Search

In the present study, we focus on dinuclear cobalt-based CO-RMs with the aim of elucidating their CO release mechanism, as well as to understand how structural changes targeted to modify the electronic properties of these compounds can modulate CO delivery. To this end, we specifically synthesized a set of phenyl-propargyl-based CO-RMs bearing –NO2, –H, and –OCH3 as para-substituents (R) with varying mesomeric influence (M) and different heteroatoms (X = NH, O, or S) linking the propargyl tail and the aromatic ring. The effects of R and X in modulating CO release were assessed by using several experimental and computational techniques to obtain a coherent picture and to shed light on the stability and release properties of Co-based CO-RMs. [ABSTRACT FROM AUTHOR]

Myocardial ischaemia reperfusion injury (IRI) occurring from acute coronary artery disease or cardiac surgical interventions such as bypass surgery can result in myocardial dysfunction, presenting as, myocardial "stunning", arrhythmias, infarction, and adverse cardiac remodelling, and may lead to both a systemic and a localised inflammatory response. This localised cardiac inflammatory response is regulated through the nucleotide-binding oligomerisation domain (NACHT), leucine-rich repeat (LRR)-containing protein family pyrin domain (PYD)-3 (NLRP3) inflammasome, a multimeric structure whose components are present within both cardiomyocytes and in cardiac fibroblasts. The NLRP3 inflammasome is activated via numerous danger signals produced by IRI and is central to the resultant innate immune response. Inhibition of this inherent inflammatory response has been shown to protect the myocardium and stop the occurrence of the systemic inflammatory response syndrome following the re-establishment of cardiac circulation. Therapies to prevent NLRP3 inflammasome formation in the clinic are currently lacking, and therefore, new pharmacotherapies are required. This review will highlight the role of the NLRP3 inflammasome within the myocardium during IRI and will examine the therapeutic value of inflammasome inhibition with particular attention to carbon monoxide, nitric oxide, and hydrogen sulphide as potential pharmacological inhibitors of NLRP3 inflammasome activation. [ABSTRACT FROM AUTHOR]

The molecular basis for circadian dependency in stroke due to subarachnoid hemorrhagic stroke (SAH) remains unclear. We reasoned that microglial erythrophagocytosis, crucial for SAH response, follows a circadian pattern involving carbon monoxide (CO) and CD36 surface expression. The microglial BV-2 cell line and primary microglia (PMG) under a clocked medium change were exposed to blood ± CO (250 ppm, 1 h) in vitro. Circadian dependency and the involvement of CD36 were analyzed in PMG isolated from control mice and CD36−/− mice and by RNA interference targeting Per-2. In vivo investigations, including phagocytosis, vasospasm, microglia activation and spatial memory, were conducted in an SAH model using control and CD36−/− mice at different zeitgeber times (ZT). In vitro, the surface expression of CD36 and its dependency on CO and phagocytosis occurred with changed circadian gene expression. CD36−/− PMG exhibited altered circadian gene expression, phagocytosis and impaired responsiveness to CO. In vivo, control mice with SAH demonstrated circadian dependency in microglia activation, erythrophagocytosis and CO-mediated protection at ZT2, in contrast to CD36−/− mice. Our study indicates that circadian rhythmicity modulates microglial activation and subsequent CD36-dependent phagocytosis. CO altered circadian-dependent neuroprotection and CD36 induction, determining the functional outcome in a hemorrhagic stroke model. This study emphasizes how circadian rhythmicity influences neuronal damage after neurovascular events. [ABSTRACT FROM AUTHOR]

Ischemia is the underlying mechanism in a wide variety of acute and persistent pathologies. As such, understanding the fine intracellular events occurring during (and after) the restriction of blood supply is pivotal to improving the outcomes in clinical settings. Among others, gaseous signaling molecules constitutively produced by mammalian cells (gasotransmitters) have been shown to be of potential interest for clinical treatment of ischemia/reperfusion injury. Nitric oxide (NO and its sibling, HNO), hydrogen sulfide (H2S), and carbon monoxide (CO) have long been proven to be cytoprotective in basic science experiments, and they are now awaiting confirmation with clinical trials. The aim of this work is to review the literature and the clinical trials database to address the state of development of potential therapeutic applications for NO, H2S, and CO and the clinical scenarios where they are more promising. [ABSTRACT FROM AUTHOR]

In conventional clinical toxicology practice, the blood level of carboxyhemoglobin is a biomarker of carbon monoxide (CO) poisoning but does not correspond to the complete clinical picture and the severity of the poisoning. Taking into account articles suggesting the relationship between oxidative stress parameters and CO poisoning, it seems reasonable to consider this topic more broadly, including experimental biochemical data (oxidative stress parameters) and patients poisoned with CO. This article aimed to critically assess oxidative-stress-related parameters as potential biomarkers to evaluate the severity of CO poisoning and their possible role in the decision to treat. The critically set parameters were antioxidative, including catalase, 2,2-diphenyl-1-picryl-hydrazyl, glutathione, thiol and carbonyl groups. Our preliminary studies involved patients (n = 82) admitted to the Toxicology Clinical Department of the University Hospital of Jagiellonian University Medical College (Kraków, Poland) during 2015–2020. The poisoning was diagnosed based on medical history, clinical symptoms, and carboxyhemoglobin blood level. Blood samples for carboxyhemoglobin and antioxidative parameters were collected immediately after admission to the emergency department. To evaluate the severity of the poisoning, the Pach scale was applied. The final analysis included a significant decrease in catalase activity and a reduction in glutathione level in all poisoned patients based on the severity of the Pach scale: I°–III° compared to the control group. It follows from the experimental data that the poisoned patients had a significant increase in level due to thiol groups and the 2,2-diphenyl-1-picryl-hydrazyl radical, with no significant differences according to the severity of poisoning. The catalase-to-glutathione and thiol-to-glutathione ratios showed the most important differences between the poisoned patients and the control group, with a significant increase in the poisoned group. The ratios did not differentiate the severity of the poisoning. The carbonyl level was highest in the control group compared to the poisoned group but was not statistically significant. Our critical assessment shows that using oxidative-stress-related parameters to evaluate the severity of CO poisoning, the outcome, and treatment options is challenging. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Carbon monoxide (CO) has shown various physiological effects including anti-inflammatory activity in several diseases, whereas the therapeutic efficacy of CO on sepsis-induced acute kidney injury (AKI) has not been reported as of yet. The purpose of the present study was to explore the effects of exogenous CO on sepsis-induced AKI and nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in rats. Male rats were subjected to cecal ligation and puncture (CLP) to induce sepsis and AKI. Exogenous CO delivered from CO-releasing molecule 2 (CORM-2) was used intraperitoneally as intervention after CLP surgery. Therapeutic effects of CORM-2 on sepsis-induced AKI were assessed by measuring serum creatinine (Scr) and blood urea nitrogen (BUN), kidney histology scores, apoptotic cell scores, oxidative stress, levels of cytokines TNF-α and IL-1β, and NLRP3 inflammasome expression. CORM-2 treatment protected against the sepsis-induced AKI as evidenced by reducing serum Scr/BUN levels, apoptotic cells scores, increasing survival rates, and decreasing renal histology scores. Furthermore, treatment with CORM-2 significantly reduced TNF-α and IL-1β levels and oxidative stress. Moreover, CORM-2 treatment significantly decreased NLRP3 inflammasome protein expressions. Our study provided evidence that CORM-2 treatment protected against sepsis-induced AKI and inhibited NLRP3 inflammasome activation, and suggested that CORM-2 could be a potential therapeutic candidate for treating sepsis-induced AKI. [ABSTRACT FROM AUTHOR]

Carbon monoxide (CO) acts as an important signal in many physiological responses in plants, but its role in plant secondary metabolism is still unknown. Nicotine is the main alkaloid generated in tobacco and the plant hormone jasmonic acid (JA) has previously been reported to efficiently induce its biosynthesis. Whether and how CO interacts with JA to regulate nicotine biosynthesis in tobacco remains elusive. In this study, we demonstrate that high temperature (HT) induces quick accumulation of nicotine in tobacco roots, combined with an increase in CO and JA concentration. Suppressing CO generation reduced both JA and nicotine biosynthesis, whereas exogenous application of CO increased JA and nicotine content. CO causes an increased expression of NtPMT1 (a key nicotine biosynthesis enzyme), via promoting NtMYC2a binding to the G-box region of its promoter, leading to heightened nicotine levels under HT conditions. These data suggest a novel function for CO in stimulating nicotine biosynthesis in tobacco under HT stress, through a JA signal. [ABSTRACT FROM AUTHOR]

Inflammation is a complex response of the body to exogenous and endogenous insults. Chronic and systemic diseases are attributed to uncontrolled inflammation. Molecules involved in the initiation of inflammation are very well studied while pathways regulating its resolution are insufficiently investigated. Approaches to down-modulate mediators relevant for the onset and duration of inflammation are successful in some chronic diseases, while all of them have failed in sepsis patients. Inflammation and immune suppression characterize sepsis, indicating that anti-inflammatory strategies alone are inappropriate for its therapy. Heme oxygenase 1 is a sensitive marker for oxidative stress and is upregulated in inflammation. Carbon monoxide, which is produced by this enzyme, initiates multiple anti-inflammatory and pro-resolving activities with higher production of omega-3 fatty acid-derived lipid metabolites being one of its protective actions. Pro-resolving lipids named maresins, resolvins and protectins originate from the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid while lipoxins are derived from arachidonic acid. These endogenously produced lipids do not simply limit inflammation but actively contribute to its resolution, and thus provide an opportunity to combat chronic inflammatory diseases and eventually sepsis. [ABSTRACT FROM AUTHOR]

During radiotherapy procedures, radiation-induced bystander effect (RIBE) can potentially lead to genetic hazards to normal tissues surrounding the targeted regions. Previous studies showed that RIBE intensities in cell cluster models were much higher than those in monolayer cultured cell models. On the other hand, low-concentration carbon monoxide (CO) was previously shown to exert biological functions via binding to the heme domain of proteins and then modulating various signaling pathways. In relation, our previous studies showed that exogenous CO generated by the CO releasing molecule, tricarbonyldichlororuthenium (CORM-2), at a relatively low concentration (20 µM), effectively attenuated the formation of RIBE-induced DNA double-strand breaks (DSB) and micronucleus (MN). In the present work, we further investigated the capability of a low concentration of exogenous CO (CORM-2) of attenuating or inhibiting RIBE in a mixed-cell cluster model. Our results showed that CO (CORM-2) with a low concentration of 30 µM could effectively suppress RIBE-induced DSB (p53 binding protein 1, p53BP1), MN formation and cell proliferation in bystander cells but not irradiated cells via modulating the inducible nitric oxide synthase (iNOS) andcyclooxygenase-2 (COX-2). The results can help mitigate RIBE-induced hazards during radiotherapy procedures. [ABSTRACT FROM AUTHOR]

Carbon monoxide (CO) produced by heme oxygenase (HO)-1 and HO-2 or released from the CO-donor, tricarbonyldichlororuthenium (II) dimer (CORM-2) causes vasodilation, with unknown efficacy against stress-induced gastric lesions. We studied whether pretreatment with CORM-2 (0.1-10 mg/kg oral gavage (i.g.)), RuCl3 (1 mg/kg i.g.), zinc protoporphyrin IX (ZnPP) (10 mg/kg intraperitoneally (i.p.)), hemin (1-10 mg/kg i.g.) and CORM-2 (1 mg/kg i.g.) combined with NG-nitro-L-arginine (L-NNA, 20 mg/kg i.p.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 mg/kg i.p.), indomethacin (5 mg/kg i.p.), SC-560 (5 mg/kg i.g.), and celecoxib (10 mg/kg i.g.) affects gastric lesions following 3.5 h of water immersion and restraint stress (WRS). Gastric blood flow (GBF), the number of gastric lesions and gastric CO and nitric oxide (NO) contents, blood carboxyhemoglobin (COHb) level and the gastric expression of HO-1, HO-2, hypoxia inducible factor 1α (HIF-1α), tumor necrosis factor α (TNF-α), cyclooxygenase (COX)-2 and inducible NO synthase (iNOS) were determined. CORM-2 (1 mg/kg i.g.) and hemin (10 mg/kg i.g.) significantly decreased WRS lesions while increasing GBF, however, RuCl3 was ineffective. The impact of CORM-2 was reversed by ZnPP, ODQ, indomethacin, SC-560 and celecoxib, but not by L-NNA. CORM-2 decreased NO and increased HO-1 expression and CO and COHb content, downregulated HIF-1α, as well as WRS-elevated COX-2 and iNOS mRNAs. Gastroprotection by CORM-2 and HO depends upon CO's hyperemic and anti-inflammatory properties, but is independent of NO. [ABSTRACT FROM AUTHOR]

The heme molecule serves as an essential prosthetic group for oxygen transport and storage proteins, as well for cellular metabolic enzyme activities, including those involved in mitochondrial respiration, xenobiotic metabolism, and antioxidant responses. Dysfunction in both heme synthesis and degradation pathways can promote human disease. Heme is a pro-oxidant via iron catalysis that can induce cytotoxicity and injury to the vascular endothelium. Additionally, heme can modulate inflammatory and immune system functions. Thus, the synthesis, utilization and turnover of heme are by necessity tightly regulated. The microsomal heme oxygenase (HO) system degrades heme to carbon monoxide (CO), iron, and biliverdin-IXα, that latter which is converted to bilirubin-IXα by biliverdin reductase. Heme degradation by heme oxygenase-1 (HO-1) is linked to cytoprotection via heme removal, as well as by activity-dependent end-product generation (i.e., bile pigments and CO), and other potential mechanisms. Therapeutic strategies targeting the heme/HO-1 pathway, including therapeutic modulation of heme levels, elevation (or inhibition) of HO-1 protein and activity, and application of CO donor compounds or gas show potential in inflammatory conditions including sepsis and pulmonary diseases. [ABSTRACT FROM AUTHOR]

Carbon monoxide (CO)—gaseous or released by CO-RMs—both possess antiplatelet properties; however, it remains uncertain whether the mechanisms involved are the same. Here, we characterise the involvement of soluble guanylate cyclase (sGC) in the effects of CO—delivered by gaseous CO–saturated buffer (COG) and generated by CORM-A1—on platelet aggregation and energy metabolism, as well as on vasodilatation in aorta, using light transmission aggregometry, Seahorse XFe technique, and wire myography, respectively. ODQ completely prevented the inhibitory effect of COG on platelet aggregation, but did not modify antiplatelet effect of CORM-A1. In turn, COG did not affect, whereas CORM-A1 substantially inhibited energy metabolism in platelets. Even though activation of sGC by BAY 41-2272 or BAY 58-2667 inhibited significantly platelet aggregation, their effects on energy metabolism in platelets were absent or weak and could not contribute to antiplatelet effects of sGC activation. In contrast, vasodilatation of murine aortic rings, induced either by COG or CORM-A1, was dependent on sGC. We conclude that the source (COG vs. CORM-A1) and kinetics (rapid vs. slow) of CO delivery represent key determinants of the mechanism of antiplatelet action of CO, involving either impairment of energy metabolism or activation of sGG. [ABSTRACT FROM AUTHOR]

Over the past decades, substantial work has established that hemoglobin oxidation and heme release play a pivotal role in hemolytic/hemorrhagic disorders. Recent reports have shown that oxidized hemoglobins, globin-derived peptides, and heme trigger diverse biological responses, such as toll-like receptor 4 activation with inflammatory response, reprogramming of cellular metabolism, differentiation, stress, and even death. Here, we discuss these cellular responses with particular focus on their mechanisms that are linked to the pathological consequences of hemorrhage and hemolysis. In recent years, endogenous gasotransmitters, such as carbon monoxide (CO) and hydrogen sulfide (H2S), have gained a lot of interest in connection with various human pathologies. Thus, many CO and H2S-releasing molecules have been developed and applied in various human disorders, including hemolytic and hemorrhagic diseases. Here, we discuss our current understanding of oxidized hemoglobin and heme-induced cell and tissue damage with particular focus on inflammation, cellular metabolism and differentiation, and endoplasmic reticulum stress in hemolytic/hemorrhagic human diseases, and the potential beneficial role of CO and H2S in these pathologies. More detailed mechanistic insights into the complex pathology of hemolytic/hemorrhagic diseases through heme oxygenase-1/CO as well as H2S pathways would reveal new therapeutic approaches that can be exploited for clinical benefit. [ABSTRACT FROM AUTHOR]

The high-pressure gas (HPG) method with carbon monoxide (CO) and oxygen (O2) mixture maintains the preserved rat heart function. The metabolites of rat hearts preserved using the HPG method (HPG group) and cold storage (CS) method (CS group) by immersion in a stock solution for 24 h were assessed to confirm CO and O2 effects. Lactic acid was significantly lower and citric acid was significantly higher in the HPG group than in the CS group. Moreover, adenosine triphosphate (ATP) levels as well as some pentose phosphate pathway (PPP) metabolites and reduced nicotinamide adenine dinucleotide phosphate (NADPH) were significantly higher in the HPG group than in the CS group. Additionally, reduced glutathione (GSH), which protects cells from oxidative stress, was also significantly higher in the HPG group than in the CS group. These results indicated that each gas, CO and O2, induced the shift from anaerobic to aerobic metabolism, maintaining the energy of ischemic preserved organs, shifting the glucose utilization from glycolysis toward PPP, and reducing oxidative stress. Both CO and O2 in the HPG method have important effects on the ATP supply and decrease oxidative stress for preventing ischemic injury. The HPG method may be useful for clinical application. [ABSTRACT FROM AUTHOR]

Regeneration of adult neural circuits after an injury is limited in the central nervous system (CNS). Heme oxygenase (HO) is an enzyme that produces HO metabolites, such as carbon monoxide (CO), biliverdin and iron by heme degradation. CO may act as a biological signal transduction effector in CNS regeneration by stimulating neuronal intrinsic and extrinsic mechanisms as well as mitochondrial biogenesis. CO may give directions by which the injured neurovascular system switches into regeneration mode by stimulating endogenous neural stem cells and endothelial cells to produce neurons and vessels capable of replacing injured neurons and vessels in the CNS. The present review discusses the regenerative potential of CO in acute and chronic neuroinflammatory diseases of the CNS, such as stroke, traumatic brain injury, multiple sclerosis and Alzheimer's disease and the role of signaling pathways and neurotrophic factors. CO-mediated facilitation of cellular communications may boost regeneration, consequently forming functional adult neural circuits in CNS injury. [ABSTRACT FROM AUTHOR]

The pharmaceutical clay montmorillonite (MMT) is, for the first time, explored as a carbon monoxide-releasing material (CORMat). MMT consists of silicate double layered structure; its exfoliation feature intercalate the CORM-2 [RuCl(μ-Cl)(CO)3]2 inside the layers to suppress the toxicity of organometallic segment. The infrared spectroscopy (IR) confirmed the existence of ruthenium coordinated carbonyl ligand in MMT layers. The energy-dispersive X-ray spectroscopy (EDX) analysis showed that ruthenium element in this material was about 5%. The scanning electron microscopy (SEM) and transmission electron microscope (TEM) images showed that the layer-structure of MMT has been maintained after loading the ruthenium carbonyl segment. Moreover, the layers have been stretched out, which was confirmed by X-ray diffraction (XRD) analysis. Thermogravimetric (TG) curves with huge weight loss around 100–200 °C were attributed to the CO hot-release of ruthenium carbonyl as well as the loss of the adsorbed solvent molecules and the water molecules between the layers. The CO-liberating properties have been assessed through myoglobin assay. The horse myoglobin test showed that the material could be hydrolyzed to slowly release carbon monoxide in physiological environments. The half-life of CO release was much longer than that of CORM-3, and it has an excellent environmental tolerance and slow release effect. [ABSTRACT FROM AUTHOR]

(1) Background: Heme oxygenase-1 (HO-1) degrades heme and generates carbon monoxide (CO), producing various anti-inflammatory, anti-oxidative, and anti-apoptotic effects. This study aimed to confirm the effects of CO on the ischemia–reperfusion injury (IRI) of donor lungs using a high-pressure gas (HPG) preservation method. (2) Methods: Donor rat and canine lungs were preserved in a chamber filled with CO (1.5 atm) and oxygen (O2; 2 atm) and were ventilated with either CO and O2 mixture (CO/O2 group) or air (air group) immediately before storage. Rat lungs were subjected to heterotopic cervical transplantation and evaluated after reperfusion, whereas canine lungs were subjected to allogeneic transplantation and evaluated. (3) Results: Alveolar hemorrhage in the CO/O2 group was significantly milder than that in the air group. mRNA expression levels of HO-1 remained unchanged in both the groups; however, inflammatory mediator levels were significantly lower in the CO/O2 group than in the air group. The oxygenation of graft lungs was comparable between the two groups, but lactic acid level tended to be higher in the air group. (4) Conclusions: The HO-1/CO system in the HPG preservation method is effective in suppressing IRI and preserving donor lungs. [ABSTRACT FROM AUTHOR]

Heme oxygenase 1 (HO-1) and carbon monoxide were shown to normalize oxidative stress and inflammatory reactions induced by neuropathic pain in the central nervous system, but their effects in the locus coeruleus (LC) of animals with peripheral inflammation and their interaction with nitric oxide are unknown. In wild-type (WT) and knockout mice for neuronal (NOS1-KO) or inducible (NOS2-KO) nitric oxide synthases with inflammatory pain induced by complete Freund's adjuvant (CFA), we assessed: (1) antinociceptive actions of cobalt protoporphyrin IX (CoPP), an HO-1 inducer; (2) effects of CoPP and tricarbonyldichlororuthenium(II) dimer (CORM-2), a carbon monoxide-liberating compound, on the expression of HO-1, NOS1, NOS2, CD11b/c, GFAP, and mitogen-activated protein kinases (MAPK) in the LC. CoPP reduced inflammatory pain in different time-dependent manners in WT and KO mice. Peripheral inflammation activated astroglia in the LC of all genotypes and increased the levels of NOS1 and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK 1/2) in WT mice. CoPP and CORM-2 enhanced HO-1 and inhibited astroglial activation in all genotypes. Both treatments blocked NOS1 overexpression, and CoPP normalized ERK 1/2 activation. This study reveals an interaction between HO-1 and NOS1/NOS2 during peripheral inflammation and shows that CoPP and CORM-2 improved HO-1 expression and modulated the inflammatory and/or plasticity changes caused by peripheral inflammation in the LC. [ABSTRACT FROM AUTHOR]

Heme oxygenase (HO) catabolizes heme to produce HO metabolites, such as carbon monoxide (CO) and bilirubin (BR), which have gained recognition as biological signal transduction effectors. The neurovascular unit refers to a highly evolved network among endothelial cells, pericytes, astrocytes, microglia, neurons, and neural stem cells in the central nervous system (CNS). Proper communication and functional circuitry in these diverse cell types is essential for effective CNS homeostasis. Neuroinflammation is associated with the vascular pathogenesis of many CNS disorders. CNS injury elicits responses from activated glia (e.g., astrocytes, oligodendrocytes, and microglia) and from damaged perivascular cells (e.g., pericytes and endothelial cells). Most brain lesions cause extensive proliferation and growth of existing glial cells around the site of injury, leading to reactions causing glial scarring, which may act as a major barrier to neuronal regrowth in the CNS. In addition, damaged perivascular cells lead to the breakdown of the blood-neural barrier, and an increase in immune activation, activated glia, and neuroinflammation. The present review discusses the regenerative role of HO metabolites, such as CO and BR, in various vascular diseases of the CNS such as stroke, traumatic brain injury, diabetic retinopathy, and Alzheimer's disease, and the role of several other signaling molecules. [ABSTRACT FROM AUTHOR]

Heme oxygenase (HO)-1 is known to metabolize heme into biliverdin/bilirubin, carbon monoxide, and ferrous iron, and it has been suggested to demonstrate cytoprotective effects against various stress-related conditions. HO-1 is commonly regarded as a survival molecule, exerting an important role in cancer progression and its inhibition is considered beneficial in a number of cancers. However, increasing studies have shown a dark side of HO-1, in which HO-1 acts as a critical mediator in ferroptosis induction and plays a causative factor for the progression of several diseases. Ferroptosis is a newly identified iron- and lipid peroxidation-dependent cell death. The critical role of HO-1 in heme metabolism makes it an important candidate to mediate protective or detrimental effects via ferroptosis induction. This review summarizes the current understanding on the regulatory mechanisms of HO-1 in ferroptosis. The amount of cellular iron and reactive oxygen species (ROS) is the determinative momentum for the role of HO-1, in which excessive cellular iron and ROS tend to enforce HO-1 from a protective role to a perpetrator. Despite the dark side that is related to cell death, there is a prospective application of HO-1 to mediate ferroptosis for cancer therapy as a chemotherapeutic strategy against tumors. [ABSTRACT FROM AUTHOR]

Recently, gaseous signaling molecules, such as carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S), which were previously considered to be highly toxic, have been of increasing interest due to their beneficial effects at low concentrations. These so-called gasotransmitters affect many cellular processes, such as apoptosis, proliferation, cytoprotection, oxygen sensing, ATP synthesis, and cellular respiration. It is thought that mitochondria, specifically their respiratory complexes, constitute an important target for these gases. On the other hand, increasing evidence of a cytoprotective role for mitochondrial potassium channels provides motivation for the analysis of the role of gasotransmitters in the regulation of channel function. A number of potassium channels have been shown to exhibit activity within the inner mitochondrial membrane, including ATP-sensitive potassium channels, Ca2+-activated potassium channels, voltage-gated Kv potassium channels, and TWIK-related acid-sensitive K+ channel 3 (TASK-3). The effects of these channels include the regulation of mitochondrial respiration and membrane potential. Additionally, they may modulate the synthesis of reactive oxygen species within mitochondria. The opening of mitochondrial potassium channels is believed to induce cytoprotection, while channel inhibition may facilitate cell death. The molecular mechanisms underlying the action of gasotransmitters are complex. In this review, we focus on the molecular mechanisms underlying the action of H2S, NO, and CO on potassium channels present within mitochondria. [ABSTRACT FROM AUTHOR]

Carbon monoxide (CO) is being increasingly recognized as a potential therapeutic with important signaling functions in various diseases. Carbon monoxide-releasing molecules (CORMs) show anti-apoptotic, anti-inflammatory, and anti-oxidant effects on the tissues of organisms, thus contributing to tissue homeostasis. An increase in reactive oxygen species production from the mitochondria after exposure to CO is also considered one of the underlying mechanisms of cardioprotection, although mitochondrial inhibition is the main toxic mechanism of CO poisoning. This review highlights the mechanism of the biological effects of CO and its potential application as a therapeutic in clinical settings, including in cardiovascular diseases. This review also discusses the obstacles and limitations of using exogenous CO or CORMs as a therapeutic option, with respect to acute CO poisoning. [ABSTRACT FROM AUTHOR]

Heme oxygenase 1 (HO-1) up-regulation is recognized as a pivotal mechanism of cell adaptation to stress. Under control of different transcription factors but with a prominent role played by Nrf2, HO-1 induction is crucial also in nervous system response to damage. However, several lines of evidence have highlighted that HO-1 expression is associated to neuronal damage and neurodegeneration especially in Alzheimer’s and Parkinson’s diseases. In this review, we summarize the current literature regarding the role of HO-1 in nervous system pointing out different molecular mechanisms possibly responsible for HO-1 up-regulation in nervous system homeostasis and neurodegeneration. [ABSTRACT FROM AUTHOR]