Such an H2S binding enhanced the electrostatic forces to guide the negatively charged substrate superoxide radicals to the catalytic copper ion, changed the geometry and energy of the frontier molecular orbitals of the active site, and subsequently facilitated the transfer of an electron from the superoxide radical to the catalytic copper ion and the breakage of the copper-His61 bridge. The physiological relevance of such an H2S effect was also examined in both in vitro and in vivo models where the cardioprotective effects of H2S were dependent on Cu/Zn-SOD.

S-propargyl-cysteine delays the progression of atherosclerosis and increases eNOS phosphorylation in endothelial cells.

The present study aimed to investigate the protective effect of S-propargyl-cysteine (SPRC) on atherosclerosis progression in mice. A mouse model of vulnerable atherosclerotic plaque was created in ApoE-/- mice by carotid artery tandem stenosis (TS) combined with a Western diet. Macrophotography, lipid profiles, and inflammatory markers were measured to evaluate the antiatherosclerotic effects of SPRC compared to atorvastatin as a control. Histopathological analysis was performed to assess the plaque stability. To explore the protective mechanism of SPRC, human umbilical vein endothelial cells (HUVECs) were cultured in vitro and challenged with oxidized low-density lipoprotein (ox-LDL). Cell viability was determined with a Cell Counting Kit-8 (CCK-8). Endothelial nitric oxide synthase (eNOS) phosphorylation and mRNA expression were detected by Western blot and RT-qPCR respectively. The results showed that the lesion area quantified by en face photographs of the aortic arch and carotid artery was significantly less, plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were reduced, plaque collagen content was increased and matrix metalloproteinase-9 (MMP-9) was decreased in 80 mg/kg per day SPRC-treated mice compared with model mice. These findings support the role of SPRC in plaque stabilization. In vitro studies revealed that 100 µmol/L SPRC increased the cell viability and the phosphorylation level of eNOS after ox-LDL challenge. These results suggest that SPRC delays the progression of atherosclerosis and enhances plaque stability. The protective effect may be at least partially related to the increased phosphorylation of eNOS in endothelial cells.

YB-1 Recruits Drosha to Promote Splicing of pri-miR-192 to Mediate the Proangiogenic Effects of H2S.

Aims: The genes targeted by miRNAs have been well studied. However, little is known about the feedback mechanisms to control the biosynthesis of miRNAs that are essential for the miRNA feedback networks in the cells. In this present study, we aimed at examining how hydrogen sulfide (H2S) promotes angiogenesis by regulating miR-192 biosynthesis. Results: H2S promoted in vitro angiogenesis and angiogenesis in Matrigel plugs embedded in mice by upregulating miR-192. Knockdown of the H2S-generating enzyme cystathionine γ-lyase (CSE) suppressed in vitro angiogenesis, and this suppression was rescued by exogenous H2S donor NaHS. Plakophilin 4 (PKP4) served as a target gene of miR-192. H2S up-regulated miR-192 via the VEGFR2/Akt pathway to promote the splicing of primary miR-192 (pri-miR-192), and it resulted in an increase in both the precursor- and mature forms of miR-192. H2S translocated YB-1 into the nuclei to recruit Drosha to bind with pri-miR-192 and promoted its splicing. NaHS treatment promoted angiogenesis in the hindlimb ischemia mouse model and the skin-wound-healing model in diabetic mice, with upregulated miR-192 and downregulated PKP4 on NaHS treatment. In human atherosclerotic plaques, miR-192 levels were positively correlated with the plasma H2S concentrations. Innovation and Conclusion: Our data reveal a role of YB-1 in recruiting Drosha to splice pri-miR-192 to mediate the proangiogenic effect of H2S. CSE/H2S/YB-1/Drosha/miR-192 is a potential therapeutic target pathway for treating diseases, including organ ischemia and diabetic complications. Antioxid. Redox Signal. 36, 760-783. The Clinical Trial Registration number is 2016-224.

Histone deacetylase 6 promotes skin wound healing by regulating fibroblast migration and differentiation in aged mice.

Skin wound healing tends to slow down with aging, which is detrimental to both minor wound recovery in daily life and the recovery after surgery. The aim of current study was to explore the effect of histone deacetylase 6 (HDAC6) on wound healing during aging. Cultured human dermal fibroblasts (HDFs) and mouse full-thickness skin wound model were used to explore the functional changes of replicative senescent dermal fibroblasts and the effect of aging on skin wound healing. Scratch wound healing assay revealed significantly decreased migration speed of senescent HDFs, and BrdU incorporation assay indicated their considerably retardant proliferation. The protein expression levels of collagen and HDAC6 were significantly decreased in both senescent HDFs and skin tissues from aged mice. HDAC6 activity inhibition with highly selective inhibitor tubastatin A (TsA) or HDAC6 knockdown with siRNA decreased the migration speed of HDFs and considerably suppressed fibroblast differentiation induced by transforming growth factor-ß1 (TGF-ß1), which suggests the involvement of HDAC6 in regulating fundamental physiological activities of dermal fibroblasts. In vivo full-thickness skin wound healing was significantly delayed in young HDAC6 knockout mice when compared with young wild type mice. In addition, the wound healing was significantly slower in aged wild type mice than that in young wild type mice, and became even worse in aged HDAC6 knockout aged mice. Compared to the aged wild type mice, aged HDAC6 knockout mice exhibited delayed angiogenesis, reduced collagen synthesis, and decreased collagen deposition in skin wounds. Together, these results suggest that delayed skin wound healing in aged mice is associated with impaired fibroblast function. Adequate expression and activity of HDAC6 are required for fibroblasts migration and differentiation.

S-Propargyl-Cysteine Attenuates Diabetic Cardiomyopathy in db/db Mice Through Activation of Cardiac Insulin Receptor Signaling.

Background: Endogenous hydrogen sulfide (H2S) is emerging as a key signal molecule in the development of diabetic cardiomyopathy. The aim of this study was to explore the effect and underlying mechanism of S-propargyl-cysteine (SPRC), a novel modulator of endogenous H2S, on diabetic cardiomyopathy in db/db diabetic mice. Methods and Results: Vehicle or SPRC were orally administered to 8-month-old male db/db mice and their wild type littermate for 12 weeks. SPRC treatment ameliorated myocardial hypertrophy, fibrosis, and cardiac systolic dysfunction assessed by histopathological examinations and echocardiography. The functional improvement by SPRC was accompanied by a reduction in myocardial lipid accumulation and ameliorated plasma lipid profiles. SPRC treatment improved glucose tolerance in db/db mice, with fasting blood glucose and peripheral insulin resistance remaining unchanged. Furthermore, insulin receptor signaling involving the phosphorylation of protein kinase B (Akt/PKB) and glycogen synthase kinase 3ß (GSK3ß) were elevated and activated by SPRC treatment. Primary neonatal mice cardiomyocytes were cultured to explore the mechanisms of SPRC on diabetic cardiomyopathy in vitro. Consistent with the results in vivo, SPRC not only up-regulated insulin receptor signaling pathway in cardiomyocytes in dose-dependent manner in the basal state, but also relieved the suppression of insulin receptor signaling induced by high concentrations of glucose and insulin. Furthermore, SPRC also enhanced the expression of glucose transporter 4 (GLUT4) and 3H glucose uptake in cardiomyocytes. Conclusions: In this study, we found a novel beneficial effect of SPRC on diabetic cardiomyopathy, which was associated with activation of insulin receptor signaling. SPRC may be a promising medication for diabetic cardiomyopathy in type 2 diabetes mellitus patients.

A Common Molecular Switch for H2S to Regulate Multiple Protein Targets.

Hydrogen sulfide, a small molecule, produced by endogenous enzymes, such as CTH, CBS, and MPST using L-cysteine as substrates, has been reported to have numerous protective effects. However, the key problem that the target of H2S and how it can affect the structure and activity of biological molecules is still unknown. Till now, there are two main theories of its working mechanism. One is that H2S can modify the free thiol in cysteine to produce the persulfide state of the thiol and the sulfhydration of cysteine can significantly change the structure and activity of target proteins. The other theory is that H2S, as an antioxidant molecule, can directly break the disulfide bond in target proteins, and the persulfide state of thiol can be an intermediate product during the reaction. Both phenomena exit for no doubt since they are both supported by large amounts of experiments. Here, we will summarize both theories and try to discuss which one is the more effective or direct mechanism for H2S and what is the relationship between them. Therefore, we will discover more protein targets of H2S with the mechanism and understand more about the effect of this small molecule.

H3K4 Methyltransferase Smyd3 Mediates Vascular Smooth Muscle Cell Proliferation, Migration, and Neointima Formation.

[Figure: see text].

Smyd3-PARP16 axis accelerates unfolded protein response and vascular aging.

Vascular endothelial cell senescence and endoplasmic reticulum (ER) stress induced unfolded protein response (UPR) are two critical contributors to individual aging. However, whether these two biological events have crosstalk and are controlled by shared upstream regulators are largely unknown. Here, we found PARP16, a member of the Poly (ADP-ribose) polymerases family that tail-anchored ER transmembrane, was upregulated in angiotensin II (Ang II)-induced vascular aging and promoted UPR. Further, PARP16 was epigenetically upregulated by Smyd3, a histone H3 lysine 4 methyltransferase that bound to the promotor region of Parp16 gene and increased H3K4me3 level to activate its host gene's transcription. Intervention of either Smyd3 or PARP16 ameliorated vascular aging associated phenotypes in both cell and mice models. This study identified Smyd3-PARP16 as a novel signal axis in regulating UPR and endothelial senescence, and targeting this axis has implications in preventing vascular aging and related diseases.

Hydrogen sulfide accumulates LDL receptor precursor via downregulating PCSK9 in HepG2 cells.

Endogenous hydrogen sulfide (H2S) affects cholesterol homeostasis and liver X receptor α (LXRα) expression. However, whether low-density lipoprotein (LDL) receptor (LDLR), a key player in cholesterol homeostasis, is regulated by exogenous H2S through LXRα signaling has not been determined. We investigated the effects of sodium hydrosulfide (NaHS, H2S donor) on LDLR expression in the presence or absence of LXR agonists, T0901317 or GW3965 in HepG2 cells. We found that H2S strongly accumulated LDLR precursor in the presence of T0901317. Hence, LDLR transcription and the genes involved in LDLR precursor maturation and degradation were studied. T0901317 increased the LDLR mRNA level, whereas H2S did not affect LDLR transcription. H2S had no significant effect on the expression of LXRα and inducible degrader of LDLR (IDOL). H2S and T0901317 altered mRNA levels of several enzymes for N- and O-glycosylation and endoplasmic reticulum (ER) chaperones assisting LDLR maturation, but did not affect their protein levels. H2S decreased proprotein convertase subtilisin/kexin type 9 (PCSK9) protein levels and its mRNA level elevated by T0901317. T0901317 with PCSK9 siRNA also accumulated LDLR precursor as did T0901317 with H2S. High glucose increased PCSK9 protein levels and attenuated LDLR precursor accumulation induced by T0901317 with H2S. Taken together, H2S accumulates LDLR precursor by downregulating PCSK9 expression but not through the LXRα-IDOL pathway, LDLR transcriptional activation, or dysfunction of glycosylation enzymes and ER chaperones. These results also indicate that PCSK9 plays an important role in LDLR maturation in addition to its well-known effect on the degradation of LDLR mature form.

eNOS-Nitric Oxide System Contributes to a Novel Antiatherogenic Effect of Leonurine via Inflammation Inhibition and Plaque Stabilization.

Leonurine (LEO) is a bioactive small molecular compound that has protective effects on the cardiovascular system and prevents the early progression of atherosclerosis; however, it is not clear whether LEO is effective for plaque stability. A novel mouse atherosclerosis model involving tandem stenosis (TS) of the right carotid artery combined with western diet (WD) feeding was used. Apolipoprotein E gene-deficient mice were fed with a WD and received LEO administration daily for 13 weeks. TS was introduced 6 weeks after the onset of experiments. We found that LEO enhanced plaque stability by increasing fibrous cap thickness and collagen content while decreasing the population of CD68-positive cells. Enhanced plaque stability by LEO was associated with the nitric oxide synthase (NOS)-nitric oxide (NO) system. LEO restored the balance between endothelial NOS(E)- and inducible NOS(iNOS)-derived NO production; suppressed the NF-κB signaling pathway; reduced the level of the inflammatory infiltration in plaque, including cytokine interleukin 6; and downregulated the expression of adhesion molecules. These findings support the distinct role of LEO in plaque stabilization. In vitro studies with oxidized low-density lipoprotein-challenged human umbilical vein endothelial cells revealed that LEO balanced NO production and inhibited NF-κB/P65 nuclear translocation, thus mitigating inflammation. In conclusion, the restored balance of the NOS-NO system and mitigated inflammation contribute to the plaque-stabilizing effect of LEO. SIGNIFICANCE STATEMENT: LEO restored the balance between endothelial NOS and inducible NOS in NO production and inhibited excessive inflammation in atherosclerotic "unstable" and rupture-prone plaques in apolipoprotein E gene-deficient mice. The protective effect of LEO for stabilizing atherosclerotic plaques was due to improved collagen content, increased fibrous cap thickness, and decreased accumulation of macrophages/foam cells. So far, LEO has passed the safety and feasibility test of phase I clinical trial.

Hydrogen sulfide rescues high glucose-induced migration dysfunction in HUVECs by upregulating miR-126-3p.

Diabetes (especially Type II) is one of the primary threats to cardiovascular health. Wound healing defects and vascular dysfunction are common in diabetic patients, and the primary cause of deterioration is sustained high plasma glucose. microRNA, a noncoding RNA, has regulatory functions that are critical to maintaining homeostasis. MicroRNA (miR)-126-3p is a potential diabetes biomarker and a proangiogenic factor, and its plasma level decreases in diabetic patients. Previous studies have revealed the proangiogenic character of the gasotransmitter hydrogen sulfide (H2S). However, little is known about the relationship between H2S and miR-126-3p when the extracellular glucose level is high, let alone their influences on deteriorated endothelial cell migration, a key component of angiogenesis, which is crucial for wound healing. Human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33.3 mmol/L) or normal glucose (5.5 mmol/L) for 48 h. Affymetrix miRNA profiling and real-time PCR were used to validate the miRNA expression. An H2S probe (HSip-1) was used to detect endogenous H2S. Scratch wound-healing assays were used to evaluate HUVEC migration. The protein levels were quantified by Western blot. Both exogenous and endogenous H2S could upregulate the miR-126-3p levels in HUVECs or muscle tissue. High glucose decreased the H2S level and the protein expression of the H2S-producing enzyme cystathionine γ-lyase (CSE) in HUVECs; however, the DNA methyltransferase 1 (DNMT1) protein level was upregulated. CSE overexpression not only increased the miR-126-3p level by decreasing the DNMT1 protein level but also rescued the deteriorated cell migration in HUVECs treated with high glucose. DNMT1 overexpression decreased the miR-126-3p level and inhibited the migration of HUVECs, whereas silencing DNMT1 improved cell migration. High glucose decreased the endogenous H2S and miR-126-3p levels and increased the DNMT1 expression, thus inducing the migration dysfunction of HUVECs. Treatment with exogenous H2S or the overexpression of the endogenously produced enzyme CSE would rescue this migration dysfunction through H2S-DNMT1-miR-126-3p.

Hydrogen Sulfide Alleviates Acute Myocardial Ischemia Injury by Modulating Autophagy and Inflammation Response under Oxidative Stress.

This study aims to investigate the influence of excessive oxidative stress on cardiac injury during acute myocardial ischemia (AMI), with a focus on apoptosis, autophagy, and inflammatory cell infiltration, and to detect the role of hydrogen sulfide (H2S) in this process. We found that SOD1 knockout (KO) mice showed excessive oxidative stress and exacerbated myocardium injury after AMI. Increased apoptosis and inflammation response in the ischemic myocardium contribute to this deterioration, whereas enhanced autophagy plays a protective role. Myocardial inflammation after AMI was much more severe in SOD1 KO mice than in wild-type mice. Pretreatment with the H2S donor NaHS reduced autophagy and apoptosis levels in the ischemic myocardium and alleviated the regional inflammation response in the cardiac tissues of SOD1 KO mice. Moreover, autophagy and apoptosis levels were significantly enhanced in SOD1 knockdown primary neonatal rat cardiomyocytes (NRCMs) under glucose deprivation. Pretreatment with NaHS can partially inhibit this elevation. Taken together, we found that excessive oxidative stress can aggravate cardiac injury during AMI. Exogenous H2S can alleviate cardiac injury during AMI by reducing apoptosis and inflammation response in heart tissues under oxidative stress.

H2S Donor NaHS Changes the Production of Endogenous H2S and NO in D-Galactose-Induced Accelerated Ageing.

Aims. The study was designed to explore whether hydrogen sulphide (H2S) and nitric oxide (NO) generation changed in D-galactose- (D-gal-) induced ageing, the possible effects of exogenous H2S supplementation, and related mechanisms. Results. In D-gal-induced senescent mice, both H2S and NO levels in the heart, liver, and kidney tissues were decreased significantly. A similar trend was observed in D-gal-challenged human umbilical vein endothelial cells (HUVECs). Sustained H2S donor (NaHS) treatment for 2 months elevated H2S and NO levels in these mice, and during this period, the D-gal-induced senescent phenotype was reversed. The protective effect of NaHS is associated with a decrease in reactive oxygen species levels and an increase in antioxidants, such as glutathione, and superoxide dismutase and glutathione peroxidase activities. Increased expression of the H2S-producing enzymes cystathionine γ-lyase (CSE) and cystathionine-ß-synthase (CBS) in the heart, liver, and kidney tissues was observed in the NaHS-treated groups. NaHS supplementation also significantly postponed D-gal-induced HUVEC senescence. Conclusions. Endogenous hydrogen sulphide production in both ageing mice and endothelial cells is insufficient. Exogenous H2S can partially rescue ageing-related dysfunction by inducing endogenous H2S and NO production and reducing oxidative stress. Restoring endogenous H2S production may contribute to healthy ageing, and H2S may have antiageing effects.

H2S regulates endothelial nitric oxide synthase protein stability by promoting microRNA-455-3p expression.

The aims of the present study are to determine whether hydrogen sulfide (H2S) is involved in the expression of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production, and to identify the role of microRNA-455-3p (miR-455-3p) during those processes. In cultured human umbilical vein endothelial cells (HUVECs), the expression of miR-455-3p, eNOS protein and the NO production was detected after administration with 50 µM NaHS. The results indicated that H2S could augment the expression of miR-455-3p and eNOS protein, leading to the increase of NO level. We also found that overexpression of miR-455-3p in HUVECs increased the protein levels of eNOS whereas inhibition of miR-455-3p decreased it. Moreover, H2S and miR-455-3p could no longer increase the protein level of eNOS in the presence of proteasome inhibitor, MG-132. In vivo, miR-455-3p and eNOS expression were considerably increased in C57BL/6 mouse aorta, muscle and heart after administration with 50 µmol/kg/day NaHS for 7 days. We also identified that H2S levels and miR-455-3p expression increased in human atherosclerosis plaque while H2S levels decreased in plasma of atherosclerosis patients. Our data suggest that the stability of eNOS protein and the NO production could be regulated by H2S through miR-455-3p.

Myocyte enhancer factor 2D provides a cross-talk between chronic inflammation and lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide. Patients with chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), are exposed to a higher risk of developing lung cancer. Chronic inflammation may play an important role in the lung carcinogenesis among those patients. The present study aimed at identifying candidate biomarker predicting lung cancer risk among patients with chronic respiratory diseases. METHODS: We applied clinical bioinformatics tools to analyze different gene profile datasets with a special focus on screening the potential biomarker during chronic inflammation-lung cancer transition. Then we adopted an in vitro model based on LPS-challenged A549 cells to validate the biomarker through RNA-sequencing, quantitative real time polymerase chain reaction, and western blot analysis. RESULTS: Bioinformatics analyses of the 16 enrolled GSE datasets from Gene Expression Omnibus online database showed myocyte enhancer factor 2D (MEF2D) level significantly increased in COPD patients coexisting non-small-cell lung carcinoma (NSCLC). Inflammation challenge increased MEF2D expression in NSCLC cell line A549, associated with the severity of inflammation. Extracellular signal-regulated protein kinase inhibition could reverse the up-regulation of MEF2D in inflammation-activated A549. MEF2D played a critical role in NSCLC cell bio-behaviors, including proliferation, differentiation, and movement. CONCLUSIONS: Inflammatory conditions led to increased MEF2D expression, which might further contribute to the development of lung cancer through influencing cancer microenvironment and cell bio-behaviors. MEF2D might be a potential biomarker during chronic inflammation-lung cancer transition, predicting the risk of lung cancer among patients with chronic respiratory diseases.

[The Molecular Switches and Atomic Biological Mechanisms Underlying the Physiological and Pathophysio-logical Effects of Hydrogen Sulfide to Regulate Its "Receptors"].

Hydrogen sulfide (H2S)has emerged as pivotal signaling molecules since it is recognized as the third gasotransmitter together with nitric oxide and carbon monoxide. The development of detecting technologies contributed to the research in H2S biology.H2S plays significant roles in human body systems, such as the cardiovascular system, nervous system, respiratory system etc.. Alterations of H2S concentrations have been connected with many diseases. Hypertension, atherosclerosis, neurodegenerative disorder, asthma and many other diseases are found to be related with abnormal H2S metabolism. It has become a potential drug for therapeutic purposes. Understanding the mechanism of H2S biology, including a molecular switch contained in its "receptor", has deepened the research on how small molecules regulate big molecules, as well as providing new strategy for the therapeutic approaches for varies of diseases.