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The enzyme heme oxygenase-1 (HO-1) is a cytoprotective and anti-inflammatory protein that degrades heme to produce biliverdin/bilirubin, ferrous iron and carbon monoxide (CO). The anti-inflammatory properties of HO-1 are related to inhibition of adhesion molecule expression and reduction of oxidative stress, while exogenous CO gas treatment decreases the production of inflammatory mediators such as cytokines and nitric oxide (NO). CO-releasing molecules (CO-RMs) are a novel group of substances identified by our group that are capable of modulating physiological functions via the liberation of CO. We aimed in this study to examine the potential anti-inflammatory characteristics of CORM-2 and CORM-3 in an in vitro model of lipopolysaccharide (LPS)-stimulated murine macrophages. Stimulation of RAW264.7 macrophages with LPS resulted in increased expression of inducible NO synthase (iNOS) and production of nitrite. CORM-2 or CORM-3 (10-100 microM) reduced nitrite generation in a concentration-dependent manner but did not affect the protein levels of iNOS. CORM-3 also decreased nitrite levels when added 3 or 6 h after LPS exposure. CORM-2 or CORM-3 did not cause any evident cytotoxicity and produced an increase in HO-1 expression and heme oxygenase activity; this effect was completely prevented by the thiol donor N-acetylcysteine. CORM-3 also considerably reduced the levels of tumor necrosis factor-alpha, another mediator of the inflammatory response. The inhibitory effects of CORM-2 and CORM-3 were not observed when the inactive compounds, which do not release CO, were coincubated with LPS. These results indicate that CO liberated by CORM-2 and CORM-3 significantly suppresses the inflammatory response elicited by LPS in cultured macrophages and suggest that CO carriers can be used as an effective strategy to modulate inflammation.

1 Carbon monoxide (CO), one of the end products of heme catabolism by heme oxygenase, possesses antihypertensive and vasodilatory characteristics. We have recently discovered that certain transition metal carbonyls are capable of releasing CO in biological fluids and modulate physiological functions via the delivery of CO. Because the initial compounds identified were not water soluble, we have synthesized new CO-releasing molecules that are chemically modified to allow solubility in water. The aim of this study was to assess the vasoactive properties of tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) in vitro and in vivo. 2 CORM-3 produced a concentration-dependent relaxation in vessels precontracted with phenylephrine, exerting significant vasodilatation starting at concentrations of 25-50 microm. Inactive CORM-3, which does not release CO, did not affect vascular tone. 3 Blockers of ATP-dependent potassium channels (glibenclamide) or guanylate cyclase activity (ODQ) considerably reduced CORM-3-dependent relaxation, confirming that potassium channels activation and cGMP partly mediate the vasoactive properties of CO. In fact, increased levels of cGMP were detected in aortas following CORM-3 stimulation. 4 The in vitro and in vivo vasorelaxant activities of CORM-3 were further enhanced in the presence of YC-1, a benzylindazole derivative which is known to sensitize guanylate cyclase to activation by CO. Interestingly, inhibiting nitric oxide production or removing the endothelium significantly decreased vasodilatation by CORM-3, suggesting that factors produced by the endothelium influence CORM-3 vascular activities. 5 These results, together with our previous findings on the cardioprotective functions of CORM-3, indicate that this molecule is an excellent prototype of water-soluble CO carriers for studying the pharmacological and biological features of CO.

Postoperative ileus (POI) is a frequent complication after abdominal surgery. The consequences of postoperative ileus can be potentially serious such as bronchial inhalation or acute functional renal failure. Numerous advances in peri-operative management, particularly early rehabilitation, have made it possible to decrease postoperative ileus. Despite this, the rate of prolonged postoperative ileus remains high and can be as high as 25% of patients in colorectal surgery. From a pathophysiological point of view, postoperative ileus has two phases, an early neurological phase and a later inflammatory phase, to which we could add a 'pharmacological' phase during which analgesic drugs, particularly opiates, play a central role. The aim of this review article is to describe the phases of the pathophysiology of postoperative ileus, to analyse the pharmacological treatments currently available through published clinical trials and finally to discuss the different research areas for potential pharmacological targets., (© 2022 The British Pharmacological Society.)

Cyclic GMP (cGMP) is a second messenger that regulates numerous physiological and pathophysiological processes. In recent years, more and more studies have uncovered multiple roles of cGMP signalling pathways in the somatosensory system. Accumulating evidence suggests that cGMP regulates different cellular processes from embryonic development through to adulthood. During embryonic development, a cGMP‐dependent signalling cascade in the trunk sensory system is essential for axon bifurcation, a specific form of branching of somatosensory axons. In adulthood, various cGMP signalling pathways in distinct cell populations of sensory neurons and dorsal horn neurons in the spinal cord play an important role in the processing of pain and itch. Some of the involved enzymes might serve as a target for future therapies. In this review, we summarise the knowledge regarding cGMP‐dependent signalling pathways in dorsal root ganglia and the spinal cord during embryonic development and adulthood, and the potential of targeting these pathways. LINKED ARTICLES: This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc [ABSTRACT FROM AUTHOR]

Background and Purpose: CX‐5461 is a novel selective RNA polymerase I (Pol I) inhibitor. Previously, we found that CX‐5461 could inhibit pathological arterial remodelling caused by angioplasty and transplantation. In the present study, we explored the pharmacological effects of CX‐5461 on experimental pulmonary arterial hypertension (PAH) and PAH‐associated vascular remodelling. Experimental Approach PAH was induced in Sprague–Dawley rats by monocrotaline or Sugen/hypoxia. Key Results: We demonstrated that CX‐5461 was well tolerated for in vivo treatments. CX‐5461 prevented the development of pulmonary arterial remodelling, perivascular inflammation, pulmonary hypertension, and improved survival. More importantly, CX‐5461 partly reversed established pulmonary hypertension. In vitro, CX‐5461 induced cell cycle arrest in human pulmonary arterial smooth muscle cells. The beneficial effects of CX‐5461 in vivo and in vitro were associated with increased activation (phosphorylation) of p53. Conclusion and Implications: Our results suggest that pharmacological inhibition of Pol I may be a novel therapeutic strategy to treat otherwise drug‐resistant PAH. [ABSTRACT FROM AUTHOR]

Despite several advances in medicine, ischaemic heart disease remains a major cause of morbidity and mortality. The unravelling of molecular mechanisms underlying disease pathophysiology has revealed targets for pharmacological interventions. However, transfer of these pharmcological possibilities to clinical use has been disappointing. Considering the complexity of ischaemic disease at the cellular and molecular levels, an equally multifaceted treatment approach may be envisioned. The pharmacological principle of 'one target, one key' may fall short in such contexts, and optimal treatment may involve one or many agents directed against complementary targets. Here, we introduce a 'multi-target approach to cardioprotection' and propose heat shock protein 90 (HSP90) as a target of interest. We report on a member of a distinct class of HSP90 inhibitor possessing pleiotropic activity, which we found to exhibit potent infarct-sparing effects. [ABSTRACT FROM AUTHOR]

Background and Purpose: Myocardial infarction (MI) is one of the leading causes of death in China and often results in the development of heart failure. In this work, we tested the therapeutic role of Interleukin-19 (IL-19) in mice with MI and investigated the underlying molecular mechanism.Experimental Approach: Mice were subjected to MI by ligation of left anterior descending coronary artery (LAD) and treated with IL-19 (10ng g-1 ; i.p.).Key Results: Protein expression of IL-19 and its receptor in myocardium were upregulated 24 hrs post-MI in male mice. IL-19 treatment decreased infarct and apoptosis in myocardium, accompanied by enhanced haem oxygenase-1 (HO-1) activities and reduced malondialdehyde (MDA) formation. Pretreatment with IL-19 upregulated HO-1 expression in cultured neonatal mouse ventricular myocytes and attenuated oxygen-glucose deprivation (OGD)-induced injuries in vitro. Furthermore, IL-19 preserved cardiac function and improved survival of mice with MI. IL-19 reduced inflammatory infiltrates and suppressed formation of TNF-α, IL-1β, and IL-6. More importantly, IL-19 inhibited polarization toward proinflammatory M1 macrophages and stimulated M2 macrophage polarization in myocardium of mice with MI. IL-19 enhanced protein levels of vascular endothelial growth factor (VEGF) and promoted angiogenesis in myocardium of mice with MI. In addition, IL-19 treatment increased DNA-binding of the transcription factor STAT3 in myocardium of mice with MI.Conclusions and Implications: Treatment with exogenous IL-19 attenuated acute ischemic injury and improved survival of mice with MI. The mechanisms underlying these effects involved induction of HO-1, M2 macrophage polarization, angiogenesis, and STAT3 activation. [ABSTRACT FROM AUTHOR]

Background and Purpose: IL-19 skews the immune response towards a Th2 type and appears to stimulate angiogenesis. In the current study, we tested if IL-19 treatment could reduce secondary injury and improve functional recovery after contusion spinal cord injury (SCI).Experimental Approach: Firstly, mice were given a moderate-severe thoracic SCI at the T9-10 level and expression of IL-19 and its receptor was measured in the injured spinal cord. Then SCI mice were treated with mouse recombinant IL-19 and its blocking antibody to investigate the therapeutic effect of IL-19.Key Results: Protein expression of IL-19 and its receptor IL-20R1 and IL-20R2 was up-regulated in the injured spinal cord of mice. IL-19 treatment promoted the recovery of locomotor function dose-dependently and reduced loss of motor neurons and microglial and glial activation following SCI. Treatment of SCI mice with IL-19 attenuated macrophage accumulation, reduced protein levels of TNF-α and CCL2 and promoted Th2 response and M2 macrophage activation in the injured region. Treatment of SCI mice with IL-19 promoted angiogenesis through up-regulating VEGF in the injured region. Treatment of SCI mice with IL-19 up-regulated HO-1 expression and decreased oxidative stress in the injured region. The beneficial effect of IL-19 was abolished by coadministration of the blocking antibody. Additionally, IL-19 deficiency in mice delayed the recovery of locomotor function following SCI.Conclusions and Implications: IL-19 treatment reduced secondary injuries and improved locomotor functional recovery after contusion SCI, through diverse mechanisms including immune cell polarization, angiogenesis and anti-oxidative responses. [ABSTRACT FROM AUTHOR]

Homocysteine is a sulphur-containing non-proteinogenic amino acid. Hyperhomocysteinaemia (HHcy), the pathogenic elevation of plasma homocysteine as a result of an imbalance of its metabolism, is an independent risk factor for various vascular diseases, such as atherosclerosis, hypertension, vascular calcification and aneurysm. Treatments aimed at lowering plasma homocysteine via dietary supplementation with folic acids and vitamin B are more effective in preventing vascular disease where the population has a normally low folate consumption than in areas with higher dietary folate. To date, the mechanisms of HHcy-induced vascular injury are not fully understood. HHcy increases oxidative stress and its downstream signalling pathways, resulting in vascular inflammation. HHcy also causes vascular injury via endoplasmic reticulum stress. Moreover, HHcy up-regulates pathogenic genes and down-regulates protective genes via DNA demethylation and methylation respectively. Homocysteinylation of proteins induced by homocysteine also contributes to vascular injury by modulating intracellular redox state and altering protein function. Furthermore, HHcy-induced vascular injury leads to neuronal damage and disease. Also, an HHcy-activated sympathetic system and HHcy-injured adipose tissue also cause vascular injury, thus demonstrating the interactions between the organs injured by HHcy. Here, we have summarized the recent developments in the mechanisms of HHcy-induced vascular injury, which are further considered as potential therapeutic targets in this condition.Linked Articles: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Haem oxygenase-1 (HO-1) could provide cytoprotection against various inflammatory diseases. However, the mechanisms underlying the protective effect of CO-releasing molecule-2 (CORM-2)-induced HO-1 expression against TNF-α-induced inflammatory responses in human pulmonary alveolar epithelial cells (HPAEpiCs) remain unknown. EXPERIMENTAL APPROACH CORM-2-induced HO-1 protein and mRNA expression, and signalling pathways were determined by Western blot and real-time PCR, coupled with respective pharmacological inhibitors or transfection with siRNAs. The effect of CORM-2 on TNF-α-induced increase in leukocyte counts in BAL fluid and VCAM-1 expression in lung was determined by cell counting and Western blot analysis. KEY RESULTS CORM-2 attenuated the TNF-α-induced pulmonary haematoma, VCAM-1 expression and increase in leukocytes through an upregulation of HO-1 in mice; this effect of CORM-2 was reversed by the HO-1 inhibitor zinc protoporphyrin IX. Furthermore, CORM-2 increased HO-1 protein and mRNA expression as well as the phosphorylation of PYK2, PKCα and ERK1/2 (p44/p42 MAPK) in HPAEpiCs; these effects were attenuated by their respective pharmacological inhibitors or transfection with siRNAs. Inhibition of PKCα by Gö6976 or Gö6983 attenuated CORM-2-induced stimulation of PKCα and ERK1/2 phosphorylation but had no effect on PYK2 phosphorylation. Moreover, inhibition of PYK2 by PF431396 reduced the phosphorylation of all three protein kinases. Finally, PYK2/PKCα/ERK1/2-mediated stimulation of activator protein 1 was shown to play a key role in CORM-2-induced HO-1 expression via an up-regulation of c-Fos mRNA. CONCLUSIONS AND IMPLICATIONS CORM-2 activates a PYK2/PKCα/ERK1/2/AP-1 pathway leading to HO-1 expression in HPAEpiCs. This HO-1/CO system might have potential as a therapeutic target in pulmonary inflammation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Carbon monoxide (CO), a gaseous mediator produced by haem oxygenases (HOs), has been shown to prevent stress-, ethanol-, aspirin- and alendronate-induced gastric damage; however, its role in gastric ulcer healing has not been fully elucidated. We investigated whether CO released from tricarbonyldichlororuthenium (II) dimer (CORM-2) can affect gastric ulcer healing and determined the mechanisms involved in this healing action.Experimental Approach: Gastric ulcers were induced in Wistar rats by serosal application of acetic acid. Animals received 9 days of treatment with RuCl3 [2.5 mg·kg-1 intragastrically (i.g.)], haemin (5 mg·kg-1 i.g.), CORM-2 (0.1-10 mg·kg-1 i.g.) administered alone or with zinc protoporphyrin IX (ZnPP, 10 mg·kg-1 i.g.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 mg·kg-1 i.g.), NG -nitro-l-arginine (l-NNA, 15 mg·kg-1 i.g.), indomethacin (5 mg·kg-1 i.g.) or glibenclamide (10 mg·kg-1 i.g.). Gastric ulcer area and gastric blood flow (GBF) were assessed planimetrically, microscopically and by laser flowmeter respectively. Gastric mRNA/protein expressions of EGF, EGF receptors, VEGFA, HOs, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), COX-2, hypoxia-inducible factor (HIF)-1α and pro-inflammatory iNOS, IL-1β and TNF-α were determined by real-time PCR or Western blots.Key Results: CORM-2 and haemin but not RuCl3 or ZnPP decreased ulcer size while increasing GBF. These effects were reduced by ODQ, indomethacin, l-NNA and glibenclamide. CORM-2 significantly decreased the expression of pro-inflammatory markers, Nrf2/HO1 and HIF-1α, and up-regulated EGF.Conclusions and Implications: CO released from CORM-2 or endogenously produced by the HO1/Nrf2 pathway accelerates gastric ulcer healing via an increase in GBF, an up-regulation in EGF expression and down-regulation of the inflammatory response. [ABSTRACT FROM AUTHOR]

In this issue of British Journal of Pharmacology, Megías and colleagues demonstrate how preincubation of human colonic Caco-2 cells with CORM-2, a carbon monoxide releasing molecule (CO-RM), reduces the expression of inducible nitric oxide synthase, interleukin (IL)-6 and IL-8 caused by proinflammatory cytokines. A role for IL-6 in the regulation of metalloproteinase (MMP)-7 expression by CORM-2 is described. However, it is the demonstration that CORM-2 inhibits MMP-7 or matrilysin expression, which is most intriguing as this small MMP has been implicated in carcinogenesis. Thus, CO-RMs appear to now possess chemoprotective properties and, in this particular case, may influence inflammation-induced colon carcinogenesis via modulation of nuclear factors participating in the transcription of genes implicated in the development of intestinal inflammation and cancer. This report opens yet another door for research involving these exciting molecules and it is now clear that further discoveries of the beneficial properties of CO-RMs will go on.British Journal of Pharmacology (2007) 150, 961–962. doi:10.1038/sj.bjp.0707185; published online 5 March 2007 [ABSTRACT FROM AUTHOR]

Background and Purpose: As the pathogenesis of postoperative ileus (POI) involves inflammation and oxidative stress, comparable to ischaemia/reperfusion injury which can be ameliorated with nitrite, we investigated whether nitrite can protect against POI and explored the mechanisms involved.Experimental Approach: We used intestinal manipulation (IM) of the small intestine to induce POI in C57BL/6J mice. Sodium nitrite (48 nmol) was administered intravenously just before IM. Intestinal transit was assessed using fluorescent imaging. Bethanechol-stimulated jejunal circular muscle contractions were measured in organ baths. Inflammatory parameters, neutrophil infiltration, inducible NOS (iNOS) activity, reactive oxygen species (ROS) levels, mitochondrial complex I activity and cGMP were measured in the intestinal muscularis.Key Results: Pre-treatment with nitrite markedly improved the delay in intestinal transit and restored the reduced intestinal contractility observed 24 h following IM. This was accompanied by reduced protein levels of TNF-α, IL-6 and the chemokine CCL2, along with reduced iNOS activity and ROS levels. The associated neutrophil influx at 24 h was not influenced by nitrite. IM reduced mitochondrial complex I activity and cGMP levels; treatment with nitrite increased cGMP levels. Pre-treatment with the NO scavenger carboxy-PTIO or the soluble guanylyl cyclase inhibitor ODQ abolished nitrite-induced protective effects.Conclusions and Implications: Exogenous nitrite deserves further investigation as a possible treatment for POI. Nitrite-induced protection of POI in mice was dependent on NO and this effect was not related to inhibition of mitochondrial complex I, but did involve activation of soluble guanylyl cyclase. [ABSTRACT FROM AUTHOR]

Ischaemic heart disease is one of the leading causes of morbidity and mortality worldwide. The development of cardioprotective therapeutic agents remains a partly unmet need and a challenge for both medicine and industry, with significant financial and social implications. Protection of the myocardium can be achieved by mechanical vascular occlusions such as preconditioning ( PC), when brief episodes of ischaemia/reperfusion ( I/R) are experienced prior to ischaemia; postconditioning ( PostC), when the brief episodes are experienced at the immediate onset of reperfusion; and remote conditioning ( RC), when the brief episodes are experienced in another vascular territory. The elucidation of the signalling pathways, which underlie the protective effects of PC, PostC and RC, would be expected to reveal novel molecular targets for cardioprotection that could be modulated by pharmacological agents to prevent reperfusion injury. Gasotransmitters including NO, hydrogen sulphide ( H2S) and carbon monoxide ( CO) are a growing family of regulatory molecules that affect physiological and pathological functions. NO, H2S and CO share several common properties; they are beneficial at low concentrations but hazardous in higher amounts; they relax smooth muscle cells, inhibit apoptosis and exert anti-inflammatory effects. In the cardiovascular system, NO, H2S and CO induce vasorelaxation and promote cardioprotection. In this review article, we summarize current knowledge on the role of the gasotransmitters NO, H2S and CO in myocardial I/R injury and cardioprotection provided by conditioning strategies and highlight future perspectives in cardioprotection by NO, H2S, CO, as well as their donor molecules. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

Carbon monoxide ( CO) is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins, it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, NO and cGMP levels, as well as regulate MAPK signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+-sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

Carbon monoxide ( CO) is an endogenous small signalling molecule in the human body, produced by the action of haem oxygenase on haem. Since it is very difficult to apply safely as a gas, solid storage and delivery forms for CO are now explored. Most of these CO-releasing molecules ( CORMs) are based on the inactivation of the CO by coordinating it to a transition metal centre in a prodrug approach. After a brief look at the potential cellular target structures of CO, an overview of the design principles and activation mechanisms for CO release from a metal coordination sphere is given. Endogenous and exogenous triggers discussed include ligand exchange reactions with medium, enzymatically-induced CO release and photoactivated liberation of CO. Furthermore, the attachment of CORMs to hard and soft nanomaterials to confer additional target specificity to such systems is critically assessed. A survey of analytical methods for the study of the stoichiometry and kinetics of CO release, as well as the tracking of CO in living systems by using fluorescent probes, concludes this review. CORMs are very valuable tools for studying CO bioactivity and might lead to new drug candidates; however, in the design of future generations of CORMs, particular attention has to be paid to their drug-likeness and the tuning of the peripheral 'drug sphere' for specific biomedical applications. Further progress in this field will thus critically depend on a close interaction between synthetic chemists and researchers exploring the physiological effects and therapeutic applications of CO. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

The ability to get and keep an erection is important to men for several reasons and the inability is known as erectile dysfunction ( ED). ED has started to be accepted as an early indicator of systemic endothelial dysfunction and subsequently of cardiovascular diseases. The role of NO in endothelial relaxation and erectile function is well accepted. The discovery of NO as a small signalling gasotransmitter led to the investigation of the role of other endogenously derived gases, carbon monoxide ( CO) and hydrogen sulphide ( H2S) in physiological and pathophysiological conditions. The role of NO and CO in sexual function and dysfunction has been investigated more extensively and, recently, the involvement of H2S in erectile function has also been confirmed. In this review, we focus on the role of these three sister gasotransmitters in the physiology, pharmacology and pathophysiology of sexual function in man, specifically erectile function. We have also reviewed the role of soluble guanylyl cyclase/c GMP pathway as a common target of these gasotransmitters. Several studies have proposed alternative therapies targeting different mechanisms in addition to PDE-5 inhibition for ED treatment, since some patients do not respond to these drugs. This review highlights complementary and possible coordinated roles for these mediators and treatments targeting these gasotransmitters in erectile function/ ED. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

Haem oxygenase ( HO) and its product carbon monoxide ( CO) are associated with cytoprotection and maintenance of homeostasis in several different organs and tissues. This review focuses upon the role of exogenous and endogenous CO (via HO activity and expression) in various CNS pathologies, based upon data from experimental models, as well as from some clinical data on human patients. The pathophysiological conditions reviewed are cerebral ischaemia, chronic neurodegenerative diseases ( Alzheimer's and Parkinson's diseases), multiple sclerosis and pain. Among these pathophysiological conditions, a variety of cellular mechanisms and processes are considered, namely cytoprotection, cell death, inflammation, cell metabolism, cellular redox responses and vasomodulation, as well as the different targeted neural cells. Finally, novel potential methods and strategies for delivering exogenous CO as a drug are discussed, particularly approaches based upon CO-releasing molecules, their limitations and challenges. The diagnostic and prognostic value of HO expression in clinical use for brain pathologies is also addressed. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

Background and Purpose: Infection with Gram‐negative bacteria has been recognized as an initiator of rheumatoid arthritis, which is characterized by chronic inflammation and infiltration of immune cells. Carbon monoxide (CO) exhibits anti‐inflammatory properties. Here we have investigated the detailed mechanisms of vascular cell adhesion molecule‐1 (VCAM‐1) expression induced by LPS and if CO inhibited LPS‐induced leukocyte adhesion to synovial fibroblasts by suppressing VCAM‐1 expression. Experimental Approach: Human rheumatoid arthritis synovial fibroblasts (RASFs) were incubated with LPS and/or the CO‐releasing compound CORM‐2. Effects of LPS on VCAM‐1 levels were determined by analysing mRNA expression, promoter activity, protein expression, and immunohistochemical staining. The molecular mechanisms were investigated by determining the expression, activation, and binding activity of transcriptional factors using target signal antagonists. Key Results: CORM‐2 significantly inhibited inflammatory responses in LPS‐treated RASFs by down‐regulating the expression of adhesion molecule VCAM‐1 and leukocyte infiltration. The down‐regulation of LPS‐induced VCAM‐1 expression involved inhibition of the expression of phosphorylated‐NF‐κB p65 and AP‐1 (p‐c‐Jun, c‐Jun and c‐Fos mRNA levels). These results were confirmed by chromatin immunoprecipitation assay to detect NF‐κB and AP‐1 DNA binding activity. Conclusions and Implications: LPS‐mediated formation of the TLR4/MyD88/TRAF6/c‐Src complex regulated NF‐κB and MAPKs/AP‐1 activation leading to VCAM‐1 expression and leukocyte adhesion. CORM‐2, which liberates CO to elicit direct biological activities, attenuated LPS‐induced VCAM‐1 expression by interfering with NF‐κB and AP‐1 activation, and significantly reduced LPS‐induced immune cell infiltration of the synovium. [ABSTRACT FROM AUTHOR]

Background and Purpose Endocannabinoids such as anandamide ( AEA) are important lipid ligands regulating cell proliferation, differentiation and apoptosis. Their levels are regulated by hydrolase enzymes, the fatty acid amide hydrolase ( FAAH) and monoacylglycerol lipase ( MGL). Here, we investigated whether FAAH or AEA are involved in NF (erythroid-derived 2)-like 2 (Nrf2)/antioxidant responsive element ( ARE) pathway. Experimental Approach The aim of this study was to analyse the effects of AEA or FAAH inhibition by the URB597 inhibitor or FAAH/ siRNA on the activation of Nrf2- ARE signalling pathway and heme oxygenase-1 ( HO-1) induction and transcription. Key Results Endogenous AEA was detected in the immortalized human mammary epithelial MCF-10A cells (0.034 ng per 106 cells) but not in MCF-7 or MDA-MB-231 breast cancer cells. Because breast tumour cells express FAAH abundantly, we examined the effects of FAAH on Nrf2/antioxidant pathway. We found that inhibition of FAAH by the URB597 inhibitor induced antioxidant HO-1 in breast cancer cells and MCF-10A cells. RNAi-mediated knockdown of FAAH or treatment with AEA-activated ARE-containing reporter induced HO-1 mRNA and protein expression, independent of the cannabinoid receptors, CB1, CB2 or TRPV1. Furthermore, URB597, AEA and siRNA- FAAH treatments induced the nuclear translocation of Nrf2, while siRNA- Nrf2 treatment and Keap1 expression blocked AEA, URB597 and si- FAAH from activation of ARE reporter and HO-1 induction. siRNA- HO-1 treatment decreased the viability of breast cancer cells and MCF-10A cells. Conclusions and Implications These data uncovered a novel mechanism by which inhibition of FAAH or exposure to AEA induced HO-1 transcripts and implicating AEA and FAAH as direct modifiers in signalling mediated activation of Nrf2- HO-1 pathway, independent of cannabinoid receptors. [ABSTRACT FROM AUTHOR]

Background and Purpose: Although carboplatin is currently used as a therapeutic drug for ovarian, breast, and non-small cell lung cancers, it has serious side effects including renal and cardiac toxicity. Herein, we examined the effect of carboplatin on murine renal tubular cell (RTC) apoptosis both in vivo and in vitro and the underlying molecular mechanisms associated with its activation of the nuclear factor of activated T-lymphocytes-3 (NFAT3).Experimental Approach: Mechanisms of carboplatin-mediated renal apoptosis were examined using NFAT-reporter transgenic mice and RTCs with NFAT3 overexpression or knockdown.Key Results: We demonstrated that carboplatin initiated an intrinsic apoptotic pathway of activating caspase-3 and -9, accompanied by a decrease in the ratio of Bcl-XL/Bax and a significant increase in Bcl-XS. Carboplatin increased NFAT activation in NFAT-luciferase reporter transgenic mice, RTCs and cells exogenously overexpressing NFAT3 that exacerbated cell death. Furthermore, the addition of either N-acetylcysteine (NAC, an antioxidant) or NFAT inhibitors, including FK-506 (tacrolimus), cyclosporin A (CsA, a calcineurin inhibitor), and BAPTA-AM (a calcium chelator) successfully reversed carboplatin-mediated cell apoptosis, which was further confirmed using siNFAT3. Additionally, NAC blocked NFAT3 activation by inhibition of NADPH oxidase activation, and ERK/JNK and PKC pathways, resulting in a decrease in cell apoptosis; the therapeutic effect of NAC was verified in vivo.Conclusion and Implications: The results presented herein show that carboplatin-mediated reactive oxygen species might signal calcineurin and NFAT3 activation in RTCs, whereas NAC and NFAT inhibitors reversed carboplatin-mediated RTC apoptosis, suggesting that oxidative stress-mediated NFAT3 activation is essential for carboplatin-mediated RTC apoptosis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Although carbon monoxide (CO) can modulate inflammatory processes, the influence of CO on adhesion molecules is less clear. This might be due to the limited amount of CO generated by haem degradation. We therefore tested the ability of a CO releasing molecule (CORM-3), used in supra-physiological concentrations, to modulate the expression of vascular cell adhesion molecule (VCAM)-1 and E-selectin on endothelial cells and the mechanism(s) involved.Experimental Approach: Human umbilical vein endothelial cells (HUVECs) were stimulated with tumour necrosis factor (TNF)-alpha in the presence or absence of CORM-3. The influence of CORM-3 on VCAM-1 and E-selectin expression and the nuclear factor (NF)-kappaB pathway was assessed by flow cytometry, Western blotting and electrophoretic mobility shift assay.Key Results: CORM-3 inhibited the expression of VCAM-1 and E-selectin on TNF-alpha-stimulated HUVEC. VCAM-1 expression was also inhibited when CORM-3 was added 24 h after TNF-alpha stimulation or when TNF-alpha was removed. This was paralleled by deactivation of NF-kappaB and a reduction in VCAM-1 mRNA. Although TNF-alpha removal was more effective in this regard, VCAM-1 protein was down-regulated more rapidly when CORM-3 was added. CORM-3 induced haem oxygenase-1 (HO-1) in a dose- and time-dependent manner, mediated by the transcription factor, Nrf2. CORM-3 was still able to down-regulate VCAM-1 expression in HUVEC transfected with siRNA for HO-1 or Nrf2.Conclusions and Implications: Down-regulation of VCAM and E-selectin expression induced by CORM-3 was independent of HO-1 up-regulation and was predominantly due to inhibition of sustained NF-kappaB activation. [ABSTRACT FROM AUTHOR]

Background and purpose: The pleiotropic effects of HMG-CoA inhibitors (statins), which include anti-inflammation, antioxidation and immunomodulation, are not yet fully understood. The present study was designed to elucidate the role of nitric oxide (NO), peroxynitrite (ONOO-) and haem oxygenase-1 (HO-1) in the anti-atherogenic effect of statins. Experimental approach: Normal and atherosclerotic New Zealand rabbits were treated with atorvastatin or simvastatin in the presence or absence of inhibitors and promoters of endothelial nitric oxide synthase (eNOS) and HO-1. NO and ONOO- released from isolated aortae by calcium ionophore were measured with nanosensors placed 6 ± 2 nm from aortic endothelium. Expression of eNOS and HO-1 protein, HO activity, plasma malondialdehyde (MDA) and vessel wall thickness were also measured. Key results: Hypercholesterolaemia decreased eNOS expression by 31 ± 3%, decreased NO (230 ± 16 vs. 433 ± 17 nmol·L−1 control) and increased cytotoxic ONOO- (299 ± 15 vs. 187 ± 11 nmol·L−1 control). The concentration ratio of [NO]/[ONOO-] decreased from 2.3 ± 0.1 (normal) to 0.7 ± 0.1 indicating an increase of nitroxidative stress in atherosclerotic endothelium. Expression of HO-1 protein increased by 20 ± 8% in atherosclerosis and further increased (about 30%) after treatment with statins. Statins partially restored the [NO]/[ONOO-] balance (1.5 ± 0.1 for atorvastatin and 1.4 ± 0.1 simvastatin), decreased MDA and wall thickening. Promoters of eNOS and HO-1 (L-arginine and haemin) ameliorated the [NO]/[ONOO-] ratio while their inhibitors (L-NAME or tin-protoporphyrin) showed no improvement in these ratio. Conclusions and implications: Atherosclerosis induced an endothelial [NO]/[ONOO-] balance indicative of endothelial dysfunction. Statins showed anti-atherosclerotic effects mediated by HO-1/eNOS, restoring the [NO]/[ONOO-] imbalance and reducing lipid peroxidation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Oxidative stress caused by cytokine exposure is a major cause of pancreatic islet death in vitro and of diabetogenesis. Antioxidant compounds may prevent cytokine-induced damage to islet cells. Hence, we studied the potential of curcumin, an antioxidant and anti-inflammatory compound, in vitro to protect islets against pro-inflammatory cytokines and in vivo to prevent the progression of diabetes induced by multiple low doses of streptozotocin (MLD-STZ).Experimental Approach: Pancreatic islets from C57/BL6J mice were pretreated with curcumin (10 microM) and then exposed to a combination of cytokines. Islet viability, reactive oxygen species (ROS), NO, inducible NO synthase and NF-kappaB translocation were studied. Curcumin pretreated (7.5 mg kg(-1) day(-1)) C57/BL6J mice were given MLD-STZ (40 mg kg(-1)), and various parameters of diabetes induction and progression were monitored.Key Results: Curcumin protected islets from cytokine-induced islet death in vitro by scavenging ROS and normalized cytokine-induced NF-kappaB translocation by inhibiting phosphorylation of inhibitor of kappa B alpha (IkappaBalpha). In vivo, curcumin also prevented MLD-STZ, as revealed by sustained normoglycaemia, normal glucose clearance and maintained pancreatic GLUT2 levels. Pro-inflammatory cytokine concentrations in the serum and pancreas were raised in STZ-treated animals, but not in animals pretreated with curcumin before STZ.Conclusions and Implications: Here, we have demonstrated for the first time that curcumin in vitro protects pancreatic islets against cytokine-induced death and dysfunction and in vivo prevents STZ-induced diabetes. [ABSTRACT FROM AUTHOR]

Injury to the CNS elicits a host defense reaction that utilizes astrocytes, microglia, neurons and oligodendrocytes. Neuroinflammation is a major host defense mechanism designed to restore normal structure and function after CNS insult, but like other forms of inflammation, chronic neuroinflammation may contribute to pathogenesis. The inducible haeme oxygenase isoform, haeme oxygenase-1 (HO-1), is a phase 2 enzyme upregulated in response to electrophilic xenobiotics, oxidative stress, cellular injury and disease. There is emerging evidence that HO-1 expression helps mediate the resolution of inflammation, including neuroinflammation. Whether this is solely because of the catabolism of haeme or includes additional mechanisms is unclear. This review provides a brief background on the molecular biology and biochemistry of haeme oxygenases and the actions of haeme, bilirubin, iron and carbon monoxide in the CNS. It then presents our current state of knowledge regarding HO-1 expression in the CNS, regulation of HO-1 induction in neural cells and discusses the prospect of pharmacological manipulation of HO-1 as therapy for CNS disorders. Because of recognized species and cellular differences in HO-1 regulation, a major objective of this review is to draw attention to areas where gaps exist in the experimental record regarding regulation of HO-1 in neural cells. The results indicate the HO-1 system to be an important therapeutic target in CNS disorders, but our understanding of HO-1 expression in human neural cells is severely lacking. [ABSTRACT FROM AUTHOR]

Background and Purpose: MP4 (Hemospan) is a Hb-based oxygen therapeutic agent, based on polyethylene-glycol (PEG) conjugation to Hb, undergoing clinical trials as an oxygen carrier. This study describes the functional interaction between MP4 and carbon monoxide (CO), as a CO delivery agent, and the effects of CO-MP4 on myocardial infarct size following ischaemia and reperfusion in rats.Experimental Approach: Kinetic measurements of CO-MP4 binding were used to evaluate the effects of PEG modification on Hb subunit structure/function and to calculate CO-MP4 equilibrium constants. CO transport by CO-MP4 was shown by ligand (O2/CO) partitioning between MP4 and red blood cell (RBC)-Hb. Pharmacological effects of CO-MP4 were studied on myocardial infarction in rats.Key Results: CO binding kinetics show primary structural/functional effects on beta chains in MP4, with alpha chains maintaining the ability to undergo tertiary conformational transition. CO confers long-term, room-temperature stability and is able to rapidly re-equilibrate between MP4 and RBCs. In a rat model of myocardial infarct, in contrast to oxy-MP4, CO-MP4 reduced infarct size when administered prior to the induction of ischaemia.Conclusions and Implications: MP4 PEGylation chemistry modifies the individual function of Hb subunits, but results in an overall CO equilibrium constant similar to that for unmodified Hb. CO-MP4 is able to deliver CO to the circulation and reduces ischaemia/reperfusion injury in rats, providing the first evidence for this drug as a CO therapeutic agent. [ABSTRACT FROM AUTHOR]

Background and Purpose: Curcumin has been used to treat cancer, diabetes and other pathologies. However, little is known regarding its role in altering post-translational modifications of histone H3. A recent report suggests that acute hyperglycaemia induces a global down-regulation of gene expression in human tissues and epigenetic regulation of gene expression could be a novel mechanism underlying the pathological processes of hyperglycaemia. The present study was undertaken to examine changes in histone modification by curcumin treatment which prevents development of type I diabetic nephropathy.Experimental Approach: Male Sprague-Dawley rats were rendered diabetic using a single dose of streptozotocin (55 mg kg(-1), i.p.). Diabetic nephropathy was assessed by measurements of blood urea nitrogen, albumin and creatinine levels. Post-translational modifications of histone H3, heat shock protein-27 (HSP-27) and mitogen-activated protein (MAP) kinase p38 expression were examined by western blotting.Key Results: Treatment of diabetic rats with curcumin significantly decreased blood urea nitrogen and creatinine and increased albumin; variables associated with the development of diabetic nephropathy. There were also increased levels of HSP-27 and MAP kinase (p38) in diabetic kidney. However, curcumin treatment prevented this increase in HSP-27 and p38 expression. Moreover, at nuclear level curcumin prevented the decrease in dephosphorylation and increases acetylation of histone H3.Conclusions and Implications: Our results suggested that protection against development of diabetic nephropathy by curcumin treatment involved changes in post-translational modifications of histone H3, expression of HSP-27 and MAP kinase p38 in diabetic kidney. [ABSTRACT FROM AUTHOR]

Background and Purpose: Prenatal patency of ductus arteriosus is maintained by prostaglandin (PG) E(2), possibly along with nitric oxide (NO) and carbon monoxide (CO), and cyclooxygenase (COX) deletion upregulates NO. Here, we have examined enzyme source and action of NO for ductus patency and whether NO and CO are upregulated by deletion of, respectively, heme oxygenase 2 (HO-2) and COX1 or COX2.Experimental Approach: Experiments were performed in vitro and in vivo with wild-type and gene-deleted, near-term mouse fetuses.Key Results: N(G)-nitro-L-arginine methyl ester (L-NAME) contracted the isolated ductus and its effect was reduced by eNOS, but not iNOS, deletion. L-NAME contraction was not modified by HO-2 deletion. Zinc protoporphyrin (ZnPP) also contracted the ductus, an action unaffected by deletion of either COX isoform. Bradykinin (BK) relaxed indomethacin-contracted ductus similarly in wild-type and eNOS-/- or iNOS-/-. BK relaxation was suppressed by either L-NAME or ZnPP. However, it reappeared with combined L-NAME and ZnPP to subside again with K(+) increase or K(+) channel inhibition. In vivo, the ductus was patent in wild-type and NOS-deleted fetuses. Likewise, no genotype-related difference was noted in postnatal closure.Conclusions and Implications: NO, formed mainly via eNOS, regulates ductal tone. NO and CO cooperatively mediate BK-induced relaxation in the absence of PGE(2). However, in the absence of PGE(2), NO and CO, BK induces a relaxant substance behaving as an endothelium-derived hyperpolarizing factor. Ductus patency is, therefore, sustained by a cohort of agents with PGE(2) and NO being preferentially coupled for reciprocal compensation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Recent evidence indicates that carbon monoxide-releasing molecules (CO-RMs) exhibit potential anti-inflammatory properties. In the present study, we have investigated whether tricarbonyl dichloro ruthenium(II) dimer (CORM-2) can control the inflammatory response induced by cytokines in a human colonic epithelial cell line, Caco-2. Experimental Approach: Caco-2 cells were preincubated with CORM-2 for 30 minutes and then stimulated with interleukin (IL)-1beta, tumor necrosis factor-alpha and interferon-gamma for different times. Gene expression was analyzed by real-time PCR. Protein expression was investigated by Western blot and ELISA. Transcription factor activation was determined by the luciferase method. Key Results: We have shown that CORM-2 significantly decreased the mRNA expression of nitric oxide synthase-2 (NOS-2) and the production of nitrite, in Caco-2 cells stimulated with cytokines. IL-8, IL-6 and metalloproteinase-7 (MMP-7) mRNA and protein were also significantly reduced by CORM-2. Time-course and small interfering RNA studies suggest that inhibition of IL-6 plays a role in the regulation of MMP-7 expression by CORM-2. These effects of CORM-2 can be dependent on the modulation of nuclear factor-kappaB (NF-kappaB), activator protein-1, CCAT/enhancer binding protein and the phosphorylated forms of NF-kappaB inhibitory protein-alpha, c-Jun N-terminal protein kinase 1/2, p38 and extracellular signal-regulated kinase 1/2. Conclusions and Implications: CORM-2 can regulate a number of genes relevant in intestinal inflammation and cancer progression. These findings provide new insights into the anti-inflammatory properties and potential applications of this class of compounds. [ABSTRACT FROM AUTHOR]

Background and Purpose: Heme oxygenase (HO) activity is known to down-regulate inflammatory events. Here, we address the role of HO and its metabolites, carbon monoxide (CO) and biliverdin (BVD), in leukocyte rolling, adhesion and neutrophil migration during inflammatory processes. Experimental Approach: Intravital microscopy was used to evaluate leukocyte rolling and adhesion in the mesenteric microcirculation of mice. TNFalpha and IL-1beta were determined by ELISA and HO-1 protein expression by Western blot. Key Results: Intraperitoneal challenge with carrageenan enhanced HO-1 protein expression in mesentery and bilirubin concentration in peritoneal exudates. Pretreatment of mice with a non-specific inhibitor of HO (ZnDPBG) or with a HO-1 specific inhibitor (ZnPP IX) enhanced neutrophil migration, rolling and adhesion on endothelium induced by carrageenan. In contrast, HO substrate (hemin), CO donor (DMDC) or BVD reduced these parameters. The reduction of neutrophil recruitment promoted by HO metabolites was independent of the production of chemotactic cytokines. Inhibitory effects of CO, but not of BVD, were counteracted by treatment with a soluble guanylate cyclase (sGC) inhibitor, ODQ. Furthermore, inhibition of HO prevented the inhibitory effect of a nitric oxide (NO) donor (SNAP) upon neutrophil migration, while the blockade of NO synthase (NOS) activity by aminoguanidine did not affect the CO or BVD effects. Conclusions and Implications: Metabolites of HO decreased leukocyte rolling, adhesion and neutrophil migration to the inflammatory site by a mechanism partially dependent on sGC. Moreover, inhibition by NO of neutrophil migration was dependent on HO activity. [ABSTRACT FROM AUTHOR]

Oregonin isolated from Alnus formosana is a diarylheptanoid derivative, which appears to have antioxidative and anti-inflammatory activities. In this study, our data demonstrated inhibitory actions of oregonin on the LPS-induced iNOS protein in RAW264.7 macrophages and BV-2 microglial cells. We also suggested that HO-1 induction by oregonin might contribute to this action.Oregonin is able to dose-dependently reduce NO production, iNOS protein and iNOS promoter activity stimulated by LPS in RAW264.7 and BV-2 cells.Oregonin also showed inhibition of LPS-mediated NF-κB promoter activity and DNA-binding ability, as well as p65 nuclear translocation and phosphorylation. However, oregonin had no effect on IKK activity. AP-1 promoter activity and p38 MAPK activation but not PKC, ERK and JNK activation induced by LPS were attenuated by oregonin.Accompanying with iNOS protein reduction, moreover, we found that oregonin was able to induce HO-1 protein level. Results using a CO donor, [Ru(CO)3Cl2]2 further showed the ability of CO in reduction of iNOS protein level induced by LPS through the blockade of NF-κB and AP-1.Taken together, these results provide new evidences into the anti-inflammatory actions of oregonin, which include the inhibition of iNOS gene transcription via suppressing transcriptional activity of NF-κB and AP-1, as well as the upregulation of anti-inflammatory molecule HO-1. The HO-1-derived CO may also be involved in the suppressive effect on iNOS gene regulation.British Journal of Pharmacology (2005) 146, 378–388. doi:10.1038/sj.bjp.0706336; published online 18 July 2005 [ABSTRACT FROM AUTHOR]

1. In systemic vessels, haem-oxygenase (HO) is induced during oxidative stress and known to modulate vasodilatation and vascular remodelling. At birth, with the transition from placental to air breathing, the pulmonary vessels are exposed to oxidative stress and undergo well-documented remodelling processes. Thus, we investigated the role of HO in the lung during adaptation to extra-uterine life using a pig and mouse model. In addition to the novel data presented with regard to one isoform, HO-1, this study is among the first to describe the pulmonary vascular remodelling in the mouse after birth. 2. We show, for the first time, that another isoform, HO-2, is present constitutively at birth and HO-1 protein is induced in the porcine and murine lung after birth in vascular and airway structures, peaking at 14 days in the pig and at about 4 days in the mouse. Furthermore, we show that HO-1 mRNA declines after birth in the mouse lung. 3. Inhibitors of HO did not modify vasodilator responses in vessels from 14-day-old pigs. 4. Moreover, lungs from HO-1-deficient mice developed normally after birth. 5. HO-1 is induced at birth but plays no role in the development of vasodilator responses or remodelling that occurs at this time. These data suggest that HO-1 expression at birth is a redundant response to oxidative stress in the lungs of healthy mammals. However, it remains possible that this pathway protects if complications occur during or after birth. [ABSTRACT FROM AUTHOR]

Presents a list of topics on the effect of various chemicals on general physiology of human beings. Effect of acute and chronic nicotine on lipogenesis in mouse adipose tissues; Contribution of plasma extravasation in a model of murine joint inflammation; Influence of endogenously produced reactive oxygen species on the inotropic and chronotropic effects of adrenoreceptors.

1 Dictary antioxidants are thought to be beneficial in reducing the incidence of coronary heart disease. In this study, we compared resveratrol and analogues on their antioxidation and free radical scavenging activities to their protective effects on ischaemia-reperfusion induced injuries of rat hearts. 2 Astringinin (3,3',4',5-tetrahydroxystilbene) was, shown to be a more potent inhibitor than other analogues against Cu[sub2]∗ -induced LDL (low-density lipoprotein) oxidation, as measured by the formation of conjugated diene and TBARS (thiobarbituric acid-reactive substance) and by the electrophoretic mobility of the oxidized LDL. 3 Resveratrol (truns-3,4'.5-trihydroxystilbene) and astringinin scavenged the stable free radical DPPH (1,1-diphenyl-2-picryl-hydrazyl) with an lC[sub0.200] of 7.1 and 4.3 μM, respectively. 4 Astringinin has a superoxide anion scavenging activity about 160 fold more potent than resveratrol. 5 After a 30 min global ischemia followed by 2 h reperfusion, astringinin (10 μM) significantly reduced infarct size, superoxide anion production and increased functional recovery of the coronary flow in Langendorff-perfused rat hearts. 6 The result showed there is a positive correlation between the anti-oxidation and cardioprotective activities among these phenolic compounds. Our finding together with the fact that astringinin is more water-soluble than resveratrol suggest that astringinin could potentially be used as an anti-oxidant and cardioprotective agent in biological systems. [ABSTRACT FROM AUTHOR]

Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]