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In the canonical pathway for mitochondrial H 2 S oxidation electrons are transferred from sulfide:quinone oxidoreductase (SQR) to complex III via ubiquinone (CoQ 10). We previously observed that a number of quinones directly oxidize H 2 S and we hypothesize that CoQ 10 may have similar properties. Here we examine H 2 S oxidation by CoQ 10 and more hydrophilic, truncated forms, CoQ 1 and CoQ 0 , in buffer using H 2 S and polysulfide fluorophores (AzMC and SSP4), silver nanoparticles to measure thiosulfate (H 2 S 2 O 3), mass spectrometry to identify polysulfides and O 2 -sensitive optodes to measure O 2 consumption. We show that all three quinones concentration-dependently catalyze the oxidization of H 2 S to polysulfides and thiosulfate in buffer with the potency CoQ 0 >CoQ 1 >CoQ 10 and that CoQ 0 specifically oxidizes H 2 S to per-polysulfides, H 2 S 2,3,4. These reactions consume and require oxygen and are augmented by addition of SOD suggesting that the quinones, not superoxide, oxidize H 2 S. Related quinones, MitoQ, menadione and idebenone, oxidize H 2 S in similar reactions. Exogenous CoQ 0 decreases cellular H 2 S and increases polysulfides and thiosulfate production and this is also O 2 -dependent, suggesting that the quinone has similar effects on sulfur metabolism in cells. Collectively, these results suggest an additional endogenous mechanism for H 2 S metabolism and a potential therapeutic approach in H 2 S-related metabolic disorders. Role of ubiquinone in H 2 S oxidation. (A) In the initial step of the canonical pathway, mitochondrial sulfide:quinone oxidoreductase (SQR) oxidizes H 2 S and the electrons are transferred to the electron transport chain (ETC) complex III via ubiquinone (Q) and then to complex IV by cytochrome C (C), ultimately reducing oxygen. The persulfide formed from H 2 S-SQR is transferred to a mobile carrier such as glutathione (GS−) and is ultimately oxidized to sulfate. (B) H 2 S can also be directly oxidized by mitochondrial and/or extramitochondrial ubiquinone in a reaction that produces polysulfides and thiosulfate and consumes oxygen but does not deliver electrons to the ETC. This pathway may serve to produce signaling polysulfides or remove H 2 S without generating ATP. [Display omitted] • Para-quinones oxidize H 2 S to polysulfides. • Ubiquinone (CoQ10), CoQ1, CoQ0, MitoQ, menadione and idebenone are para-quinones. • All oxidize H 2 S to polysulfides. • Polysulfides are potent antioxidants. • Regulation of sulfur metabolism is a promising target of antioxidant therapies. [ABSTRACT FROM AUTHOR]

Nutraceutical polyphenol catechins in green tea oxidize H 2 S to polysulfides (PS) in buffer and in cells thereby conveying their cytoprotective effects. Here we measure H 2 S oxidation in buffer and HEK293 cells by over-the-counter nutraceuticals, blueberry, bilberry and cranberry, and by polyphenols, cyanadin (Cya), quercetin (Que), rosmarinic acid (RA) and resveratrol (Res). H 2 S and PS were measured with specific fluorophores, AzMc and SSP4 respectively, and thiosulfate (TS) production was measured in buffer using silver nanoparticles (AgNPs). All compounds increased polysulfide production from H 2 S in buffer and increased polysufides in cells. Decreasing oxygen from 100% to 21% and 0% progressively decreased PS production by Que and RA in buffer and Que decreased PS production in cells incubated in 5% O 2 compared to 21% O 2. Que, RA and Res, but not Cya, increased TS production from H 2 S in 21% O 2 but not in 0% O 2. Superoxide dismutase did not affect PS production from H 2 S by Que or TS production from H 2 S by Que, RA or Res, whereas catalase inhibited TS production by all three polyphenols. Conversely, these polyphenols only slightly reduce a mixed polysulfide (K 2 S n) or thiosulfate to H 2 S in 0% O 2. Collectively, our results suggest that polyphenols are autoxidized to a semiquinone radical and that this, in turn, oxidizes H 2 S to a thiyl radical from which polysulfides and thiosulfate derived. They also suggest that this is catalyzed by a semiquinone radical and it is independent of either superoxide or hydrogen peroxide concomitantly produced during polyphenol autoxidation. The polysulfides produced in these reactions are potent antioxidants and also initiate a variety of downstream cytoprotective effector mechanisms. It is also possible that H 2 S can be regenerated from the thiosulfate produced in these reactions by other cellular reductants and reused in subsequent reactions. [Display omitted] • Health benefits of nutraceutical polyphenols (NP) are attributed to their antioxidant activity. • Autoxidation of NPs produces oxidative semiquinones. • Semiquinones oxidize hydrogen sulfide (H 2 S) to polysulfides. • Polysulfides are potent antioxidants and activate antioxidant effector mechanisms. • We propose that many health benefits of NPs are mediated by sulfur metabolism. [ABSTRACT FROM AUTHOR]

The health benefits of lipoic acid (LA) are generally attributed to mitigating the harmful effects of reactive oxygen species (ROS). ROS are chemically similar to reactive sulfur species (RSS) and signal through identical mechanisms. Here we examined the effects of LA on RSS in HEK293 cells using H 2 S and polysulfide (PS) specific fluorophores, AzMC and SSP4. We show that LA concentration-dependently increased both H 2 S and PS. Physioxia (5% O 2) augmented the effects of LA on H 2 S production but decreased PS production. Thiosulfate, a known substrate for reduced LA, and an intermediate in the catabolism of H 2 S enhanced the effects of LA on H 2 S and PS production. Inhibiting peroxiredoxins with conoidin A and gluraredoxins with tiopronin augmented the effects of LA on PS and H 2 S, respectively while decreasing glutathione with buthionine-sulfoximine (BSO) or diethyl maleate (DEM) decreased the stimulatory effect of LA on H 2 S production but augmented LA's effect on PS. Aminooxyacetate (AOA) and propargylglycine (PPG), inhibitors of H 2 S production from cysteine partially inhibited LA augmentation of H 2 S production and further decreased the LA effect when applied concurrently with BSO and DEM. The selective and cell-permeable H 2 S scavenger, SS20, inhibited the effects of LA on cellular H 2 S. Estimates of single-cell H 2 S production suggest that 0.1–0.2% of O 2 consumption is used to metabolize H 2 S and these requirements may increase to 1–2% with 1 mM LA. Collectively, these results suggest that LA rescues H 2 S from irreversible oxidation and that the effects of LA on RSS directly confer antioxidant, anti-inflammatory and cytoprotective responses. They also suggest that TS may be an effective supplement to increase the efficacy of LA in clinical settings. Protective effects of lipoic acid through rescue of reactive sulfur species (RSS). H 2 S derived from glutathione (GSH), cysteine (Cys) and protein catabolism is normally oxidized to sulfate (SO 4 2-) and excreted with thiosulfate (S 2 O 3 2-) as an intermediate in oxidation. Exogenous lipoic acid (LA) taken up by the cell is reduced to dihydrolipoic acid (DHLA) by thioredoxin (Trx), glutaredoxin (Grx) or peroxiredoxin (Prx) utilizing NADH as the reductant. DHLA reduces thiosulfate regenerating H 2 S which is then oxidized to persulfide (H 2 S 2), possibly by LA as the oxidant, although a catalyst for this reaction has not been identified. Persulfide is not only a strong antioxidant but it persulfidates regulatory cysteines that initiate a variety of transcriptional and post-transcriptional antioxidant, anti-inflammatory and cytoprotective defenses. Many of the "antioxidant" properties of LA can be explained by these RSS metabolic pathways. Image 1 [ABSTRACT FROM AUTHOR]

Life began in a ferruginous (anoxic and Fe2+ dominated) world around 3.8 billion years ago (bya). Hydrogen sulfide (H 2 S) and other sulfur molecules from hydrothermal vents and other fissures provided many key necessities for life's origin including catalytic platforms (primordial enzymes) that also served as primitive boundaries (cell walls), substrates for organic synthesis and a continuous source of energy in the form of reducing equivalents. Anoxigenic photosynthesis oxidizing H 2 S followed within a few hundred million years and laid the metabolic groundwork for oxidative photosynthesis some half-billion years later that slightly and episodically increased atmospheric oxygen around 2.3 bya. This oxidized terrestrial sulfur to sulfate which was washed to the sea where it was reduced creating vast euxinic (anoxic and sulfidic) areas. It was in this environment that eukaryotic cells appeared around 1.5 bya and where they evolved for nearly 1 billion additional years. Oxidative photosynthesis finally oxidized the oceans and around 0.6 bya oxygen levels in the atmosphere and oceans began to rise toward present day levels. This is purported to have been a life-threatening event due to the prevalence of reactive oxygen species (ROS) and thus necessitated the elaboration of chemical and enzymatic antioxidant mechanisms. However, these antioxidants initially appeared around the time of anoxigenic photosynthesis suggesting a commitment to metabolism of reactive sulfur species (RSS). This review examines these events and suggests that many of the biological attributes assigned to ROS may, in fact, be due to RSS. This is underscored by observations that ROS and RSS are chemically similar, often indistinguishable by analytical methods and the fact that the bulk of biochemical and physiological experiments are performed in unphysiologically oxic environments where ROS are artifactually favored over RSS. Image 1 • Sulfide (H 2 S) was key to the origin of life. • Nearly 80% of evolution occurred in sulfidic and hypoxic conditions. • Similarities between reactive sulfide species (RSS) and reactive oxygen species (ROS) blur the distinction between the two. • In extant organisms the significance of ROS may be over-estimated and the importance of RSS underappreciated. [ABSTRACT FROM AUTHOR]

Umbilical mesenchymal stem cells (USC) have been shown to reduce illness in animal models of necrotizing enterocolitis (NEC), possibly through the paracrine release of hydrogen sulfide (H 2 S). We hypothesized that animals treated with USCs with inhibited H 2 S synthesis would exhibit more severe disease. NEC was induced in five-day-old mouse pups by formula feeding and hypoxic and hypothermic stress. Experimental groups received intraperitoneal injection of either saline vehicle or 80,000cells/gram of one of the following cell types: USC, USCs with negative-control siRNA, or USCs with targeted siRNA inhibition of the H 2 S-producing enzymes. Pups were monitored by clinical assessment and after euthanasia, intestine and lung histologic injury were scored. Tissue was homogenized, and concentrations of IL-6, IL-10, and VEGF were determined by ELISA. For statistical analysis, p < 0.05 was considered significant. Animals treated with negative-control siRNA USCs were significantly improved compared to vehicle. Clinical sickness scores as well as intestinal and lung histologic injury scores in the targeted siRNA groups were significantly worse when compared to the negative-control siRNA group. IL-6, IL-10, and VEGF had varying patterns of expression in the different groups. Inhibition of H 2 S production in USCs reduces the beneficial effects of these cells during therapy in experimental NEC. Animal studies are typically described as "foundational evidence" without a true level assigned. Animal Study. [ABSTRACT FROM AUTHOR]

Elaborate antioxidant pathways have evolved to minimize the threat of excessive reactive oxygen species (ROS) and to regulate ROS as signaling entities. ROS are chemically and functionally similar to reactive sulfur species (RSS) and both ROS and RSS have been shown to be metabolized by the antioxidant enzymes, superoxide dismutase and catalase. Here we use fluorophores to examine the effects of a variety of inhibitors of antioxidant pathways on metabolism of two important RSS, hydrogen sulfide (H 2 S with AzMC) and polysulfides (H 2 S n , where n = 2–7, with SSP4) in HEK293 cells. Cells were exposed to inhibitors for up to 5 days in normoxia (21% O 2) and hypoxia (5% O 2), conditions also known to affect ROS production. Decreasing intracellular glutathione (GSH) with l -buthionine-sulfoximine (BSO) or diethyl maleate (DEM) decreased H 2 S production for 5 days but did not affect H 2 S n. The glutathione reductase inhibitor, auranofin, initially decreased H 2 S and H 2 S n but after two days H 2 S n increased over controls. Inhibition of peroxiredoxins with conoidin A decreased H 2 S and increased H 2 S n , whereas the glutathione peroxidase inhibitor, tiopronin, increased H 2 S. Aminoadipic acid, an inhibitor of cystine uptake did not affect either H 2 S or H 2 S n. In buffer, the glutathione reductase and thioredoxin reductase inhibitor, 2-AAPA, the glutathione peroxidase mimetic, ebselen, and tiopronin variously reacted directly with AzMC and SSP4, reacted with H 2 S and H 2 S 2 , or optically interfered with AzMC or SSP4 fluorescence. Collectively these results show that antioxidant inhibitors, generally known for their ability to increase cellular ROS, have various effects on cellular RSS. These findings suggest that the inhibitors may affect cellular sulfur metabolism pathways that are not related to ROS production and in some instances they may directly affect RSS or the methods used to measure them. They also illustrate the importance of carefully evaluating RSS metabolism when biologically or pharmacologically attempting to manipulate ROS. Image 1 • Reactive oxygen species (ROS) and reactive sulfide species (RSS) are chemically and biologically similar. • Evolution of antioxidant pathways is more consistent with RSS metabolism than with ROS metabolism • Here we show that canonical inhibitors of ROS antioxidant pathways affect RSS in HEK293 cells independent of ROS. • These results indicate that antioxidant pathways are involved in RSS metabolism in cells. • RSS may be the actual effector pathway(s) of ROS antioxidant therapies. [ABSTRACT FROM AUTHOR]

It is now well established that hydrogen sulfide (H 2 S) is an effector of a wide variety of physiological processes. It is also clear that many of the effects of H 2 S are mediated through reactions with cysteine sulfur on regulatory proteins and most of these are not mediated directly by H 2 S but require prior oxidation of H 2 S and the formation of per- and polysulfides (H 2 S n , n = 2–8). Attendant with understanding the regulatory functions of H 2 S and H 2 S n is an appreciation of the mechanisms that control, i.e., both increase and decrease, their production and catabolism. Although a number of standard “conventional” pathways have been described and well characterized, novel “unconventional” pathways are continuously being identified. This review summarizes our current knowledge of both the conventional and unconventional. [ABSTRACT FROM AUTHOR]

Abstract: Hydrogen sulfide (H2S) metabolism has been proposed as the oxygen (O2) sensing mechanism coupling hypoxia to effector responses in a variety of tissues including vascular and chemoreceptor cells. Implicit in this sensing system is a mechanism for regulating intracellular H2S concentration, presumably through oxidation. However, verification of this mechanism, or any other pathway of H2S signaling has been hampered by the lack of suitable methods for measuring intracellular concentration and distribution profiles. Here, intracellular H2S concentration profiles are modeled using simple monoexponential diffusion equations and current knowledge of H2S biosynthetic and metabolic pathways. The models predict that; (1) while both mitochondrial oxidation and simple diffusion out of the cell can reduce H2S concentration, the former is considerably more effective as an effector of intracellular H2S and (2) exogenously applied H2S may have unanticipated effects on endogenous signaling processes. In addition, these models provide additional support for mitochondrial H2S oxidation as the key couple in H2S-mediated O2 sensing. [Copyright &y& Elsevier]

Abstract: Hydrogen sulfide, H2S, is a colorless gas with a strong odor that until recently was only considered to be a toxic environmental pollutant with little or no physiological significance. However, the past few years have demonstrated its role in many biological systems and it is becoming increasingly clear that H2S is likely to join nitric oxide (NO) and carbon monoxide (CO) as a major player in mammalian biology. In this review, we have provided an overview of the chemistry and biology of H2S and have summarized the chemistry and biological activity of some natural and synthetic H2S-donating compounds. The naturally occurring compounds discussed include, garlic, sulforaphane, erucin, and iberin. The synthetic H2S donors reviewed include, GYY4137; cysteine analogs; S-propyl cysteine, S-allyl cysteine, S-propargyl cysteine, and N-acetyl cysteine. Dithiolethione and its NSAID and other chimeras such as, L-DOPA, sildenafil, aspirin, diclofenac, naproxen, ibuprofen, indomethacin, and mesalamine have also been reviewed in detail. The newly reported NOSH-aspirin that releases both NO and H2S has also been discussed. [Copyright &y& Elsevier]

Abstract: The concept that non-respiratory gases, such as nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) functioned as signaling moieties is a relatively recent development, due in part to their ephemeral existence in biological tissues. However, from an evolutionary perspective these gases dominated the prebiotic and anoxic Earth and were major contributors to the origin of life and the advent of eukaryotic animals. As Earth''s oxygen levels rose, NO, CO and H2S disappeared from the environment and cells began to utilize their now well-developed metabolic pathways to compartmentalize and regulate these three gases for signaling purposes. Ironically, many of the signaling pathways have become now intimately involved in regulating oxygen delivery and their evolution has continued well into the vertebrates. This review examines the role NO, CO and H2S played in early life and their regulatory roles in oxygen delivery during the course of vertebrate evolution. [Copyright &y& Elsevier]

Abstract: There is considerable controversy surrounding the initial step that transduces a fall in into a physiological signal, i.e., the “oxygen sensor” in chemoreceptors. Initial studies on systemic and respiratory vessels suggested that the metabolism of hydrogen sulfide (H2S) could serve as the oxygen sensor. This model was subsequently extended to chemoreceptors in fish and tissues of other animals. In this model, constitutive production of biologically active H2S is offset by H2S oxidation; when oxygen availability falls, production of H2S exceeds metabolism, and the resultant increase in intracellular H2S initiates the appropriate physiological responses. This model is supported by observations that the effects of hypoxia and H2S are similar, if not identical in many tissues: hypoxic responses are inhibited by inhibitors of H2S biosynthesis and augmented by sulfur donating molecules, and the tipping point between H2S production and oxidation occurs at physiologically relevant . Recent studies from other laboratories support this mechanism of O2 sensing in the carotid body. This review summarizes information that supports the H2S metabolic hypothesis in these tissues with emphasis on the carotid chemoreceptors. Evidence suggesting that H2S is not involved in oxygen sensing in the carotid body is also critically evaluated. [Copyright &y& Elsevier]

Abstract: Hydrogen sulfide (H2S) is gaining acceptance as a signaling molecule and has been shown to elicit a variety of biological effects at concentrations between 10 and 1000 μmol/l. Dissolved H2S is a weak acid in equilibrium with HS− and S2− and under physiological conditions these species, collectively referred to as sulfide, exist in the approximate ratio of 20% H2S, 80% HS− and 0% S2−. Numerous analyses over the past 8 years have reported plasma or blood sulfide concentrations also in this range, typically between 30 and 300 μmol/l, thus supporting the biological studies. However, there is some question whether or not these concentrations are physiological. First, many of these values have been obtained from indirect methods using relatively harsh chemical conditions. Second, most studies conducted prior to 2000 failed to find blood sulfide in micromolar concentrations while others showed that radiolabeled 35S-sulfide is rapidly removed from blood and that mammals have a relatively high capacity to metabolize exogenously administered sulfide. Very recent studies using H2S gas-sensing electrodes to directly measure sulfide in plasma or blood, or HPLC analysis of head-space gas, have also indicated that sulfide does not circulate at micromolar levels and is rapidly consumed by blood or tissues. Third, micromolar concentrations of sulfide in blood or exhaled air should be, but are not, malodorous. Fourth, estimates of dietary sulfur necessary to sustain micromolar levels of plasma sulfide greatly exceed the daily intake. Collectively, these studies imply that many of the biological effects of sulfide are only achieved at supra-physiological concentrations and they question whether circulating sulfide is a physiologically relevant signaling molecule. This review examines the blood/plasma sulfide measurements that have been reported over the past 30 years from the perspective of the analytical methods used and the potential sources of error. [Copyright &y& Elsevier]

Summary: The origins and actions of gaseous signaling molecules, nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) in the mammalian cardiovascular system have received considerable attention and it is evident that these three “gasotransmitters” perform a variety of homeostatic functions. The origins, actions and disposition of these gasotransmitters in the piscine vasculature are far from resolved. In most fish examined to date, NO or NO donors are generally in vitro and in vivo vasodilators acting via soluble guanylyl cyclase, although there is evidence for NO-mediated vasoconstriction. Injection of sodium nitroprusside into trout causes hypotension that is attributed to a reduction in systemic resistance. Unlike mammals, NO does not appear to have an endothelial origin in fish blood vessels as an endothelial NO synthase has not identified. However, neural NO synthase is prevalent in perivascular nerves and is the most likely source of NO for cardiovascular control in fish. CO is a vasodilator in lamprey and trout vessels, and it, like NO, appears to exert its action, at least in part, via guanylyl cyclase and potassium channel activation. Inhibition of CO production increases resting tone in trout vessels suggestive of tonic CO activity, but little else is known about the origin or control of CO in the fish vasculature. H2S is synthesized by fish vessels and its constrictory, dilatory, or even multi-phasic actions, are both species- and vessel-specific. A small component of H2S-mediated basal activity may be endothelial in origin, but to a large extent H2S affects vascular smooth muscle directly and the mechanisms are unclear. H2S injected into the dorsal aorta of unanesthetized trout often produces oscillations in arterial blood pressure suggestive of H2S activity in the central nervous system as well as peripheral vasculature. Collectively, these studies hint at significant involvement of the gasotransmitters in piscine cardiovascular function and hopefully provide a variety of avenues for future research. [Copyright &y& Elsevier]

Abstract: Two separate factor analyses of Big Five traits have independently identified two higher-order factors. These factors have been interpreted quite differently by their respective researchers. This conceptual paper posits the superordinate personality dimensions of Engagement (engaged versus disengaged) and Self-Control as the common elements of these higher-order factors. A review and integration of existing research shows that Engagement traits decline and Self-Control traits increase during adulthood. The Big Five traits of the Engagement dimension are each empirically related to positive affect, academic engagement in the form of classroom participation, benefiting from major life challenges, sensation seeking, and the construct of inspiration. Self-Control traits are negatively related to variables such as problematic work-related behaviors and job performance, personality disorders, negative affect, and attention deficit-hyperactivity disorder. [Copyright &y& Elsevier]

This study examined the relationship between two aspects of personality, fundamental motives and five-factor traits, and the three components of love (intimacy, passion, and commitment) in Sternberg''s Triangular Love Theory [Sternberg, R. J. (1998). Cupid''s arrow: The course of love through time. London: Cambridge University Press; Sternberg, R. J. (1986). A triangular theory of love. Psychological Bulletin, 93, 119–138]. Relationship satisfaction was also assessed. Conscientiousness was a significant predictor of love for both males and females in close opposite-sex relationships. The motives and personality subscales (facets) that were related to components of love and satisfaction differed for males and females. Reasons for these relationships and their implications are discussed. [Copyright &y& Elsevier]

The tegmentum vasculosum of the duckling consists of a highly folded epithelium which extends over the dorsal and lateral walls of the cochlear duct, separating the scala media from the scala vestibuli. This epithelium consists of two distinct cell types, dark cells and light cells, and is well vascularized. The surface of the epithelium is formed by a mosaic of alternating dark and light cells. The goblet-shaped dark cells have an electron-dense, organelle-rich cytoplasm, and are expanded basally by extensive basolateral plasma membrane infoldings, within which are numerous mitochondria. Dark cells are isolated from each other and from the capillaries within the epithelium by intervening light cells. In contrast, columnar light cells exhibit an electron-lucent, organelle-poor cytoplasm and may extend from the underlying capillaries to the endolymphatic surface. Light cells contain abundant, coated endocytic vesicles on their apical surfaces and are bound, apically, to other light cells or to dark cells by tight junctions and desmosomes. Laterally, light cells are linked to each other either by complex, fluid-filled membrane interdigitations or by extensive gap junctions. Plasma membrane interdigitations and obvious, fluid-filled intercellular spaces characterize the lateral borders between light and dark cells. Vascular corrosion casting reveals the three-dimensional anatomy of the cochlear vasculature. A continuous arteriolar loop fed by anterior and posterior cochlear arterioles encircles the cochlear duct. The rich capillary beds of the tegmentum vasculosum are supplied by arching arterioles arising from this loop. These capillaries are the continuous type and are situated primarily within the core of the epithelium or along its border with the scala vestibuli. The structure and blood supply of the tegmentum vasculosum are characteristic of an epithelium involved in active transport. [ABSTRACT FROM AUTHOR]

"Nothing in biology makes sense except in the light of evolution" (Theodosius Dobzhansky) and "For such a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied" (August Krogh); dictums that can be used to illustrate the past and provide a guide to the future. Although sulfur was integral in the origin of life, and nearly seven-eights of subsequent evolution, its physiological importance is largely overlooked because much of contemporary life it is based on oxygen and the adherent problems associated with oxygen deficit (hypoxia) or excess (oxidative stress). This graphical review will summarize sulfur's role in evolution and make a case that many of the regulatory activities attributed to oxygen and reactive oxygen species (ROS) can also be ascribed to reactive sulfur species (RSS). ROS and RSS are chemically similar and signal via identical cysteine residues on regulatory proteins and have identical downstream effector responses. Antioxidant mechanisms, generally attributed to the advent of an oxic existence, actually appeared over 2 billion years prior, in sulfur metabolizing organisms. Recent evidence suggests they are active in sulfur metabolism to this day. Understanding these aspects of ROS and RSS suggests that alternative mechanisms for oxidant/antioxidant pathways and therapies must be considered. As oxygen and reduced sulfur do not coexist, either in cells or the environment, it is also important to design and conduct experiments in oxygen levels that are physiologically relevant. For every experiment there are optimal conditions under which it must be studied. Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract: We used myography on five different arteries and three veins of the hagfish, Eptatretus cirrhatus, to test the response of vessels to vasoactive drugs. Concentration–response curves were generated for carbachol, endothelin-1, arginine vasotocin and the adrenergic agonists, phenylephrine and isoprenaline. pEC50 values indicated that veins were more sensitive to endothelin-1 than were arteries, but the arteries were more sensitive to the cholinergic agonist, carbachol. Segmental arteries did not react to arginine vasotocin, but all other vessels did, and on a molar basis it was the most potent agonist tested. That ventral and dorsal aortas were more sensitive to arginine vasotocin than smaller vessels might indicate that this neurohypophysial peptide has the potential to exert a profound influence on branchial vascular resistance and cardiac output in hagfishes. The results also demonstrate the potential for a variety of endogenous peptides to contribute to central venous tone. [Copyright &y& Elsevier]

Abstract: Hydrogen sulfide (H2S), nitric oxide (NO) and nitrite (NO2 −) are formed in vivo and are of crucial importance in the tissue response to hypoxia, particularly in the cardiovascular system, where these signaling molecules are involved in a multitude of processes including the regulation of vascular tone, cellular metabolic function and cytoprotection. This report summarizes current advances on the mechanisms by which these signaling pathways act and may have evolved in animals with different tolerance to hypoxia, as presented and discussed during the scientific sessions of the annual meeting of the Society for Experimental Biology in 2011 in Glasgow. It also highlights the need and potential for a comparative approach of study and collaborative effort to identify potential link(s) between the signaling pathways involving NO, nitrite and H2S in the whole-body responses to hypoxia. [Copyright &y& Elsevier]

Abstract: Terrestrial, but not aquatic, species of snakes have hepatic portal veins with a corkscrew morphology immediately posterior of the liver. Relatively large volumes of venous blood are associated with this region, and the corkscrew vein has been proposed to function as a bidirectional valve that impedes gravitational shifts of intravascular volume. To better understand the functional significance of the corkscrew anatomy, we investigated the histology and contractile mechanisms in isolated corkscrew segments of the hepatic portal vein of a yellow rat snake (Pantherophis obsoletus). Morphologically, the corkscrew portal vein is here shown to have two distinct layers of smooth muscle – an inner circular layer, and an outer longitudinal layer, separated by a layer of collagen, – whereas only a single circular layer of smooth muscle is present in the adjacent posterior caval vein. Low frequency (~0.3 cycles*min−1) spontaneous and catecholamine-induced rhythms were observed in 11% and 89% of portal vein segments, respectively, but neither spontaneous nor agonist-induced cycling was observed in adjacent posterior (non-corkscrew) caval veins. Catecholamines, angiotensin II, or stretch increased the amplitude and/or frequency of contractile cycles. Ouabain, verapamil or indomethacin, but not tetrodotoxin, α-, or ß-adrenergic receptor antagonists, inhibited cyclical contractions indicating a dependence of these cycles on Na+/K+ ATPase, extracellular Ca2+ and prostanoid(s). These data suggest that the rhythmic contractility of the corkscrew segment of the ophidian portal vein may act in conjunction with its morphological features to improve venous return and to prevent retrograde shifts of blood that might otherwise pool in posterior veins. [Copyright &y& Elsevier]