The Experts below are selected from a list of 231 Experts worldwide ranked by ideXlab platform
Irshad H Chaudry - One of the best experts on this subject based on the ideXlab platform.
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Androstenediol administration after trauma hemorrhage attenuates inflammatory response reduces organ damage and improves survival following sepsis
American Journal of Physiology-gastrointestinal and Liver Physiology, 2006Co-Authors: Laszlo Szalay, Takao Suzuki, Tomoharu Shimizu, Mashkoor A Choudhry, Kirby I Bland, Irshad H Chaudry, Yaching Hsieh, Martin G SchwachaAbstract:Although Androstenediol (adiol or 5-androstene-3β,17β-diol), a metabolite of dehydroepiandrosterone (DHEA), has protective effects following trauma-hemorrhage (T-H), it remains unknown whether admi...
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a role of ppar γ in Androstenediol mediated salutary effects on cardiac function following trauma hemorrhage
Annals of Surgery, 2006Co-Authors: Tomoharu Shimizu, Takao Suzuki, Laszlo Szalay, Mashkoor A Choudhry, Kirby I Bland, Yaching Hsieh, Irshad H ChaudryAbstract:Hemorrhagic shock results in a rapid decrease in cardiac output and organ blood flow.1 The depressed organ perfusion and excessive production of pro-inflammatory mediators play an important role in the development of multiple organ dysfunction following hemorrhagic shock.2,3 It has been reported that systemic IL-6 levels increase following trauma-hemorrhage (T-H), and a sustained elevation in plasma IL-6 levels is correlated with the evolving organ dysfunction.4–6 Clinical data also confirmed that the increased IL-6 production is associated with poor outcome in patients with trauma or hemorrhagic shock.7 IL-6 has been described as a multifunctional cytokine, produced during the acute phase by macrophages, T and B cells, and nonimmune cells such as myocytes or endothelial cells.8–10 Studies have demonstrated that the IL-6-mediated elevation in nitric oxide (NO) production is likely to be one of the detrimental effects induced by the IL-6 in the heart.11,12 Yu et al demonstrated that IL-6 decreases cardiac contractility and enhances the synthesis of the inducible nitric oxide synthase (iNOS) resulting in an excess of NO production.11 In line with these findings, previous studies from our laboratory have shown that cardiac dysfunction was associated with elevated plasma IL-6 levels.6,13–15 Furthermore, our recent study suggested that the depressed cardiac function following T-H is associated with an increase in cardiomyocyte IL-6 production.16 The causal role of IL-6 in producing organ dysfunction has been further substantiated by studies which showed that administration of anti-IL-6 antibodies results in improved organ function following T-H.17 The peroxisome proliferator-activated receptor-gamma (PPAR-γ), a member of the nuclear hormone receptor superfamily, was originally reported to have a role in adipocyte differentiation and glucose homeostasis. However, subsequent studies revealed that PPAR-γ is a potent regulator of genes implicated in inflammatory responses.18 PPAR-γ activators can exert anti-inflammatory activity in a wide variety of cell types such as monocyte/macrophages, endothelial cells, epithelial cells, and smooth muscle cells.19 In agreement with these results, recent studies have reported that PPAR-γ agonists can reduce organ injury in hemorrhagic shock20,21 and attenuate the inflammatory response in sepsis.22 Additional studies have demonstrated that ligands of the PPAR-γ also have protective effects on heart against ischemia/reperfusion injury via reduction of pro-inflammatory factors as TNF-α, MCP-1, or iNOS.23,24 Androstenediol (adiol or 5-androstene-3β,17β-diol), which is one of the metabolites of dehydroepiandrosterone (DHEA), was shown to have greater protective capacity than DHEA in lethal bacterial infections and endotoxin shock.25 Following T-H shock, Androstenediol administration also proved to be effective in reducing plasma IL-6 production and improving cardiovascular function and splanchnic perfusion.26 Since Androstenediol has been reported to influence the activity of a peroxisome proliferator,27 we hypothesized that the salutary effects of Androstenediol on cardiac functions following T-H are mediated via PPAR-γ activation. To test the hypothesis, we first determined the effect of Androstenediol administration on expression and PPAR-γ DNA binding activity and measured plasma level of its endogenous agonist, 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) following T-H. In a second set of experiments, we used the PPAR-γ antagonist GW9662 along with Androstenediol to determine the effects of PPAR-γ blockade on Androstenediol-induced effects on cardiac functions following T-H.
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Androstenediol ameliorates alterations in immune cells cytokine production capacity in a two hit model of trauma hemorrhage and sepsis
Cytokine, 2006Co-Authors: Takao Suzuki, Tomoharu Shimizu, Laszlo Szalay, Mashkoor A Choudhry, Loring W Rue, Kirby I Bland, Irshad H ChaudryAbstract:Although administration of Androstenediol (a metabolite of dehydroepiandrosterone) following trauma-hemorrhage (T-H) produces beneficial effects on inflammatory cytokines and organ function, it remains unknown whether this metabolite has any salutary effects in preventing alterations in immune cell cytokine production following a combined insult of T-H and sepsis. To examine this, male rats underwent laparotomy, hemorrhagic shock (mean BP 40 mmHg for 90 min) and resuscitation or sham operation. Androstenediol (1 mg/kg BW i.v.) or vehicle was administered at the end of resuscitation. Twenty hrs after T-H or sham operation, sepsis was induced by cecal ligation and puncture (CLP). Five hours thereafter, plasma cytokine levels and cytokine production of various immune cells were determined. In a separate set of experiments, survival was monitored for 10 days after the induction of sepsis. Administration of Androstenediol markedly decreased plasma IL-6 and TNF-alpha levels following T-H and CLP. Furthermore, it prevented the increased production of IL-6 and TNF-alpha by Kupffer cells and alveolar macrophages and attenuated the decrease in IL-6 and TNF-alpha production by splenic macrophages; however, it had no significant effects on the depressed IL-6 and TNF-alpha production by PBMC following T-H and CLP. The depressed IL-2 and IFN-gamma production by splenocytes under those conditions was attenuated by the administration of Androstenediol. Furthermore, survival rate following T-H and subsequent sepsis was improved by Androstenediol treatment. Since Androstenediol administration following T-H attenuated cytokine production and reduced mortality in a double-hit model of T-H and sepsis, this agent appears to be a novel and useful adjunct for maintaining the immune cell functions following T-H and for decreasing the mortality rate from subsequent susceptibility to sepsis.
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mechanism of salutary effects of Androstenediol on hepatic function after trauma hemorrhage role of endothelial and inducible nitric oxide synthase
American Journal of Physiology-gastrointestinal and Liver Physiology, 2005Co-Authors: Tomoharu Shimizu, Laszlo Szalay, Mashkoor A Choudhry, Loring W Rue, Kirby I Bland, Martin G Schwacha, Irshad H ChaudryAbstract:Recent studies have shown that administration of dehydroepiandrosterone (DHEA) after trauma-hemorrhage (T-H) improves cardiovascular and hepatic function in male animals. Although Androstenediol, o...
Gregory A Brown - One of the best experts on this subject based on the ideXlab platform.
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acute resistance exercise does not change the hormonal response to sublingual Androstenediol intake
European Journal of Applied Physiology, 2006Co-Authors: Gregory A Brown, Drew MckenzieAbstract:Sublingual intake of 21.4 mg Androstenediol increases serum testosterone concentrations whereas swallowing 200 mg Androstenediol does not. The duration of increase in serum testosterone following sublingual Androstenediol (SL-DIOL) is unknown. Resistance exercise (EX) following SL-DIOL may cause larger increases in serum estradiol concentrations than while at rest. This project evaluated the duration of change in, and the effects of acute EX on, the hormonal response to SL-DIOL. Six young resistance trained males consumed either placebo (PL) or SL-DIOL before a single session of EX or no exercise (Rest) in a random, double blind, crossover manner (for a total of four trials). Blood samples were collected before supplementation, and at 60, 120, 180, 240, 480, and 720 min post-supplementation, with the exercise occurring between 60 and 120 min. The serum [total testosterone] increased (P < 0.05) at 60 min similarly in SL-DIOL-EX and SL-DIOL-Rest by approximately 115%, and at 120 min by approximately 107% with no differences due to exercise. The serum [estradiol] increased (P < 0.05) similarly in SL-DIOL-EX and SL-DIOL-Rest by approximately 33% at 60 min and approximately 45% at 120 min, with no differences due to exercise. Serum [testosterone] returned to baseline by 240 min and serum [estradiol] returned to baseline by 720 min post-intake. These findings indicate that SL-DIOL acutely elevates serum testosterone and estradiol concentrations, that EX does not alter the endocrine response to SL-DIOL, and that the increases in serum estradiol last between 480 and 720 min while the increases in serum testosterone last <240 min following acute SL-DIOL intake.
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Testosterone prohormone supplements
Medicine and Science in Sports and Exercise, 2006Co-Authors: Gregory A Brown, Matthew Vukovich, Douglas S. KingAbstract:Testosterone prohormones such as androstenedione, Androstenediol, and dehydroepiandrosterone (DHEA) have been heavily marketed as testosterone-enhancing and muscle-building nutritional supplements for the past decade. Concerns over the safety of prohormone supplement use prompted the United States Food and Drug Administration to call for a ban on androstenedione sales, and Congress passed the Anabolic Steroid Control Act of 2004, which classifies androstenedione and 17 other steroids as controlled substances. As of January 2005, these substances cannot be sold without prescription. Here, we summarize the current scientific knowledge regarding the efficacy and safety of prohormone supplementation in humans. We focus primarily on androstenedione, but we also discuss DHEA, Androstenediol, 19-nor androstenedione, and 19-nor Androstenediol supplements. Contrary to marketing claims, research to date indicates that the use of prohormone nutritional supplements (DHEA, androstenedione, Androstenediol, and other steroid hormone supplements) does not produce either anabolic or ergogenic effects in men. Moreover, the use of prohormone nutritional supplements may raise the risk for negative health consequences.
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acute hormonal response to sublingual Androstenediol intake in young men
Journal of Applied Physiology, 2002Co-Authors: Gregory A Brown, Matthew Vukovich, Emily R Martini, Scott B Roberts, D S KingAbstract:The effectiveness of orally ingested Androstenediol in raising serum testosterone concentrations may be limited because of hepatic breakdown of the ingested androgens. Because Androstenediol admini...
Tomoharu Shimizu - One of the best experts on this subject based on the ideXlab platform.
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Androstenediol administration after trauma hemorrhage attenuates inflammatory response reduces organ damage and improves survival following sepsis
American Journal of Physiology-gastrointestinal and Liver Physiology, 2006Co-Authors: Laszlo Szalay, Takao Suzuki, Tomoharu Shimizu, Mashkoor A Choudhry, Kirby I Bland, Irshad H Chaudry, Yaching Hsieh, Martin G SchwachaAbstract:Although Androstenediol (adiol or 5-androstene-3β,17β-diol), a metabolite of dehydroepiandrosterone (DHEA), has protective effects following trauma-hemorrhage (T-H), it remains unknown whether admi...
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a role of ppar γ in Androstenediol mediated salutary effects on cardiac function following trauma hemorrhage
Annals of Surgery, 2006Co-Authors: Tomoharu Shimizu, Takao Suzuki, Laszlo Szalay, Mashkoor A Choudhry, Kirby I Bland, Yaching Hsieh, Irshad H ChaudryAbstract:Hemorrhagic shock results in a rapid decrease in cardiac output and organ blood flow.1 The depressed organ perfusion and excessive production of pro-inflammatory mediators play an important role in the development of multiple organ dysfunction following hemorrhagic shock.2,3 It has been reported that systemic IL-6 levels increase following trauma-hemorrhage (T-H), and a sustained elevation in plasma IL-6 levels is correlated with the evolving organ dysfunction.4–6 Clinical data also confirmed that the increased IL-6 production is associated with poor outcome in patients with trauma or hemorrhagic shock.7 IL-6 has been described as a multifunctional cytokine, produced during the acute phase by macrophages, T and B cells, and nonimmune cells such as myocytes or endothelial cells.8–10 Studies have demonstrated that the IL-6-mediated elevation in nitric oxide (NO) production is likely to be one of the detrimental effects induced by the IL-6 in the heart.11,12 Yu et al demonstrated that IL-6 decreases cardiac contractility and enhances the synthesis of the inducible nitric oxide synthase (iNOS) resulting in an excess of NO production.11 In line with these findings, previous studies from our laboratory have shown that cardiac dysfunction was associated with elevated plasma IL-6 levels.6,13–15 Furthermore, our recent study suggested that the depressed cardiac function following T-H is associated with an increase in cardiomyocyte IL-6 production.16 The causal role of IL-6 in producing organ dysfunction has been further substantiated by studies which showed that administration of anti-IL-6 antibodies results in improved organ function following T-H.17 The peroxisome proliferator-activated receptor-gamma (PPAR-γ), a member of the nuclear hormone receptor superfamily, was originally reported to have a role in adipocyte differentiation and glucose homeostasis. However, subsequent studies revealed that PPAR-γ is a potent regulator of genes implicated in inflammatory responses.18 PPAR-γ activators can exert anti-inflammatory activity in a wide variety of cell types such as monocyte/macrophages, endothelial cells, epithelial cells, and smooth muscle cells.19 In agreement with these results, recent studies have reported that PPAR-γ agonists can reduce organ injury in hemorrhagic shock20,21 and attenuate the inflammatory response in sepsis.22 Additional studies have demonstrated that ligands of the PPAR-γ also have protective effects on heart against ischemia/reperfusion injury via reduction of pro-inflammatory factors as TNF-α, MCP-1, or iNOS.23,24 Androstenediol (adiol or 5-androstene-3β,17β-diol), which is one of the metabolites of dehydroepiandrosterone (DHEA), was shown to have greater protective capacity than DHEA in lethal bacterial infections and endotoxin shock.25 Following T-H shock, Androstenediol administration also proved to be effective in reducing plasma IL-6 production and improving cardiovascular function and splanchnic perfusion.26 Since Androstenediol has been reported to influence the activity of a peroxisome proliferator,27 we hypothesized that the salutary effects of Androstenediol on cardiac functions following T-H are mediated via PPAR-γ activation. To test the hypothesis, we first determined the effect of Androstenediol administration on expression and PPAR-γ DNA binding activity and measured plasma level of its endogenous agonist, 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) following T-H. In a second set of experiments, we used the PPAR-γ antagonist GW9662 along with Androstenediol to determine the effects of PPAR-γ blockade on Androstenediol-induced effects on cardiac functions following T-H.
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Androstenediol ameliorates alterations in immune cells cytokine production capacity in a two hit model of trauma hemorrhage and sepsis
Cytokine, 2006Co-Authors: Takao Suzuki, Tomoharu Shimizu, Laszlo Szalay, Mashkoor A Choudhry, Loring W Rue, Kirby I Bland, Irshad H ChaudryAbstract:Although administration of Androstenediol (a metabolite of dehydroepiandrosterone) following trauma-hemorrhage (T-H) produces beneficial effects on inflammatory cytokines and organ function, it remains unknown whether this metabolite has any salutary effects in preventing alterations in immune cell cytokine production following a combined insult of T-H and sepsis. To examine this, male rats underwent laparotomy, hemorrhagic shock (mean BP 40 mmHg for 90 min) and resuscitation or sham operation. Androstenediol (1 mg/kg BW i.v.) or vehicle was administered at the end of resuscitation. Twenty hrs after T-H or sham operation, sepsis was induced by cecal ligation and puncture (CLP). Five hours thereafter, plasma cytokine levels and cytokine production of various immune cells were determined. In a separate set of experiments, survival was monitored for 10 days after the induction of sepsis. Administration of Androstenediol markedly decreased plasma IL-6 and TNF-alpha levels following T-H and CLP. Furthermore, it prevented the increased production of IL-6 and TNF-alpha by Kupffer cells and alveolar macrophages and attenuated the decrease in IL-6 and TNF-alpha production by splenic macrophages; however, it had no significant effects on the depressed IL-6 and TNF-alpha production by PBMC following T-H and CLP. The depressed IL-2 and IFN-gamma production by splenocytes under those conditions was attenuated by the administration of Androstenediol. Furthermore, survival rate following T-H and subsequent sepsis was improved by Androstenediol treatment. Since Androstenediol administration following T-H attenuated cytokine production and reduced mortality in a double-hit model of T-H and sepsis, this agent appears to be a novel and useful adjunct for maintaining the immune cell functions following T-H and for decreasing the mortality rate from subsequent susceptibility to sepsis.
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mechanism of salutary effects of Androstenediol on hepatic function after trauma hemorrhage role of endothelial and inducible nitric oxide synthase
American Journal of Physiology-gastrointestinal and Liver Physiology, 2005Co-Authors: Tomoharu Shimizu, Laszlo Szalay, Mashkoor A Choudhry, Loring W Rue, Kirby I Bland, Martin G Schwacha, Irshad H ChaudryAbstract:Recent studies have shown that administration of dehydroepiandrosterone (DHEA) after trauma-hemorrhage (T-H) improves cardiovascular and hepatic function in male animals. Although Androstenediol, o...
Laszlo Szalay - One of the best experts on this subject based on the ideXlab platform.
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Androstenediol administration after trauma hemorrhage attenuates inflammatory response reduces organ damage and improves survival following sepsis
American Journal of Physiology-gastrointestinal and Liver Physiology, 2006Co-Authors: Laszlo Szalay, Takao Suzuki, Tomoharu Shimizu, Mashkoor A Choudhry, Kirby I Bland, Irshad H Chaudry, Yaching Hsieh, Martin G SchwachaAbstract:Although Androstenediol (adiol or 5-androstene-3β,17β-diol), a metabolite of dehydroepiandrosterone (DHEA), has protective effects following trauma-hemorrhage (T-H), it remains unknown whether admi...
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a role of ppar γ in Androstenediol mediated salutary effects on cardiac function following trauma hemorrhage
Annals of Surgery, 2006Co-Authors: Tomoharu Shimizu, Takao Suzuki, Laszlo Szalay, Mashkoor A Choudhry, Kirby I Bland, Yaching Hsieh, Irshad H ChaudryAbstract:Hemorrhagic shock results in a rapid decrease in cardiac output and organ blood flow.1 The depressed organ perfusion and excessive production of pro-inflammatory mediators play an important role in the development of multiple organ dysfunction following hemorrhagic shock.2,3 It has been reported that systemic IL-6 levels increase following trauma-hemorrhage (T-H), and a sustained elevation in plasma IL-6 levels is correlated with the evolving organ dysfunction.4–6 Clinical data also confirmed that the increased IL-6 production is associated with poor outcome in patients with trauma or hemorrhagic shock.7 IL-6 has been described as a multifunctional cytokine, produced during the acute phase by macrophages, T and B cells, and nonimmune cells such as myocytes or endothelial cells.8–10 Studies have demonstrated that the IL-6-mediated elevation in nitric oxide (NO) production is likely to be one of the detrimental effects induced by the IL-6 in the heart.11,12 Yu et al demonstrated that IL-6 decreases cardiac contractility and enhances the synthesis of the inducible nitric oxide synthase (iNOS) resulting in an excess of NO production.11 In line with these findings, previous studies from our laboratory have shown that cardiac dysfunction was associated with elevated plasma IL-6 levels.6,13–15 Furthermore, our recent study suggested that the depressed cardiac function following T-H is associated with an increase in cardiomyocyte IL-6 production.16 The causal role of IL-6 in producing organ dysfunction has been further substantiated by studies which showed that administration of anti-IL-6 antibodies results in improved organ function following T-H.17 The peroxisome proliferator-activated receptor-gamma (PPAR-γ), a member of the nuclear hormone receptor superfamily, was originally reported to have a role in adipocyte differentiation and glucose homeostasis. However, subsequent studies revealed that PPAR-γ is a potent regulator of genes implicated in inflammatory responses.18 PPAR-γ activators can exert anti-inflammatory activity in a wide variety of cell types such as monocyte/macrophages, endothelial cells, epithelial cells, and smooth muscle cells.19 In agreement with these results, recent studies have reported that PPAR-γ agonists can reduce organ injury in hemorrhagic shock20,21 and attenuate the inflammatory response in sepsis.22 Additional studies have demonstrated that ligands of the PPAR-γ also have protective effects on heart against ischemia/reperfusion injury via reduction of pro-inflammatory factors as TNF-α, MCP-1, or iNOS.23,24 Androstenediol (adiol or 5-androstene-3β,17β-diol), which is one of the metabolites of dehydroepiandrosterone (DHEA), was shown to have greater protective capacity than DHEA in lethal bacterial infections and endotoxin shock.25 Following T-H shock, Androstenediol administration also proved to be effective in reducing plasma IL-6 production and improving cardiovascular function and splanchnic perfusion.26 Since Androstenediol has been reported to influence the activity of a peroxisome proliferator,27 we hypothesized that the salutary effects of Androstenediol on cardiac functions following T-H are mediated via PPAR-γ activation. To test the hypothesis, we first determined the effect of Androstenediol administration on expression and PPAR-γ DNA binding activity and measured plasma level of its endogenous agonist, 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) following T-H. In a second set of experiments, we used the PPAR-γ antagonist GW9662 along with Androstenediol to determine the effects of PPAR-γ blockade on Androstenediol-induced effects on cardiac functions following T-H.
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Androstenediol ameliorates alterations in immune cells cytokine production capacity in a two hit model of trauma hemorrhage and sepsis
Cytokine, 2006Co-Authors: Takao Suzuki, Tomoharu Shimizu, Laszlo Szalay, Mashkoor A Choudhry, Loring W Rue, Kirby I Bland, Irshad H ChaudryAbstract:Although administration of Androstenediol (a metabolite of dehydroepiandrosterone) following trauma-hemorrhage (T-H) produces beneficial effects on inflammatory cytokines and organ function, it remains unknown whether this metabolite has any salutary effects in preventing alterations in immune cell cytokine production following a combined insult of T-H and sepsis. To examine this, male rats underwent laparotomy, hemorrhagic shock (mean BP 40 mmHg for 90 min) and resuscitation or sham operation. Androstenediol (1 mg/kg BW i.v.) or vehicle was administered at the end of resuscitation. Twenty hrs after T-H or sham operation, sepsis was induced by cecal ligation and puncture (CLP). Five hours thereafter, plasma cytokine levels and cytokine production of various immune cells were determined. In a separate set of experiments, survival was monitored for 10 days after the induction of sepsis. Administration of Androstenediol markedly decreased plasma IL-6 and TNF-alpha levels following T-H and CLP. Furthermore, it prevented the increased production of IL-6 and TNF-alpha by Kupffer cells and alveolar macrophages and attenuated the decrease in IL-6 and TNF-alpha production by splenic macrophages; however, it had no significant effects on the depressed IL-6 and TNF-alpha production by PBMC following T-H and CLP. The depressed IL-2 and IFN-gamma production by splenocytes under those conditions was attenuated by the administration of Androstenediol. Furthermore, survival rate following T-H and subsequent sepsis was improved by Androstenediol treatment. Since Androstenediol administration following T-H attenuated cytokine production and reduced mortality in a double-hit model of T-H and sepsis, this agent appears to be a novel and useful adjunct for maintaining the immune cell functions following T-H and for decreasing the mortality rate from subsequent susceptibility to sepsis.
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mechanism of salutary effects of Androstenediol on hepatic function after trauma hemorrhage role of endothelial and inducible nitric oxide synthase
American Journal of Physiology-gastrointestinal and Liver Physiology, 2005Co-Authors: Tomoharu Shimizu, Laszlo Szalay, Mashkoor A Choudhry, Loring W Rue, Kirby I Bland, Martin G Schwacha, Irshad H ChaudryAbstract:Recent studies have shown that administration of dehydroepiandrosterone (DHEA) after trauma-hemorrhage (T-H) improves cardiovascular and hepatic function in male animals. Although Androstenediol, o...
Kirby I Bland - One of the best experts on this subject based on the ideXlab platform.
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Androstenediol administration after trauma hemorrhage attenuates inflammatory response reduces organ damage and improves survival following sepsis
American Journal of Physiology-gastrointestinal and Liver Physiology, 2006Co-Authors: Laszlo Szalay, Takao Suzuki, Tomoharu Shimizu, Mashkoor A Choudhry, Kirby I Bland, Irshad H Chaudry, Yaching Hsieh, Martin G SchwachaAbstract:Although Androstenediol (adiol or 5-androstene-3β,17β-diol), a metabolite of dehydroepiandrosterone (DHEA), has protective effects following trauma-hemorrhage (T-H), it remains unknown whether admi...
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a role of ppar γ in Androstenediol mediated salutary effects on cardiac function following trauma hemorrhage
Annals of Surgery, 2006Co-Authors: Tomoharu Shimizu, Takao Suzuki, Laszlo Szalay, Mashkoor A Choudhry, Kirby I Bland, Yaching Hsieh, Irshad H ChaudryAbstract:Hemorrhagic shock results in a rapid decrease in cardiac output and organ blood flow.1 The depressed organ perfusion and excessive production of pro-inflammatory mediators play an important role in the development of multiple organ dysfunction following hemorrhagic shock.2,3 It has been reported that systemic IL-6 levels increase following trauma-hemorrhage (T-H), and a sustained elevation in plasma IL-6 levels is correlated with the evolving organ dysfunction.4–6 Clinical data also confirmed that the increased IL-6 production is associated with poor outcome in patients with trauma or hemorrhagic shock.7 IL-6 has been described as a multifunctional cytokine, produced during the acute phase by macrophages, T and B cells, and nonimmune cells such as myocytes or endothelial cells.8–10 Studies have demonstrated that the IL-6-mediated elevation in nitric oxide (NO) production is likely to be one of the detrimental effects induced by the IL-6 in the heart.11,12 Yu et al demonstrated that IL-6 decreases cardiac contractility and enhances the synthesis of the inducible nitric oxide synthase (iNOS) resulting in an excess of NO production.11 In line with these findings, previous studies from our laboratory have shown that cardiac dysfunction was associated with elevated plasma IL-6 levels.6,13–15 Furthermore, our recent study suggested that the depressed cardiac function following T-H is associated with an increase in cardiomyocyte IL-6 production.16 The causal role of IL-6 in producing organ dysfunction has been further substantiated by studies which showed that administration of anti-IL-6 antibodies results in improved organ function following T-H.17 The peroxisome proliferator-activated receptor-gamma (PPAR-γ), a member of the nuclear hormone receptor superfamily, was originally reported to have a role in adipocyte differentiation and glucose homeostasis. However, subsequent studies revealed that PPAR-γ is a potent regulator of genes implicated in inflammatory responses.18 PPAR-γ activators can exert anti-inflammatory activity in a wide variety of cell types such as monocyte/macrophages, endothelial cells, epithelial cells, and smooth muscle cells.19 In agreement with these results, recent studies have reported that PPAR-γ agonists can reduce organ injury in hemorrhagic shock20,21 and attenuate the inflammatory response in sepsis.22 Additional studies have demonstrated that ligands of the PPAR-γ also have protective effects on heart against ischemia/reperfusion injury via reduction of pro-inflammatory factors as TNF-α, MCP-1, or iNOS.23,24 Androstenediol (adiol or 5-androstene-3β,17β-diol), which is one of the metabolites of dehydroepiandrosterone (DHEA), was shown to have greater protective capacity than DHEA in lethal bacterial infections and endotoxin shock.25 Following T-H shock, Androstenediol administration also proved to be effective in reducing plasma IL-6 production and improving cardiovascular function and splanchnic perfusion.26 Since Androstenediol has been reported to influence the activity of a peroxisome proliferator,27 we hypothesized that the salutary effects of Androstenediol on cardiac functions following T-H are mediated via PPAR-γ activation. To test the hypothesis, we first determined the effect of Androstenediol administration on expression and PPAR-γ DNA binding activity and measured plasma level of its endogenous agonist, 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) following T-H. In a second set of experiments, we used the PPAR-γ antagonist GW9662 along with Androstenediol to determine the effects of PPAR-γ blockade on Androstenediol-induced effects on cardiac functions following T-H.
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Androstenediol ameliorates alterations in immune cells cytokine production capacity in a two hit model of trauma hemorrhage and sepsis
Cytokine, 2006Co-Authors: Takao Suzuki, Tomoharu Shimizu, Laszlo Szalay, Mashkoor A Choudhry, Loring W Rue, Kirby I Bland, Irshad H ChaudryAbstract:Although administration of Androstenediol (a metabolite of dehydroepiandrosterone) following trauma-hemorrhage (T-H) produces beneficial effects on inflammatory cytokines and organ function, it remains unknown whether this metabolite has any salutary effects in preventing alterations in immune cell cytokine production following a combined insult of T-H and sepsis. To examine this, male rats underwent laparotomy, hemorrhagic shock (mean BP 40 mmHg for 90 min) and resuscitation or sham operation. Androstenediol (1 mg/kg BW i.v.) or vehicle was administered at the end of resuscitation. Twenty hrs after T-H or sham operation, sepsis was induced by cecal ligation and puncture (CLP). Five hours thereafter, plasma cytokine levels and cytokine production of various immune cells were determined. In a separate set of experiments, survival was monitored for 10 days after the induction of sepsis. Administration of Androstenediol markedly decreased plasma IL-6 and TNF-alpha levels following T-H and CLP. Furthermore, it prevented the increased production of IL-6 and TNF-alpha by Kupffer cells and alveolar macrophages and attenuated the decrease in IL-6 and TNF-alpha production by splenic macrophages; however, it had no significant effects on the depressed IL-6 and TNF-alpha production by PBMC following T-H and CLP. The depressed IL-2 and IFN-gamma production by splenocytes under those conditions was attenuated by the administration of Androstenediol. Furthermore, survival rate following T-H and subsequent sepsis was improved by Androstenediol treatment. Since Androstenediol administration following T-H attenuated cytokine production and reduced mortality in a double-hit model of T-H and sepsis, this agent appears to be a novel and useful adjunct for maintaining the immune cell functions following T-H and for decreasing the mortality rate from subsequent susceptibility to sepsis.
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mechanism of salutary effects of Androstenediol on hepatic function after trauma hemorrhage role of endothelial and inducible nitric oxide synthase
American Journal of Physiology-gastrointestinal and Liver Physiology, 2005Co-Authors: Tomoharu Shimizu, Laszlo Szalay, Mashkoor A Choudhry, Loring W Rue, Kirby I Bland, Martin G Schwacha, Irshad H ChaudryAbstract:Recent studies have shown that administration of dehydroepiandrosterone (DHEA) after trauma-hemorrhage (T-H) improves cardiovascular and hepatic function in male animals. Although Androstenediol, o...