Abstract-Carbon monoxide, which is generated in mammals during the degradation of heme by the enzyme heme oxygenase, is an important signaling mediator. Transition metal carbonyls have been recently shown to function as carbon monoxide-releasing molecules (CO-RMs) and to elicit distinct pharmacological activities in biological systems.In the present study, we report that a water-soluble form of CO-RM promotes cardioprotection in vitro and in vivo. Specifically, we found that tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) is stable in water at acidic pH but in physiological buffers rapidly liberates CO in solution. Cardiac cells pretreated with CORM-3 (10 to 50 mol/L) become more resistant to the damage caused by hypoxia-reoxygenation and oxidative stress. In addition, isolated hearts reperfused in the presence of CORM-3 (10 mol/L) after an ischemic event displayed a significant recovery in myocardial performance and a marked and significant reduction in cardiac muscle damage and infarct size. The cardioprotective effects mediated by CORM-3 in cardiac cells and isolated hearts were totally abolished by 5-hydroxydecanoic acid, an inhibitor of mitochondrial ATP-dependent potassium channels. Predictably, cardioprotection is lost when CORM-3 is replaced by an inactive form (iCORM-3) that is incapable of liberating CO. Using a model of cardiac allograft rejection in mice, we also found that treatment of recipients with CORM-3 but not iCORM-3 considerably prolonged the survival rate of transplanted hearts. These data corroborate the notion that transition metal carbonyls could be used as carriers to deliver CO and highlight the bioactivity and potential therapeutic features of CO-RMs in the mitigation of cardiac dysfunction. Key Words: transition metal carbonyls Ⅲ carbon monoxide-releasing molecules Ⅲ myocardial ischemia Ⅲ heart transplantation Ⅲ reperfusion injury M ammalian cells constantly generate carbon monoxide (CO) gas via the endogenous degradation of heme by a family of constitutive (HO-2) and inducible (HO-1) heme oxygenase enzymes. 1,2 Firstly described as a putative neural messenger, 3 CO is now regarded as a versatile signaling molecule having essential regulatory roles in a variety of physiological and pathophysiological processes that take place within the cardiovascular, nervous, and immune systems. Indeed, CO produced in the vessel wall by heme oxygenase enzymes possesses vasorelaxing properties and has been shown to prevent vasoconstriction and both acute and chronic hypertension through stimulation of soluble guanylate cyclase. 4 -10 Endogenous CO appears to modulate sinusoidal tone in the hepatic circulation, 11 control the proliferation of vascular smooth muscle cells 12 and suppress the rejection of transplanted hearts. 13 The biological action of heme oxygenase-derived CO is substantiated by the pharmacological effects observed when this gas is applied exogenously to in vitro and in vivo systems. At concentrations ranging from 10 to 500 ppm, CO gas has been reported to mediate potent antiinfl...

A two-by-two factorial experiment with pigs was conducted to study the effect of feed grinding (fine and coarse) and feed processing (pelleted and nonpelleted) on physicochemical properties, microbial populations, and survival of Salmonella enterica serovar Typhimurium DT12 in the gastrointestinal tracts of pigs. Results demonstrated a strong effect of diet on parameters measured in the stomachs of the pigs, whereas the effect was less in the other parts of the gastrointestinal tract. Pigs fed the coarse nonpelleted (C-NP) diet showed more solid gastric content with higher dry matter content than pigs fed the fine nonpelleted (F-NP), coarse pelleted (C-P), or fine pelleted (F-P) diet. Pigs fed the C-NP diet also showed significantly increased number of anaerobic bacteria (P < 0.05), increased concentrations of organic acids, and reduced pH in the stomach. In addition, pigs fed the C-NP diet showed increased in vitro death rate of S. enterica serovar Typhimurium DT12 in content from the stomach (P < 0.001). Pigs fed the C-NP diet had a significantly higher concentration of undissociated lactic acid in gastric content than pigs fed the other diets (P < 0.001). A strong correlation between the concentration of undissociated lactic acid and the death rate of S. enterica serovar Typhimurium DT12 was found. In the distal small intestine, cecum, and midcolon, significantly lower numbers of coliform bacteria were observed in pigs fed the coarse diets than in pigs fed the fine diets (P < 0.01). Pigs fed the C-NP diet showed the lowest number of coliform bacteria in these segments of the gastrointestinal tract. Pigs fed the coarse diets showed increased concentration of butyric acid in the cecum (P < 0.05) and colon (P < 0.10) compared with pigs fed the fine diets. It was concluded that feeding a coarsely ground meal feed to pigs changes the physicochemical and microbial properties of content in the stomach, which decreases the survival of Salmonella during passage through the stomach. In this way the stomach acts as a barrier preventing harmful bacteria from entering and proliferating in the lower part of the gastrointestinal tract.Human food-borne disease outbreaks are a public health concern and have economic importance to the food-producing industry. Subclinical Salmonella enterica infections in pig herds are recognized as an important source of human salmonellosis in Denmark (29). A Danish Salmonella surveillance and control program in pig herds and slaughterhouses has been applied nationally since 1995, and the goal is to reduce the Salmonella prevalence in pork meat to 0.5% (23). In year 2002, the incidence of Salmonella-positive carcass samples in Danish slaughterhouses was 1.4% and the corresponding Salmonella prevalence at herd level monitored by serological testing was 3.2% (1).There is a growing awareness that it is only possible to reduce the prevalence of Salmonella in pork, and consequently the number of infections in people consuming pork and pork products, through an integration and cooperation of all sta...

Bilirubin (BR) and biliverdin (BV), two metabolites produced during haem degradation by haem oxygenase, possess strong antioxidant activities toward peroxyl radical, hydroxyl radical and hydrogen peroxide. Considering the importance attributed to nitric oxide (NO) and its congeners in the control of physiological and pathophysiological processes, we examined the interaction of BR and BV with NO and NO-related species in vitro. Exposure of BR and BV to agents that release NO or nitroxyl resulted in a concentration-and time-dependent loss of BR and BV, as assessed by high performance liquid chromatography. Peroxynitrite, a strong oxidant derived from the reaction of NO with superoxide anion, also showed high reactivity toward BR and BV. The extent of BR and BV consumption largely depended on the NO species being analysed and on the half-lives of the pharmacological compounds considered. Of major importance, BR and BV decomposition occurred also in the presence of pure NO under anaerobic conditions, con¢rming the ability of bile pigments to scavenge the gaseous free radical. Increasing concentrations of thiols prevented BR consumption by nitroxyl, indicating that bile pigments and thiol groups can compete and/or synergise the cellular defence against NO-related species. In view of the high inducibility of haem oxygenase-1 by NO-releasing agents in di¡erent cell types, the present ¢ndings highlight novel anti-nitrosative characteristics of BR and BV suggesting a potential function for bile pigments against the damaging e¡ects of uncontrolled NO production. ß

Synthetic surfactants are becoming increasingly unpopular in many applications due to previously disregarded effects on biological systems and this has led to a new focus on replacing such products with biosurfactants that are biodegradable and produced from renewal resources. Microbially derived biosurfactants have been investigated in numerous studies in areas including: increasing feed digestibility in an agricultural context, improving seed protection and fertility, plant pathogen control, antimicrobial activity, antibiofilm activity, wound healing and dermatological care, improved oral cavity care, drug delivery systems and anticancer treatments. The development of the potential of biosurfactants has been hindered somewhat by the myriad of approaches taken in their investigations, the focus on pathogens as source species and the costs associated with large‐scale production. Here, we focus on various microbial sources of biosurfactants and the current trends in terms of agricultural and biomedical applications.