An Examination of Chemical Tools for Hydrogen Selenide Donation and Detection.

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.

Gasotransmitters and noble gases in cardioprotection: unraveling molecular pathways for future therapeutic strategies.

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.

Recent advances in the application of gasotransmitters in spinal cord injury.

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.

Neurobehavioral dysfunction in a mouse model of Down syndrome: upregulation of cystathionine ß-synthase, H2S overproduction, altered protein persulfidation, synaptic dysfunction, endoplasmic reticulum stress, and autophagy.

Down syndrome (DS) is a genetic condition where the person is born with an extra chromosome 21. DS is associated with accelerated aging; people with DS are prone to age-related neurological conditions including an early-onset Alzheimer's disease. Using the Dp(17)3Yey/ + mice, which overexpresses a portion of mouse chromosome 17, which encodes for the transsulfuration enzyme cystathionine ß-synthase (CBS), we investigated the functional role of the CBS/hydrogen sulfide (H2S) pathway in the pathogenesis of neurobehavioral dysfunction in DS. The data demonstrate that CBS is higher in the brain of the DS mice than in the brain of wild-type mice, with primary localization in astrocytes. DS mice exhibited impaired recognition memory and spatial learning, loss of synaptosomal function, endoplasmic reticulum stress, and autophagy. Treatment of mice with aminooxyacetate, a prototypical CBS inhibitor, improved neurobehavioral function, reduced the degree of reactive gliosis in the DS brain, increased the ability of the synaptosomes to generate ATP, and reduced endoplasmic reticulum stress. H2S levels in the brain of DS mice were higher than in wild-type mice, but, unexpectedly, protein persulfidation was decreased. Many of the above alterations were more pronounced in the female DS mice. There was a significant dysregulation of metabolism in the brain of DS mice, which affected amino acid, carbohydrate, lipid, endocannabinoid, and nucleotide metabolites; some of these alterations were reversed by treatment of the mice with the CBS inhibitor. Thus, the CBS/H2S pathway contributes to the pathogenesis of neurological dysfunction in DS in the current animal model.

Electrochemical Detection of Gasotransmitters: Status and Roadmap.

Gasotransmitters, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), are a class of gaseous, endogenous signaling molecules that interact with one another in the regulation of critical cardiovascular, immune, and neurological processes. The development of analytical sensing mechanisms for gasotransmitters, especially multianalyte mechanisms, holds vast importance and constitutes a growing area of study. This review provides an overview of electrochemical sensing mechanisms with an emphasis on opportunities in multianalyte sensing. Electrochemical methods demonstrate good sensitivity, adequate selectivity, and the most well-developed potential for the multianalyte detection of gasotransmitters. Future research will likely address challenges with sensor stability and biocompatibility (i.e., sensor lifetime and cytotoxicity), sensor miniaturization, and multianalyte detection in biological settings.

Evolution of reactive oxygen species cellular targets for plant development.

Reactive oxygen species (ROS) are the key players in regulating developmental processes of plants. Plants have evolved a large array of gene families to facilitate the ROS-regulated developmental process in roots and leaves. However, the cellular targets of ROS during plant evolutionary development are still elusive. Here, we found early evolution and large expansions of protein families such as mitogen-activated protein kinases (MAPK) in the evolutionarily important plant lineages. We review the recent advances in interactions among ROS, phytohormones, gasotransmitters, and protein kinases. We propose that these signaling molecules act in concert to maintain cellular ROS homeostasis in developmental processes of root and leaf to ensure the fine-tuning of plant growth for better adaptation to the changing climate.

NO and H2S Contribute to Crop Resilience against Atmospheric Stressors.

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.

Modulatory effect of olanzapine on neuronal nitric oxide synthase (nNOS) expression in the rat striatum.

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.

Role of Gasotransmitters in Inflammatory Edema.

Significance: Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are, to date, the identified members of the gasotransmitter family, which consists of gaseous signaling molecules that play central roles in the regulation of a wide variety of physiological and pathophysiological processes, including inflammatory edema. Recent Advances: Recent studies show the potential anti-inflammatory and antiedematogenic effects of NO-, CO-, and H2S-donors in vivo. In general, it has been observed that the therapeutical effects of NO-donors are more relevant when administered at low doses at the onset of the inflammatory process. Regarding CO-donors, their antiedematogenic effects are mainly associated with inhibition of proinflammatory mediators (such as inducible NO synthase [iNOS]-derived NO), and the observed protective effects of H2S-donors seem to be mediated by reducing some proinflammatory enzyme activities. Critical Issues: The most recent investigations focus on the interactions among the gasotransmitters under different pathophysiological conditions. However, the biochemical/pharmacological nature of these interactions is neither general nor fully understood, although specifically dependent on the site where the inflammatory edema occurs. Future Directions: Considering the nature of the involved mechanisms, a deeper knowledge of the interactions among the gasotransmitters is mandatory. In addition, the development of new pharmacological tools, either donors or synthesis inhibitors of the three gasotransmitters, will certainly aid the basic investigations and open new strategies for the therapeutic treatment of inflammatory edema. Antioxid. Redox Signal. 40, 272-291.

Gasotransmitter-Mediated Cysteinome Oxidative Posttranslational Modifications: Formation, Biological Effects, and Detection.

Significance: Gasotransmitters, including nitric oxide (NO), hydrogen sulfide (H2S) and sulfur dioxide (SO2), participate in various cellular processes via corresponding oxidative posttranslational modifications (oxiPTMs) of specific cysteines. Recent Advances: Accumulating evidence has clarified the mechanisms underlying the formation of oxiPTMs derived from gasotransmitters and their biological functions in multiple signal pathways. Because of the specific existence and functional importance, determining the sites of oxiPTMs in cysteine is crucial in biology. Recent advances in the development of selective probes, together with upgraded mass spectrometry (MS)-based proteomics, have enabled the quantitative analysis of cysteinome. To date, several cysteine residues have been identified as gasotransmitter targets. Critical Issues: To clearly understand the underlying mechanisms for gasotransmitter-mediated biological processes, it is important to identify modified targets. In this review, we summarize the chemical formation and biological effects of gasotransmitter-dependent oxiPTMs and highlight the state-of-the-art detection methods. Future Directions: Future studies in this field should aim to develop the next generation of probes for in situ labeling to improve spatial resolution and determine the dynamic change of oxiPTMs, which can lay the foundation for research on the molecular mechanisms and clinical translation of gasotransmitters. Antioxid. Redox Signal. 40, 145-167.

Strategies for gaseous neuromodulator release in chemical neuroscience: Experimental approaches and translational validation.

Gasotransmitters are a group of short-lived gaseous signaling molecules displaying diverse biological functions depending upon their localized concentration. Nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO) are three important examples of endogenously produced gasotransmitters that play a crucial role in human neurophysiology and pathogenesis. Alterations in their optimal physiological concentrations can lead to various severe pathophysiological consequences, including neurological disorders. Exogenous administration of gasotransmitters has emerged as a prominent therapeutic approach for treating such neurological diseases. However, their gaseous nature and short half-life limit their therapeutic delivery. Therefore, developing synthetic gasotransmitter-releasing strategies having control over the release and duration of these gaseous molecules has become imperative. However, the complex chemistry of synthesis and the challenges of specific quantified delivery of these gases, make their therapeutic application a challenging task. This review article provides a focused overview of emerging strategies for delivering gasotransmitters in a controlled and sustained manner to re-establish neurophysiological homeostasis.

Olanzapine alters the expression of gasotransmitter-related enzymes: CBS and HO-2 in the rat hippocampus and striatum.

BACKGROUND: Gaseous neurotransmitters have been thought to be novel factors involved in the mechanisms of mental disorders pathogenesis for quite some time. However, little is known about the potential crosstalk between neuronal gasotransmitter signaling and neuroleptics action. The present work was, therefore, focused on gene expression of H2S and CO-producing enzymes in the brains of rats chronically treated with olanzapine, an atypical antipsychotic drug. METHODS: 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 a dose of 5 mg/kg daily). All individuals were sacrificed under anesthesia and the whole brains excised. Immunohistochemical procedure was used for histological assessment of the whole brain and for quantitative analysis of cystathionine ß-synthase (CBS) and heme oxygenase 2 (HO-2) protein distribution in selected brain structures. RESULTS: Long-term treatment with olanzapine is reflected in different changes in the number of enzymes-expressing cells in the rat brain. Olanzapine decreased the number of CBS-expressing cells and possibly reduced H2S synthesis in the hippocampus and striatum. The antipsychotic administration increased the number of HO-2 immunopositive cells and probably stimulated the CO production in the hippocampus. CONCLUSIONS: Modulatory effect of olanzapine on cellular mechanisms of gasotransmitter synthesis may be an alternative way of their pharmacological action.

Photoactivable AIEgen-based Lipid-Droplet-Specific Drug Delivery Model for Live Cell Imaging and Two-Photon Light-Triggered Anticancer Drug Delivery.

Lipid droplets (LDs) are dynamic complex organelles involved in various physiological processes, and their number and activity are linked to multiple diseases, including cancer. In this study, we have developed LD-specific near-infrared (NIR) light-responsive nano-drug delivery systems (DDSs) based on chalcone derivatives for cancer treatment. The reported nano-DDSs localized inside the cancer microenvironment of LDs, and upon exposure to light, they delivered the anticancer drug valproic acid in a spatiotemporally controlled manner. The developed systems, namely, 2'-hydroxyacetophenone-dimethylaminobenzaldehyde-valproic (HA-DAB-VPA) and 2'-hydroxyacetophenone-diphenylaminobenzaldehyde-valproic (HA-DPB-VPA) ester conjugates, required only two simple synthetic steps. Our reported DDSs exhibited interesting properties such as excited-state intramolecular proton transfer (ESIPT) and aggregation-induced emission (AIE) phenomena, which provided advantages such as AIE-initiated photorelease and ESIPT-enhanced rate of photorelease upon exposure to one- or two-photon light. Further, colocalization studies of the nano-DDSs by employing two cancerous cell lines (MCF-7 cell line and CT-26 cell line) and one normal cell line (HEK cell line) revealed LD concentration-dependent enhanced fluorescence intensity. Furthermore, systematic investigations of both the nano-DDSs in the presence and absence of oleic acid inside the cells revealed that nano-DDS HA-DPB-VPA accumulated more selectively in the LDs. This unique selectivity by the nano-DDS HA-DPB-VPA toward the LDs is due to the hydrophobic nature of the diphenylaminobenzaldehyde (mimicking the LD core), which significantly leads to the aggregation and ESIPT (at 90% volume of fw, ΦF = 20.4% and in oleic acid ΦF = 24.6%), respectively. Significantly, we used this as a light-triggered anticancer drug delivery model to take advantage of the high selectivity and accumulation of the nano-DDS HA-DPB-VPA inside the LDs. Hence, these findings give a prototype for designing drug delivery models for monitoring LD-related intracellular activities and significantly triggering the release of LD-specific drugs in the biological field.

T-type calcium channel modulation by hydrogen sulfide in neuropathic pain conditions.

Neuropathic pain can appear as a direct or indirect nerve damage lesion or disease that affects the somatosensory nervous system. If the neurons are damaged or indirectly stimulated, immune cells contribute significantly to inflammatory and neuropathic pain. After nerve injury, peripheral macrophages/spinal microglia accumulate around damaged neurons, producing endogenous hydrogen sulfide (H2S) through the cystathionine-γ-lyase (CSE) enzyme. H2S has a pronociceptive modulation on the Cav3.2 subtype, the predominant Cav3 isoform involved in pain processes. The present review provides relevant information about H2S modulation on the Cav3.2 T-type channels in neuropathic pain conditions. We have discussed that the dual effect of H2S on T-type channels is concentration-dependent, that is, an inhibitory effect is seen at low concentrations of 10 µM and an augmentation effect on T-current at 100 µM. The modulation mechanism of the Cav3.2 channel by H2S involves the direct participation of the redox/Zn2+ affinity site located in the His191 in the extracellular loop of domain I of the channel, involving a group of extracellular cysteines, comprising C114, C123, C128, and C1333, that can modify the local redox environment. The indirect interaction pathways involve the regulation of the Cav3.2 channel through cytokines, kinases, and post-translational regulators of channel expression. The findings conclude that the CSE/H2S/Cav3.2 pathway could be a promising therapeutic target for neuropathic pain disorders.

Hydrogen sulfide: Recent development of its dual donors and hybrid drugs.

Hydrogen sulfide (H2 S) is an important gaseous signalling molecule known to be critically involved in regulating cellular redox homeostasis. As the beneficial and therapeutic effects of H2 S in pathophysiology, such as in cardiovascular and neurodegenerative diseases, have emerged, so too has the drive for the development of H2 S-releasing compounds (aka donors) and their therapeutic applications. Most reported donor compounds singularly release H2 S through biocompatible triggers. An emerging area in the field is the development of compounds that can co-deliver H2 S with other drugs or biologically relevant species, such as reactive oxygen and nitrogen species (ROS and RNS, respectively). These H2 S-based dual donors and hybrid drugs are expected to offset negative side effects from individual treatments or achieve synergistic effects rendering them more clinically effective. Additionally, considering that molecules exist and interact physiologically, dual donors may more accurately mimic biological systems as compared to single donors and allow for the elucidation of fundamental chemistry and biology. This review focuses on the recent advances in the development of H2 S-based dual donors and hybrid drugs along with their design principles and synergistic effects.

Signal Mediators in the Implementation of Jasmonic Acid's Protective Effect on Plants under Abiotic Stresses.

Plant cells respond to stress by activating signaling and regulatory networks that include plant hormones and numerous mediators of non-hormonal nature. These include the universal intracellular messenger calcium, reactive oxygen species (ROS), gasotransmitters, small gaseous molecules synthesized by living organisms, and signal functions such as nitrogen monoxide (NO), hydrogen sulfide (H2S), carbon monoxide (CO), and others. This review focuses on the role of functional linkages of jasmonic acid and jasmonate signaling components with gasotransmitters and other signaling mediators, as well as some stress metabolites, in the regulation of plant adaptive responses to abiotic stressors. Data on the involvement of NO, H2S, and CO in the regulation of jasmonic acid formation in plant cells and its signal transduction were analyzed. The possible involvement of the protein components of jasmonate signaling in stress-protective gasotransmitter effects is discussed. Emphasis is placed on the significance of the functional interaction between jasmonic acid and signaling mediators in the regulation of the antioxidant system, stomatal apparatus, and other processes important for plant adaptation to abiotic stresses.

Gasotransmitters in non-alcoholic fatty liver disease: just the tip of the iceberg.

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by fatty lesions and fat accumulation in hepatic parenchymal cells, which is in the absence of excessive alcohol consumption or definite liver damage factors. The exact pathogenesis of NAFLD is not fully understood, but it is now recognized that oxidative stress, insulin resistance, and inflammation are essential mechanisms involved in the development and treatment of NAFLD. NAFLD therapy aims to stop, delay or reverse disease progressions, as well as improve the quality of life and clinical outcomes of patients with NAFLD. Gasotransmitters are produced by enzymatic reactions, regulated through metabolic pathways in vivo, which can freely penetrate cell membranes with specific physiological functions and targets. Three gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide have been discovered. Gasotransmitters exhibit the effects of anti-inflammatory, anti-oxidant, vasodilatory, and cardioprotective agents. Gasotransmitters and their donors can be used as new gas-derived drugs and provide new approaches to the clinical treatment of NAFLD. Gasotransmitters can modulate inflammation, oxidative stress, and numerous signaling pathways to protect against NAFLD. In this paper, we mainly review the status of gasotransmitters research on NAFLD. It provides clinical applications for the future use of exogenous and endogenous gasotransmitters for the treatment of NAFLD.

Click chemistry and drug delivery: A bird's-eye view.

Click chemistry has been proven to be very useful in drug delivery. Due to the availability of a large number of click reactions with a various characteristics, selection of appropriate chemistry for a given application is often not a trivial task. This review is written for pharmaceutical researchers who are interested in click chemistry applications and yet may not be click chemistry experts. For this, the review gives an overview of available click reactions organized by application types. Further, the general understanding of click reactions being fast and high yielding sometimes overshadows the need to analyze reaction kinetics in assessing suitability of a given reaction for certain applications. For this, we highlight the need to analyze the relationship among reaction kinetics, concentration effects, and reaction time scales, knowing that lack of such analysis could easily lead to failures. Further, possible issues such as chemical stability with various click reagents are also discussed to aid experimental designs. Recent examples and extensive references are also provided to aid in-depth understanding of technical details. We hope this review will help those interested in using click chemistry in drug delivery to select the appropriate reactions/reagents and minimize the number of pitfalls.

The Role of Gasotransmitter-Dependent Signaling Mechanisms in Apoptotic Cell Death in Cardiovascular, Rheumatic, Kidney, and Neurodegenerative Diseases and Mental Disorders.

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.

Platelets and Cardioprotection: The Role of Nitric Oxide and Carbon Oxide.

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(-•)) 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.