RESUMO
Despite recent progress, ischemic heart disease poses a persistent global challenge, driving significant morbidity and mortality. The pursuit of therapeutic solutions has led to the emergence of strategies such as ischemic preconditioning, postconditioning, and remote conditioning to shield the heart from myocardial ischemia/reperfusion injury (MIRI). These ischemic conditioning approaches, applied before, after, or at a distance from the affected organ, inspire future therapeutic strategies, including pharmacological conditioning. Gasotransmitters, comprising nitric oxide, hydrogen sulfide, sulfur dioxide, and carbon monoxide, play pivotal roles in physiological and pathological processes, exhibiting shared features such as smooth muscle relaxation, antiapoptotic effects, and anti-inflammatory properties. Despite potential risks at high concentrations, physiological levels of gasotransmitters induce vasorelaxation and promote cardioprotective effects. Noble gases, notably argon, helium, and xenon, exhibit organ-protective properties by reducing cell death, minimizing infarct size, and enhancing functional recovery in post-ischemic organs. The protective role of noble gases appears to hinge on their modulation of molecular pathways governing cell survival, leading to both pro- and antiapoptotic effects. Among noble gases, helium and xenon emerge as particularly promising in the field of cardioprotection. This overview synthesizes our current understanding of the roles played by gasotransmitters and noble gases in the context of MIRI and cardioprotection. In addition, we underscore potential future developments involving the utilization of noble gases and gasotransmitter donor molecules in advancing cardioprotective strategies.
Assuntos
Gasotransmissores , Traumatismo por Reperfusão Miocárdica , Gases Nobres , Humanos , Gasotransmissores/metabolismo , Gasotransmissores/uso terapêutico , Animais , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Gases Nobres/metabolismo , Precondicionamento Isquêmico Miocárdico , Transdução de Sinais , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologiaRESUMO
Nitric oxide (NO) has been thought to be a novel factor involved in the mechanisms of mental disorders pathogenesis for quite some time. However, little is known about potential crosstalk between neuronal NO signaling and neuroleptics action. The present work was, therefore, focused on gene expression of neuronal NO synthase (nNOS) in the brains of rats chronically treated with olanzapine, an atypical antipsychotic drug. Studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28-day-long intraperitoneal injection, at dose 5 mg/kg daily). All individuals were killed under anesthesia and the whole brains excised. Immunohistochemical procedure was used for histological assessment of the whole brain, and for both descriptive and quantitative analysis of nNOS protein distribution in selected brain structures. Long-term treatment with olanzapine is reflected in different changes in the number of enzyme-expressing cells in the rat brain. Olanzapine decreased the number of nNOS-expressing cells and possibly reduced NO synthesis in the rat striatum. Olanzapine can be taken into account as a potential inhibitor of NO synthesis in the rat striatum.
Assuntos
Antipsicóticos , Corpo Estriado , Animais , Masculino , Ratos , Antipsicóticos/farmacologia , Corpo Estriado/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Olanzapina/farmacologia , Ratos Sprague-DawleyRESUMO
Spinal Cord Injury (SCI) is a condition characterized by complete or incomplete motor and sensory impairment, as well as dysfunction of the autonomic nervous system, caused by factors such as trauma, tumors, or inflammation. Current treatment methods primarily include traditional approaches like spinal canal decompression and internal fixation surgery, steroid pulse therapy, as well as newer techniques such as stem cell transplantation and brain-spinal cord interfaces. However, the above methods have limited efficacy in promoting axonal and neuronal regeneration. The challenge in medical research today lies in promoting spinal cord neuron regeneration and regulating the disrupted microenvironment of the spinal cord. Studies have shown that gas molecular therapy is increasingly used in medical research, with gasotransmitters such as hydrogen sulfide, nitric oxide, carbon monoxide, oxygen, and hydrogen exhibiting neuroprotective effects in central nervous system diseases. The gas molecular protect against neuronal death and reshape the microenvironment of spinal cord injuries by regulating oxidative, inflammatory and apoptotic processes. At present, gas therapy mainly relies on inhalation for systemic administration, which cannot effectively enrich and release gas in the spinal cord injury area, making it difficult to achieve the expected effects. With the rapid development of nanotechnology, the use of nanocarriers to achieve targeted enrichment and precise control release of gas at Sites of injury has become one of the emerging research directions in SCI. It has shown promising therapeutic effects in preclinical studies and is expected to bring new hope and opportunities for the treatment of SCI. In this review, we will briefly outline the therapeutic effects and research progress of gasotransmitters and nanogas in the treatment of SCI.
Assuntos
Gasotransmissores , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/terapia , Humanos , Animais , Gasotransmissores/uso terapêutico , Gasotransmissores/metabolismo , Óxido Nítrico/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Monóxido de Carbono/metabolismo , Monóxido de Carbono/uso terapêutico , Oxigênio/metabolismo , Medula Espinal , Hidrogênio/uso terapêutico , Hidrogênio/farmacologiaRESUMO
In mammalian cells, cyanide is viewed as a cytotoxic agent, which exerts its effects through inhibition of mitochondrial Complex IV (Cytochrome C oxidase [CCOx]). However, the current report demonstrates that cyanide's effect on CCOx is biphasic; low (nanomolar to low-micromolar) concentrations stimulate CCOx activity, while higher (high-micromolar) concentrations produce the "classic" inhibitory effect. Low concentrations of cyanide stimulated mitochondrial electron transport and elevated intracellular adenosine triphosphate (ATP), resulting in the stimulation of cell proliferation. The stimulatory effect of cyanide on CCOx was associated with the removal of the constitutive, inhibitory glutathionylation on its catalytic 30- and 57-kDa subunits. Transfer of diluted Pseudomonas aeruginosa (a cyanide-producing bacterium) supernatants to mammalian cells stimulated cellular bioenergetics, while concentrated supernatants were inhibitory. These effects were absent with supernatants from mutant Pseudomonas lacking its cyanide-producing enzyme. These results raise the possibility that cyanide at low, endogenous levels serves regulatory purposes in mammals. Indeed, the expression of six putative mammalian cyanide-producing and/or -metabolizing enzymes was confirmed in HepG2 cells; one of them (myeloperoxidase) showed a biphasic regulation after cyanide exposure. Cyanide shares features with "classical" mammalian gasotransmitters NO, CO, and H2S and may be considered the fourth mammalian gasotransmitter.
Assuntos
Cianetos/farmacologia , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Cianetos/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/fisiologia , Células HCT116 , Células HT29 , Humanos , Mitocôndrias/metabolismoRESUMO
Atmospheric stressors include a variety of pollutant gases such as CO2, nitrous oxide (NOx), and sulfurous compounds which could have a natural origin or be generated by uncontrolled human activity. Nevertheless, other atmospheric elements including high and low temperatures, ozone (O3), UV-B radiation, or acid rain among others can affect, at different levels, a large number of plant species, particularly those of agronomic interest. Paradoxically, both nitric oxide (NO) and hydrogen sulfide (H2S), until recently were considered toxic since they are part of the polluting gases; however, at present, these molecules are part of the mechanism of response to multiple stresses since they exert signaling functions which usually have an associated stimulation of the enzymatic and non-enzymatic antioxidant systems. At present, these gasotransmitters are considered essential components of the defense against a wide range of environmental stresses including atmospheric ones. This review aims to provide an updated vision of the endogenous metabolism of NO and H2S in plant cells and to deepen how the exogenous application of these compounds can contribute to crop resilience, particularly, against atmospheric stressors stimulating antioxidant systems.
Assuntos
Gasotransmissores , Sulfeto de Hidrogênio , Resiliência Psicológica , Humanos , Óxido Nítrico/metabolismo , Antioxidantes/metabolismo , Gasotransmissores/metabolismo , Sulfeto de Hidrogênio/metabolismo , GasesRESUMO
Hydrogen selenide (H2Se) is an emerging biomolecule of interest with similar properties to that of other gaseous signaling molecules (i.e., gasotransmitters that include nitric oxide, carbon monoxide, and hydrogen sulfide). H2Se is enzymatically generated in humans where it serves as a key metabolic intermediate in the production of selenoproteins and other selenium-containing biomolecules. However, beyond its participation in biosynthetic pathways, its involvement in cellular signaling or other biological mechanisms remains unclear. To uncover its true biological significance, H2Se-specific chemical tools capable of functioning under physiological conditions are required but lacking in comparison to those that exist for other gasotransmitters. Recently, researchers have begun to fill this unmet need by developing new H2Se-releasing compounds, along with pioneering methods for selenide detection and quantification. In combination, the chemical tools highlighted in this review have the potential to spark groundbreaking explorations into the chemical biology of H2Se, which may lead to its branding as the fourth official gasotransmitter.
Assuntos
Compostos de Selênio , Compostos de Selênio/química , Humanos , Gasotransmissores/metabolismo , Gasotransmissores/química , Sulfeto de Hidrogênio/análise , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/metabolismo , Selenoproteínas/química , Selenoproteínas/metabolismo , AnimaisRESUMO
BACKGROUND: Hydrogen sulfide (H2S) donors are crucial tools not only for understanding the role of H2S in cellular function but also as promising therapeutic agents for oxidative stress-related diseases. This study aimed to explore the effect of amino acid-derived N-thiocarboxyanhydrides (NTAs), which release physiological H2S levels in the presence of carbonic anhydrase, on porcine sperm function during short-term incubation with and without induced oxidative stress. For this purpose, we employed two H2S-releasing NTAs with release half-lives (t1/2) in the range of hours that derived from the amino acids glycine (Gly-NTA) or leucine (Leu-NTA). Because carbonic anhydrase is crucial for H2S release from NTAs, we first measured the activity of this enzyme in the porcine ejaculate. Then, we tested the effect of Gly- and Leu-NTAs at 10 and 1 nM on sperm mitochondrial activity, plasma membrane integrity, acrosomal status, motility, motile subpopulations, and redox balance during short-term incubation at 38 °C with and without a reactive oxygen species (ROS)-generating system. RESULTS: Our results show that carbonic anhydrase is found both in spermatozoa and seminal plasma, with activity notably higher in the latter. Both Gly- and Leu-NTAs did not exert any noxious effects, but they enhanced sperm mitochondrial activity in the presence and absence of oxidative stress. Moreover, NTAs (except for Leu-NTA 10 nM) tended to preserve the sperm redox balance against the injuries provoked by oxidative stress, which provide further support to the antioxidant effect of H2S on sperm function. Both compounds also increased progressive motility over short-term incubation, which may translate into prolonged sperm survival. CONCLUSIONS: The presence of carbonic anhydrase activity in mammalian spermatozoa makes NTAs promising molecules to investigate the role of H2S in sperm biology. For the first time, beneficial effects of NTAs on mitochondrial activity have been found in mammalian cells in the presence and absence of oxidative stress. NTAs are interesting compounds to investigate the role of H2S in sperm mitochondria-dependent events and to develop H2S-related therapeutic protocols against oxidative stress in assisted reproductive technologies.
Assuntos
Aminoácidos , Anidrases Carbônicas , Masculino , Animais , Suínos , Aminoácidos/metabolismo , Sementes/metabolismo , Espermatozoides , Estresse Oxidativo , Mitocôndrias , Espécies Reativas de Oxigênio/metabolismo , Anidrases Carbônicas/metabolismo , Anidrases Carbônicas/farmacologia , MamíferosRESUMO
Nitric oxide (NO) and carbon monoxide (CO) represent a pair of biologically active gases with an increasingly well-defined range of effects on circulating platelets. These gases interact with platelets and cells in the vessels and heart and exert fundamentally similar biological effects, albeit through different mechanisms and with some peculiarity. Within the cardiovascular system, for example, the gases are predominantly vasodilators and exert antiaggregatory effects, and are protective against damage in myocardial ischemia-reperfusion injury. Indeed, NO is an important vasodilator acting on vascular smooth muscle and is able to inhibit platelet activation. NO reacts with superoxide anion (O2(-â¢)) to form peroxynitrite (ONOO(-)), a nitrosating agent capable of inducing oxidative/nitrative signaling and stress both at cardiovascular, platelet, and plasma levels. CO reduces platelet reactivity, therefore it is an anticoagulant, but it also has some cardioprotective and procoagulant properties. This review article summarizes current knowledge on the platelets and roles of gas mediators (NO, and CO) in cardioprotection. In particular, we aim to examine the link and interactions between platelets, NO, and CO and cardioprotective pathways.
Assuntos
Gasotransmissores , Traumatismo por Reperfusão Miocárdica , Humanos , Óxido Nítrico/metabolismo , Óxidos , Gasotransmissores/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Gases , VasodilatadoresRESUMO
Cardiovascular, rheumatic, kidney, and neurodegenerative diseases and mental disorders are a common cause of deterioration in the quality of life up to severe disability and death worldwide. Many pathological conditions, including this group of diseases, are based on increased cell death through apoptosis. It is known that this process is associated with signaling pathways controlled by a group of gaseous signaling molecules called gasotransmitters. They are unique messengers that can control the process of apoptosis at different stages of its implementation. However, their role in the regulation of apoptotic signaling in these pathological conditions is often controversial and not completely clear. This review analyzes the role of nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S), and sulfur dioxide (SO2) in apoptotic cell death in cardiovascular, rheumatic, kidney, and neurodegenerative diseases. The signaling processes involved in apoptosis in schizophrenia, bipolar, depressive, and anxiety disorders are also considered. The role of gasotransmitters in apoptosis in these diseases is largely determined by cell specificity and concentration. NO has the greatest dualism; scales are more prone to apoptosis. At the same time, CO, H2S, and SO2 are more involved in cytoprotective processes.
Assuntos
Gasotransmissores , Sulfeto de Hidrogênio , Transtornos Mentais , Doenças Neurodegenerativas , Humanos , Gasotransmissores/metabolismo , Qualidade de Vida , Sulfeto de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Monóxido de Carbono/metabolismo , Rim/metabolismo , ApoptoseRESUMO
The important role of gasotransmitters in physiology and pathophysiology suggest employing gasotransmitters for biomedical treatment. Unfortunately, the difficulty in storage and controlled delivery of these gaseous molecules hindered the development of effective gasotransmitters-based therapies. The design of a safe, facile, and wide-scale method to delivery multiple gasotransmitters is a great challenge. Herein, we use an ultrasonic assisted preparation γ-cyclodextrin metal organic framework (γ-CD-MOF) as a broad-spectrum delivery vehicle for various gasotransmitters, such as SO2, NO, and H2S. The release rate of gasotransmitters could be tuned by modifying the γ-CD-MOF with different Pluronics. The biological relevance of the exogenous gasotransmitters produced by this method is evidenced by the DNA cleavage ability and the anti-inflammatory effects. Furthermore, the γ-CD-MOF composed of food-grade γ-CD and nontoxic metal salts shows good biocompatibility and particle size (180 nm). Therefore, γ-CD-MOF is expected to be an excellent tool for the study of co-delivery and cooperative therapy of gasotransmitters.
Assuntos
Ciclodextrinas , Gasotransmissores , Estruturas Metalorgânicas , MetaisRESUMO
Inflammation and resolution are dynamic processes comprised of inflammatory activation and neutrophil influx, followed by mediator catabolism and efferocytosis. These critical pathways ensure a return to homeostasis and promote repair. Over the past decade research has shown that diverse mediators play a role in the active process of resolution. Specialized pro-resolving mediators (SPMs), biosynthesized from fatty acids, are released during inflammation to facilitate resolution and are deficient in a variety of lung disorders. Failed resolution results in remodeling and cellular deposition through pro-fibrotic myofibroblast expansion that irreversibly narrows the airways and worsens lung function. Recent studies indicate environmental exposures may perturb and deregulate critical resolution pathways. Environmental xenobiotics induce lung inflammation and generate reactive metabolites that promote oxidative stress, injuring the respiratory mucosa and impairing gas-exchange. This warrants recognition of xenobiotic associated molecular patterns (XAMPs) as new signals in the field of inflammation biology, as many environmental chemicals generate free radicals capable of initiating the inflammatory response. Recent studies suggest that unresolved, persistent inflammation impacts both resolution pathways and endogenous regulatory mediators, compromising lung function, which over time can progress to chronic lung disease. Chronic ozone (O3) exposure overwhelms successful resolution, and in susceptible individuals promotes asthma onset. The industrial contaminant cadmium (Cd) bioaccumulates in the lung to impair resolution, and recurrent inflammation can result in chronic obstructive pulmonary disease (COPD). Persistent particulate matter (PM) exposure increases systemic cardiopulmonary inflammation, which reduces lung function and can exacerbate asthma, COPD, and idiopathic pulmonary fibrosis (IPF). While recurrent inflammation underlies environmentally induced pulmonary morbidity and may drive the disease process, our understanding of inflammation resolution in this context is limited. This review aims to explore inflammation resolution biology and its role in chronic environmental lung disease(s).
Assuntos
Asma , Pneumopatias , Doença Pulmonar Obstrutiva Crônica , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pneumopatias/induzido quimicamente , Pneumopatias/metabolismo , MorbidadeRESUMO
Endogenous production of carbon monoxide (CO) is affected by inflammatory phenomena and ischemia-reperfusion injury. Precise measurement of exhaled endogenous CO (eCO) is possible thanks to a laser spectrometer (ProCeas® from AP2E company). We assessed eCO levels of human lung grafts during the normothermic Ex-Vivo Lung Perfusion (EVLP). ProCeas® was connected in bypass to the ventilation circuit. The surgical team took the decision to transplant the lungs without knowing eCO values. We compared eCO between accepted and rejected grafts. EVLP parameters and recipient outcomes were also compared with eCO values. Over 7 months, eCO was analyzed in 21 consecutive EVLP grafts. Two pairs of lungs were rejected by the surgical team. In these two cases, there was a tendency for higher eCO values (0.358 ± 0.52 ppm) compared to transplanted lungs (0.240 ± 0.76 ppm). During the EVLP procedure, eCO was correlated with glucose consumption and lactate production. However, there was no association of eCO neither with edema formation nor with the PO2/FiO2 ratio per EVLP. Regarding post-operative data, every patient transplanted with grafts exhaling high eCO levels (>0.235 ppm) during EVLP presented a Primary Graft Dysfunction score of 3 within the 72 h post-transplantation. There was also a tendency for a longer stay in ICU for recipients with grafts exhaling high eCO levels during EVLP. eCO can be continuously monitored during EVLP. It could serve as an additional and early marker in the evaluation of the lung grafts providing relevant information for post-operative resuscitation care.
Assuntos
Expiração , Transplante de Pulmão , Humanos , Lasers , Pulmão , Transplante de Pulmão/métodos , Perfusão/métodosRESUMO
Hydrogen sulfide (H2S) modulates many biological processes, including ageing. Initially considered a hazardous toxic gas, it is now recognised that H2S is produced endogenously across taxa and is a key mediator of processes that promote longevity and improve late-life health. In this review, we consider the key developments in our understanding of this gaseous signalling molecule in the context of health and disease, discuss potential mechanisms through which H2S can influence processes central to ageing and highlight the emergence of novel H2S-based therapeutics. We also consider the major challenges that may potentially hinder the development of such therapies.
Assuntos
Envelhecimento/metabolismo , Extremidades/irrigação sanguínea , Gasotransmissores/metabolismo , Sulfeto de Hidrogênio/metabolismo , Isquemia/metabolismo , Longevidade , Osteoporose/metabolismo , Progéria/metabolismo , Transdução de Sinais , Envelhecimento/efeitos dos fármacos , Animais , Gasotransmissores/farmacologia , Humanos , Sulfeto de Hidrogênio/farmacologia , Longevidade/efeitos dos fármacos , Metaloproteínas/metabolismo , Processamento de Proteína Pós-TraducionalRESUMO
Nitroxyl shows a unique biological profile compared to the gasotransmitters nitric oxide and hydrogen sulfide. Nitroxyl reacts with thiols as an electrophile, and this redox chemistry mediates much of its biological chemistry. This reactivity necessitates the use of donors to study nitroxyl's chemistry and biology. The preparation and evaluation of a small library of new redox-triggered nitroxyl sources is described. The condensation of sulfonyl chlorides and properly substituted O-benzyl hydroxylamines produced O-benzyl-substituted sulfohydroxamic acid derivatives with a 27-79% yield and with good purity. These compounds were designed to produce nitroxyl through a 1, 6 elimination upon oxidation or reduction via a Piloty's acid derivative. Gas chromatographic headspace analysis of nitrous oxide, the dimerization and dehydration product of nitroxyl, provides evidence for nitroxyl formation. The reduction of derivatives containing nitro and azide groups generated nitrous oxide with a 25-92% yield, providing evidence of nitroxyl formation. The oxidation of a boronate-containing derivative produced nitrous oxide with a 23% yield. These results support the proposed mechanism of nitroxyl formation upon reduction/oxidation via a 1, 6 elimination and Piloty's acid. These compounds hold promise as tools for understanding nitroxyl's role in redox biology.
Assuntos
Sulfeto de Hidrogênio , Óxido Nitroso , Sulfeto de Hidrogênio/química , Óxido Nítrico , Óxidos de Nitrogênio/química , OxirreduçãoRESUMO
Hydrogen sulphide (H2 S) is an endogenously produced gasotransmitter that has rapidly emerged as an active signalling component of several plant processes, stomatal movement regulation among them. The guard cells (GCs), pairs of cells that neighbour the stomatal pores, transduce endogenous and environmental signals, through signalling network, to control stomatal pore size. In this complex network, which has become a model system for plant signalling, few highly connected components form a core that links most of the pathways. The evidence summarized in this insight, on the interplay between H2 S and different key components of the GC networks, points towards H2 S as a regulator of the GC core signalling pathway.
Assuntos
Sulfeto de Hidrogênio , Ácido Abscísico , Estômatos de Plantas , Transdução de SinaisRESUMO
It is estimated that 10% of carbon throughout the cosmos is in the form of carbon monoxide (CO). Earth's earliest prebiotic atmosphere included the trinity of gasotransmitters CO, nitric oxide (NO), and hydrogen sulfide (H2S), for which all of life has co-evolved with. The history of CO can be loosely traced to mythological and prehistoric origins with rudimentary understanding emerging in the middle ages. Ancient literature is focused on CO's deadly toxicity which is understandable in the context of our primitive relationship with coal and fire. Scientific inquiry into CO appears to have emerged throughout the 1700s followed by chemical and toxicological profiling throughout the 1800s. Despite CO's ghastly reputation, several of the 18th and 19th century scientists suggested a therapeutic application of CO. Since 2000, the fundamental understanding of CO as a deadly nuisance has undergone a paradigm shift such that CO is now recognized as a neurotransmitter and viable pharmaceutical candidate. This review is intended to provide a brief history on the trace origins pertaining to endogenous formation and therapeutic application of CO.
Assuntos
Monóxido de Carbono/história , Monóxido de Carbono/uso terapêutico , Animais , Monóxido de Carbono/fisiologia , Monóxido de Carbono/toxicidade , História do Século XV , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , História Medieval , HumanosRESUMO
Our understanding of the gaseous signaling molecules that play important roles in diverse physiological processes keeps expanding. These gas molecules, also called gasotransmitters, include NO, H2S, 1O2, CO, and CO2 and are generated within the cell through enzymatic pathways and photochemical reactions. These molecules are chemically unstable and directly react with amino acids such as cysteine, histidine, and so on. Compared to well-characterized reactive oxygen species (ROS), including H2O2, ONOO-, O2-, and OH·, the gasotransmitters are in general less polar and show higher solubility in hydrophobic environments like the lipid membrane. Correspondingly, accumulating evidence has begun to unveil the broad impacts of these gaseous molecules on the function of membrane proteins, including ion channels. This review summarizes the major physicochemical characteristics of representative gasotransmitters and their regulation of ion channel functions.
Assuntos
Gasotransmissores , Sulfeto de Hidrogênio , Canais Iônicos/metabolismo , Gasotransmissores/metabolismo , Peróxido de Hidrogênio , Sulfeto de Hidrogênio/metabolismo , Óxido Nítrico/metabolismoRESUMO
This review focuses on the effects of hydrogen sulfide (H2S) on the unique bioenergetic molecular machines in mitochondria and bacteria-the protein complexes of electron transport chains and associated enzymes. H2S, along with nitric oxide and carbon monoxide, belongs to the class of endogenous gaseous signaling molecules. This compound plays critical roles in physiology and pathophysiology. Enzymes implicated in H2S metabolism and physiological actions are promising targets for novel pharmaceutical agents. The biological effects of H2S are biphasic, changing from cytoprotection to cytotoxicity through increasing the compound concentration. In mammals, H2S enhances the activity of FoF1-ATP (adenosine triphosphate) synthase and lactate dehydrogenase via their S-sulfhydration, thereby stimulating mitochondrial electron transport. H2S serves as an electron donor for the mitochondrial respiratory chain via sulfide quinone oxidoreductase and cytochrome c oxidase at low H2S levels. The latter enzyme is inhibited by high H2S concentrations, resulting in the reversible inhibition of electron transport and ATP production in mitochondria. In the branched respiratory chain of Escherichia coli, H2S inhibits the bo3 terminal oxidase but does not affect the alternative bd-type oxidases. Thus, in E. coli and presumably other bacteria, cytochrome bd permits respiration and cell growth in H2S-rich environments. A complete picture of the impact of H2S on bioenergetics is lacking, but this field is fast-moving, and active ongoing research on this topic will likely shed light on additional, yet unknown biological effects.
Assuntos
Bactérias/efeitos dos fármacos , Metabolismo Energético , Sulfeto de Hidrogênio/farmacologia , Mitocôndrias/patologia , Fosforilação Oxidativa , Poluentes Atmosféricos/farmacologia , Animais , Bactérias/crescimento & desenvolvimento , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismoRESUMO
NEW FINDINGS: What is the central question of this study? Low dose carbon monoxide (CO) inhalation plays a role in regulating proteins involved in glucose metabolism; does low dose CO improve glucose and insulin responses to an oral glucose tolerance test in overweight adults? What is the main finding and its importance? Five days of intermittent CO inhalation does not alter the glucose or insulin responses to ingestion of a glucose bolus in overweight adults. Low dose CO is utilized in various physiological assessment procedures; these findings allow researchers and clinicians to utilize these procedures without concern of altering glucose metabolism. ABSTRACT: Low dose carbon monoxide (CO) inhalation upregulates several proteins important for glucose metabolism. Such changes could be clinically significant and may be relevant to those who use CO as a research tool. We hypothesized that low dose CO inhalation would improve glucose and insulin responses to an oral glucose bolus in overweight humans. Eleven young adults (5 men, 6 women; body mass index: 25-35 kg m-2 ) were included in this randomized, placebo-controlled, single-blinded crossover study. Following screening, participants completed two 7-day protocols with a 4-week washout. Twenty-four hours prior to and following five consecutive days of either once daily CO (men: 1.2 ml (kg body mass)-1 ; women: 1.0 ml (kg body mass)-1 ) or placebo (room air) inhalation, participants underwent oral glucose tolerance tests (OGTT). For key outcome variables, there were no significant main effects or interactions across condition or time point (mean ± SD), including fasting glucose (mg dl-1 : pre-placebo: 85.2 ± 10.1; post-placebo: 82.9 ± 10.6; pre-CO: 83.6 ± 7.7; post-CO: 84.0 ± 9.0), 2 h post glucose (mg dl-1 : pre-placebo: 100.9 ± 20.0; post-placebo: 98.7 ± 13.1; pre-CO: 94.2 ± 23.2; post-CO: 94.4 ± 14.9), or the Matsuda index (pre-placebo: 16.1 ± 11.5; post-placebo: 20.3 ± 24.7; pre-CO: 15.6 ± 15.3; post-CO: 17.5 ± 16.8). In conclusion, 5 days of low dose CO administration did not influence glucose and insulin responses to an OGTT in overweight adults. Low dose CO inhalation is utilized in a variety of physiological assessment procedures; these findings allow researchers to utilize these procedures without concern of altering glucose metabolism.
Assuntos
Monóxido de Carbono/administração & dosagem , Glucose/metabolismo , Sobrepeso/tratamento farmacológico , Adulto , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Índice de Massa Corporal , Estudos Cross-Over , Jejum/metabolismo , Feminino , Teste de Tolerância a Glucose/métodos , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Sobrepeso/metabolismo , Método Simples-Cego , Adulto JovemRESUMO
Hydrogen sulfide (H2S), produced by various endogenous enzyme systems, serves various biological regulatory roles in mammalian cells in health and disease. Over recent years, a new concept emerged in the field of H2S biology, showing that various cancer cells upregulate their endogenous H2S production, and utilize this mediator in autocrine and paracrine manner to stimulate proliferation, bioenergetics and tumor angiogenesis. Initial work identified cystathionine-beta-synthase (CBS) in many tumor cells as the key source of H2S. In other cells, cystathionine-gamma-lyase (CSE) has been shown to play a pathogenetic role. However, until recently, less attention has been paid to the third enzymatic source of H2S, 3-mercaptopyruvate sulfurtransferase (3-MST), even though several of its biological and biochemical features - e.g. its partial mitochondrial localization, its ability to produce polysulfides, which, in turn, can induce functionally relevant posttranslational protein modifications - makes it a potential candidate. Indeed, several lines of recent data indicate the potential role of the 3-MST system in cancer biology. In many cancers (e.g. colon adenocarcinoma, lung adenocarcinoma, urothelial cell carcinoma, various forms of oral carcinomas), 3-MST is upregulated compared to the surrounding normal tissue. According to in vitro studies, 3-MST upregulation is especially prominent in cancer cells that recover from oxidative damage and/or develop a multidrug-resistant phenotype. Emerging data with newly discovered pharmacological inhibitors of 3-MST, as well as data using 3-MST silencing approaches suggest that the 3-MST/H2S system plays a role in maintaining cancer cell proliferation; it may also regulate bioenergetic and cell-signaling functions. Many questions remain open in the field of 3-MST/cancer biology; the last section of current article highlights these open questions and lays out potential experimental strategies to address them.