Is Timing as Critical With H2s Readings Why or Why Not

Antioxid Redox Signal. 2012 Jul 1; 17(1): 68–fourscore.

Roles of Hydrogen Sulfide in the Pathogenesis of Diabetes Mellitus and Its Complications

Received 2011 Dec ii; Revised 2011 Dec 5; Accustomed 2011 Dec eleven.

Abstract

Significance

Diabetes and its complications correspond a major socioeconomic problem.

Contempo Advances

Changes in the balance of hydrogen sulfide (H_twoS) play an important function in the pathogenesis of β-cell dysfunction that occurs in response to type i and blazon 2 diabetes. In addition, changes in H_twoS homeostasis likewise play a role in the pathogenesis of endothelial injury, which develop on the basis of chronically or intermittently elevated circulating glucose levels in diabetes.

Critical Issues

In the first part of this review, experimental evidence is summarized implicating H_twoS overproduction as a causative factor in the pathogenesis of β-prison cell death in diabetes. In the second part of our review, experimental prove is presented supporting the role of H_iiS deficiency (as a result of increased H₂Southward consumption by hyperglycemic cells) in the pathogenesis of diabetic endothelial dysfunction, diabetic nephropathy, and cardiomyopathy.

Future Directions

In the final section of the review, future research directions and potential experimental therapeutic approaches around the pharmacological modulation of H₂S homeostasis in diabetes are discussed.

Introduction

Hydrogen sulfide (H₂Due south) is a colorless, flammable, water-soluble gas with the characteristic smell of rotten eggs. Until recently, H₂Due south was viewed primarily as a toxic gas and environmental hazard. However, research conducted over the last decade demonstrates that H₂S is synthesized by mammalian tissues, and it serves various important regulatory functions (8, 41, 60, 61). There are multiple lines of evidence showing that H₂S modulates the role of β cells as well as that H₂Due south modulates and possibly mediates the injury of β cells, which underlies the pathogenesis of blazon 1 diabetes. Similarly, multiple lines of evidence implicate that changes in H₂S homeostasis contribute to the pathogenesis of endothelial dysfunction induced past elevated extracellular glucose. Endothelial dysfunction is a cardinal process in the pathogenesis of diabetic complications, because information technology is directly connected to the pathogenesis of various diabetic complications, including vascular dysfunction, neuropathy, nephropathy, retinopathy, and heart failure (27, 62). The electric current article provides an overview of the experimental evidence implicating H₂S as a pathophysiological effector in the pathogenesis of type 1 diabetes and in the pathogenesis of diabetic complications in vitro and in vivo.

H_twoS Regulates β Cell Part and Vascular Role

A growing body of data accumulating over the last decade shows that H₂S is synthesized past mammalian tissues via two cytosolic pyridoxal-5′-phosphate-dependent enzymes responsible for metabolism of l-cysteine—cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE)—likewise as by a mitochondrial tertiary pathway involves the production from l-cysteine of H₂S via the combined action of 3-mercaptopyruvate sulfurtransferase and cysteine aminotransferase (8, 41, lx, 61) (Fig. i). As a gaseotransmitter, H_twoS quickly travels through cell membranes without utilizing specific transporters and exerts a host of biological effects on a multifariousness of biological targets resulting in a variety of biological responses. Similarly to the other two gaseotransmitters (nitric oxide and carbon monoxide), many of the biological responses to H_twoS follow a biphasic dose–response: the effects of H_iiS range from physiological, cytoprotective effects (which occur at depression concentrations) to cytotoxic effects (which are generally only apparent at college concentrations) (lx). Depending on the experimental arrangement studied, the molecular mechanisms of the biological actions of H₂S include antioxidant effects, both via direct chemic reactions with diverse oxidant species, as well equally via increased cellular glutathione levels via activation/expression of gamma-glutamylcysteine synthetase; modulation of intracellular caspase and kinase pathways; stimulatory effects on the production of cyclic AMP and modulation of intracellular calcium levels; equally well equally opening of potassium-opened ATP channels (Thou_ATP channels) (41, 60, 61).

Schematic presentation of the three hydrogen sulfide (H₂South)-producing enzymes. H_twoS is synthesized by mammalian cells tissues via two cytosolic pyridoxal-5′-phosphate-dependent enzymes responsible for metabolism of l-cysteine: cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), besides as by a mitochondrial 3rd pathway involves the production from 50-cysteine of H₂S via the combined action of 3-mercaptopyruvate sulfurtransferase (3-MST) and cysteine aminotransferase (CAT).

The biological roles of endogenous H_iiS are multiple and rapidly expanding. Its regulatory functions span the primal and peripheral nervous system, the regulation of cellular metabolism, regulation of immunological/inflammatory responses, and various aspects of cardiovascular biology (21, 41, 60, 61). For the purpose of the current article, we restrict our discussion to a cursory overview the physiological roles of H₂S in the endocrine pancreas (relevant for the pathogenesis of diabetic β-cell injury) and in the vascular endothelium (relevant for the pathogenesis of diabetic cardiovascular complications).

In the pancreas, both CSE and CBS are involved in the production of H₂S (twoscore). The production of high levels of H₂Southward has been demonstrated in pancreatic β-cell lines (1, 40, 76). For instance, H_iiSouth production in homogenates of rat (INS-1E) and hamster (Striking-T15) β-prison cell lines was demonstrated in the presence of l-cysteine (ane, 76). Significant H₂S production was besides reported in the mouse insulin-secreting cell line MIN6 (twoscore). Interestingly, expression of CSE, but not CBS, dramatically increased in the islet cells after glucose stimulation, resulting in increased H₂S production in these cells (39). In contrast, glucose stimulation has been reported to subtract the H_iiDue south-producing activity in the homogenates of INS-1E cells (76). The contradictory furnishings of glucose on H_twoS production may be due to species-specific differences in the conditions for gene induction of CSE and/or cell-type differences. Although the precise functional part of H₂S in pancreatic β-cells remains to be investigated in additional detail, according to most studies, intraislet H₂South exerts a physiological inhibitory effect on insulin release (1, xl, 41, 76]. This inhibition occurs via multiple mechanisms (opening of K_ATP channels, decrease of cellular ATP levels, and regulation of intracellular Caⁱⁱ⁺ concentration) (1, 46): the relative contribution of these mechanisms remains to be antiseptic.

In the cardiovascular organization, the principal enzyme involved in the formation of H₂Due south is CSE, expressed in vascular endothelial cells, smooth muscle cells, and cardiac myocytes (41, 60, 61). The vascular regulatory roles of H₂S include vasodilatation, vascular protection, and the stimulation of angiogenesis (59, 75). The multiple roles of H_twoS in vascular and cardiac physiology have been subject of recent reviews (41, 59–61).

Part of H₂S in the Pathogenesis of Autoimmune β-Cell Death in Type 1 Diabetes

Type ane diabetes (or insulin-dependent diabetes mellitus) is an autoimmune affliction occurring predominantly in children and young adults resulting in devastation of the pancreatic β-cells. Information technology is characterized past prolonged periods of hyperglycemia, via reduced uptake of glucose and relative increase in glucagon secretion and gluconeogenesis. The destruction of the islet β-cells is caused by an autoimmune set on involving an initial hyperexpression of grade I major histocompatibility circuitous (MHC) molecules by all of the islet endocrine cells, which is followed by β-cell exclusive expression of MHC form II molecules. Expression of the MHC proteins induces an insulitis, whereby the islet is islet infiltrated past mononuclear cells, including lymphocytes, macrophages, and plasma cells. The actual trigger for the process of β-cell devastation is all the same unknown, but it has been proposed that information technology is an external factor (viral, chemic) or an internal stimulus (cytokines, gratuitous radical) which damages a proportion of the β-cells, leading to release of specific β-cell proteins, which can be taken upwards by antigen presenting cells and candy to antigenic peptides (37, 38, 70).

The potential role of H_iiS in the pathogenesis of type 1 diabetes was initially investigated using in vitro model systems. These investigations yielded somewhat conflicting results, presumably due to the substantial differences in the experimental weather employed, besides as the biphasic nature of the pharmacological deportment of H_twoS that include cytoprotection at lower concentrations, likewise as cytotoxicity at higher local levels (60). Yang and colleagues have demonstrated that H₂S assistants or CSE overexpression results in the expression of endoplasmatic reticulum (ER)-stress-related molecules and apoptosis in rat insulinoma INS-1E cells, and showed that this effect was mediated past p38 MAP kinase activation (76). The same grouping later demonstrated that streptozotocin-induced death of the same insulinoma cells can be prevented by pharmacological inhibition of CSE, indicating an active pro-apoptotic role of endogenously produced H₂S in this system and information technology occurs via the activation of ER stress also as mitogen-activated protein (MAP) kinases (76). In contrast, other groups accept reported that H₂S may act equally a cytoprotective hormone in mouse islets and in MIN6 cells exposed to high glucose, fat acids, or a mixture of cytotoxic cytokines (39, 64). The cytoprotective effects included both a protection from loss of viability, and a prevention of the deterioration of insulin secretion in response to elevated glucose (64).

Only a limited number of studies accept investigated the role of H₂S in the pathogenesis of blazon i diabetes in vivo. Moore and colleagues demonstrated the induction of H₂S-producing enzyme CBS (merely not of CSE) in the pancreas of animals treated with the β-prison cell toxin streptozotocin (79). Moreover, in Zucker diabetic fat rats (a diabetic model with obesity and hyperinsulinemia), CSE expression was found to exist upregulated in the islets (73). Overall, these observations suggested that intrapancreatic or intraislet H_iiSouth production is increasing in various models of diabetes. The question, then arose, whether this increment in intraislet H₂South biosynthesis is part of a protective machinery (whereby increased H_iiSouth levels counteract the increased oxidative/nitrosative stress atmospheric condition during the process of islet cell death), or, alternatively, is it office of the pathophysiology of the illness (suppressing insulin production and contributing to β-cell devastation)? Studies from Wang's laboratory have recently provided testify for the latter pathomechanism (74). Using pharmacological tools (dl-propargylglycine, a pharmacological inhibitor of CSE) an comeback of glycemic command was demonstrated in the Zucker diabetic model (73). Similarly, treatment of mice subjected to streptozotocin-diabetes with the CSE inhibitor dl-propargylglycine protected the animals from hyperglycemia and hypoinsulinemia (74). Finally, CSE knockout mice subjected to streptozotocin exhibited a delayed onset of diabetic condition (74). Histopathological evaluation of the pancreas of these animals revealed that CSE-scarce animals maintained a larger number of functional β-cells and maintained higher intraislet insulin levels (74).

How, then, can i reconcile the contrasting (cytoprotective or cytotoxic) effects of H₂S in the in vitro islet studies with the in vivo studies demonstrating overexpression of H₂S-producing enzymes in the islets of animals that develop diabetes, and with the in vivo studies showing that CSE inhibition or CSE deficiency protects against the onset of diabetes in the streptozotocin model? Why would the body purposefully overexpress a cytotoxic hormone in its β-cells, thereby actively contributing to their destruction? Although much more than work needs to be conducted to accost all mechanistic aspects of the procedure, we propose the following working hypothesis (Fig. 2). Nosotros hypothesize that in the early phase of diabetes development, a loftier-glucose-induced pancreatic CSE overexpression may serve as a protective mechanism, because it may neutralize oxidative/nitrosative stress and autoimmune attack. All the same, equally a past-product of this procedure, an increase in intraislet H₂S production may lead to an inhibition of insulin product via K_ATP aqueduct activation, and the resulting increase in circulating glucose may atomic number 82 to progressive β-cell toxicity. Nosotros further speculate that—equally this positive feedback cycle amplifies—local levels of H_twoSouth may reach a threshold concentration where an autocrine-blazon cytotoxic response may exist induced. This response may be especially prominent on a background of an oxidant-mediated and autoimmune attack against the β-cell (i.e., in a cell that has weakened cellular defenses). Ultimately, the above processes may culminate a progressive destruction (apoptosis) of the β-cells. However, it must be noted that in that location are marked species differences in the regulation of CSE expression in islets (65). For example, H₂Southward production can exist increased past hyperglycemia, which has been observed in mouse islets and MIN6 cells (65), only not in rat insulinoma cells (80). It should be also noted that the hypothesis that increased product of H_iiSouth is eventually toxic ex vivo has been proven in rat INS-1E insulinoma cells (76) merely non in normal mouse islets or MIN6 cells (39, 64). Thus, the above working hypothesis also as additional mechanistic details of the role of H_iiSouthward in diabetic β-jail cell destruction need to be further elucidated in hereafter studies.

A working hypothesis depicting the cytoprotective and cytotoxic roles of H₂S in the β-cell during diabetes development. We hypothesize that in the early stage of diabetes development, a high-glucose-induced pancreatic CSE overexpression may serve as a protective machinery, considering it may neutralize oxidative/nitrosative stress and autoimmune assail. However, as a by-production of this procedure, an increase in intraislet H₂S production may lead to an inhibition of insulin production via potassium-opened ATP channels (K_ATP) aqueduct activation, and the resulting increase in circulating glucose may lead to progressive β-prison cell toxicity, which, ultimately, results in a lowering of circulating insulin levels. We further speculate that—as this positive feedback cycle amplifies—local levels of H₂S may reach a threshold concentration where an autocrine-blazon cytotoxic response may be induced. This response may be especially prominent on a groundwork of an oxidant-mediated and autoimmune attack against the β-jail cell. Ultimately, the above processes may culminate a progressive destruction (apoptosis) of the β-cells, leading to hypoinsulinemia and further hyperglycemia. ROS, reactive oxygen species; RNS, reactive nitrogen species.

Office of H₂S in the Pathogenesis of Diabetic Complications

The quality of life and life expectations of diabetic patients are adamant past the complications of the affliction. Endothelial dysfunction is a well-documented complexity in diverse forms of diabetes, and in prediabetic individuals. The pathogenesis of this endothelial dysfunction includes increased polyol pathway flux, altered cellular redox state, increased formation of diacylglycerol, activation of specific protein kinase C isoforms, and accelerated nonenzymatic formation of advanced glycation endproducts (27, 62). Many of these pathways trigger the production of oxygen- and nitrogen-derived oxidants and free radicals, such every bit superoxide anion and peroxynitrite, and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP), which play a significant role in the pathogenesis of the diabetes-associated endothelial dysfunction and other diabetic complications. While the cellular sources of reactive oxygen species (ROS) such every bit superoxide anion are multiple and include advanced glycation endproducts, NADH/NADPH oxidases, the mitochondrial respiratory chain, xanthine oxidase, the arachidonic acid cascade, and microsomal enzymes, a dysregulated mitochondrial electron ship concatenation is increasingly being recognized as the central effector in this procedure (27, 62).

H₂S plays multiple protective roles in the vascular system, effecting vasodilatation, angiogenesis, inhibition of leukocyte adhesion, and cell death processes (Fig. 3) (45). In the context of hyperglycemic endothelial dysfunction, information technology is important to consider the local, biologically active levels of H₂S that the blood vessels really experience. As discussed in the previous department, several studies suggested the induction of H₂South-producing enzymes CBS and/or CSE in the pancreas in rats treated with the pro-diabetic β-cell toxin streptozotocin (79), and similar findings pertain to the liver and kidney of streptozotocin-diabetic rats (78, 79). On the other hand, Denizalti and colleagues failed to demonstrate significant alterations in CSE mRNA in the thoracic aorta of rats subjected to diabetes (14), and our recent study failed to demonstrate whatever notable changes in the expression of CSE or CBS in the brain, heart, kidney, lung, liver, or thoracic aorta of rats subjected to streptozotocin diabetes (58). Thus, H₂S-producing enzymes may or may not go upregulated in various models of diabetes, perhaps depending on the experimental model and/or the severity of the disease (but it appears that they are certainly not downward-regulated). In dissimilarity to these enzyme expression data, yet, the circulating H₂S levels in creature models of diabetes are either decreased, as shown in studies using streptozotocin-model of diabetes (33, 58) and in a study past using the nonobese diabetic (NOD) mouse model (v) or tend to decrease (as seen in another streptozotocin-diabetic rat model) (79). Furthermore, lower circulating H_twoDue south levels accept been detected in plasma samples of type 2 diabetic patients by 2 independent groups of investigators (33, 71).

Summary of the physiological actions of H₂S in blood vessels. H_iiS is produced in the cardiovascular organization and exerts a number of critical effects on the cardiovascular organization. H₂S has been shown to induce vasodilation and inhibit leukocyte-endothelial prison cell interactions in the circulation. H_iiS is a potent antioxidant and inhibits cellular apoptosis. H₂Southward also has been shown to transiently and reversibly inhibit mitochondrial respiration. Taken together, this physiological contour is ideally suited for protection of the cardiovascular system against illness states. Reproduced with permission from ref. (45).

This paradox of the unchanged or potentially increased tissue H₂Due south production versus the lower circulating H₂Southward may be resolved by our contempo studies demonstrating that hyperglycemic endothelial cells show an increased rate of H_twoS consumption due to ROS generation (58). We know from the original studies of Kraus and colleagues that product and consumption of H₂South is a dynamic procedure in tissues (sixteen). We have recently observed that endothelial cells placed in elevated glucose weather consume both exogenous and endogenous H₂South compared to cells that are grown in normal extracellular glucose (58). This accelerated H₂S consumption can be reduced past either treatment of the cells with ROS scavengers, or treatment with mitochondrial uncoupling agents, pointing to the importance of mitochondrially derived ROS in this procedure (58). The pathophysiological implication of the higher up findings is that in hyperglycemia, the increased mitochondrial ROS production is the cause of a relative H₂S deficiency in endothelial cells.

The next question, then, became, whether modulation of endothelial H₂S levels (either by inhibiting it or by supplementing it) affects hyperglycemic endothelial cells functionally. We have shown that inhibition of H_iiS production (by CSE siRNA silencing) exacerbates ROS production in hyperglycemic endothelial cells, while supplementation/replacement of H₂S (either by pharmacological ways or past adenoviral overexpression of CSE) reduces mitochondrial ROS production and protects the cells from hyperglycemic prison cell dysfunction (58). Based on these findings, we hypothesized that H₂South provides a physiological reducing/antioxidant intracellular environment inside the endothelial cells, which helps to maintain normal mitochondrial role (58). Our results suggest that this residual becomes perturbed when mitochondrial ROS production is stimulated by hyperglycemia. We hypothesized, therefore, that the ROS from hyperglycemic mitochondria directly reacts with and consumes the intracellular H₂S, which then creates additional mitochondrial dysfunction, possibly by oxidative modification to mitochondrial proteins and proposed that such a positive feed-forward cycle may so culminate in a dysfunctional mitochondrial state where molecular oxygen is utilized to produce ROS (as opposed to ATP), and where mitochondrial efficacy is diminished (58). Our data indicate that the higher up sequence of events, ultimately, leads to a loss of mitochondrial membrane potential and, finally, a spillage of ROS to the cytosolic and nuclear compartments, which contributes to the development of hyperglycemic endothelial cell dysfunction (Fig. 4) (58). One of the pathways that are and then triggered is the activation of the nuclear enzyme PARP, which—as demonstrated in previous studies (26, 51)—is known to pb to an impairment of endothelium-dependent relaxations in hyperglycemia and diabetes. The activation of this enzyme, likewise as the degree of DNA breakage (which is the proximal cause of PARP activation), is attenuated by H_twoDue south in hyperglycemic endothelial cells (Fig. 5) (58). Taken together, the data show that supplementation of H₂South to hyperglycemic endothelial cells exerts marked protective effects. Like conclusions were fatigued by an contained grouping of investigators, who take demonstrated that handling with H_twoS protects human umbilical vein endothelial cells against high glucose-induced apoptosis (29).

Proposed scheme of H₂S/ROS interactions in hyperglycemic endothelial cells. In normal endothelial cells, physiological product of H₂S (as well as many other antioxidant systems) protects against oxidative stress generated past the mitochondria, and mitochondrial ROS do not spill over to the cytosolic or nuclear compartment. When cells are placed in elevated glucose, mitochondrial ROS product gradually consumes H_iiS. This process, coupled with the depletion of other antioxidant defenses, eventually culminates in the spillage of ROS into the cytosolic and nuclear compartments. ROS product, ultimately, on its own, or past combining with nitric oxide (NO) to form peroxynitrite (ONOO⁻), activates multiple pathways of diabetic complications, such as the nuclear enzyme poly(ADP-ribose) polymerase (PARP), the polyol pathway, the advanced glycation endproduct system (AGE), protein kinase C (PKC), and the hexosamine system. Supplementation of H₂S can protect against these processes.

Replacement of H₂S attenuates cellular responses that lay downstream from hyperglycemic mitochondrial ROS production in curve.3 endothelial cells. (a) DNA strand breakage was measured in low (5.v kM, LG) or high (40 one thousandM, HG) glucose conditions at 7 days using the Comet assay. High glucose induced an increase in DNA strand breakage every bit compared with depression glucose (*p<0.05) and H_twoSouthward (300 μThou) afforded a significant suppression of this response (#p<0.05). In the inset, representative images are shown for the four respective groups (LG/HG with and without 300 μThou H_twoS). (b) Activation of the nuclear enzyme PARP was measured by detection of the poly(ADP-ribose) polymers using western blotting. Loftier glucose induced an increase in PARP activation (*p<0.05) and H₂S (300 μM) afforded a suppression of this response (#p<0.05). In the insert a representative western blot is shown for the four respective groups (low and high glucose with and without 300 μYard H₂S). Reproduced with permission from ref. (58).

We next investigated what functional role does the modulation (inhibition or supplementation) of H₂Southward production take on the loss of endothelium-dependent relaxant role in hyperglycemic or diabetic blood vessels. One of the simplest models to study diabetic vascular dysfunction is to incubate isolated vascular rings in elevated extracellular glucose, followed by the measurement of isometric contractions and relaxations. Using this organisation, we have demonstrated that the absence of vascular H₂S production (i.e., rings from CSE deficient mice) accelerates the development of endothelial dysfunction in rings placed into elevated extracellular glucose, whereas supplementation of H₂South by pharmacological supplementation or by overexpressing CSE (Fig. 6) protects the claret vessels against this process (58).

CSE overexpression protects confronting the development of endothelial dysfunction in thoracic aortic rings placed in elevated extracellular glucose. (a) Rat aortic rings were incubated in low (5.5 mOne thousand, LG) or high (40 mM, HG) glucose for 48 h. High glucose induced a suppression of endothelium-dependent relaxant responses (*p<0.05), an issue that was attenuated in the rings overexpressing CSE (#p<0.05). northward=4. (b) Depicts representative western blots and densitometric assay for CSE in rings exposed to adenovirus expressing greenish fluorescent poly peptide (GFP) or CSE. **p<0.01 shows a pregnant upregulation of CSE. Reproduced with permission from ref. (58).

The protection of H_twoS past diabetic cardiac or vascular dysfunction tin besides exist demonstrated in vivo, in rodent models of diabetes. In a rat model of streptozotocin-induced diabetes, we have recently demonstrated that supplementation of H₂S (applied by a H₂S-releasing minipump) corrects the subtract in plasma H₂Due south levels, and improves the endothelium-dependent relaxant responses of the thoracic aorta ex vivo, without affecting the degree of hyperglycemia (Fig. 7) (58). Also, in an independent study focusing on diabetic renal dysfunction, treatment of streptozotocin-diabetic rats with intraperitoneal H_twoS reduced the diabetes-induced increases in claret urea nitrogen levels, and attenuated renal collagen and tumor growth factor β1 (TGF-β1) expression (78), without affecting the degree of hyperglycemia. Furthermore, in a streptozotocin model of diabetic cardiomyopathy, intraperitoneal or oral assistants of H_twoSouth was plant to reduce myocardial hypertrophy, improved the histological picture of the diabetic hearts, and reduced the degree of fibrosis (19). These effects were associated with marked reductions in the up-regulation of matrix metalloproteinase 2 and TGF-β1 in the hearts of H₂S-treated diabetic animals. Furthermore, H_iiS therapy resulted in an improved antioxidant status, evidenced by elevated levels of glutathione levels and reduced levels of myocardial hydroxyproline (19). However, in contrast to our written report, the study of El-Seweidy and colleagues institute that H₂S therapy also improved the diabetic status (evidenced by reduced caste of hyperglycemia and increased levels of insulin and C-peptide). Thus, the improvements in myocardial improvements in this report may non be due to a directly issue of H₂S to the inflammatory and redox processes in the myocardium, just may be due to the reduced degree of hyperglycemia in the H_iiSouth-treated animals. The differing effects of H₂S on the streptozotocin-induced hyperglycemia are unclear and require boosted investigation; as noted above, in 2 out of three studies, no upshot was seen (58, 78), whereas in one study, in that location was an improvement of diabetic condition (19). Taken together, the above information suggest a protective effect of H₂South against diabetic vasculopathy, nephropathy, and cardiomyopathy. These effects may be mediated by antioxidant effects also as by the suppression of pro-fibrotic mediator expression.

Comeback of endothelial function by H_twoS in diabetic rats ex vivo . (a) Streptozotocin-diabetic vehicle-treated rats (STZ/V) exhibit reduced blood H₂S levels (*p<0.05), an result that is normalized by supplementation of H₂S using the H_twoS-releasing minipumps (STZ/Due south; #p<0.05). (b) The streptozotocin-induced hyperglycemic response is unaffected by H_twoSouthward-releasing minipumps: *p<0.05 shows pregnant and comparable degree of hyperglycemia in STZ rats treated with vehicle or H₂S-releasing pumps, compared to initial blood glucose values. (c) The thoracic aortas of streptozotocin-diabetic rats (STZ/Five) showroom reduced endothelium-dependent relaxant part in response to acetylcholine (1 nThou–30 μYard; *p<0.05); supplementation of H_iiS using the H₂South-releasing minipumps (STZ/S) adulterate the degree of this endothelial dysfunction (#p<0.05). Reproduced with permission from ref. (58).

H₂South and Diabetes: Unanswered Questions and Future Directions

The field of H₂S and diabetes, or H₂S and diabetic complications is a new and expanding research area. The sections below represent a partial list of open questions and potential future research directions.

The conflict of H₂Southward-mediated protection versus cytotoxicity in β-cells

As it is credible from the earlier section of this review, there is a clear conflict in the field as to whether H_iiS is cytoprotective or cytotoxic in β-cells in vitro. H₂South exerts biphasic responses to prison cell viability (lower concentrations tends to be cytoprotective, while higher concentrations begin to exert cytotoxicity). While it is likely that the total range of cytoprotective or cytotoxic mechanisms of H₂S are not fully understood, a number of mechanisms accept been identified to contribute to both the pro-survival/cytoprotective effects of H₂S, and to the cytotoxic effects. Cytoprotective mechanisms include various direct and indirect antioxidant/redox/based mechanisms (x, 34, 35); upregulation of antioxidant pathways and mechanisms such as thioredoxin (35), Nrf2 (9, 24), and Hsp90 (77); modulation of cytoprotective kinase pathways (43); and possibly a straight energetic machinery whereby H_twoS can donate electrons to mitochondrial Complex Two, thereby enhancing ATP germination (28, 42). Cytotoxic mechanisms include pro-oxidative cellular responses and the depletion of antioxidants (17, 68), release of gratuitous intracellular iron, DNA injury, and the inhibition of mitochondrial Complex Four, resulting in the inhibition of mitochondrial role (3, 31, 48, 66) (Fig. 8). Equally far as the effects of H₂S in β-cells, however, a concentration-based explanation can requite a only partial reply, equally the concentrations used in the bachelor reports practice not necessarily support the in a higher place simplistic view. While cell type differences, cell culture conditions, times of exposure, and other weather condition may explain some of these differences, a bigger question remains to be answered: Does H₂Southward in vivo in pancreatic β-jail cell exert cytotoxic or cytoprotective furnishings?

Cytotoxic/cytoprotective effects of H₂S. Under low oxidative stress weather condition, H₂S exerts cytoprotective effects at low concentrations, but becomes cytotoxic at higher concentrations. However, under loftier levels of baseline oxidative/nitrosative stress, H_twoS exerts cytoprotective furnishings. Encounter text for more detailed delineation of the pathways/mechanisms involved in each response.

The role of H_twoSouthward in diabetic β-jail cell destruction

Further to the last point, additional work needs to be conducted on the role of endogenously produced H₂South in the pathogenesis of autoimmune β-cell destruction. From the recent study of Wang and colleagues using a streptozotocin model of diabetes in mice, information technology appears that intraislet H₂Due south, in office produced in directly response to streptozotocin activity on islet cell G_ATP channels, induces intraislet H_twoS production, which then contributes to the death of the β-cells (74). However, the streptozotocin model (while it is an acceptable model of diabetic hyperglycemia and associated complications) is an imperfect model to report the evolution of β-cell destruction; autoimmune models are generally considered closer to the human disease. Currently, in that location are no interventional studies on the function of H₂S in the pathogenesis of diabetes in autoimmune models of diabetes (such as the NOD model); a cross of the CSE-deficient mice with the NOD mice may answer this question.

The regulation of H_twoS-producing enzymes in diabetes

As discussed earlier, at that place are conflicting reports in the literature as to whether CSE and/or CBS is upregulated in diabetes; in some studies no alter was seen; in others an upregulation was reported. It is possible that these alterations are cell type- and tissue-dependent; information technology is also possible that these alterations are different at dissimilar times or different severity of the disease; these questions as well equally the actual molecular regulation of these enzymes on the signal transduction and transcription/translational level need to exist investigated in additional detail in time to come studies.

The levels of H₂S in biological fluids in general and in diabetes in specific

I of the biggest controversies in the field of H_iiS relates to the quantification of biological levels of H₂Southward. As discussed in several articles, the absolute value of the H₂South level in extracellular fluids or in plasma depends on the experimental method used (due east.g., derivatization of H₂S with monobromobimane, or other methods, or measurement using the methylene bluish assay, or free H_twoSouth gas measurements using headspace analysis, or readings taken by H₂S electrode), also as the tissue blazon studied, with vascular tissues exhibiting essentially high levels than many other tissues (46, 49, 56, 72). While the current review cannot offer a articulate resolution to this discrepancy, it is of import to emphasize that farther work is needed to resolve this upshot, and, in the meantime, the method of detection must be taken into pregnant consideration when interpreting the information obtained by various groups and methodologies. Every bit far equally H₂S levels in diabetes, it appears to exist consequent across most beast models of diabetes, likewise equally the small amount of human information, that H_iiS levels subtract in the circulation. However, in the diabetic Zucker rats (an animal model of type 2 diabetes), patently the circulating H_iiDue south levels are increased (73): the relevance of this finding is non known at the moment. Boosted work needs to be done to determine the effect of diabetes specifically on the costless forms of H₂S in the circulation. Both animals and humans breathe significant amounts of H₂Due south (32, 67); measurements of exhaled H_iiDue south in diabetic animals or patients with diabetes may be a possible approach to address this question. Farther work too needs to exist conducted to make up one's mind the verbal role of obesity versus diabetic status on the modulation of circulating H₂S levels; a recent study suggests that obesity is a significant contained contributing gene to lower circulating H₂S levels in diabetes (71).

Another, rather contentious issue to be mentioned here, which also relates to the discrepancy of the biological levels of H₂South, is the amount of biologically relevant H_twoDue south in studies where it is supplemented/added to cells or tissues. Given the fact that at that place is no clear understanding in the literature as to what the endogenous concentrations of H₂S are, it is hard to determine what concentration of H_iiS can be considered physiological when added to cells or tissues. Clearly, the published concentrations of H₂Southward (including the studies discussed in the current review) range from depression μChiliad to several hundreds of μM. Information technology must exist noted, however, that these concentrations stand for initial and extracellular concentrations. When H_twoS is added to culture medium, its concentration rapidly decreases due to a combination of outgassing, reaction with oxygen and oxidants in the medium, as well every bit due to biological decomposition (active metabolism) by the cells. Although the intracellular concentrations take non yet been measured, nosotros tin can assume that they are essentially lower than the initial, extracellular concentrations that the experimenters take started out with. Clearly, much additional work is required to resolve this event.

The molecular details of the regulation by H₂S of the hyperglycemic endothelial dysfunction

Our recent studies (58) accept demonstrated that hyperglycemic endothelial cell damage is exacerbated in the absence of endogenous H₂S and is protected by H₂S supplementation. Nosotros have investigated several intracellular processes (mitochondrial ROS formation, mitochondrial membrane permeability transition, switch between oxidative phosphorylation, and glycolysis), and a express number of downstream processes (Dna damage and PARP activation), but the potential regulation by H₂S of many boosted pathways relevant to diabetic complications remain to be explored (activation of pro-inflammatory signaling, activation of protein kinase C, upregulation of pro-fibrotic mediators, potential changes in mitochondrial biogenesis and mitochondrial fission, etc.) In add-on, the nature of the high glucose-induced mitochondrial dysfunction (due east.thousand., specific transcriptional or mail-translational changes to specific mitochondrial proteins), and the potential regulation by H_iiS of these processes remains to be elucidated.

The functional consequences of the regulation by H₂Southward of diabetic endothelial dysfunction on the development of diabetic complications

While several lines of very interesting information beginning to emerge showing that H₂S improves diabetic vasculopathy (58), nephropathy (78), and cardiomyopathy (19), there are no published data then far on the potential event of H_twoS on diabetic retinopathy, diabetic erectile dysfunction, and the accelerated atherosclerosis in diabetes. Fifty-fifty in the published models, at that place are some pregnant gaps. The information on vasculopathy are currently restricted on macrovasculature (just not microvasculature) (58), the data on cardiomyopathy are restricted on histological and biochemical alterations (lacking functional information, e.g., myocardial contractility) (19), and the data on nephropathy are, in some respects, functionally inconclusive (eastward.g., H₂Southward appears to normalize claret urea nitrogen levels but evidently does not bear upon creatinine levels) (78). Studies in autoimmune diabetes models (due east.g., the NOD mice or the db/db mice) are besides needed. In addition, the therapeutic window of the action of H₂South (pretreatment vs. post-treatment, intermittent treatments, rebound effects after discontinuation, etc.) needs to be investigated, and longer-term studies need to be performed.

Regulation of angiogenesis by H_iiSouthward: potential relevance for diabetic retinopathy, diabetic wound healing, and diabetic foot disease

Emerging data support the role of H_iiS in the regulation of angiogenesis. Addition of H₂S promotes endothelial cell proliferation, migration, and tube formation, while inhibition of H_twoS production attenuates these processes (Fig. 9) (6, 53, 59). Furthermore, the pro-angiogenic effect of vascular endothelial growth cistron (VEGF) is mediated by the endogenous production of H₂S; pharmacological inhibition or siRNA knock-down of CSE attenuates VEGF-induced angiogenesis (53). Finally, wound healing is accelerated after H_iiSouth supplementation, while it is delayed in the CSE-deficient mice, when compared to corresponding wild-type animals (53). The H_twoS-mediated angiogenic phenomena have not yet been investigated nether the weather of hyperglycemia or diabetes, and this remains an interesting future enquiry management. One tin can speculate that inhibition of H₂S biosynthesis may have uses in hyperproliferative weather (perhaps inhibition of H₂Due south biosynthesis may accept a therapeutic utility in diabetic retinopathy), whereas H₂S supplementation may accept a therapeutic utility to ameliorate wound healing in diabetic patients.

Pathways involved in the pro-angiogenic effects of H₂S in endothelial cells. Further work needs to determine whether diabetes/hyperglycemia modulates these pathways.

The potential protective outcome of H₂S against myocardial reperfusion injury in diabetic patients

Diabetic patients have an increased incidence of myocardial infarction and other acute cardiac events, at least in part due to increased oxidative/nitrosative stress (fifteen). In this context information technology is interesting to mention that H₂S administration exerts marked protective effects in rodent and large animal models of myocardial ischemia-reperfusion injury (twenty, 57, 63), and that H_twoS elicits cardioprotection by myocardial pre and postconditioning (nine, 36, 52). Co-ordinate to a recent written report, H₂Southward also exerts cardioprotection against myocardial reperfusion in diabetic rats (25). Much additional work needs to be conducted in this area in society to expand on these findings, and to study the consequence of H₂Due south in diabetic animals in reperfusion injury of organs other than the eye, on the evolution of congestive cardiomyopathy, as well as on the process of postischemic angiogenesis. It also needs to be investigated whether or not the preconditioning consequence of H_twoS is maintained in diabetes, because it is known that the efficacy of many preconditioning approaches is diminished in diabetes (xiii, 23).

Role of H₂S in the development of insulin resistance in diabetes and in metabolic syndrome

Although several studies have begun to characterize the potential function of H₂S in the regulation of tissue glucose uptake, in insulin resistance, the body of the published literature is inconclusive and conflicting. In an in vitro study, H_iiSouthward was found to inhibit glucose uptake into adipocytes (22). Furthermore, in an insulin resistance model in rats induced past fructose feeding, a negative correlation was found between glucose uptake into fat tissue and the corporeality of H₂S produced past the same tissue (22). These information would contend for a potential active role of H₂S in the pathogenesis of insulin resistance, and would peradventure advise that pharmacological inhibition of H_iiS may be a possible therapeutic arroyo. This notion, withal, is not supported by a second report where H_twoS was not found to have any event on the evolution of insulin resistance in diabetic rats (54). Clearly, additional studies need to exist conducted to bring clarity and mechanistic insight into this very important area.

Conclusions and Therapeutic Implications

Information technology appears that inhibition of pancreatic H_twoDue south biosynthesis emerges equally a potential approach to protect β-cells from destruction during the induction stage of diabetes, whereas supplementation/donation of H₂South emerges every bit a potential arroyo to maintain diabetic blood vessel patency, and mayhap to protect against the evolution of diabetic complications such equally diabetic nephropathy and cardiomyopathy.

The therapeutic inhibition of H₂S biosynthesis to prevent diabetes onset appears to exist problematic for several reasons. Commencement, there are no potent and therapeutically applicable inhibitors of CSE; the available inhibitors are of low (millimolar) say-so, and of questionable selectivity. Second, in that location are no proficient means to predict autoimmune attack to the β-cell; in fact, the various interventional studies conducted so far that aimed to forbid diabetes onset take not been very successful (thirty, 69). Conspicuously, much more work needs to be washed in this area to develop a valid therapeutic concept.

The therapeutic donation of H_twoSouthward, on the other hand, may exist more straightforward. There are a number of compounds that have been synthesized specifically to deliver therapeutic H_iiS to tissues (seven, 47). Some of these molecules are stand-solitary H_twoS donors; others are combined molecules where an existing drug molecule is coupled with a H_twoS-altruistic grouping. It may exist an interesting research direction to examination some of these compounds in experimental models of diabetic complications. Additionally, a report by Benavides and colleagues has demonstrated that certain polysulfide molecules contained in garlic release biologically active H₂Due south upon reaction with tissue glutathione (4). Subsequent studies take demonstrated that these polysulfides release H₂S in vivo (32) and that they exert cardioprotective potential therapeutic furnishings via the release of H₂S (12, 44, 55). In fact, there are several articles in the literature reporting the beneficial effects of garlic extracts in various models of diabetic complications and wound healing (2, xi, 18, 50). However, in these studies the specific function of H_iiS every bit a mediator of these therapeutic actions remains to be investigated.

Abbreviations Used

Historic period	advanced glycation endproduct organization
CAT	cysteine aminotransferase
CBS	cystathionine β-synthase
CSE	cystathionine γ-lyase
ER	endoplasmatic reticulum
GFP	green fluorescent poly peptide
HG	high glucose
HiiDue south	hydrogen sulfide
GATP channels	potassium-opened ATP channels
LG	low glucose
MAP kinase	mitogen-activated protein kinase
MHC	major histocompatibility circuitous
3-MST	mercaptopyruvate sulfurtransferase
NO	nitric oxide
NOD	nonobese diabetic
ONOO−	peroxynitrite
PARP	poly(ADP-ribose) polymerase
PKC	protein kinase C
ROS	reactive oxygen species
RNS	reactive nitrogen species
STZ	streptozotocin
TGF-β1	tumor growth factor β1
VEGF	vascular endothelial growth cistron

Acknowledgments

The work of C.S. is supported by the Juvenile Diabetes Foundation and the Shriners Hospitals for Children. The editorial aid of Lili Szabo is appreciated.

Author Disclosure Statement

C.Due south. has stock buying in Ikaria, Inc., a for-profit arrangement involved in the evolution of H_twoS-based therapies.

References

one. Ali MY. Whiteman M. Low CM. Moore PK. Hydrogen sulphide reduces insulin secretion from HIT-T15 cells past a K_ATP channel-dependent pathway. J Endocrinol. 2007;195:105–112. [PubMed] [Google Scholar]

2. Baluchnejadmojarad T. Roghani M. Endothelium-dependent and -contained upshot of aqueous extract of garlic on vascular reactivity on diabetic rats. Fitoterapia. 2003;74:630–637. [PubMed] [Google Scholar]

3. Baskar R. Li L. Moore PK. Hydrogen sulfide-induces Dna damage and changes in apoptotic gene expression in man lung fibroblast cells. FASEB J. 2007;21:247–255. [PubMed] [Google Scholar]

4. Benavides GA. Squadrito GL. Mills RW. Patel Hard disk drive. Isbell TS. Patel RP. Darley-Usmar VM. Doeller JE. Kraus DW. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci U South A. 2007;104:17977–17982. [PMC gratis article] [PubMed] [Google Scholar]

5. Brancaleone Five. Roviezzo F. Vellecco V. De Gruttola L. Bucci Thou. Cirino 1000. Biosynthesis of H₂South is impaired in non-obese diabetic (NOD) mice. Br J Pharmacol. 2008;155:673–680. [PMC complimentary commodity] [PubMed] [Google Scholar]

6. Cai WJ. Wang MJ. Moore PK. Jin HM. Yao T. Zhu YC. The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation. Cardiovasc Res. 2007;76:29–xl. [PubMed] [Google Scholar]

7. Caliendo M. Cirino G. Santagada Five. Wallace JL. Synthesis and biological effects of hydrogen sulfide (H₂S): development of H₂S-releasing drugs as pharmaceuticals. J Med Chem. 2010;53:6275–6286. [PubMed] [Google Scholar]

8. Calvert JW. Coetzee WA. Lefer DJ. Novel insights into hydrogen sulfide-mediated cytoprotection. Antioxid Redox Signal. 2010;12:1203–1217. [PMC free article] [PubMed] [Google Scholar]

ix. Calvert JW. Jha Southward. Gundewar Southward. Elrod JW. Ramachandran A. Pattillo CB. Kevil CG. Lefer DJ. Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res. 2009;105:365–374. [PMC costless article] [PubMed] [Google Scholar]

10. Carballal Southward. Trujillo M. Cuevasanta E. Bartesaghi S. Möller MN. Folkes LK. García-Bereguiaín MA. Gutiérrez-Merino C. Wardman P. Denicola A. Radi R. Alvarez B. Reactivity of hydrogen sulfide with peroxynitrite and other oxidants of biological interest. Gratuitous Radic Biol Med. 2011;50:196–205. [PubMed] [Google Scholar]

11. Chang SH. Liu CJ. Kuo CH. Chen H. Lin WY. Teng KY. Chang SW. Tsai CH. Tsai FJ. Huang CY. Tzang BS. Kuo WW. Garlic oil alleviates MAPKs- and IL-half-dozen-mediated diabetes-related cardiac hypertrophy in STZ-induced DM rats. Evid Based Complement Alternat Med. 2011;2011:950150. [PMC costless commodity] [PubMed] [Google Scholar]

12. Chuah SC. Moore PK. Zhu YZ. S-allylcysteine mediates cardioprotection in an acute myocardial infarction rat model via a hydrogen sulfide-mediated pathway. Am J Physiol Heart Circ Physiol. 2007;293:H2693–H2701. [PubMed] [Google Scholar]

13. Del Valle HF. Lascano EC. Negroni JA. Crottogini AJ. Absence of ischemic preconditioning protection in diabetic sheep hearts: function of sarcolemmal One thousand_ATP channel dysfunction. Mol Jail cell Biochem. 2003;249:21–thirty. [PubMed] [Google Scholar]

fourteen. Denizalti M. Bozkurt TE. Akpulat U. Sahin-Erdemli I. Abacioglu N. The vasorelaxant outcome of hydrogen sulfide is enhanced in streptozotocin-induced diabetic rats. Naunyn Schmiedebergs Arch Pharmacol. 2011;383:509–517. [PubMed] [Google Scholar]

fifteen. Di Filippo C. Cuzzocrea S. Rossi F. Marfella R. D'Amico Thousand. Oxidative stress as the leading cause of acute myocardial infarction in diabetics. Cardiovasc Drug Rev. 2006;24:77–87. [PubMed] [Google Scholar]

16. Doeller JE. Isbell TS. Benavides Chiliad. Koenitzer J. Patel H. Patel RP. Lancaster JR., Jr. Darley-Usmar VM. Kraus DW. Polarographic measurement of hydrogen sulfide product and consumption by mammalian tissues. Anal Biochem. 2005;341:40–51. [PubMed] [Google Scholar]

17. Eghbal MA. Pennefather PS. O'Brien PJ. H₂S cytotoxicity machinery involves reactive oxygen species formation and mitochondrial depolarisation. Toxicology. 2004;203:69–76. [PubMed] [Google Scholar]

18. Ejaz S. Chekarova I. Cho JW. Lee SY. Ashraf S. Lim CW. Upshot of aged garlic extract on wound healing: a new frontier in wound management. Drug Chem Toxicol. 2009;32:191–203. [PubMed] [Google Scholar]

xix. El-Seweidy MM. Sadik NA. Shaker OG. Role of sulfurous mineral water and sodium hydrosulfide equally potent inhibitors of fibrosis in the heart of diabetic rats. Arch Biochem Biophys. 2011;506:48–57. [PubMed] [Google Scholar]

20. Elrod JW. Calvert JW. Morrison J. Doeller JE. Kraus DW. Tao L. Jiao X. Scalia R. Kiss L. Szabo C. Kimura H. Chow CW. Lefer DJ. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci U South A. 2007;104:15560–15565. [PMC free article] [PubMed] [Google Scholar]

21. Elsey DJ. Fowkes RC. Baxter GF. Regulation of cardiovascular cell function by hydrogen sulfide. Cell Biochem Funct. 2010;28:95–106. [PubMed] [Google Scholar]

22. Feng X. Chen Y. Zhao J. Tang C. Jiang Z. Geng B. Hydrogen sulfide from adipose tissue is a novel insulin resistance regulator. Biochem Biophys Res Commun. 2009;380:153–159. [PubMed] [Google Scholar]

23. Ferdinandy P. Schulz R. Baxter GF. Interaction of cardiovascular hazard factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev. 2007;59:418–458. [PubMed] [Google Scholar]

24. Francis RC. Vaporidi K. Bloch KD. Ichinose F. Zapol WM. Protective and detrimental furnishings of sodium sulfide and hydrogen sulfide in murine ventilator-induced lung injury. Anesthesiology. 2011;115:1012–1021. [PMC free article] [PubMed] [Google Scholar]

25. Gao Y. Yao X. Zhang Y. Li W. Kang K. Sun L. Sun X. The protective office of hydrogen sulfide in myocardial ischemia-reperfusion-induced injury in diabetic rats. Int J Cardiol. 2011;152:177–183. [PubMed] [Google Scholar]

26. Garcia Soriano F. Virag 50. Jagtap P. Szabo Due east. Mabley JG. Liaudet L. Marton A. Hoyt DG. Murthy KG. Salzman AL. Southan GJ. Szabo C. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med. 2001;7:108–113. [PubMed] [Google Scholar]

27. Giacco F. Brownlee One thousand. Oxidative stress and diabetic complications. Circ Res. 2010;107:1058–1070. [PMC free article] [PubMed] [Google Scholar]

28. Goubern Grand. Andriamihaja Chiliad. Nübel T. Blachier F. Bouillaud F. Sulfide, the get-go inorganic substrate for human cells. FASEB J. 2007;21:1699–1706. [PubMed] [Google Scholar]

29. Guan Q. Zhang Y. Yu C. Liu Y. Gao Fifty. Zhao J. Hydrogen sulfide protects against loftier glucose-induced apoptosis in endothelial cells. J Cardiovasc Pharmacol. 2011;152:177–183. [Google Scholar]

30. Haller MJ. Atkinson MA. Schatz DA. Efforts to prevent and halt autoimmune β cell destruction. Endocrinol Metab Clin North Am. 2010;39:527–539. [PMC free article] [PubMed] [Google Scholar]

31. Hildebrandt TM. Modulation of sulfide oxidation and toxicity in rat mitochondria past dehydroascorbic acid. Biochim Biophys Acta. 2011;1807:1206–1213. [PubMed] [Google Scholar]

32. Insko MA. Deckwerth TL. Colina P. Toombs CF. Szabo C. Detection of exhaled hydrogen sulphide gas in rats exposed to intravenous sodium sulphide. Br J Pharmacol. 2009;157:944–951. [PMC free commodity] [PubMed] [Google Scholar]

33. Jain SK. Bull R. Rains JL. Bass PF. Levine SN. Reddy S. McVie R. Bocchini JA. Low levels of hydrogen sulfide in the claret of diabetes patients and streptozotocin-treated rats causes vascular inflammation? Antioxid Redox Signal. 2010;12:1333–1337. [PMC complimentary article] [PubMed] [Google Scholar]

34. Jeney V. Komódi Eastward. Nagy E. Zarjou A. Vercellotti GM. Eaton JW. Balla G. Balla J. Supression of hemin-mediated oxidation of low-density lipoprotein and subsequent endothelial reactions by hydrogen sulfide. Free Radic Biol Med. 2009;46:616–623. [PMC free article] [PubMed] [Google Scholar]

35. Jha S. Calvert JW. Duranski MR. Ramachandran A. Lefer DJ. Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: part of antioxidant and antiapoptotic signaling. Am J Physiol Heart Circ Physiol. 2008;295:H801–H806. [PMC complimentary commodity] [PubMed] [Google Scholar]

36. Ji Y. Pang QF. Xu G. Wang Fifty. Wang JK. Zeng YM. Exogenous hydrogen sulfide postconditioning protects isolated rat hearts against ischemia-reperfusion injury. Eur J Pharmacol. 2008;587:1–7. [PubMed] [Google Scholar]

37. Johnson JD. Luciani DS. Mechanisms of pancreatic β-prison cell apoptosis in diabetes and its therapies. Adv Exp Med Biol. 2010;654:447–462. [PubMed] [Google Scholar]

38. Kaminitz A. Stein J. Yaniv I. Askenasy North. The vicious cycle of apoptotic β-prison cell death in blazon 1 diabetes. Immunol Cell Biol. 2007;85:582–589. [PubMed] [Google Scholar]

39. Kaneko Y. Kimura T. Taniguchi S. Souma Yard. Kojima Y. Kimura Y. Kimura H. Niki I. Glucose-induced production of hydrogen sulfide may protect the pancreatic β-cells from apoptotic jail cell expiry by loftier glucose. FEBS Lett. 2009;583:377–382. [PubMed] [Google Scholar]

twoscore. Kaneko Y. Kimura Y. Kimura H. Niki I. Fifty-cysteine inhibits insulin release from the pancreatic β-cell: possible involvement of metabolic production of hydrogen sulfide, a novel gasotransmitter. Diabetes. 2006;55:1391–1397. [PubMed] [Google Scholar]

41. Kimura H. Hydrogen sulfide: its product, release and functions. Amino Acids. 2011;41:113–121. [PubMed] [Google Scholar]

42. Lagoutte E. Mimoun Southward. Andriamihaja M. Chaumontet C. Blachier F. Bouillaud F. Oxidation of hydrogen sulfide remains a priority in mammalian cells and causes reverse electron transfer in colonocytes. Biochim Biophys Acta. 2010;1797:1500–1511. [PubMed] [Google Scholar]

43. Lan A. Liao Ten. Mo 50. Yang C. Yang Z. Wang X. Hu F. Chen P. Feng J. Zheng D. Xiao L. Hydrogen sulfide protects against chemic hypoxia-induced injury past inhibiting ROS-activated ERK1/two and p38MAPK signaling pathways in PC12 cells. PLoS One. 2011;six:e25921. [PMC free commodity] [PubMed] [Google Scholar]

44. Lavu M. Bhushan Due south. Lefer DJ. Hydrogen sulfide-mediated cardioprotection: mechanisms and therapeutic potential. Clin Sci (Lond) 2011;120:219–229. [PubMed] [Google Scholar]

45. Lefer DJ. A new gaseous signaling molecule emerges: cardioprotective role of hydrogen sulfide. Proc Natl Acad Sci U S A. 2007;104:17907–17908. [PMC gratuitous article] [PubMed] [Google Scholar]

46. Levitt Medico. Abdel-Rehim MS. Furne J. Free and acid-labile hydrogen sulfide concentrations in mouse tissues: anomalously high free hydrogen sulfide in aortic tissue. Antioxid Redox Betoken. 2011;15:373–378. [PubMed] [Google Scholar]

47. Martelli A. Testai L. Breschi MC. Blandizzi C. Virdis A. Taddei South. Calderone V. Hydrogen sulphide: novel opportunity for drug discovery. Med Res Rev. 2011 [Epub ahead of impress]. PMID: [PubMed] [Google Scholar]

48. Nicholls P. Inhibition of cytochrome c oxidase past sulphide. Biochem Soc Trans. 1975;3:316–319. [PubMed] [Google Scholar]

49. Olson KR. Is hydrogen sulfide a circulating "gasotransmitter" in vertebrate blood? Biochim Biophys Acta. 2009;1787:856–863. [PubMed] [Google Scholar]

l. Ou HC. Tzang BS. Chang MH. Liu CT. Liu HW. Lii CK. Bau DT. Chao PM. Kuo WW. Cardiac contractile dysfunction and apoptosis in streptozotocin-induced diabetic rats are ameliorated by garlic oil supplementation. J Agric Nutrient Chem. 2010;58:10347–10355. [PubMed] [Google Scholar]

51. Pacher P. Liaudet L. Soriano FG. Mabley JG. Szabo Eastward. Szabo C. The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes. Diabetes. 2002;51:514–521. [PubMed] [Google Scholar]

52. Pan TT. Chen YQ. Bian JS. All in the timing: a comparison betwixt the cardioprotection induced by H_iiS preconditioning and post-infarction treatment. Eur J Pharmacol. 2009;616:160–165. [PubMed] [Google Scholar]

53. Papapetropoulos A. Pyriochou A. Altaany Z. Yang G. Marazioti A. Zhou Z. Jeschke MG. Branski LK. Herndon DN. Wang R. Szabo C. Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc Natl Acad Sci U Due south A. 2009;106:21972–21977. [PMC free article] [PubMed] [Google Scholar]

54. Patel Grand. Shah G. Possible role of hydrogen sulfide in insulin secretion and in development of insulin resistance. J Immature Pharm. 2010;2:148–151. [PMC free article] [PubMed] [Google Scholar]

55. Shaik IH. George JM. Thekkumkara TJ. Mehvar R. Protective effects of diallyl sulfide, a garlic constituent, on the warm hepatic ischemia-reperfusion injury in a rat model. Pharm Res. 2008;25:2231–2242. [PubMed] [Google Scholar]

56. Shen X. Pattillo CB. Pardue Due south. Bir SC. Wang R. Kevil CG. Measurement of plasma hydrogen sulfide in vivo and in vitro. Costless Radic Biol Med. 2011;l:1021–1031. [PMC costless article] [PubMed] [Google Scholar]

57. Sodha NR. Clements RT. Feng J. Liu Y. Bianchi C. Horvath EM. Szabo C. Stahl GL. Sellke FW. Hydrogen sulfide therapy attenuates the inflammatory response in a porcine model of myocardial ischemia/reperfusion injury. J Thorac Cardiovasc Surg. 2009;138:977–984. [PMC costless article] [PubMed] [Google Scholar]

58. Suzuki K. Olah G. Modis K. Coletta C. Kulp G. Gero D. Szoleczky P. Chang T. Zhou Z. Wu 50. Wang R. Papapetropoulos A. Szabo C. Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function. Proc Natl Acad Sci U S A. 2011;108:13829–13834. [PMC costless article] [PubMed] [Google Scholar]

59. Szabo C. Papapetropoulos A. Hydrogen sulfide and angiogenesis: mechanisms and applications. Br J Pharmacol. 2011;164:853–865. [PMC free commodity] [PubMed] [Google Scholar]

60. Szabo C. Gaseotransmitters: new frontiers for translational science. Sci Transl Med. 2010;2:59ps54. [PMC gratis article] [PubMed] [Google Scholar]

61. Szabo C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov. 2007;6:917–935. [PubMed] [Google Scholar]

62. Szabo C. Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction. Br J Pharmacol. 2009;156:713–727. [PMC free article] [PubMed] [Google Scholar]

63. Szabo Thou. Veres 1000. Radovits T. Gero D. Modis One thousand. Miesel-Gröschel C. Horkay F. Karck M. Szabo C. Cardioprotective effects of hydrogen sulfide. Nitric Oxide. 2011;25:201–210. [PMC gratis article] [PubMed] [Google Scholar]

64. Taniguchi South. Kang L. Kimura T. Niki I. Hydrogen sulphide protects mouse pancreatic β-cells from cell death induced by oxidative stress, but non by endoplasmic reticulum stress. Br J Pharmacol. 2011;162:1171–1178. [PMC free article] [PubMed] [Google Scholar]

65. Taniguchi S. Niki I. Significance of hydrogen sulfide production in the pancreatic beta-jail cell. J Pharmacol Sci. 2011;116:i–five. [PubMed] [Google Scholar]

66. Thompson RW. Valentine HL. Valentine WM. Cytotoxic mechanisms of hydrosulfide anion and cyanide anion in primary rat hepatocyte cultures. Toxicology. 2003;188:149–159. [PubMed] [Google Scholar]

67. Toombs CF. Insko MA. Wintner EA. Deckwerth TL. Usansky H. Jamil Grand. Goldstein B. Cooreman M. Szabo C. Detection of exhaled hydrogen sulphide gas in healthy human being volunteers during intravenous administration of sodium sulphide. Br J Clin Pharmacol. 2010;69:626–636. [PMC free article] [PubMed] [Google Scholar]

68. Truong DH. Mihajlovic A. Gunness P. Hindmarsh Due west. O'Brien PJ. Prevention of hydrogen sulfide-induced mouse lethality and cytotoxicity by hydroxocobalamin (vitamin B_12a) Toxicology. 2007;242:16–22. [PubMed] [Google Scholar]

69. van Belle TL. Coppieters KT. von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev. 2011;91:79–118. [PubMed] [Google Scholar]

70. Watson D. Loweth AC. Oxidative and nitrosative stress in β-cell apoptosis: their contribution to β-cell loss in type 1 diabetes mellitus. Br J Biomed Sci. 2009;66:208–215. [PubMed] [Google Scholar]

71. Whiteman One thousand. Gooding KM. Whatmore JL. Ball CI. Mawson D. Skinner G. Tooke JE. Shore AC. Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia. 2010;53:1722–1726. [PubMed] [Google Scholar]

72. Wintner EA. Deckwerth TL. Langston West. Bengtsson A. Leviten D. Hill P. Insko MA. Dumpit R. VandenEkart E. Toombs CF. Szabo C. A monobromobimane-based assay to measure the pharmacokinetic profile of reactive sulphide species in blood. Br J Pharmacol. 2010;160:941–957. [PMC free commodity] [PubMed] [Google Scholar]

73. Wu L. Yang W. Jia X. Yang G. Duridanova D. Cao K. Wang R. Pancreatic islet overproduction of H₂S and suppressed insulin release in Zucker diabetic rats. Lab Invest. 2009;89:59–67. [PubMed] [Google Scholar]

74. Yang G. Tang M. Zhang L. Wu 50. Wang R. The pathogenic role of cystathionine γ-lyase/hydrogen sulfide in streptozotocin-induced diabetes in mice. Am J Pathol. 2011;179:869–879. [PMC costless commodity] [PubMed] [Google Scholar]

75. Yang Thousand. Wu L. Jiang B. Yang W. Qi J. Cao K. Meng Q. Mustafa AK. Mu West. Zhang S. Snyder SH. Wang R. H₂S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science. 2008;322:587–590. [PMC gratis commodity] [PubMed] [Google Scholar]

76. Yang G. Yang W. Wu L. Wang R. H_twoS, endoplasmic reticulum stress, and apoptosis of insulin-secreting β cells. J Biol Chem. 2007;282:16567–16576. [PubMed] [Google Scholar]

77. Yang Z. Yang C. Xiao L. Liao X. Lan A. Wang X. Guo R. Chen P. Hu C. Feng J. Novel insights into the office of HSP90 in cytoprotection of H₂S confronting chemic hypoxia-induced injury in H9c2 cardiac myocytes. Int J Mol Med. 2011;28:397–403. [PubMed] [Google Scholar]

78. Yuan P. Xue H. Zhou L. Qu Fifty. Li C. Wang Z. Ni J. Yu C. Yao T. Huang Y. Wang R. Lu Fifty. Rescue of mesangial cells from high glucose-induced over-proliferation and extracellular matrix secretion by hydrogen sulfide. Nephrol Dial Transplant. 2011;26:2119–2126. [PubMed] [Google Scholar]

79. Yusuf Thou. Kwong Huat BT. Hsu A. Whiteman M. Bhatia Thou. Moore PK. Streptozotocin-induced diabetes in the rat is associated with enhanced tissue hydrogen sulfide biosynthesis. Biochem Biophys Res Commun. 2005;333:1146–1152. [PubMed] [Google Scholar]

80. Zhang L. Yang G. Tang G. Wu L. Wang R. Rat pancreatic level of cystathionine γ-lyase is regulated past glucose level via specificity protein 1 (SP1) phosphorylation. Diabetologia. 2011;54:2615–2625. [PubMed] [Google Scholar]

palaciosbriat1956.blogspot.com

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701125/

Share this post