Gaseous Messenger Molecule Research Articles

Hydrogen sulfide improves tall fescue photosynthesis response to low-light stress by regulating chlorophyll and carotenoid metabolisms

Hydrogen sulfide (H2S), as a gaseous messenger molecule, plays critical roles in signal transduction and biological modulation. In the present study, the roles of H2S in regulating chlorophyll (Chl) and carotenoid (Car) contents to improve photosynthesis in tall fescue were investigated under low-light (LL) stress. Compared to control conditions, LL stress significantly reduced total biomass, net photosynthetic rate (Pn), maximal quantum yield of photosystem II (PSII) photochemistry (Fv/Fm), and the contents of Chl and Car. Under exogenous sodium hydrosulfide (NaHS, H2S donor) application, these parameters were enhanced, ultimately increasing photosynthesis. Moreover, exogenous H2S up-regulated the expression of chlorophyll biosynthesis genes while down-regulated chlorophyll degradation genes, resulting in increases in chlorophyll precursors. Components of carotenoids and expression of genes encoding biosynthesis and degradation enzymes varied similarly. Additionally, application exogenous H2S up-regulated expression of FaDES1 and FaDCD. Thus, it enhanced L-cysteine desulfhydrase 1 (DES1, EC 4.4.1.1) and D-cysteine desulfhydrase (DCD, EC 4.4.1.15) activities leading to elevated endogenous H2S. However, these responses were reversed by treatment with hypotaurine (HT, H2S scavenger). These results suggested that H2S is involved in regulating photosynthesis to improve LL tolerance via modulating Chl and Car metabolisms in tall fescue.

Nitric oxide and hydrogen sulfide: Sibling rivalry in the family of epigenetic regulators

Nitric oxide (NO) and hydrogen sulfide (H2S) were previously only known for their toxic properties. Now they are regarded as potent gaseous messenger molecules (gasotransmitters) that rapidly transverse cell membranes and transduce cellular signals through their chemical reactions and modifications to protein targets. Both are known to regulate numerous physiological functions including angiogenesis, vascular tone, and immune response, to name a few. NO and H2S often work synergistically and in competition to regulate each other's synthesis, target protein activity via posttranslational modifications (PTMs), and chemical interactions. In addition to their canonical modes of action, increasing evidence has demonstrated that NO and H2S share another signaling mechanism: epigenetic regulation. This review will compare and contrast biosynthesis and metabolism of NO and H2S, their individual and shared interactions, and the growing body of evidence for their roles as endogenous epigenetic regulatory molecules.

Long Range Emissive Water-Soluble Fluorogenic Molecular Platform for Imaging Carbon Monoxide in Live Cells.

Despite its murderous act, carbon monoxide (CO) is found to be a very crucial small gaseous messenger molecule in dictating prime biological and physiological processes. Determination of endogenous or exhaled CO levels can throw significant light on smoking status and can be used as a breath biomarker of inflammatory diseases. Therefore, fluorescence imaging of CO in biofluids will empower one with the minute details of various disease states that involve CO. Unfortunately, such efficient fluorescent probes are less in number and also associated with tedious protocols. This enticed our attention and inspired us to look upon developing perceptive imaging agents for CO in a living system. In this report, a resorufin-based "turn-on" orange emissive molecular probe has been successfully utilized to detect CO in an aqueous system. The mono protection of a resorufin unit with an allyl chloroformate furnished a weakly fluorescent small molecular probe P1. Further, the P1+Pd2+ ensemble has been successfully developed in situ using PdCl2 (as Pd2+) and utilized as a light-up signaling mechanism tool for the sensing of CO at the nanomolar level (62 nM) through deprotection mechanism. The probe selectively detects CO without any interference from other anions, gasotransmitters and fatty acids. The present integrated probe P1+Pd2+ system has been found to be highly sensitive to detect CO in cellular systems as well.

The Role of Estrogen and Nitric Oxide in the Prevention of Cardiac Arrhythmias in the Embryonic Zebrafish (Danio Rerio)

Nitric oxide (NO) is a gaseous messenger molecule found to be critical in the regulation of cardiomyocyte contraction and blood vessel vasodilation in the cardiovascular system (CVS) of a diverse variety of organisms. NO is released by catalyzing the enzymatic transformation of L-arginine to L-citrulline by NO synthase (NOS), which is found in four distinct isoforms in the human body. The most prominent isoform in the sarcoplasmic reticulum (SR) of the CVS; however, is neuronal NO (nNOS or NOS1). Research shows that NOS1 is critical to the contraction and relaxation of cardiomyocytes. More specifically, NOS1 is believed to protect the regulation of cardiomyocyte calcium (Ca2+) release. This phenomenon occurs through specific ryanodine influenced Ca2+ channels and receptors, which allows for excitation coupling to occur. It has been hypothesized by prior research that diastolic Ca2+ leaks due to abnormally open SR ryanodine channels increases the presence of ventricular arrhythmias. The main hypothesis offered up by this research focuses on the mechanism of action in which deprivation of nNOS and its upstream regulation by estrogen leads to ventricular arrhythmias in the embryonic zebrafish via a dysregulated S-nitrosylation pathway. It was also determined that this S-nitrosylation pathway is independent of soluble guanylyl cyclase (sGC)-GMP mediated pathway, which is normally responsible for exerting NO effects throughout the body. Additionally, the goal of this research was to identify a highly successful rescue treatment that would restore normal CVS activity to the embryos. The most successful treatment option was Dantrolene, a hydantoin derivative whose mechanism of action revolves around closing ryanodine channels. When populations of nNOS deprived fish became 100% arrhythmic, Dantrolene was entirely successful as a treatment paradigm. This data allows for a better understanding of not only the entire CVS as a whole, but potentially elucidates a better understanding of ventricular arrhythmias.

Nitric Oxide: A Regulator of Cellular Function in Health and Disease

Nitric oxide (NO) is a gaseous messenger molecule synthesized from L-arginine and molecular oxygen by three different NO synthases, that is, neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) form [1]. Since its discovery in the early 1980s by the three Nobel Laureates Furchgott, Ignarro & Murad [2], NO has been widely recognised as an important signalling molecule in many physiological processes. The initial identification of NO as an endothelium-derived relaxing factor (EDRF) [3] generated great interest in its function in vascular biology. Over the following years, however, the focus on NO research rapidly expanded from the vascular system to its role in immunity and inflammation, the nervous system, pregnancy, aging, and cell death. Many studies suggest that excessive or abnormal production of NO plays a crucial role in neuronal cell death associated with neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, as well as various conditions of vascular dysfunction. At physiological levels, NO is essential for neuronal function, differentiation and survival through activation of signalling pathways that include the cyclic guanosine monophosphate (cGMP)/soluble guanylyl cyclase pathway [4] and S-nitrosylation, in which NO reversibly binds to thiol groups of proteins [5]. The vast network of NO-associated signalling paradigms further includes acetylation/deacetylation and methylation/demethylation modifications and peroxynitrite formation (leading to nitrotyrosination of protein residues), as well as modulation of gene expression via epigenetic changes [5–8]. How controlled S-nitrosylation/nitrotyrosination of proteins and activation of the NO/cGMP signalling pathway promote cellular survival and induce epigenetic changes while uncontrolled signalling promotes cell death and dysfunction remains to be elucidated. The aim of this Special Issue is to gather information encapsulating the above signalling pathways. The articles published in this Special Issue largely cover (1) NO signalling in neuronal function and disease as well as (2) vascular targets in endothelial function and dysfunction, both of which involve the broad range of actions of this signalling molecule. In order to understand the contribution of NO to neuronal dysfunction, one has to consider that NO is a crucial molecule in cellular physiology. Numerous studies show the involvement of NO in neuronal development, plasticity, excitability, and transmission [8–12]. However, the common mechanisms across several neurodegenerative disorders relate to the neurotoxicity of NO and its downstream reactive nitrogen species (RNS). Enhanced nitrotyrosine immunoreactivity is evident in brains from patients with Alzheimer's and Parkinson's disease. Nitrated proteins are associated with β-amyloid deposition and nitrotyrosination of Tau protein and synaptophysin has been reported in brain samples from patients with Alzheimer's disease. The potential downstream signalling pathways of these posttranslational modifications are discussed in the review by S. A. Bradley and J. R. Steinert in this Issue. The cellular roles of NO in neurodegenerative disease, such as Alzheimer's, are reviewed by R. Balez and L. Ooi with a focus on neurotoxicity versus neuroprotection while the role of aberrant NO signalling in neurodevelopmental disorders such as Fragile X syndrome is investigated in the study by E. Lima-Cabello et al. Other topics of this issue focus on aspects of vascular NO signalling with particular interest in fetoplacental dysfunction caused by abnormal eNOS regulation (as discussed by A. Leiva et al.). Endothelial function and eNOS regulation are essential for healthy cardiovascular responses but are also critical for adaptations during pregnancy. Several diseases associated with vascular dysfunction such as atherosclerosis, diabetes mellitus, hypertension, or preeclampsia involve altered NO signalling [13–15]. The paper by A. Leiva et al. reviews the mechanisms leading to abnormal NO signalling, which include reduced bioavailability of L-arginine (NOS substrate) and tetrahydrobiopterin (BH4), abnormal calcium-calmodulin signalling, and activation and inhibition of eNOS activity through phosphorylation of Ser1177 or Thr495, respectively [16]. NO has also been reported to play a crucial role in the transition of fetoplacental endothelial cells from a mitogenic to a metabolic phenotype in the macrocirculation, compared with a change from a metabolic to a mitogenic phenotype in the microcirculation in response to insulin in gestational diabetes mellitus [17]. Thus, the actions of NO are not only important during vascular adaptations to pregnancy and related dysfunctions but also essential during vascular signalling induced by physical training resulting in elevated nitrite and nitrate levels as reported in the study by A. M. Jacomini et al. Together, this Special Issue highlights the tremendous diversity of NO signalling pathways with regard to its function in health and disease. All contributing publications have emphasised that NO represents an important signalling molecule and future research required in this field will extend the understanding of the broad actions of NO. Luis Sobrevia Lezanne Ooi Scott Ryan Joern R. Steinert

Neuroprotective effect of hydrogen sulfide on acute cauda equina injury in rats

BackgroundHydrogen sulfide (H2S), as a novel gaseous messenger molecule, plays an important role in signal transduction and biological modulation. PurposeIn the present study the effect of H2S after compression injury of cauda equina was studied. Study DesignThe setting of this study is the laboratory investigation. MethodsA total of 162 rats were randomly allocated into three groups: sham group, compression group, and H2S group. Cauda equina compression (CEC) injury in rats was induced by implanting silicone gels (10×1×1 mm) into the epidural spaces L5 and L6; laminectomy was performed at the L4 level of the vertebra in the sham-operated group. The experimental group was treated with sodium hydrosulfide intraperitoneally (20 µmol/kg body weight), whereas the compression and sham groups received equal volumes of physiological saline. Levels of malonaldehyde (MDA) and glutathione (GSH) were determined immediately before CEC surgery, 12 h, 24 h, 48 h, and 72 h after CEC surgery. Furthermore, hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling (TUNEL) assay were performed 48 h after CEC. ResultsHematoxylin and eosin staining showed that myelin sheath and the cauda equina fibers in the compression group were less compact and highly degenerated compared with the sham group, and that H2S treatment could improve the status. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling staining exhibited that decreased number of TUNEL positive cells was found in the H2S group than in the compression group. The level of MDA was increased in the sham and H2S groups compared with the compression group (p<.05, p<.01), whereas the level of GSH was decreased (p<.05, p<.01). ConclusionsWith the above data, we conclude that H2S could reduce the oxidative stress and has neuroprotective effect in acute cauda equina syndrome.

Elevated hydrogen sulfide levels in vitreous body and plasma in patients with proliferative diabetic retinopathy.

Hydrogen sulfide (H2S), a colorless gas, has been confirmed to be a gaseous messenger molecule and an endogenous stimulus for angiogenesis recently. This study was performed to investigate the role of H2S in diabetic retinopathy. Blood samples were collected from normal controls and patients with diabetes. Vitreous samples were collected from patients with proliferative diabetic retinopathy (PDR) and patients with rhegmatogenous retinal detachment. Patients were grouped into diabetic patients without diabetic retinopathy (non-DR), with nonproliferative DR, and with PDR. Concentrations of H2S and vascular endothelial growth factor in the plasma and vitreous body were detected using a spectrophotometer. A decreased H2S level in the plasma was observed in non-DR group (41.89 ± 8.52 μM, P < 0.05), and an increased H2S level in the plasma was observed in PDR group (60.49 ± 11.14 μM, P < 0.001), when compared with that in normal controls (49.67 ± 9.72 μM). There was no difference in plasma H2S level between patients with nonproliferative DR (54.13 ± 8.61 μM) and normal controls. In the vitreous body, H2S levels in PDR group were significantly higher (76.80 ± 24.08 μM, P < 0.001) than that in rhegmatogenous retinal detachment group (24.37 ± 11.25 μM). Levels of vascular endothelial growth factor in plasma from patients with diabetes were significantly lower (P < 0.001) than that in normal controls. Vascular endothelial growth factor levels in the vitreous body from diabetic patients with PDR were significantly higher (885.61 ± 190.41 pg/mL, P < 0.001) than that from patients with rhegmatogenous retinal detachment (89.98 ± 19.56 pg/mL). Seven days after an intravitreal injection of ranibizumab, a significantly decreased H2S level (55.58 ± 7.20 μM, P < 0.05) was observed in the vitreous body in patients with PDR when compared with that (75.07 ± 12.95 μM) in the vitreous body collected just before intravitreal injection. These results indicated that anti-vascular endothelial growth factor may downregulate the H2S level in the vitreous body, and H2S may play a role in the development of DR. Hydrogen sulfide may be a novel target for the therapy of DR.

Nitric oxide synthase inhibition decreases l-DOPA-induced dyskinesia and the expression of striatal molecular markers in Pitx3−/− aphakia mice

Nitric oxide (NO), a gaseous messenger molecule synthesized by nitric oxide synthase (NOS), plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). To study the role of the nitrergic system in l-DOPA-induced dyskinesia (LID), we assessed the effect of the pharmacological manipulation of NO levels and NO/cyclic guanosine monophosphate (cGMP) signaling on LID in the Pitx3−/− aphakia mouse, a genetic model of PD. To evaluate the effect of decreased NO signaling on the development of LID, Pitx3−/− mice were chronically treated with l-DOPA and 7-nitroindazole (7-NI, a neuronal NOS inhibitor). To evaluate its effect on the expression of established LID, 7-NI was administered acutely to dyskinetic mice. The chronic 7-NI treatment attenuated the development of LID in the Pitx3−/− mice, and the sub-acute 7-NI treatment attenuated established dyskinesia without affecting the beneficial therapeutic effect of l-DOPA. Moreover, 7-NI significantly reduced FosB and pAcH3 expression in the acutely and chronically l-DOPA-treated mice. We also examined how increasing NO/cGMP signaling affects LID expression by acutely administering molsidomine (an NO donor) or zaprinast (a cGMP phosphodiesterase 5-PDE5 inhibitor) before l-DOPA in mice with established dyskinesia. Paradoxically, the administration of either of these drugs also significantly diminished the expression of established LID; however, the effect occurred at the expense of the antiparkinsonian l-DOPA properties. We demonstrate that targeting the NO/cGMP signaling pathway reduces dyskinetic behaviors and molecular markers, but only the 7-NI treatment preserved the antiparkinsonian effect of l-DOPA, indicating that NOS inhibitors represent a potential therapy to reduce LID.

TRPs as chemosensors (ROS, RNS, RCS, gasotransmitters).

The transient receptor potential (trp) gene superfamily encodes TRP proteins that act as multimodal sensor cation channels for a wide variety of stimuli from outside and inside the cell. Upon chemical or physical stimulation of cells, TRP channels transduce electrical and/or Ca(2+) signals via their cation channel activities. These functional features of TRP channels allow the body to react and adapt to different forms of environmental changes. Indeed, members of one class of TRP channels have emerged as sensors of reactive oxygen species (ROS), reactive nitrogen species (RNS), reactive carbonyl species (RCS), and gaseous messenger molecules including molecular oxygen (O2), hydrogen sulfide (H2S), and carbon dioxide (CO2). Hydrogen peroxide (H2O2), an ROS, triggers the production of ADP-ribose, which binds and activates TRPM2. In addition to TRPM2, TRPC5, TRPV1, and TRPA1 are also activated by H2O2 via modification of cysteine (Cys) free sulfhydryl groups. Nitric oxide (NO), a vasoactive gaseous molecule, regulates TRP channels directly via Cys S-nitrosylation or indirectly via cyclic GMP (cGMP)/protein kinase G (PKG)-dependent phosphorylation. Anoxia induced by O2-glucose deprivation and severe hypoxia activates TRPM7 and TRPC6, respectively, whereas TRPA1 serves as a sensor of mild hypoxia and hyperoxia in vagal and sensory neurons. TRPA1 also detects other gaseous molecules, such as hydrogen sulfide (H2S) and carbon dioxide (CO2). In this review, we highlight our current knowledge of TRP channels as chemosensors for ROS, RNS, RCS, and gaseous molecules and discuss their functional impacts on physiological and pathological events.

P55 Endogenous hydrogen sulfide ameliorates secretory phospholipase A2 (sPLA2)-induced acute pancreatitis model in the rat

Acute pancreatitis (AP), a painful and inflammatory disease of the pancreas, is one of the most common patient gastrointestinal diseases worldwide, but there is still no effective pharmacological treatment. It is usually associated with high serum concentrations of phospholipase A2 (PLA2). Recently, it has been suggested that the endogenous gasotransmitter hydrogen sulfide (H2S) acts as a mediator of acute pancreatitis. Endogenously, H2S is produced as a metabolite of homocysteine (Hcy) by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST). This study aimed to investigate the effects of endogenous H2S in a model of AP in rats. AP was evoked by injection of secretory PLA2 from Crotallus durrisus terrificus (Cdt; 300 mg/kg) snake venom into the common bile duct of rats pretreated with an inhibitor of CSE, propargylglycine (Pgly; 50 mg/kg; i.p., −30 min) or vehicle (0.1 ml). Four hours later, rats were submitted to abdominal nociceptive behavioral test (von Frey) and euthanized. Blood and pancreas were collected and processed to measure plasma amylase, H2S generation and inflammatory parameters (oedema, myeloperoxidase activity) in pancreas. Treatment with PGly markedly reduced inflammation in the pancreas of rats with pancreatitis, but neither increased serum amylase nor abdominal hyperalgesia was affected by this treatment. The kinetics of H2S generation over 60 min in pancreas revealed that CSE and CBS are both expressed in naive pancreas tissue, and a significant difference is seen between control and inflamed pancreas. Inhibition of CSE and CBS reduces H2S generation in pancreas. We conclude that endogenous gaseous messenger molecule H2S plays a functional role in mediating microvascular and cellular changes (oedema and cell influx) in the pancreas, but not the related nociceptive mechanisms of PLA2-induced AP.

Dynamic Change of Hydrogen Sulfide After Traumatic Brain Injury and its Effect in Mice

Hydrogen sulfide (H2S) is a lipid-soluble, endogenously produced gaseous messenger molecule collectively known as gasotransmitter. Over the last several decades, gasotransmitters have emerged as potent cytoprotective mediators in various models of tissue and cellular injury. In this study, we performed a weight-drop traumatic brain injury (TBI) model in adult mice and investigated changes of H2S and its possible role in the pathogenesis after TBI. Expression of Cystathionine-β-synthase (CBS) mRNA as H2S-producing enzymes in mouse brain was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). From the results of RT-PCR, it was found that the expression of CBS was down-regulated in mouse brain cortex and hippocampus after brain injury. Western blot analysis revealed that CBS was present in normal mouse brain cortex and the hippocampus. It gradually decreased, reached its lowest level and then increased. Hydrogen sulfide in the cortex and hippocampus exhibited dynamic changes after brain injury, in parallel with CBS mRNA and protein expression. Moreover, pretreatment with the H2S donor (NaHS) could protect the neuron against the injury induced by TBI. Noticeably, the H2S donor NaHS could reduce TBI-induced injury assessed with lesion volume. These data suggested that H2S may have a therapeutic potential against neuron damage.

Role of Protein &lt;i&gt;S&lt;/i&gt;-nitrosylation in Central Nervous System Survival and Regeneration

The retina has been regarded as 'an approachable part of the brain' for investigating central nervous system (CNS). The optic nerve injury is a well-accepted model to study the mechanisms of neural degeneration and/or axonal regeneration after trauma in the CNS. Nitric oxide (NO) is a gaseous messenger molecule biosynthesized from L-arginine and molecular oxygen by NO synthase. Many reports suggest that excess production of NO plays a crucial role in neuronal cell death including in death of retinal ganglion cells (RGCs). In contrast, several lines of evidence indicate that NO can prevent neuronal death. In general, NO mediates neuroprotection through two main signaling pathways: the NO/cyclic guanosine monophosphate (cGMP) pathway and the S-nitrosylation pathway. Especially, whether S-nitrosylation of proteins promotes RGCs survival and its axonal regeneration after injury is unclear. Thus, we focused on the S-nitrosylation-dependent mechanism of RGCs survival and axonal regeneration by NO after nerve injury.

H₂S signalling through protein sulfhydration and beyond.

Hydrogen sulfide (H(2)S) has recently emerged as a mammalian gaseous messenger molecule, akin to nitric oxide and carbon monoxide. H(2)S is predominantly formed from Cys or its derivatives by the enzymes cystathionine β-synthase and cystathionine γ-lyase. One of the mechanisms by which H(2)S signals is by sulfhydration of reactive Cys residues in target proteins. Although analogous to protein nitrosylation, sulfhydration is substantially more prevalent and usually increases the catalytic activity of targeted proteins. Physiological actions of sulfhydration include the regulation of inflammation and endoplasmic reticulum stress signalling as well as of vascular tension.

Hydrogen sulfide as an endogenous modulator in mitochondria and mitochondria dysfunction.

Hydrogen sulfide (H2S) has historically been considered to be a toxic gas, an environmental and occupational hazard. However, with the discovery of its presence and enzymatic production through precursors of L-cysteine and homocysteine in mammalian tissues, H2S has recently received much interest as a physiological signaling molecule. H2S is a gaseous messenger molecule that has been implicated in various physiological and pathological processes in mammals, including vascular relaxation, angiogenesis, and the function of ion channels, ischemia/reperfusion (I/R), and heart injury. H2S is an endogenous neuromodulator and present studies show that physiological concentrations of H2S enhance NMDA receptor-mediated responses and aid in the induction of hippocampal long-term potentiation. Moreover, in the field of neuronal protection, physiological concentrations of H2S in mitochondria have many favorable effects on cytoprotection.

TRP channels: sensors and transducers of gasotransmitter signals

The transient receptor potential (trp) gene superfamily encodes cation channels that act as multimodal sensors for a wide variety of stimuli from outside and inside the cell. Upon sensing, they transduce electrical and Ca2+ signals via their cation channel activities. These functional features of TRP channels allow the body to react and adapt to different forms of environmental changes. Indeed, members of one class of TRP channels have emerged as sensors of gaseous messenger molecules that control various cellular processes. Nitric oxide (NO), a vasoactive gaseous molecule, regulates TRP channels directly via cysteine (Cys) S-nitrosylation or indirectly via cyclic GMP (cGMP)/protein kinase G (PKG)-dependent phosphorylation. Recent studies have revealed that changes in the availability of molecular oxygen (O2) also control the activation of TRP channels. Anoxia induced by O2-glucose deprivation and severe hypoxia (1% O2) activates TRPM7 and TRPC6, respectively, whereas TRPA1 has recently been identified as a novel sensor of hyperoxia and mild hypoxia (15% O2) in vagal and sensory neurons. TRPA1 also detects other gaseous molecules such as hydrogen sulfide (H2S) and carbon dioxide (CO2). In this review, we focus on how signaling by gaseous molecules is sensed and integrated by TRP channels.

Editorial Neuroimmune-vascular cells and their pathological disorders

The initiation and persistence of multiple organ pathologies, which may occur during life, are intimately associated with acute and chronic dysregulatory metabolic processes. Multiple organ pathologies may also be functionally associated with initiating traumatic events leading to a chronic state of proinflammatory cellular insults with resultant prolonged debilitation and negative quality of life. Along these lines, a large body of preclinical and clinical literature has established that acute and chronic perturbations of the functional coupling of vascular endothelial, immune, and neural cell types represent major contributory factors to the initiation and persistence of pathological states [1]. Furthermore, metabolic rundown in each of these cell types is intimately linked to primary functional deficits in their endosymbiont mitochondria. Mechanistically, dysregulation of mitochondrial respiration leads to impairment of intermediary energy metabolism, ATP production, and insufficient buffering of harmful reactive oxygen species [2]. Resultant damage to mtDNA has profound effects on mitochondrial rescue and biogenesis upon physiological demand. Similar criteria may relate to the elucidation of key cellular mechanisms underlying normal and premature ageing. In light of the above, common regulatory events and their potential dysregulation in neuroimmune-vascular disorders are listed below. Endothelia serve as major cellular conduits mediating oxygen and carbon dioxide exchange, nutrient transport, and autonomic tone in the peripheral and CNS vasculature. Notably, functional deficiencies in vascular endothelia has been documented in variety of human metabolic disorders including diabetes and cardiovascular disease [3–19]. Mitochondria-associated oxidative stress has been proposed as a major contributing factor to the severity of endothelial malfunction in these same metabolic disorders [3–19]. The immune system serves to defend the body from external and internal threats and keep multiple organ systems in metabolic homeostasis. Ongoing host-defense mechanisms utilize complementary regulatory processes to perform existential functions ranging from antibody production to immune surveillance and phagocytosis. Functional immunodeficiencies including perturbations in neuroimmune and vascular endothelial cellular coupling has been observed in multiple human pathological disorders [1, 20–34]. It has also become apparent that dysregulation of mitochondrial function mediated by disruption of constitutive nitric oxide signaling mechanisms represents a strong contributing factor in neuroimmune/vascular endothelial-coupled cellular pathologies [1, 20–34]. The nervous system serves an existential integrative capacity for functional entrainment of multiple organ function. Within the central and peripheral nervous systems, sensory, motor, and intrinsic neurons employ a wide variety of chemical and gaseous messenger molecules. Accordingly, central and peripheral neurons integrate sensory input and coordinated motor responses via immediate and long lasting chemical messengers. As stated above, vital neuroimmune/vascular endothelial-coupled metabolic regulation modulates homeostasis of cellular energy production in multiple organ systems. Its dysregulation is intimately associated with a variety of acute and chronic pathophysiological disorders [35–55]. Multiple organ pathologies are intimately associated with acute and chronic dysregulation of metabolic processes responsible for normal neuroimmune/vascular endothelial coupling events. An in depth analysis of perturbation of common regulatory events underlying normal mitochondrial function will elucidate convergent mechanisms leading to the initiation and persistence of multiple organ pathologies in human metabolic disorders.

Emergent role of gasotransmitters in ischemia-reperfusion injury.

Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are lipid-soluble, endogenously produced gaseous messenger molecules collectively known as gasotransmitters. Over the last several decades, gasotransmitters have emerged as potent cytoprotective mediators in various models of tissue and cellular injury. Specifically, when used at physiological levels, the exogenous and endogenous manipulation of these three gases has been shown to modulate ischemia/reperfusion injury by inducing a number of cytoprotective mechanisms including: induction of vasodilatation, inhibition of apoptosis, modulation of mitochondrial respiration, induction of antioxidants, and inhibition of inflammation. However, while the actions are similar, there are some differences in the mechanisms by which these gasotransmitters induce these effects and the regulatory actions of the enzyme systems can vary depending upon the gas being investigated. Furthermore, there does appear to be some crosstalk between the gases, which can provide synergistic effects and additional regulatory effects. This review article will discuss several models and mechanisms of gas-mediated cytoprotection, as well as provide a brief discussion on the complex interactions between the gasotransmitter systems.

NO/cGMP signalling: L-citrulline and cGMP immunostaining in the central complex of the desert locust Schistocerca gregaria

Nitric oxide (NO) is a gaseous messenger molecule formed during conversion of L: -arginine into L: -citrulline by the enzyme NO synthase (NOS), which belongs to a group of NADPH diaphorases. Because of its gaseous diffusion properties, NO differs from classical neurotransmitters in that it is not restricted to synaptic terminals. In target cells, NO activates soluble guanylyl cyclase leading to an increase in cGMP levels. In insects, this NO/cGMP-signalling pathway is involved in development, memory formation and processing of visual, olfactory and mechanosensory information. We have analysed the distribution of putative NO donor and target cells in the central complex, a brain area involved in sky-compass orientation, of the locust Schistocerca gregaria by immunostaining for L: -citrulline and cGMP. Six types of citrulline-immunostained neurons have been identified including a bilateral pair of hitherto undescribed neurons that connect the lateral accessory lobes with areas anterior to the medial lobes of the mushroom bodies. Three-dimensional reconstructions have revealed the connectivity pattern of a set of 18 immunostained pontine neurons of the central body. All these neurons appear to be a subset of previously mapped NADPH-diaphorase-positive neurons of the central complex. At least three types of central-complex neurons show cGMP immunostaining including a system of novel columnar neurons connecting the upper division of the central body and the lateral triangle of the lateral accessory lobe. Our results provide the morphological basis for further studies of the function of the labelled neurons and new insights into NO/cGMP signalling.

Regulation of enteric neuron migration by the gaseous messenger molecules CO and NO

The enteric nervous system (ENS) of insects is a useful model to study cell motility. Using small-molecule compounds to activate or inactivate biosynthetic enzymes, we demonstrate that the gaseous messenger molecules carbon monoxide (CO) and nitric oxide (NO) regulate neuron migration in the locust ENS. CO is produced by heme oxygenase (HO) enzymes and has the potential to signal via the sGC/cGMP pathway. While migrating on the midgut, the enteric neurons express immunoreactivity for HO. Here, we show that inhibition of HO by metalloporphyrins promotes enteric neuron migration in intact locust embryos. Thus, the blocking of enzyme activity results in a gain of function. The suppression of migratory behavior by activation of HO or application of a CO donor strongly implicates the release of CO as an inhibitory signal for neuron migration in vivo. Conversely, inhibition of nitric oxide synthase or application of the extracellular gaseous molecule scavenger hemoglobin reduces cell migration. The cellular distribution of NO and CO biosynthetic enzymes, together with the results of the chemical manipulations in whole embryo culture suggest CO as a modulator of transcellular NO signals during neuronal migration. Thus, we provide the first evidence that CO regulates embryonic nervous system development in a rather simple invertebrate model.

A Newly Found Gasotransmitter, Hydrogen Sulfide, in the Pathogenesis of Hypertension and Other Cardiovascular Diseases

In the 1980s, nitric oxide (NO) and carbon monoxide (CO) were determined to be gaseous messenger molecules which is capable of relaxing vessels and interfering with vascular structure remodeling. However there are many mechanisms that have not been clear about the regulation of human functions under both physiological and pathophysiological conditions. Hydrogen sulfide (H2S) is a newly found gasotrasmitter that was demonstrated to play similar role as that of NO and CO in many organs and tissues, especially in the cardiovascular system. In this review, firstly, we described the production of H2S in the body, and the functions of H2S in the cardiovascular system, especially in the vascular relaxing and vascular remodeling. Secondly, we further discussed the role of H2S in hypertension, hypoxic pulmonary hypertension, shock and ischemic hear disease. Finally, the interaction between H2S and the other two gasotransmitters, NO and CO, was also discussed. Keywords: Hydrogen sulfide, cardiovascular system, hypertension, pulmonary hypertension