Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2015 / Article
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Oxidative Stress-Mediated Reperfusion Injury 2014

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Review Article | Open Access

Volume 2015 |Article ID 568634 | https://doi.org/10.1155/2015/568634

Fu-Chao Liu, Hsin-I Tsai, Huang-Ping Yu, "Organ-Protective Effects of Red Wine Extract, Resveratrol, in Oxidative Stress-Mediated Reperfusion Injury", Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 568634, 15 pages, 2015. https://doi.org/10.1155/2015/568634

Organ-Protective Effects of Red Wine Extract, Resveratrol, in Oxidative Stress-Mediated Reperfusion Injury

Academic Editor: Zhengyuan Xia
Received10 Sep 2014
Accepted09 Oct 2014
Published16 Jun 2015

Abstract

Resveratrol, a polyphenol extracted from red wine, possesses potential antioxidative and anti-inflammatory effects, including the reduction of free radicals and proinflammatory mediators overproduction, the alteration of the expression of adhesion molecules, and the inhibition of neutrophil function. A growing body of evidence indicates that resveratrol plays an important role in reducing organ damage following ischemia- and hemorrhage-induced reperfusion injury. Such protective phenomenon is reported to be implicated in decreasing the formation and reaction of reactive oxygen species and pro-nflammatory cytokines, as well as the mediation of a variety of intracellular signaling pathways, including the nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, deacetylase sirtuin 1, mitogen-activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, hemeoxygenase-1, and estrogen receptor-related pathways. Reperfusion injury is a complex pathophysiological process that involves multiple factors and pathways. The resveratrol is an effective reactive oxygen species scavenger that exhibits an antioxidative property. In this review, the organ-protective effects of resveratrol in oxidative stress-related reperfusion injury will be discussed.

1. Introduction

Resveratrol, found in various plants, nuts, and fruits and especially abundant in grapes and red wine, is a naturally occurring plant antibiotic known as phytoalexins [1, 2]. Previous reports have demonstrated the protective effects of resveratrol in different pathological models and experimental conditions [36]. Many clinical studies indicate the beneficial effects of resveratrol in human diseases [712]. Recent report indicates that intake of a McDonald’s meal with red wine could decrease oxidized low density lipoprotein level and increase antioxidative gene expression in healthy human [13]. A growing body of evidence indicates that resveratrol may play potential therapeutic roles in human health by its antioxidant, anti-inflammatory, antiaging, antidiabetic, and apoptotic properties [12, 1417]. A number of target molecules mediating the abovementioned protective effects of resveratrol have been identified, including the endothelial nitric oxide synthase (eNOS) [18, 19], the mitogen-activated protein kinase (MAPK) [20, 21], the hemeoxygenase-1 (HO-1) [3], the estrogen receptor (ER) [20, 2224], the histone deacetylase sirtuin 1 (SIRT1) [2528], the nuclear factor E2-related factor-2 (Nfr2) [3, 29], and nuclear factor-kappa B (NF-κB) [30, 31]. A variety of laboratory and clinical studies also indicate that resveratrol may lead to tissue and organ protective effects against various injuries [6, 19, 3235]. Ischemia-reperfusion (I/R) injury induces free radical formation and inflammation within hours and results in the excessive production of oxidants and proinflammatory mediators and that play a significant role in the development of multiple organ dysfunctions under those conditions [3638]. Resveratrol has been suggested as an organ-protective agent to prevent and treat ischemia and shock-like and reperfusion injury due to its antioxidative activities [20, 3949]. In this review, we summarize the protective effects and possible mechanisms of resveratrol on the preservation of organ function in oxidative stress-mediated I/R injury (Table 1).


Species/targets Model of reperfusion injuryEffective doseEffects and mechanismsReferences

Male Wistar rats rat/heartLangendorff-perfused mode
(ischemia 45 min, reperfusion 10 min).
25 mg/kg
(pretreatment 7 days, IP)
MDA↓, CAT↓, peroxidase↑, and SOD↑[80]

Spraque-Dawley rats/heartLangendorff-perfused mode
(ischemia 60 min, reperfusion 60 min)
20 mg/kg
(pretreatment 14 days intragastric tube),
10 μM (30 min before ischemia)
MDA↓, LDH↓, carbonyl↓, and GSH↑[68]

Male Sprague-Dawley rats/heartLangendorff-perfused mode
(ischemia 30 min, reperfusion 2 h)
10 μM
(30 min before ischemia, IV perfused)
MDA↓ and infarct volume↓[49]

Male Sprague Dawley rats/heartLangendorff-perfused mode
(ischemia 15 min, reperfusion 10 min).
resveratrol
1–100 μM (pretreatment 7 days, IP)
MDA↓ and no improvement in heart function[82]

Sprague-Dawley/BrainRight middle cerebral artery occlusion
(ischemia 30 min, reperfusion 5.5 h)
0.1–1.0 μM
(10 min before ischemia, IV)
Activation of ER-α and ER-β and infarct volume ↓ [23]

Male Wistar rats/brainBilateral common carotid occlusion (occlusion 4 h) 5–30 mg/kg
(5 min before reperfusion, IP)
MDA↓, MPO↓, TNF-α↓, IL-6↓, ICAM-I↓, Catalase↑, SOD↑, and IL-10↑[99]

Male Sprague-Dawley rats/brainMiddle cerebral artery occlusion. (occlusion 2 h) 30 mg/kg
(pretreatment 7 days, IP)
Adesonine↑, inosine↑, hypoxanthine↓, and xanthine↓[92]

Male Wistar rats/BrainBilateral common carotid occlusion (occlusion 10 min) 30 mg/kg
(pretreatment 7 days, IP)
ROS↓, MDA↓, NO↓, and Na+K+-aTPase↓[61]

Male Wistar rats/brainBilateral common carotid occlusion (occlusion 10 min) 30 mg/kg
(pretreatment 7 days, IP)
COX-2↓ and iNOS↓ and NF-kB and JNK activation↓ [100]

Male Sprague-Dawley rats/brainMiddle cerebral artery occlusion (occlusion 30 min) 15 and 30 mg/kg
(pretreatment 7 days, IP)
MDA↓, SOD↑, Nrf2↑, HO-1↑, and caspase-3↓ [3]

Mongolian gerbils/brainBilateral common carotid occlusion (occlusion 5 min) 30 mg/kg
(during occlusion, IP)
Neuronal cell death↓[48]

Male Wistar rats/BrainMiddle cerebral artery occlusion (occlusion 2 h) 20 mg/kg
(pretreatment 21 days, IP)
MDA↓, GSH↑, and infarct volume and motor impairment↓[96]

Male New Zealand white rabbits/spinal cord Occlusion of the infrarenal aorta (ischemia 30 min) 1–10 mg/kg
(pretreatment 30 minutes, IV)
MDA↓ and NO↑ [101]

Male New Zealand white rabbits/spinal cordAbdominal aorta clamp
(ischemia 30 minute)
100 μg/kg
(pretreatment 15 minutes before occluding, IV)
MPO↓, MDA↓, and spinal cord gray matter motor neurons injury↓ [46]

Male Wistar albino rats/intestineSuperior mesenteric artery occlusion
(ischemia 60 min, reperfusion 60 min)
15 mg/kg
(both before ischemia and before reperfusion, IP)
CAT↑, total antioxidant capacity↑, MPO↓, total oxidative status↓, and oxidative stress index (OSI) ↓ [105]

Male BALB/c mice/intestineSuperior mesenteric artery occlusion
(ischemia 1 h, reperfusion 24 h)
50 mg/kg
(pretreatment 10 days, PO)
NO↓, iNOS↓, MPO↓, MDA↓, SOD↑, GSH-Px↑, SIRT1↑, and NF-kB↓[41]

Wistar albino rats/intestineSuperior mesenteric artery occlusion
(ischemia 1 hour, reperfusion 24 h)
15 mg/kg
(pretreatment 5 days and 15 min before occlusion, IP)
MPO↓, MDA↓, NO↓, and SOD↑ [43]

Male Wistar rat/intestineSuperior mesenteric artery occlusion
(ischemia 90 min h, reperfusion 120 min)
0.056 mg/kg
(30 min before occlusion, IV)
Intestine damage score↓, MPO↓, and hemoglobin content↓[42]

Male Wistar albino rats/spleen, ileumHepatic artery clamping
(ischemia 45 min, reperfusion 30 min)
15 mg/kg
(pretreatment 5 days and 15 min before occlusion, IP)
MDA↓, NO↓, and GSH↑[107]

Male Wistar albino rats/kidneyRight nephrectomy and left renal pedicle clamping
(ischemia 45 min, reperfusion 6 h)
30 mg/kg
(30 min prior to ischemia and immediately before the reperfusion period, IP)
ROS↓, MDA↓, MPO↓, LDH↓, TNF-α↓, SOD↑, and GSH↑[112]

Male Wistar rats/kidney Renal pedicles clamping
(ischemia 45 min, reperfusion 24 h)
5 mg/kg,
(pretrentment 30 minutes before surgery, PO)
NO↑, BUN↓, creatinine↓, SOD↑, GSH↑, and CAT↑ [117]

Male Wistar rats/kidneyRight nephrectomy and left renal pedicle clamping
(ischemia 45 min, reperfusion 24 h)
5 mg/kg,
(before I/R, PO)
BUN↓, creatinine↓, SOD↑, GSH↑, CAT↑, and NO↑[45]

Male Wistar rats/kidneyBoth renal pedicles cross-clamping
(ischemia 40 min, reperfusion 24 h)
0.23 μg/kg
(40 min before I/R, IV)
Mortality rate↓, renal damage↓, and NO↑[113]

Male Sprague-Dawley rat/liverClamping the portal vein and hepatic artery
(ischemia 1 h, reperfusion 3 h)
0.02 and 0.2 mg/kg
(after reperfusion, IV)
IL-1β↓, IL-6↓, MPO↓, TNF-α↓, KC↓, and HO-1 mRNA↓[122]

Male Sprague-Dawley rats/liverClamping the portal vein and hepatic artery
(ischemia 45 min, reperfusion 45 min)
10 mg/kg
(15 min before reperfusion, IV)
MDA↓, SOD↑, GSH↑, and CAT↑[121]

Sprague-Dawley rat/lungLeft hilum
(occlusion 60 min)
20 mg/kg
(4 days and 15 min before ischemia, PO)
ROS↓, MDA↓, PGC1-α mRNA↑, and leukocyte infiltration↓[126]

Male Sprague-Dawley rat/testisLeft testis torsion/detorsion
(ischemia 4 h)
20 mg/kg
(30 min before detorsion, IP)
MDA↓, H2O2↓, and oxidative stress index↓[39]

Male Wistar rats/testisRight testis torsion/detorsion
(ischemia 4 h)
30 mg/kg
(30 min before detorsion, IP; 7 days postoperatively, PO)
Improved contralateral spermatozoid production and some fertility parameters.[133]

Wistar albino rat/ovaryRight unilateral adnexal torsion/detorsion
(torsion 3 h, detorsion 3 h)
10 mg/kg
(30 min before detorsion, IP)
MDA↓, XO↓, and GSH↑[140]

Male Sprague Dawley rats/retinalAnterior chamber saline bag
(intraocular pressure 70–80 mm Hg for 45 min)
30 mg/kg
(pretreatment 5 days, IP)
Reduce inner retinal layers thinning [145]

Male Wistar rats rat/RetinalAnterior chamber saline bag
(intraocular pressure 120 mm Hg for 60 min)
0.5 nmole
(pretreatment 15 min, IV)
MMP-9↓, iNOS↓, and HO-1↑ [149]

Male Spraque-Dawley rats/skeletal muscle Abdominal aorta clamp
(ischemia 120 min, reperfusion 60 min)
20 mg/kg
(pretreatment for 14 days, gastric tube)
MDA↓, CPK↓, LDH↓, GSH↑ carbonyl↓, and myoglobin↓, [157]

Sprague-Dawley rats/bladder Abdominal aorta occlusion
(ischemia 60 min, reperfusion 60 min)
10 mg/kg
(15 min before I/R, IP)
MPO↓, MDA↓, and GSH↑[164]

Abbreviations: I/R, ischemia-reperfusion; IP, intraperitonium; IV: intravenous; PO, Orally; MAP mean arterial pressure; ROS, reactive oxygen species; ER, estrogen receptor; HO-1, hemeoxygenase-1; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha; NF-kB, nuclear factor-kappa B; JNK, c-Jun N-terminal kinase; MMP-9, metallopeptidase 9; SOD, superoxide dismutase; CAT, catalase; GSH, glutathione; MDA, malondialdehyde; NOX, nicotinamide adenine dinucleotide phosphate-oxidase; XO, xanthine oxidase; H2O2, hydrogen peroxide; TNF-α, tumor necrosis factor-alpha; IL-6, interleukin 6; IL-10, interleukin 10; ICAM-1, intercellular adhesion molecule 1; MPO, myeloperoxidase; NO, nitric oxide; iNOS, inducible nitric oxide synthase.

2. The Organ-Protective Effects of Resveratrol in Ischemia and Reperfusion Injury

2.1. Oxidative Stress and Ischemia-Reperfusion Injury

The oxidative stress is still considered to be an important cause of I/R-induced tissue injury. There is a massive increase in oxidants and oxygen radicals during the initiation and progression of I/R injury [5053]. Ischemia and reperfusion can promote production of ROS, such as superoxide anions (), hydroxyl free radicals (HO), hydrogen peroxide (H2O2), and nitric oxide (NO), which is a major factor contributing to I/R-induced organ injury [50, 51, 54, 55]. I/R-induced reactive oxygen species (ROS) formation is the end result of several different oxidant-producing pathways, such as the mitochondria, xanthine oxidase (XO), and nicotinamide adenine dinucleotide phosphate-oxidase (NOX) [50, 52, 56, 57]. Oxygen radicals cause lipid peroxidation that can lead to cell membrane breakdown and mitochondrial damage triggering cell death [21, 58]. NO plays a protective role in I/R injury as increased NO expression can decrease I/R-induced organ injury [59, 60]. In controversy, previous studies have also shown that the inducible NO synthase is upregulated after I/R and can switch from NO to oxygen radical generation under oxidant stress [41, 61]. Oxidative stress could perturb the balance between oxidant and antioxidant status. In most cells, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) are endogenous free radical scavenging enzymes induced by oxidative stress [6264]. These antioxidant enzymes play a critical role in the prevention of oxidative damage during ischemia and reperfusion. In addition, the oxidant formation is generated through a series of interacting pathways in various organs and endothelial cells, triggering subsequent leukocyte chemotaxis and inflammation [20, 50, 65]. However, the pathophysiology of I/R injuries has not yet been fully elucidated due to complex interactions and signaling pathways. Previous evidence shows that resveratrol plays an important role organ protection against I/R injury via its antioxidative and anti-inflammatory properties [20, 66, 67]. The protective pathways and mechanisms of resveratrol in ischemia-reperfusion (I/R) will be further discussed in this paper.

2.2. The Cardioprotective Effect of Resveratrol in Ischemia-Reperfusion Injury

Myocardial ischemia-reperfusion injury is a complex pathophysiological process that involves various factors and pathways [6871]. An excess amount of ROS is increased during I/R injury that results in myocardiocyte damage. Resveratrol exerts cardiovascular beneficial effects on atherosclerosis, ventricular arrhythmia, and myocardial I/R injury [4, 72, 73].

Resveratrol could reduce oxidative stress by inhibiting ROS production and has been reported to be a scavenger of hydroxyl, superoxide, metal-induced radicals, and H2O2 [31, 7477]. However, the protective effects of resveratrol against oxidative injury are likely to be attributed to the upregulation of the endogenous cellular antioxidant systems rather than its direct ROS scavenging activity. Resveratrol also induces antioxidant enzymes in cardiovascular tissues including SOD, GSH, CAT [72, 74, 78], and NOX [74, 79], all of which are major ROS producing enzymes in the cardiovascular system.

Previous studies have shown that resveratrol-provided cardioprotection is achieved by preserving postischemic ventricular function and reducing myocardial infarct size and cardiomyocytes apoptosis [80]. Pretreatment of rats with resveratrol resulted in cardioprotection in the isolated heart following ischemia and reperfusion [49, 81, 82] and protected neonatal rat cardiomyocytes against anoxia/reoxygenation injury by antiapoptosis [31]. A recent study has shown that resveratrol improved diabetic cardiomyopathy and postischemic ventricular function through regulating myocardial lipoperoxidation and antioxidant enzyme activities [72, 77, 83]. The protective effect is related with an increased activity of peroxidase and superoxide dismutase and a decreased expression of catalase, malondialdehyde (MDA) and isoprostanes [80, 84]. However, MDA is not used as a relaible biomarker of oxidative stress. Instead, isoprostane is considered a specific marker of lipid peroxidation for monitoring oxidative stress [8587].

NO has been identified as a crucial factor mediating the protective effects of resveratrol [18, 88]. Resveratrol enhances endothelial NO synthase (eNOS) expression in endothelial cells and improves the ventricular function during I/R [18, 88]. SIRT1 has been shown to regulate mammalian genes transcription and has a regulatory function of intracellular signaling in hypoxia or stress [26, 27]. Recent studies indicated that the upregulation of eNOS expression was mediated by SIRT1 [74, 75, 89]. SIRT1 activation may be necessary for the cardioprotective effect, which is mediated by NO signaling [90]. However, other studies have shown that acutely infused resveratrol had no beneficial effect in intestinal ischemia/reperfusion or stroke and it is not mediated by NO elevation [41, 61].

The cardioprotective mechanisms of resveratrol are complex in I/R injury. A previous report demonstrated that there was less myocardial injury and inflammation in Toll-like receptor 4- (TLR4-) deficient mice in I/R. This protective mechanism was possibly associated to the TLR4/nuclear factor-kappa B (NF-κB) signaling pathway [31, 41]. Furthermore, resveratrol attenuates postischemic leukocyte recruitment and subsequent endothelial dysfunction by superoxide-related proinflammatory stimulis, such as hypoxanthine (HX)/XO and platelet-activating factor (PAF) [91].

2.3. The Neuroprotective Effect of Resveratrol in Ischemia-Reperfusion Injury

The mechanisms of brain and spinal cord injuries are complex and multifactorial. Oxidative stress has been regarded as important pathogenesis for neurologic damage after cerebral I/R injury. ROS, like superoxide anions, hydroxyl free radicals, hydrogen peroxide, and nitric oxide, are produced during abnormal metabolic reactions or central nervous system activation in I/R [61, 92]. Previous experimental evidence has demonstrated that resveratrol exhibits neuroprotective effect in various cerebral ischemic stroke animal model [3, 9395]. Treatment with transresveratrol prevented motor impairment, reduced glutathione levels, and also significantly decreased the infarct size after middle cerebral artery occlusion and reperfusion in rat [96]. The neuroprotective effects of resveratrol were shown to be due to its antioxidative and NO promoting properties [48, 92, 97]. Wang and colleagues also showed that resveratrol decreased cerebral microglial activation and delayed neuronal cell death in gerbils, a beneficial effect attributed to its strong antioxidative activity [48]. Previous studies also showed that resveratrol significantly increased the basal levels of adesonine and inosine, inhibited the elevations of hypoxanthine and xanthine levels, remarkably decreased xanthine oxidase activity, and depressed oxidative biomarker (8-isoprostane) levels [84, 92].

Previous studies suggested that the cerebroprotective action of resveratrol could be mediated by both antioxidative and anti-inflammatory effects [98]. Resveratrol treatment decreased oxidative stress and inflammatory markers like isoprostane, tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), myeloperoxidase (MPO), and intercellular adhesion molecule 1 (ICAM-1) and increased antioxidative and anti-inflammatory markers like superoxide dismutase, catalase, and interleukin 10 (IL-10) levels in brain I/R injury [84, 99]. Resveratrol pretreatment also reduced astroglial and microglial cells activation by attenuating NF-κB and JNK activation associated with a decrease in inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) production [100]. A recent study has shown that intracortical injection of resveratrol reduced rat cortex infarct volume. This neuroprotective effect was attenuated when resveratrol and a selective estrogen receptor- (ER-) α and ER-β antagonist injections were given in combination. These results indicated that neuroprotection of resveratrol is mediated via ER-α and ER-β subtypes [23].

In addition, the resveratrol also has protective effect in spinal cord I/R injury. In a rabbit study, prophylactic use of resveratrol decreased malondialdehyde and myeloperoxidase activity and reduced spinal cord gray matter motor neurons damage following abdominal aorta clamping and reperfusion [46]. Kiziltepe et al. [101] also showed that neuroprotective function of resveratrol in spinal cord I/R injury by scavenging free radicals, inhibiting oxidative stress, and upregulating NO.

2.4. The Intestinoprotective Effect of Resveratrol in Ischemia-Reperfusion Injury

Gastrointestinal tract is highly sensitive to I/R injury. Intestinal I/R could trigger the release of oxidants and tissue injurious factors, leading to interstitial edema, microvascular permeability change, vasoregulation impairment, mucosal barrier dysfunction, and inflammatory cell infiltration [65, 102105].

Resveratrol plays a crucial role in intestinal I/R injuries. Previous study demonstrated that resveratrol exerted its broad spectrum of protective mechanisms through increasing its antioxidative capacity and reducing oxidative status and MPO in intestinal I/R injury [20, 42, 43, 105, 106]. Resveratrol ameliorated the intestinal tissue injury and decreased bacterial translocation in mesenteric lymph nodes via decreased MPO and NO levels and restored SOD activity [43].

Resveratrol at a dose of 0.056 mg/kg significantly decreased the hemoglobin content, the histopathologic score, and tissue myeloperoxidase activity in intestinal I/R injury, without improving the systemic and metabolic parameters [42]. One study showed that intraperitoneal administration of resveratrol reduced excessive NO formation and diminished rat spleen and ileum oxidative damage after hepatic I/R [107]. Furthermore, resveratrol rendered subacute intestinal protection in vivo. Resveratrol significantly ameliorated subacute intestinal I/R injury [41, 42], related to a reduction of NO production and the activation of the SIRT1-NF-κB pathway, which was associated with a decrease in iNOS expression as well as NO production [41]. NO is an important signaling molecule in antioxidative defense mechanisms and resveratrol relieved tissue I/R injuries through an NO-dependent manner [15, 16, 30, 108]. However, its protective or detrimental effect in intestinal I/R injury is still controversial. Some studies showed that an augmented NO production can protect the intestine following I/R injury [12, 109]. Other evidence indicated that a decreased production of NO may have a protective role via with the suppression of inducible NOS in the small intestine I/R [41, 98, 110].

2.5. The Renoprotective Effect of Resveratrol in Ischemia-Reperfusion Injury

Renal I/R causes an increase in ROS and isoprostane levels and a decrease of the antioxidant enzyme glutathione in the urological system [111]. Resveratrol may induce the GSH synthesis enzymes and maintain the GSH levels during oxidative stress [45, 112, 113]. It has been shown that resveratrol could maintain antioxidant defenses and reduce the oxidative damage of kidney [45, 113]. Pretreatment with resveratrol prevented the renal I/R-induced lipid peroxidation and protected the depletion of antioxidant enzyme in the renal I/R-treated rats. Moreover, oxidative injury of the kidneys was accompanied by neutrophil infiltration, as evidenced by the elevated tissue MPO levels. In addition, oxidative stress could be involved in renal glomerular lesions caused by a series of proinflammatory mediators, including cytokines and chemokines that lead to the ROS production, leukocyte activation, and glomerular damage [112]. ROS play an important role in the pathologic process of renal ischemia reperfusion injury. Previous study showed that the short-term treatment of resveratrol inhibited renal lipid peroxidation induced by IR. Resveratrol administration decreased renal cortex and medulla damage and reduced the mortality of ischemic rats from 50% to 10% [113].

NO expression is generated in renal tissue and plays an important role in the regulation of renal blood flow and glomerular filtration function. In kidney, resveratrol was found to exert its protective action through the upregulation of NO. Previous studies demonstrated that resveratrol could stimulate NO production during renal I/R [45, 113116]. Preconditioning and resveratrol treatment also led to a marked increase in NO levels in kidneys and protect renal cells from I/R injury [117]. The protective phenomenon of resveratrol was suggested to be through the NO-dependent mechanism [113]. Another report also evidenced that treatment with L-NAME (an NO synthase inhibitor) attenuated this protection afforded by resveratrol, indicating that resveratrol exerted its protective effect through the release of NO [45].

2.6. The Hepatoprotective Effect of Resveratrol in Ischemia-Reperfusion Injury

I/R stimulates the hepatic Kupffer cells and the residing macrophage activation, to generate ROS and proinflammatory cytokines and to upregulate iNOS [60, 118]. The activation of Kupffer cell (KC) with enhanced ROS production and secretion of inflammatory cytokines and proteolytic enzymes is considered to play an important role in liver reperfusion injury [40, 119]. Additionally, the activation of polymorphonuclear leukocytes migration and infiltration in the injury site may enhance the production of inflammatory cytokines, adhesion molecules, and ROS [40, 120].

Previous studies showed that resveratrol reduced liver damage after ischemia-reperfusion. This beneficial effect was due to the replacement of the depleted antioxidant defense system in hepatic I/R injury [121, 122]. Transresveratrol has also been suggested to decrease the superoxide and improve NO bioavailability. Postischemic treatment with lower dose transresveratrol (0.02 mg/kg) reduced TNF-α, interleukin 1β (IL-1β), keratinocyte chemoattractant (KC), and HO-1 hepatic mRNA expression and decreased hepatic neutrophil recruitment [122]. Gedik et al. [121] reported that resveratrol treatment decreased the lipid peroxidation and protected the depletion of antioxidant enzymes (SOD, CAT, and GSH) in rat model of common hepatic artery and portal vein clamping and reperfusion-induced hepatic injury.

2.7. The Pulmonoprotective Effect of Resveratrol in Ischemia-Reperfusion Injury

Lung I/R injury occurs in lung transplantation and cardiopulmonary surgery, resulting in an excessive production of reactive ROS [37, 123125]. The exact mechanism in I/R-induced lung injury is not completely understood. However, an overproduction of ROS such as superoxide and peroxides, activation of macrophages, and infiltration of polymorphonuclear leukocytes are implicated in pulmonary injury [125]. Previous study [89] demonstrated that I/R-induced lung tissue damage was related to pulmonary mitochondrial dysfunction. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) was a coactivator controlling aerobic capacity and mitochondrial biogenesis, and an increase in PGC-1α mRNA expression was associated with a decreased pulmonary oxidative stress and improved aerobic capacity. Recent study [126] demonstrated that PGC-1α mRNA expression in the lungs was markedly improved with resveratrol, providing protection against pulmonary damage induced by contralateral lung I/R injury. Resveratrol treatment also effectively reduced the lipid peroxidation and alveolar neutrophils and maintained mitochondrial homeostasis. In addition, resveratrol could increase mitochondrial activity through upregulating PGC-1α and SIRT1 expression [89].

2.8. The Reproductive Organs Protective Effect of Resveratrol in Ischemia-Reperfusion Injury

Testicular torsion is urological emergency in which damaged germinal cells may lead to infertility [127129]. Testicular torsion and detorsion may be regarded as an ischemia/reperfusion (I/R) injury. Oxidative stress is thought to be a major responsible in I/R injury; however, the mechanism involved in testicular injury has not been fully understood. Previous reports demonstrated that ipsilateral testicular torsion could affect the contralateral testis. The injuries caused by I/R were observed in the ipsilateral and contralateral testis [130, 131]. Resveratrol could decrease the cell injury by preventing lipid peroxidation in the cell membrane and DNA damage caused by excessive ROS production [39, 47, 132]. Previous study indicated that treatment with resveratrol improved fertility parameters and contralateral spermatozoid production [133]. A recent report showed that resveratrol pretreatment decreased tissue lipid peroxidation and had a protective effect in the prevention of apoptosis in rat testicular torsion/detorsion (T/D) model [39].

Ovarian torsion is also a gynecological emergency due to the twisting of the adnexa on its ligamentous support. Insufficiency in tissue blood flow due to various reasons such as torsion or embolism leads to ischemia [134, 135]. The levels of ROS and MDA are increased during the reperfusion period following ischemia. It is known that xanthine oxidase is an important source of the ROS production [136, 137] during I/R and GSH is an essential component of the cellular defense mechanism against oxidative cell damage [138, 139]. Hascalik et al. [140] reported that intraperitoneal resveratrol (10 mg/kg) administration reduced the tissue XO products, as well as restored GSH levels, and decreased rat ovarian damage following T/D injury.

2.9. The Ophthalmoprotective Effect of Resveratrol in Ischemia-Reperfusion Injury

The retina is a very sensitive neural structure that is easily damaged by free radicals and inflammation following ischemia-reperfusion injury [141, 142]. Retinal ischemia is a common cause of visual loss and impairment. I/R-induced neural injuries are associated with enhanced production of endogenous oxidants such as oxygen free radicals, NO, and calcium [141, 143, 144]. Previous studies showed that resveratrol was capable of crossing the blood-retina barrier and exerting its neuroprotective effects, including cerebral and retinal IR injuries. Vin et al. [145] reported that resveratrol prophylactic treatment attenuated ischemic-induced loss of retinal function and reduced ischemia-mediated thinning of inner retinal layers [145]. Li et al. also showed that pretreatment of resveratrol decreased retinal vascular degeneration by inhibiting endoplasmic reticulum stress in retinal ischemic injury; however, it did not prevent retinal neuronal cell loss [146].

Previous studies showed that matrix metallopeptidase 9 (MMP-9) expression was upregulated during brain ischemia [147] and HO-1 overexpression attenuated retinal cellular damage by intense light exposure [148]. In addition, resveratrol exerted retinal protective effects via modulation of NOS in oxygen-induced retinopathy. Recent study also evidenced that the administration of resveratrol might protect the retina against ischemia by inhibiting iNOS and MMP-9 expression and upregulating HO-1 levels [149].

2.10. The Musculoprotective Effect of Resveratrol in Ischemia-Reperfusion Injury

I/R injuries of skeletal muscles are serious clinical problems and are commonly seen in a variety of injuries including traumatic damage, peripheral vascular surgery, plastic surgery, or limb surgery with long time tourniquet application [150152]. I/R injury of skeletal muscle can increase free radicals production and activate ROS generation, with the ability to produce cell membrane damage and leukocyte infiltration [153155]. Resveratrol is an effective scavenger of hydroxyl and superoxide and exhibits a protective effect to decrease cell membranes lipid peroxidation and free radicals induced DNA damage [153, 154, 156]. Previous studies have shown that dietary flavonoid resveratrol can protect the skeletal muscle tissue against ischemia and reperfusion injury because of its strong antioxidant properties [157]. Elmali et al. indicated that intraperitoneal resveratrol treatment could exert a protective effect against tourniquet-induced I/R injury in rat gastrocnemius muscle. However, resveratrol not only functioned as an antioxidant but also attenuated the neutrophil infiltration in damaged skeletal muscle [158].

2.11. The Vesicoprotective Effect of Resveratrol in Ischemia-Reperfusion Injury

Urinary bladder I/R injury is associated with vascular atherosclerotic disease or pelvic embolization operations [159, 160]. Bladder ischemia could result in detrusor contractility impairment and bladder dysfunction [161, 162]. Previous study showed that I/R injury induced a production of isoprostanes [85, 86] and a decrease in endogenous GSH, as well as an enhanced neutrophil infiltration in rat bladder [162, 163]. However, resveratrol treatment reduced bladder inflammatory cell infiltration, lipid peroxidation, and the myeloperoxidase activity in I/R injury. Resveratrol treatment also reversed the bladder contractile responses to carbachol and prevented oxidative tissue damage following I/R [164].

3. The Organ-Protective Effect of Resveratrol in Hemorrhage and Reperfusion Injury

Reperfusion injury after hemorrhage results in an excessive production of oxidants and proinflammatory mediators. The enhanced ROS and proinflammatory cytokines play important factors in the initiation and perpetuation of organ injury [67, 165]. Previous studies have shown that vascular endothelial cell dysfunction can lead to inadequate tissue perfusion, which occurs after hemorrhagic shock and persists despite fluid resuscitation [166, 167]. Oxidative stress and superoxide radical generation are believed to contribute to the pathogenesis of endothelial dysfunction in low-flow states [167, 168]. Endothelial NOX is a major source of ROS of the vasculature, and previous studies have shown that there is a marked increase in NOX-generated ROS by the endothelium under stressful conditions [169, 170]. Elevated ROS is considered a major contributing factor to endothelial dysfunction, and antioxidants have been found to attenuate ROS-induced injuries [168, 169]. Resveratrol has been shown to have broad antioxidative activities in a number of biological systems [170]. Our previous studies have shown that resveratrol prevented hemorrhagic shock-elicited oxidative stress and protected endothelium from subsequent functional damages [168]. The beneficial effects included the suppression of the NOX activity and direct scavenging of ROS. The inhibitory effect of resveratrol on the NOX activity appeared to be mediated through influence of the active NOX enzyme complex assembly in the cell membrane and the cytosol, as evidenced from reduced membrane-bound proteins p22phox and gp91phox and cytosolic protein p47phox [166, 168].

The SIRT1 transcription-modulating proteins showed a fine balance in response to intracellular cues such as hypoxia or stress signals. The beneficial effects of resveratrol mediated by SIRT1 activation can be contributed to by different organs [26, 171, 172]. Studies showed that resveratrol decreased oxidative stress-induce ROS elevation and reduced brain neuron injury by radiation through the activation of SIRT1 [171].

HO-1 appears to act as a protective agent in many organs against insults, such as ischemia and oxidative stress [173, 174]. Previous studies have shown that resveratrol binds and increases the transcriptional activity of ER-α and ER-β. Resveratrol can modulate HO-1 induction and previous studies have shown that estrogen or flutamide enhances HO-1 expression via ER [174176]. Our previous studies suggested that the upregulation in HO-1 was associated with the prevention of endothelial dysfunction and the salutary effects of resveratrol on endothelial function, mediated in part by an upregulation of the HO-1-related pathway via ER [165]. The p38 MAPK and Akt have been reported to regulate inflammatory response after trauma hemorrhage [20, 174]. PI3K/Akt pathway is known to play a pivotal role in the ability of neutrophils to undergo chemotaxis. Blockade of Akt activation abolishes the salutary effects of resveratrol in the heart following reperfusion injury [177, 178]. Estrogen-mediated attenuation of the inflammatory response to shock-induced organ injury is abolished by the presence of a p38 MAPK inhibitor (SB-203580) [20, 174]. Previous study also showed that resveratrol administration after hemorrhagic shock upregulated p38 MAPK and Akt expression via HO-1-related pathway [20, 179]. Neutrophils are activated following hemorrhage/reperfusion injury and activated neutrophils appear to infiltrate the injured organs in parallel with increased expression of adhesion molecules on endothelial cells. Upregulation of HO-1 causes a reduction of cytokines, adhesion molecules, chemokines, and neutrophil accumulation and ameliorates organ injury in shock status [20, 180].

4. Conclusions

Resveratrol has been indicated to have many beneficial effects in various studies and experimental conditions. There is increasing evidence suggesting that resveratrol protects organ function after ischemia or shock-like reperfusion injury. Resveratrol can attenuate organs reperfusion injury through multiple pathways. However, the protective benefits of resveratrol may not simply be attributed by its scavenging, antioxidative, or anti-inflammatory effect. It is implicated that resveratrol is also mediated in part via a variety of intracellular signaling pathways including the regulation of the NOS, HO-1, SIRT1, ER, MAPK, PGC-1α, TLR4, and NF-κB (Figure 1). This complex network needs additional elucidation, more experimental studies, and clinical trials. Resveratrol might be a preventive and therapeutic agent to protect reperfusion-induced organ injury in future clinical treatment.

Abbreviations

I/R:Ischemia-reperfusion
IP:Intraperitonium
IV:Intravenous
PO:Orally
MAP:Mean arterial pressure
ROS:Reactive oxygen species
ER:Estrogen receptor
HO-1:Hemeoxygenase-1
PGC-1α:Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha
NF-κB:Nuclear factor-kappa B
JNK:c-Jun N-terminal kinase
MMP-9:Metallopeptidase 9
SOD:Superoxide dismutase
CAT:Catalase; GSH: glutathione
NOX:Nicotinamide adenine dinucleotide phosphate-oxidase
XO:Xanthine oxidase
H2O2:Hydrogen peroxide
TNF-α:Tumor necrosis factor-alpha
IL-6:Interleukin 6
IL-10:Interleukin 10
ICAM-1:Intercellular adhesion molecule 1
MPO:Myeloperoxidase
NO:Nitric oxide
iNOS:Inducible nitric oxide synthase.

Conflict of Interests

The authors declare that they have no competing interests.

Authors’ Contribution

Huang-Ping Yu, MD, PhD, is the principle investigator for the studies providing oversight and contributed fundamental conceptualization for the research, writing a grant proposal and paper. Fu-Chao Liu, MD, PhD contributed to paper preparation and data collection and assisted in writing the paper. Hsin-I Tsai, MD, assisted in writing the paper.

Acknowledgments

This work was partially supported by grants from the National Science Council (NSC102-2314-B-182A-051-MY3) and Chang Gung Memorial Hospital (CMRPG3B1052 and CMRPG3B1053) to Huang-Ping Yu. Support was also provided by the National Science Council (NSC103-2314-B-182-046-MY2) and Chang Gung Memorial Hospital (CMRPG3B1622) to Fu-Chao Liu.

References

  1. J. A. Santos, G. S. G. de Carvaho, V. Oliveira, N. R. B. Raposo, and A. D. Da Silva, “Resveratrol and analogues: a review of antioxidant activity and applications to human health,” Recent Patents on Food, Nutrition & Agriculture, vol. 5, no. 2, pp. 144–153, 2013. View at: Publisher Site | Google Scholar
  2. R. F. Guerrero, M. C. Garcia-Parrilla, B. Puertas, and E. Cantos-Villar, “Wine, resveratrol and health: a review,” Natural Product Communications, vol. 4, no. 5, pp. 635–658, 2009. View at: Google Scholar
  3. J. Ren, C. Fan, N. Chen, J. Huang, and Q. Yang, “Resveratrol pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in Rats,” Neurochemical Research, vol. 36, no. 12, pp. 2352–2362, 2011. View at: Publisher Site | Google Scholar
  4. P. K. Gupta, D. J. DiPette, and S. C. Supowit, “Protective effect of resveratrol against pressure overload-induced heart failure,” Food Science & Nutrition, vol. 2, no. 3, pp. 218–229, 2014. View at: Google Scholar
  5. L. Liu, H. Gu, H. Liu et al., “Protective effect of resveratrol against IL-1β-induced inflammatory response on human osteoarthritic chondrocytes partly via the TLR4/MyD88/NF-κB signaling pathway: an “in vitro study”,” International Journal of Molecular Sciences, vol. 15, no. 4, pp. 6925–6940, 2014. View at: Publisher Site | Google Scholar
  6. M. Kitada and D. Koya, “Renal protective effects of resveratrol,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 568093, 8 pages, 2013. View at: Publisher Site | Google Scholar
  7. J. Tome-Carneiro, M. Gonzalvez, M. Larrosa et al., “Resveratrol in primary and secondary prevention of cardiovascular disease: a dietary and clinical perspective,” Annals of the New York Academy of Sciences, vol. 1290, no. 1, pp. 37–51, 2013. View at: Publisher Site | Google Scholar
  8. K. Legg, “Metabolic disease: identifying novel targets of resveratrol,” Nature Reviews Drug Discovery, vol. 11, no. 4, article 273, 2012. View at: Publisher Site | Google Scholar
  9. K. Magyar, R. Halmosi, A. Palfi et al., “Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease,” Clinical Hemorheology and Microcirculation, vol. 50, no. 3, pp. 179–187, 2012. View at: Publisher Site | Google Scholar
  10. F. Li, Q. Gong, H. Dong, and J. Shi, “Resveratrol, a neuroprotective supplement for Alzheimer's disease,” Current Pharmaceutical Design, vol. 18, no. 1, pp. 27–33, 2012. View at: Publisher Site | Google Scholar
  11. L. M. Chu, A. D. Lassaletta, M. P. Robich, and F. W. Sellke, “Resveratrol in the prevention and treatment of coronary artery disease,” Current Atherosclerosis Reports, vol. 13, no. 6, pp. 439–446, 2011. View at: Publisher Site | Google Scholar
  12. L. G. Wood, P. A. B. Wark, and M. L. Garg, “Antioxidant and anti-inflammatory effects of resveratrol in airway disease,” Antioxidants & Redox Signaling, vol. 13, no. 10, pp. 1535–1548, 2010. View at: Publisher Site | Google Scholar
  13. L. Di Renzo, A. Carraro, R. Valente, L. Iacopino, C. Colica, and A. De Lorenzo, “Intake of red wine in different meals modulates oxidized LDL level, oxidative and inflammatory gene expression in healthy people: a randomized crossover trial,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 681318, 9 pages, 2014. View at: Publisher Site | Google Scholar
  14. W. Yu, Y.-C. Fu, and W. Wang, “Cellular and molecular effects of resveratrol in health and disease,” Journal of Cellular Biochemistry, vol. 113, no. 3, pp. 752–759, 2012. View at: Publisher Site | Google Scholar
  15. A. Csiszar, “Anti-inflammatory effects of resveratrol: possible role in prevention of age-related cardiovascular disease,” Annals of the New York Academy of Sciences, vol. 1215, no. 1, pp. 117–122, 2011. View at: Publisher Site | Google Scholar
  16. A. A. E. Bertelli, M. Migliori, V. Panichi et al., “Resveratrol, a component of wine and grapes, in the prevention of kidney disease,” Annals of the New York Academy of Sciences, vol. 957, pp. 230–238, 2002. View at: Publisher Site | Google Scholar
  17. A. Gulcubuk, D. Haktanir, A. Cakiris et al., “The effects of resveratrol on tissue injury, oxidative damage, and pro-inflammatory cytokines in an experimental model of acute pancreatitis,” Journal of Physiology and Biochemistry, vol. 70, no. 2, pp. 397–406, 2014. View at: Publisher Site | Google Scholar
  18. S. Wang, Y. Qian, D. Gong, Y. Zhang, and Y. Fan, “Resveratrol attenuates acute hypoxic injury in cardiomyocytes: correlation with inhibition of iNOS-NO signaling pathway,” European Journal of Pharmaceutical Sciences, vol. 44, no. 3, pp. 416–421, 2011. View at: Publisher Site | Google Scholar
  19. B. Budak, M. Seren, N. N. Turan, Z. Sakaogullari, and A. T. Ulus, “The protective effects of resveratrol and L-NAME on visceral organs following aortic clamping,” Annals of Vascular Surgery, vol. 23, no. 5, pp. 675–685, 2009. View at: Publisher Site | Google Scholar
  20. H.-P. Yu, T.-L. Hwang, P.-W. Hsieh, and Y.-T. Lau, “Role of estrogen receptor-dependent upregulation of P38 MAPK/heme oxygenase 1 in resveratrol-mediated attenuation of intestinal injury after trauma-hemorrhage,” Shock, vol. 35, no. 5, pp. 517–523, 2011. View at: Publisher Site | Google Scholar
  21. P. Antonuccio, L. Minutoli, C. Romeo et al., “Lipid peroxidation activates mitogen-activated protein kinases in testicular ischemia-reperfusion injury,” The Journal of Urology, vol. 176, no. 4, part 1, pp. 1666–1672, 2006. View at: Publisher Site | Google Scholar
  22. J. C. Nwachukwu, S. Srinivasan, N. E. Bruno et al., “Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network,” eLife, vol. 3, Article ID e02057, 2014. View at: Publisher Site | Google Scholar
  23. M. C. Saleh, B. J. Connell, and T. M. Saleh, “Resveratrol induced neuroprotection is mediated via both estrogen receptor subtypes, ERα and ERβ,” Neuroscience Letters, vol. 548, pp. 217–221, 2013. View at: Publisher Site | Google Scholar
  24. H.-P. Yu, J.-C. Hsu, T.-L. Hwang, C.-H. Yen, and Y.-T. Lau, “Resveratrol attenuates hepatic injury after trauma-hemorrhage via estrogen receptor-related pathway,” Shock, vol. 30, no. 3, pp. 324–328, 2008. View at: Publisher Site | Google Scholar
  25. W. Xu, Y. Lu, J. Yao et al., “Novel role of resveratrol: suppression of HMGB1 nucleocytoplasmic translocation by the up-regulation of SIRT1 in sepsis-induced liver injury,” Shock, 2014. View at: Publisher Site | Google Scholar
  26. B. Jian, S. Yang, I. H. Chaudry, and R. Raju, “Resveratrol restores sirtuin 1 (SIRT1) activity and pyruvate dehydrogenase kinase 1 (PDK1) expression after hemorrhagic injury in a rat model,” Molecular Medicine, vol. 20, no. 1, pp. 10–16, 2014. View at: Publisher Site | Google Scholar
  27. T. Li, J. Zhang, J. Feng et al., “Resveratrol reduces acute lung injury in a LPS-induced sepsis mouse model via activation of Sirt1,” Molecular Medicine Reports, vol. 7, no. 6, pp. 1889–1895, 2013. View at: Publisher Site | Google Scholar
  28. Y. Fu, Y. Wang, L. Du et al., “Resveratrol inhibits ionising irradiation-induced inflammation in MSCs by activating Sirt1 and limiting NLRP-3 inflammasome activation,” International Journal of Molecular Sciences, vol. 14, no. 7, pp. 14105–14118, 2013. View at: Publisher Site | Google Scholar
  29. V. Kesherwani, F. Atif, S. Yousuf, and S. K. Agrawal, “Resveratrol protects spinal cord dorsal column from hypoxic injury by activating Nrf-2,” Neuroscience, vol. 241, pp. 80–88, 2013. View at: Publisher Site | Google Scholar
  30. J. Zhang, J. Chen, J. Yang et al., “Resveratrol attenuates oxidative stress induced by balloon injury in the rat carotid artery through actions on the ERK1/2 and NF-kappa B pathway,” Cellular Physiology and Biochemistry, vol. 31, no. 2-3, pp. 230–241, 2013. View at: Publisher Site | Google Scholar
  31. C. Zhang, G. Lin, W. Wan et al., “Resveratrol, a polyphenol phytoalexin, protects cardiomyocytes against anoxia/reoxygenation injury via the TLR4/NF-κB signaling pathway,” International Journal of Molecular Medicine, vol. 29, no. 4, pp. 557–563, 2012. View at: Publisher Site | Google Scholar
  32. N. Atmaca, H. T. Atmaca, A. Kanici, and T. Anteplioglu, “Protective effect of resveratrol on sodium fluoride-induced oxidative stress, hepatotoxicity and neurotoxicity in rats,” Food and Chemical Toxicology, vol. 70, pp. 191–197, 2014. View at: Publisher Site | Google Scholar
  33. W. Zhang, C. Guo, R. Gao, M. Ge, Y. Zhu, and Z. Zhang, “The protective role of resveratrol against arsenic trioxide-induced cardiotoxicity,” Evidence-Based Complementary and Alternative Medicine, vol. 2013, Article ID 407839, 8 pages, 2013. View at: Publisher Site | Google Scholar
  34. H. X. Zhang, G. L. Duan, C. N. Wang et al., “Protective effect of resveratrol against endotoxemia-induced lung injury involves the reduction of oxidative/ nitrative stress,” Pulmonary Pharmacology and Therapeutics, vol. 27, no. 2, pp. 150–155, 2014. View at: Google Scholar
  35. G. Şimşek, Ş. Gürocak, N. Karadag et al., “Protective effects of resveratrol on salivary gland damage induced by total body irradiation in rats,” Laryngoscope, vol. 122, no. 12, pp. 2743–2748, 2012. View at: Publisher Site | Google Scholar
  36. Y.-F. Liao, W. Zhu, D.-P. Li, and X. Zhu, “Heme oxygenase-1 and gut ischemia/reperfusion injury: a short review,” World Journal of Gastroenterology, vol. 19, no. 23, pp. 3555–3561, 2013. View at: Publisher Site | Google Scholar
  37. P. D. Weyker, C. A. J. Webb, D. Kiamanesh, and B. C. Flynn, “Lung ischemia reperfusion injury: a bench-to-bedside review,” Seminars in Cardiothoracic and Vascular Anesthesia, vol. 17, no. 1, pp. 28–43, 2013. View at: Publisher Site | Google Scholar
  38. A. J. Vardanian, R. W. Busuttil, and J. W. Kupiec-Weglinski, “Molecular mediators of liver ischemia and reperfusion injury: a brief review,” Molecular Medicine, vol. 14, no. 5-6, pp. 337–345, 2008. View at: Publisher Site | Google Scholar
  39. E. Yulug, S. Türedi, E. Karagüzel, O. Kutlu, A. MenteSe, and A. Alver, “The short term effects of resveratrol on ischemia-reperfusion injury in rat testis,” Journal of Pediatric Surgery, vol. 49, no. 3, pp. 484–489, 2014. View at: Publisher Site | Google Scholar
  40. R. D. Powell, J. H. Swet, K. L. Kennedy, T. T. Huynh, I. H. McKillop, and S. L. Evans, “Resveratrol attenuates hypoxic injury in a primary hepatocyte model of hemorrhagic shock and resuscitation,” Journal of Trauma and Acute Care Surgery, vol. 76, no. 2, pp. 409–417, 2014. View at: Publisher Site | Google Scholar
  41. W. Dong, F. Li, Z. Pan et al., “Resveratrol ameliorates subacute intestinal ischemia-reperfusion injury,” Journal of Surgical Research, vol. 185, no. 1, pp. 182–189, 2013. View at: Publisher Site | Google Scholar
  42. F. Petrat and H. De Groot, “Protection against severe intestinal ischemia/reperfusion injury in rats by intravenous resveratrol,” Journal of Surgical Research, vol. 167, no. 2, pp. e145–e155, 2011. View at: Publisher Site | Google Scholar
  43. O. V. Ozkan, M. F. Yuzbasioglu, H. Ciralik et al., “Resveratrol, a natural antioxidant attenuates intestinal ischemia/reperfusion injury in rats,” The bTohoku Journal of Experimental Medicine, vol. 218, no. 3, pp. 251–258, 2009. View at: Publisher Site | Google Scholar
  44. W. Dong, X. Zhang, D. Gao, and N. Li, “Cerebral angiogenesis induced by resveratrol contributes to relieve cerebral ischemic-reperfusion injury,” Medical Hypotheses, vol. 69, no. 1, pp. 226–227, 2007. View at: Publisher Site | Google Scholar
  45. V. Chander and K. Chopra, “Protective effect of nitric oxide pathway in resveratrol renal ischemia-reperfusion injury in rats,” Archives of Medical Research, vol. 37, no. 1, pp. 19–26, 2006. View at: Publisher Site | Google Scholar
  46. S. Kaplan, G. Bisleri, J. A. Morgan, F. H. Cheema, and M. C. Oz, “Resveratrol, a natural red wine polyphenol, reduces ischemia-reperfusion- induced spinal cord injury,” Annals of Thoracic Surgery, vol. 80, no. 6, pp. 2242–2249, 2005. View at: Publisher Site | Google Scholar
  47. S. Uguralp, B. Mizrak, and A. B. Karabulut, “Resveratrol reduces ischemia reperfusion injury after experimental testicular torsion,” European Journal of Pediatric Surgery, vol. 15, no. 2, pp. 114–119, 2005. View at: Publisher Site | Google Scholar
  48. Q. Wang, J. Xu, G. E. Rottinghaus et al., “Resveratrol protects against global cerebral ischemic injury in gerbils,” Brain Research, vol. 958, no. 2, pp. 439–447, 2002. View at: Publisher Site | Google Scholar
  49. P. S. Ray, G. Maulik, G. A. Cordis, A. A. E. Bertelli, and D. K. Das, “The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury,” Free Radical Biology & Medicine, vol. 27, no. 1-2, pp. 160–169, 1999. View at: Publisher Site | Google Scholar
  50. Z. Xia, Y. Chen, Q. Fan, and M. Xue, “Oxidative stress-mediated reperfusion injury: mechanism and therapies,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 373081, 2 pages, 2014. View at: Publisher Site | Google Scholar
  51. D. K. de Vries, K. A. Kortekaas, D. Tsikas et al., “Oxidative damage in clinical ischemia/reperfusion injury: a reappraisal,” Antioxidants & Redox Signaling, vol. 19, no. 6, pp. 535–545, 2013. View at: Publisher Site | Google Scholar
  52. P. W. Kleikers, K. Wingler, J. J. Hermans et al., “NADPH oxidases as a source of oxidative stress and molecular target in ischemia/reperfusion injury,” Journal of Molecular Medicine, vol. 90, no. 12, pp. 1391–1406, 2012. View at: Publisher Site | Google Scholar
  53. L. Ji, F. Fu, L. Zhang et al., “Insulin attenuates myocardial ischemia/reperfusion injury via reducing oxidative/nitrative stress,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 298, no. 4, pp. E871–E880, 2010. View at: Publisher Site | Google Scholar
  54. G. H. Heeba and A. A. El-Hanafy, “Nebivolol regulates eNOS and iNOS expressions and alleviates oxidative stress in cerebral ischemia/reperfusion injury in rats,” Life Sciences, vol. 90, no. 11-12, pp. 388–395, 2012. View at: Publisher Site | Google Scholar
  55. S. C. Weight and M. L. Nicholson, “Nitric oxide and renal reperfusion injury: a review,” European Journal of Vascular and Endovascular Surgery, vol. 16, no. 2, pp. 98–103, 1998. View at: Publisher Site | Google Scholar
  56. Y. Yang, W. Duan, Y. Lin et al., “SIRT1 activation by curcumin pretreatment attenuates mitochondrial oxidative damage induced by myocardial ischemia reperfusion injury,” Free Radical Biology & Medicine, vol. 65, pp. 667–679, 2013. View at: Publisher Site | Google Scholar
  57. H. Okabe, “The role of xanthine dehydrogenase (xanthine oxidase) in ischemia-reperfusion injury in rat kidney,” Japanese Journal of Nephrology, vol. 38, no. 12, pp. 577–584, 1996. View at: Google Scholar
  58. F. Yaylak, H. Canbaz, M. Caglikulekci et al., “Liver tissue inducible nitric oxide synthase ( iNOS ) expression and lipid peroxidation in experimental hepatic ischemia reperfusion injury stimulated with lipopolysaccharide: the role of aminoguanidine,” Journal of Surgical Research, vol. 148, no. 2, pp. 214–223, 2008. View at: Publisher Site | Google Scholar
  59. A. Folino, G. Losano, and R. Rastaldo, “Balance of nitric oxide and reactive oxygen species in myocardial reperfusion injury and protection,” Journal of Cardiovascular Pharmacology, vol. 62, no. 6, pp. 567–575, 2013. View at: Publisher Site | Google Scholar
  60. M. Abu-Amara, S. Y. Yang, A. Seifalian, B. Davidson, and B. Fuller, “The nitric oxide pathway–evidence and mechanisms for protection against liver ischaemia reperfusion injury,” Liver International, vol. 32, no. 4, pp. 531–543, 2012. View at: Publisher Site | Google Scholar
  61. F. Simão, A. Matté, C. Matté et al., “Resveratrol prevents oxidative stress and inhibition of Na+K+-ATPase activity induced by transient global cerebral ischemia in rats,” The Journal of Nutritional Biochemistry, vol. 22, no. 10, pp. 921–928, 2011. View at: Publisher Site | Google Scholar
  62. A. M. Arent, L. F. D. Souza, R. Walz, and A. L. Dafre, “Perspectives on molecular biomarkers of oxidative stress and antioxidant strategies in traumatic brain injury,” BioMed Research International, vol. 2014, Article ID 723060, 18 pages, 2014. View at: Publisher Site | Google Scholar
  63. P. O. Eghwrudjakpor and A. B. Allison, “Oxidative stress following traumatic brain injury: enhancement of endogenous antioxidant defense systems and the promise of improved outcome,” Nigerian Journal of Medicine, vol. 19, no. 1, pp. 14–21, 2010. View at: Google Scholar
  64. M. Sasaki and T. Joh, “Oxidative stress and ischemia-reperfusion injury in gastrointestinal tract and antioxidant, protective agents,” Journal of Clinical Biochemistry and Nutrition, vol. 40, no. 1, pp. 1–12, 2007. View at: Publisher Site | Google Scholar
  65. H. Khastar, M. Kadkhodaee, H. R. Sadeghipour et al., “Liver oxidative stress after renal ischemia-reperfusion injury is leukocyte dependent in inbred mice,” Iranian Journal of Basic Medical Sciences, vol. 14, no. 6, pp. 534–539, 2011. View at: Google Scholar
  66. S. Bereswill, M. Muñoz, A. Fischer et al., “Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation,” PLoS ONE, vol. 5, no. 12, Article ID e15099, 2010. View at: Publisher Site | Google Scholar
  67. C. T. Wu, H. P. Yu, C. Y. Chung, Y. T. Lau, and S. K. Liao, “Attenuation of lung inflammation and pro-inflammatory cytokine production by resveratrol following trauma-hemorrhage,” The Chinese journal of physiology, vol. 51, no. 6, pp. 363–368, 2008. View at: Google Scholar
  68. S. Dernek, M. Ikizler, N. Erkasap et al., “Cardioprotection with resveratrol pretreatment: improved beneficial effects over standard treatment in rat hearts after global ischemia,” Scandinavian Cardiovascular Journal, vol. 38, no. 4, pp. 245–254, 2004. View at: Publisher Site | Google Scholar
  69. V. Sharma, R. M. Bell, and D. M. Yellon, “Targeting reperfusion injury in acute myocardial infarction: a review of reperfusion injury pharmacotherapy,” Expert Opinion on Pharmacotherapy, vol. 13, no. 8, pp. 1153–1175, 2012. View at: Publisher Site | Google Scholar
  70. E. Dongó, I. Hornyák, Z. Benko, and L. Kiss, “The cardioprotective potential of hydrogen sulfide in myocardial ischemia/reperfusion injury (review),” Acta Physiologica Hungarica, vol. 98, no. 4, pp. 369–381, 2011. View at: Publisher Site | Google Scholar
  71. S. K. Powers, Z. Murlasits, M. Wu, and A. N. Kavazis, “Ischemia-reperfusion-induced cardiac injury: a brief review,” Medicine & Science in Sports & Exercise, vol. 39, no. 9, pp. 1529–1536, 2007. View at: Publisher Site | Google Scholar
  72. A. Movahed, L. Yu, S. J. Thandapilly, X. L. Louis, and T. Netticadan, “Resveratrol protects adult cardiomyocytes against oxidative stress mediated cell injury,” Archives of Biochemistry and Biophysics, vol. 527, no. 2, pp. 74–80, 2012. View at: Publisher Site | Google Scholar
  73. S. Bradamante, L. Barenghi, and A. Villa, “Cardiovascular protective effects of resveratrol,” Cardiovascular Drug Reviews, vol. 22, no. 3, pp. 169–188, 2004. View at: Google Scholar
  74. Y. Tang, J. Xu, W. Qu et al., “Resveratrol reduces vascular cell senescence through attenuation of oxidative stress by SIRT1/NADPH oxidase-dependent mechanisms,” Journal of Nutritional Biochemistry, vol. 23, no. 11, pp. 1410–1416, 2012. View at: Publisher Site | Google Scholar
  75. C.-L. Kao, L.-K. Chen, Y.-L. Chang et al., “Resveratrol protects human endothelium from H2O2-induced oxidative stress and senescence via SirT1 activation,” Journal of Atherosclerosis and Thrombosis, vol. 17, no. 9, pp. 970–979, 2010. View at: Publisher Site | Google Scholar
  76. Y. Zheng, Y. Liu, J. Ge et al., “Resveratrol protects human lens epithelial cells against H2O2-induced oxidative stress by increasing catalase, SOD-1, and HO-1 expression,” Molecular Vision, vol. 16, pp. 1467–1474, 2010. View at: Google Scholar
  77. B. Wang, Q. Yang, Y. Y. Sun et al., “Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice,” Journal of Cellular and Molecular Medicine, vol. 18, no. 8, pp. 1599–1611, 2014. View at: Publisher Site | Google Scholar
  78. G. Spanier, H. Xu, N. Xia et al., “Resveratrol reduces endothelial oxidative stress by modulating the gene expression of superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPx1) and NADPH oxidase subunit (Nox4),” Journal of Physiology and Pharmacology, vol. 60, supplement 4, pp. 111–116, 2009. View at: Google Scholar
  79. P.-W. Cheng, W.-Y. Ho, Y.-T. Su et al., “Resveratrol decreases fructose-induced oxidative stress, mediated by NADPH oxidase via an AMPK-dependent mechanism,” British Journal of Pharmacology, vol. 171, no. 11, pp. 2739–2750, 2014. View at: Publisher Site | Google Scholar
  80. M. Mokni, S. Hamlaoui, I. Karkouch et al., “Resveratrol provides cardioprotection after ischemia/reperfusion injury via modulation of antioxidant enzyme activities,” Iranian Journal of Pharmaceutical Research, vol. 12, no. 4, pp. 867–875, 2013. View at: Google Scholar
  81. M. Shen, R.-X. Wu, L. Zhao et al., “Resveratrol attenuates ischemia/reperfusion injury in neonatal cardiomyocytes and its underlying mechanism,” PLoS ONE, vol. 7, no. 12, Article ID e51223, 2012. View at: Publisher Site | Google Scholar
  82. M. Mokni, F. Limam, S. Elkahoui, M. Amri, and E. Aouani, “Strong cardioprotective effect of resveratrol, a red wine polyphenol, on isolated rat hearts after ischemia/reperfusion injury,” Archives of Biochemistry and Biophysics, vol. 457, no. 1, pp. 1–6, 2007. View at: Publisher Site | Google Scholar
  83. M. Mohammadshahi, F. Haidari, and F. G. Soufi, “Chronic resveratrol administration improves diabetic cardiomyopathy in part by reducing oxidative stress,” Cardiology Journal, vol. 21, no. 1, pp. 39–46, 2014. View at: Publisher Site | Google Scholar
  84. P. Toth, S. Tarantini, Z. Tucsek et al., “Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase,” American Journal of Physiology: Heart and Circulatory Physiology, vol. 306, no. 3, pp. H299–H308, 2014. View at: Publisher Site | Google Scholar
  85. E. Miller, A. Morel, L. Saso, and J. Saluk, “Isoprostanes and neuroprostanes as biomarkers of oxidative stress in neurodegenerative diseases,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 572491, 10 pages, 2014. View at: Publisher Site | Google Scholar
  86. X. Qiao, J. Xu, Q.-J. Yang et al., “Transient acidosis during early reperfusion attenuates myocardium ischemia reperfusion injury VIA PI3K-AKT-eNOS signaling pathway,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 126083, 6 pages, 2013. View at: Publisher Site | Google Scholar
  87. T. Wang, X. Mao, H. Li et al., “N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes,” Free Radical Biology and Medicine, vol. 63, pp. 291–303, 2013. View at: Publisher Site | Google Scholar
  88. L.-M. Hung, M.-J. Su, and J.-K. Chen, “Resveratrol protects myocardial ischemia-reperfusion injury through both NO-dependent and NO-independent mechanisms,” Free Radical Biology and Medicine, vol. 36, no. 6, pp. 774–781, 2004. View at: Publisher Site | Google Scholar
  89. M. Lagouge, C. Argmann, Z. Gerhart-Hines et al., “Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α,” Cell, vol. 127, no. 6, pp. 1109–1122, 2006. View at: Publisher Site | Google Scholar
  90. M. Shalwala, S.-G. Zhu, A. Das, F. N. Salloum, L. Xi, and R. C. Kukreja, “Sirtuin 1 (SIRT1) activation mediates sildenafil induced delayed cardioprotection against ischemia-reperfusion injury in mice,” PLoS ONE, vol. 9, no. 1, Article ID e86977, 2014. View at: Publisher Site | Google Scholar
  91. S. Shigematsu, S. Ishida, M. Hara et al., “Resveratrol, a red wine constituent polyphenol, prevents superoxide-dependent inflammatory responses induced by ischemia/reperfusion, platelet-activating factor, or oxidants,” Free Radical Biology and Medicine, vol. 34, no. 7, pp. 810–817, 2003. View at: Publisher Site | Google Scholar
  92. H. Li, Z. Yan, J. Zhu, J. Yang, and J. He, “Neuroprotective effects of resveratrol on ischemic injury mediated by improving brain energy metabolism and alleviating oxidative stress in rats,” Neuropharmacology, vol. 60, no. 2-3, pp. 252–258, 2011. View at: Publisher Site | Google Scholar
  93. X. M. Zhou, M. L. Zhou, X. S. Zhang, Z. Zhuang, T. Li, and J. X. Shi, “Resveratrol prevents neuronal apoptosis in an early brain injury model,” Journal of Surgical Research, vol. 189, no. 1, pp. 159–165, 2014. View at: Publisher Site | Google Scholar
  94. J. W. Gatson, M.-M. Liu, K. Abdelfattah et al., “Resveratrol decreases inflammation in the brain of mice with mild traumatic brain injury,” Journal of Trauma and Acute Care Surgery, vol. 74, no. 2, pp. 470–475, 2013. View at: Publisher Site | Google Scholar
  95. F. Karalis, V. Soubasi, T. Georgiou et al., “Resveratrol ameliorates hypoxia/ischemia-induced behavioral deficits and brain injury in the neonatal rat brain,” Brain Research, vol. 1425, pp. 98–110, 2011. View at: Publisher Site | Google Scholar
  96. K. Sinha, G. Chaudhary, and Y. Kumar Gupta, “Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats,” Life Sciences, vol. 71, no. 6, pp. 655–665, 2002. View at: Publisher Site | Google Scholar
  97. S.-K. Tsai, L.-M. Hung, Y.-T. Fu et al., “Resveratrol neuroprotective effects during focal cerebral ischemia injury via nitric oxide mechanism in rats,” Journal of Vascular Surgery, vol. 46, no. 2, pp. 346–353, 2007. View at: Publisher Site | Google Scholar
  98. E. Barocelli, V. Ballabeni, P. Ghizzardi et al., “The selective inhibition of inducible nitric oxide synthase prevents intestinal ischemia-reperfusion injury in mice,” Nitric Oxide—Biology and Chemistry, vol. 14, no. 3, pp. 212–218, 2006. View at: Publisher Site | Google Scholar
  99. P. Orsu, B. V. S. N. Murthy, and A. Akula, “Cerebroprotective potential of resveratrol through anti-oxidant and anti-inflammatory mechanisms in rats,” Journal of Neural Transmission, vol. 120, no. 8, pp. 1217–1223, 2013. View at: Publisher Site | Google Scholar
  100. F. Simão, A. Matté, A. S. Pagnussat, C. A. Netto, and C. G. Salbego, “Resveratrol preconditioning modulates inflammatory response in the rat hippocampus following global cerebral ischemia,” Neurochemistry International, vol. 61, no. 5, pp. 659–665, 2012. View at: Publisher Site | Google Scholar
  101. U. Kiziltepe, N. N. D. Turan, U. Han, A. T. Ulus, and F. Akar, “Resveratrol, a red wine polyphenol, protects spinal cord from ischemia-reperfusion injury,” Journal of Vascular Surgery, vol. 40, no. 1, pp. 138–145, 2004. View at: Publisher Site | Google Scholar
  102. H. S. Ozacmak, V. H. Ozacmak, F. Barut, M. Arasli, and B. H. Ucan, “Pretreatment with mineralocorticoid receptor blocker reduces intestinal injury induced by ischemia and reperfusion: involvement of inhibition of inflammatory response, oxidative stress, nuclear factor κB, and inducible nitric oxide synthase,” Journal of Surgical Research, vol. 191, no. 2, pp. 350–361, 2014. View at: Publisher Site | Google Scholar
  103. J. Cui, L. Liu, J. Zou et al., “Protective effect of endogenous hydrogen sulfide against oxidative stress in gastric ischemia-reperfusion injury,” Experimental and Therapeutic Medicine, vol. 5, no. 3, pp. 689–694, 2013. View at: Publisher Site | Google Scholar
  104. P. R. Bertoletto, A. T. Ikejiri, F. S. Neto et al., “Oxidative stress gene expression profile in inbred mouse after ischemia/reperfusion small bowel injury,” Acta Cirurgica Brasileira, vol. 27, no. 11, pp. 772–782, 2012. View at: Google Scholar
  105. F. Yildiz, A. Terzi, S. Coban et al., “Protective effects of resveratrol on small intestines against intestinal ischemia-reperfusion injury in rats,” Journal of Gastroenterology and Hepatology, vol. 24, no. 11, pp. 1781–1785, 2009. View at: Publisher Site | Google Scholar
  106. H. Namazi, “A novel molecular mechanism to account for the action of resveratrol against reperfusion injury,” Annals of Vascular Surgery, vol. 22, no. 3, p. 492, 2008. View at: Publisher Site | Google Scholar
  107. A. B. Karabulut, V. Kirimlioglu, H. Kirimlioglu, S. Yilmaz, B. Isik, and O. Isikgil, “Protective effects of resveratrol on spleen and ileum in rats subjected to ischemia-reperfusion,” Transplantation Proceedings, vol. 38, no. 2, pp. 375–377, 2006. View at: Publisher Site | Google Scholar
  108. L. Phillips, A. H. Toledo, F. Lopez-Neblina, R. Anaya-Prado, and L. H. Toledo-Pereyra, “Nitric oxide mechanism of protection in ischemia and reperfusion injury,” Journal of Investigative Surgery, vol. 22, no. 1, pp. 46–55, 2009. View at: Publisher Site | Google Scholar
  109. M. Yamaguchi and M. Uchida, “α-Lactalbumin suppresses interleukin-6 release after intestinal ischemia/reperfusion via nitric oxide in rats,” Inflammopharmacology, vol. 15, no. 1, pp. 43–47, 2007. View at: Publisher Site | Google Scholar
  110. L. Gu, N. Li, W. Yu et al., “Berberine reduces rat intestinal tight junction injury induced by ischemia-reperfusion associated with the suppression of inducible nitric oxide synthesis,” The American Journal of Chinese Medicine, vol. 41, no. 6, pp. 1297–1312, 2013. View at: Publisher Site | Google Scholar
  111. M. Y. Kim, J. H. Lim, H. H. Youn et al., “Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1α axis in db/db mice,” Diabetologia, vol. 56, no. 1, pp. 204–217, 2013. View at: Publisher Site | Google Scholar
  112. G. Şener, H. Tuǧtepe, M. Yüksel, Ş. Çetinel, N. Gedik, and B. Ç. Yeǧen, “Resveratrol improves ischemia/reperfusion-induced oxidative renal injury in rats,” Archives of Medical Research, vol. 37, no. 7, pp. 822–829, 2006. View at: Publisher Site | Google Scholar
  113. L. Giovannini, M. Migliori, B. M. Longoni et al., “Resveratrol, a polyphenol found in wine, reduces ischemia reperfusion injury in rat kidneys,” Journal of Cardiovascular Pharmacology, vol. 37, no. 3, pp. 262–270, 2001. View at: Publisher Site | Google Scholar
  114. X. Fu, S. Li, G. Jia et al., “Protective effect of the nitric oxide pathway in L-citrulline renal ichaemia-reperfusion injury in rats,” Folia Biologica, vol. 59, no. 6, pp. 225–232, 2013. View at: Google Scholar
  115. A. Korkmaz and D. Kolankaya, “Inhibiting inducible nitric oxide synthase with rutin reduces renal ischemia/reperfusion injury,” Canadian Journal of Surgery, vol. 56, no. 1, pp. 6–14, 2013. View at: Publisher Site | Google Scholar
  116. R. Schneider, M. Meusel, B. Betz et al., “Nitric oxide-induced regulation of renal organic cation transport after renal ischemia-reperfusion injury,” The American Journal of Physiology—Renal Physiology, vol. 301, no. 5, pp. F997–F1004, 2011. View at: Publisher Site | Google Scholar
  117. V. Chander and K. Chopra, “Role of nitric oxide in resveratrol-induced renal protective effects of ischemic preconditioning,” Journal of Vascular Surgery, vol. 42, no. 6, pp. 1198–1205, 2005. View at: Publisher Site | Google Scholar
  118. L. Y. Guan, P. Y. Fu, P. D. Li et al., “Mechanisms of hepatic ischemia-reperfusion injury and protective effects of nitric oxide,” World Journal of Gastrointestinal Surgery, vol. 6, no. 7, pp. 122–128, 2014. View at: Google Scholar
  119. G. K. Glantzounis, H. J. Salacinski, W. Yang, B. R. Davidson, and A. M. Seifalian, “The contemporary role of antioxidant therapy in attenuating liver ischemia-reperfusion injury: a review,” Liver Transplantation, vol. 11, no. 9, pp. 1031–1047, 2005. View at: Publisher Site | Google Scholar
  120. F.-C. Liu, Y.-F. Tsai, and H.-P. Yu, “Maraviroc attenuates trauma-hemorrhage-induced hepatic injury through PPAR gamma-dependent pathway in rats,” PLoS ONE, vol. 8, no. 10, Article ID e78861, 2013. View at: Publisher Site | Google Scholar
  121. E. Gedik, S. Girgin, H. Ozturk, B. D. Obay, H. Ozturk, and H. Buyukbayram, “Resveratrol attenuates oxidative stress and histological alterations induced by liver ischemia/reperfusion in rats,” World Journal of Gastroenterology, vol. 14, no. 46, pp. 7101–7106, 2008. View at: Publisher Site | Google Scholar
  122. S. Hassan-Khabbar, M. Vamy, C.-H. Cottart et al., “Protective effect of post-ischemic treatment with trans-resveratrol on cytokine production and neutrophil recruitment by rat liver,” Biochimie, vol. 92, no. 4, pp. 405–410, 2010. View at: Publisher Site | Google Scholar
  123. S. Gennai, C. Pison, and R. Briot, “Ischemia-reperfusion injury after lung transplantation,” La Presse Médicale, vol. 43, no. 9, pp. 921–930, 2014. View at: Google Scholar
  124. J. Rong, S. Ye, M.-Y. Liang et al., “Receptor for advanced glycation end products involved in lung ischemia reperfusion injury in cardiopulmonary bypass attenuated by controlled oxygen reperfusion in a canine model,” ASAIO Journal, vol. 59, no. 3, pp. 302–308, 2013. View at: Publisher Site | Google Scholar
  125. R. Campos, M. H. M. Shimizu, R. A. Volpini et al., “N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 302, no. 7, pp. L640–L650, 2012. View at: Publisher Site | Google Scholar
  126. D. Y.-W. Yeh, Y. H. Fu, Y.-C. Yang, and J.-J. Wang, “Resveratrol alleviates lung ischemia and reperfusion-induced pulmonary capillary injury through modulating pulmonary mitochondrial metabolism,” Transplantation Proceedings, vol. 46, no. 4, pp. 1131–1134, 2014. View at: Publisher Site | Google Scholar
  127. S. Çayan, B. Saylam, N. Tiftik et al., “Rho-kinase levels in testicular ischemia-reperfusion injury and effects of its inhibitor, Y-27632, on oxidative stress, spermatogenesis, and apoptosis,” Urology, vol. 83, no. 3, pp. 675–678, 2014. View at: Publisher Site | Google Scholar
  128. S. M. Wei, Z. Z. Yan, and J. Zhou, “Protective effect of rutin on testicular ischemia-reperfusion injury,” Journal of Pediatric Surgery, vol. 46, no. 7, pp. 1419–1424, 2011. View at: Publisher Site | Google Scholar
  129. D. Y. Woodruff, G. Horwitz, J. Weigel, and A. K. Nangia, “Fertility preservation following torsion and severe ischemic injury of a solitary testis,” Fertility and Sterility, vol. 94, no. 1, pp. 352–355, 2010. View at: Publisher Site | Google Scholar
  130. H. Yildiz, A. S. Durmus, H. Şimşek, and M. Yaman, “Protective effect of sildenafil citrate on contralateral testis injury after unilateral testicular torsion/detorsion,” Clinics, vol. 66, no. 1, pp. 137–142, 2011. View at: Publisher Site | Google Scholar
  131. R. M. Vigueras, G. Reyes, J. Rojas-Castañeda, P. Rojas, and R. Hernández, “Testicular torsion and its effects on the spermatogenic cycle in the contralateral testis of the rat,” Laboratory Animals, vol. 38, no. 3, pp. 313–320, 2004. View at: Publisher Site | Google Scholar
  132. B. Etensel, S. Özkisacik, E. Özkara et al., “Dexpanthenol attenuates lipid peroxidation and testicular damage at experimental ischemia and reperfusion injury,” Pediatric Surgery International, vol. 23, no. 2, pp. 177–181, 2007. View at: Publisher Site | Google Scholar
  133. C. T. Ribeiro, R. Milhomem, D. B. De Souza, W. S. Costa, F. J. B. Sampaio, and M. A. Pereira-Sampaio, “Effect of antioxidants on outcome of testicular torsion in rats of different ages,” Journal of Urology, vol. 191, no. 5, pp. 1578–1584, 2014. View at: Publisher Site | Google Scholar
  134. H. G. Piper, S. C. Oltmann, L. Xu, S. Adusumilli, and A. C. Fischer, “Ovarian torsion: diagnosis of inclusion mandates earlier intervention,” Journal of Pediatric Surgery, vol. 47, no. 11, pp. 2071–2076, 2012. View at: Publisher Site | Google Scholar
  135. S. Krishnan, H. Kaur, J. Bali, and K. Rao, “Ovarian torsion in infertility management—missing the diagnosis means losing the ovary: a high price to pay,” Journal of Human Reproductive Sciences, vol. 4, no. 1, pp. 39–42, 2011. View at: Publisher Site | Google Scholar
  136. H. Jaeschke, “Xanthine oxidase-induced oxidant stress during hepatic ischemia-reperfusion: are we coming full circle after 20 years?” Hepatology, vol. 36, no. 3, pp. 761–763, 2002. View at: Publisher Site | Google Scholar
  137. P. E. Canas, “The role of xanthine oxidase and the effects of antioxidants in ischemia reperfusion cell injury,” Acta Physiologica Pharmacologica et Therapeutica Latinoamericana, vol. 49, no. 1, pp. 13–20, 1999. View at: Google Scholar
  138. T. A. Johnson, N. A. Stasko, J. L. Matthews et al., “Reduced ischemia/reperfusion injury via glutathione-initiated nitric oxide-releasing dendrimers,” Nitric Oxide—Biology and Chemistry, vol. 22, no. 1, pp. 30–36, 2010. View at: Publisher Site | Google Scholar
  139. H. J. Stein, M. M. J. Oosthuizen, R. A. Hinder, and H. Lamprechts, “Oxygen free radicals and glutathione in hepatic ischemia/reperfusion injury,” Journal of Surgical Research, vol. 50, no. 4, pp. 398–402, 1991. View at: Publisher Site | Google Scholar
  140. S. Hascalik, O. Celik, Y. Turkoz et al., “Resveratrol, a red wine constituent polyphenol, protects from ischemia-reperfusion damage of the ovaries,” Gynecologic and Obstetric Investigation, vol. 57, no. 4, pp. 218–223, 2004. View at: Publisher Site | Google Scholar
  141. M. He, H. Pan, R. C.-C. Chang, K.-F. So, N. C. Brecha, and M. Pu, “Activation of the Nrf2/HO-1 antioxidant pathway contributes to the protective effects of lycium barbarum polysaccharides in the rodent retina after ischemia-reperfusion-induced damage,” PLoS ONE, vol. 9, no. 1, Article ID e84800, 2014. View at: Publisher Site | Google Scholar
  142. N. Dilsiz, A. Sahaboglu, M. Z. Yildiz, and A. Reichenbach, “Protective effects of various antioxidants during ischemia-reperfusion in the rat retina,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 244, no. 5, pp. 627–633, 2006. View at: Publisher Site | Google Scholar
  143. O. Lewden, C. Garcher, C. Morales, A. Javouhey, L. Rochette, and A. M. Bron, “Changes of catalase activity after ischemia-reperfusion in rat retina,” Ophthalmic Research, vol. 28, no. 6, pp. 331–335, 1996. View at: Publisher Site | Google Scholar
  144. M. E. Szabo, M. T. Droy-Lefaix, M. Doly, and P. Braquet, “Modification of ischemia/reperfusion-induced ion shifts (Na+, K+, Ca2+ and Mg2+) by free radical scavengers in the rat retina,” Ophthalmic Research, vol. 25, no. 1, pp. 1–9, 1993. View at: Publisher Site | Google Scholar
  145. A. P. Vin, H. Hu, Y. Zhai et al., “Neuroprotective effect of resveratrol prophylaxis on experimental retinal ischemic injury,” Experimental Eye Research, vol. 108, pp. 72–75, 2013. View at: Publisher Site | Google Scholar
  146. C. Li, L. Wang, K. Huang, and L. Zheng, “Endoplasmic reticulum stress in retinal vascular degeneration: protective role of resveratrol,” Investigative Ophthalmology & Visual Science, vol. 53, no. 6, pp. 3241–3249, 2012. View at: Publisher Site | Google Scholar
  147. D. Gao, X. Zhang, X. Jiang et al., “Resveratrol reduces the elevated level of MMP-9 induced by cerebral ischemia-reperfusion in mice,” Life Sciences, vol. 78, no. 22, pp. 2564–2570, 2006. View at: Publisher Site | Google Scholar
  148. M. H. Sun, J. H. Pang, S. L. Chen et al., “Photoreceptor protection against light damage by AAV-mediated overexpression of heme oxygenase-1,” Investigative Ophthalmology & Visual Science, vol. 48, no. 12, pp. 5699–5707, 2007. View at: Google Scholar
  149. X. Q. Liu, B. J. Wu, W. H. Pan et al., “Resveratrol mitigates rat retinal ischemic injury: the roles of matrix metalloproteinase-9, inducible nitric oxide, and heme oxygenase-1,” Journal of Ocular Pharmacology and Therapeutics, vol. 29, no. 1, pp. 33–40, 2013. View at: Publisher Site | Google Scholar
  150. H. Yagmurdur, N. Ozcan, F. Dokumaci, K. Kilinc, F. Yilmaz, and H. Basar, “Dexmedetomidine reduces the ischemia-reperfusion injury markers during upper extremity surgery with tourniquet,” Journal of Hand Surgery, vol. 33, no. 6, pp. 941–947, 2008. View at: Publisher Site | Google Scholar
  151. W. R. Carroll and R. M. Esclamado, “Ischemia/reperfusion injury in microvascular surgery,” Head & Neck, vol. 22, no. 7, pp. 700–713, 2000. View at: Publisher Site | Google Scholar
  152. M. Mathru, D. J. Dries, L. Barnes, P. Tonino, R. Sukhani, and M. W. Rooney, “Tourniquet-induced exsanguination in patients requiring lower limb surgery: an ischemia-reperfusion model of oxidant and antioxidant metabolism,” Anesthesiology, vol. 84, no. 1, pp. 14–22, 1996. View at: Publisher Site | Google Scholar
  153. A. Lejay, A. Meyer, A.-I. Schlagowski et al., “Mitochondria: mitochondrial participation in ischemia-reperfusion injury in skeletal muscle,” The International Journal of Biochemistry and Cell Biology, vol. 50, no. 1, pp. 101–105, 2014. View at: Publisher Site | Google Scholar
  154. S. Gillani, J. Cao, T. Suzuki, and D. J. Hak, “The effect of ischemia reperfusion injury on skeletal muscle,” Injury, vol. 43, no. 6, pp. 670–675, 2012. View at: Publisher Site | Google Scholar
  155. H. T. Hua, H. Al-Badawi, F. Entabi et al., “CXC chemokine expression and synthesis in skeletal muscle during ischemia/reperfusion,” Journal of Vascular Surgery, vol. 42, no. 2, pp. 337–343, 2005. View at: Publisher Site | Google Scholar
  156. A. Kadambi and T. C. Skalak, “Role of leukocytes and tissue-derived oxidants in short-term skeletal muscle ischemia-reperfusion injury,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 278, no. 2, pp. H435–H443, 2000. View at: Google Scholar
  157. M. Ikizler, C. Ovali, S. Dernek et al., “Protective effects of resveratrol in ischemia-reperfusion injury of skeletal muscle: a clinically relevant animal model for lower extremity ischemia,” The Chinese Journal of Physiology, vol. 49, no. 4, pp. 204–209, 2006. View at: Google Scholar
  158. N. Elmali, I. Esenkaya, N. Karadağ, and F. Taş, “Effects of resveratrol on skeletal muscle in ischemia-reperfusion injury,” Ulusal Travma ve Acil Cerrahi Dergisi, vol. 13, no. 4, pp. 274–280, 2007. View at: Google Scholar
  159. M. Nomiya, O. Yamaguchi, K.-E. Andersson et al., “The effect of atherosclerosis-induced chronic bladder ischemia on bladder function in the rat,” Neurourology and Urodynamics, vol. 31, no. 1, pp. 195–200, 2012. View at: Publisher Site | Google Scholar
  160. A. Ali, G. Nabi, S. Swami, and B. Somani, “Bladder necrosis secondary to internal iliac artery embolization following pelvic fracture,” Urology Annals, vol. 6, no. 2, pp. 166–168, 2014. View at: Publisher Site | Google Scholar
  161. G. E. Senturk, K. Erkanli, U. Aydin et al., “The protective effect of oxytocin on ischemia/reperfusion injury in rat urinary bladder,” Peptides, vol. 40, pp. 82–88, 2013. View at: Publisher Site | Google Scholar
  162. Y.-S. Juan, S. M. Chuang, B. A. Kogan et al., “Effect of ischemia/reperfusion on bladder nerve and detrusor cell damage,” International Urology and Nephrology, vol. 41, no. 3, pp. 513–521, 2009. View at: Publisher Site | Google Scholar
  163. A. Yildirim, F. F. Onol, G. Haklar, and T. Tarcan, “The role of free radicals and nitric oxide in the ischemia-reperfusion injury mediated by acute bladder outlet obstruction,” International Urology and Nephrology, vol. 40, no. 1, pp. 71–77, 2008. View at: Publisher Site | Google Scholar
  164. H. Toklu, I. Alican, F. Ercan, and G. Sener, “The beneficial effect of resveratrol on rat bladder contractility and oxidant damage following ischemia/reperfusion,” Pharmacology, vol. 78, no. 1, pp. 44–50, 2006. View at: Publisher Site | Google Scholar
  165. H.-P. Yu, T.-L. Hwang, C.-H. Yen, and Y.-T. Lau, “Resveratrol prevents endothelial dysfunction and aortic superoxide production after trauma hemorrhage through estrogen receptor-dependent hemeoxygenase-1 pathway,” Critical Care Medicine, vol. 38, no. 4, pp. 1147–1154, 2010. View at: Publisher Site | Google Scholar
  166. Z. F. Ba, J. F. Kuebler, L. W. Rue III, K. I. Bland, P. Wang, and I. H. Chaudry, “Gender dimorphic tissue perfusion response after acute hemorrhage and resuscitation: role of vascular endothelial cell function,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 284, no. 6, pp. H2162–H2169, 2003. View at: Google Scholar
  167. P. Wang, Z. F. Ba, and I. H. Chaudry, “Endothelial cell dysfunction occurs very early following trauma- hemorrhage and persists despite fluid resuscitation,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 265, no. 3, part 2, pp. H973–H979, 1993. View at: Google Scholar
  168. H.-P. Yu, P.-W. Lui, T.-L. Hwang, C.-H. Yen, and Y.-T. Lau, “Propofol improves endothelial dysfunction and attenuates vascular superoxide production in septic rats,” Critical Care Medicine, vol. 34, no. 2, pp. 453–460, 2006. View at: Publisher Site | Google Scholar
  169. L. Szalay, T. Shimizu, M. G. Schwacha et al., “Mechanism of salutary effects of estradiol on organ function after trauma-hemorrhage: upregulation of heme oxygenase,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 289, no. 1, pp. H92–H98, 2005. View at: Publisher Site | Google Scholar
  170. C.-C. Chang, C.-Y. Chang, J.-P. Huang, and L.-M. Hung, “Effect of resveratrol on oxidative and inflammatory stress in liver and spleen of streptozotocin-induced type 1 diabetic rats,” The Chinese Journal of Physiology, vol. 55, no. 3, pp. 192–201, 2012. View at: Publisher Site | Google Scholar
  171. J. Li, L. Feng, Y. Xing et al., “Radioprotective and antioxidant effect of resveratrol in hippocampus by activating Sirt1,” International Journal of Molecular Sciences, vol. 15, no. 4, pp. 5928–5939, 2014. View at: Publisher Site | Google Scholar
  172. B. Jian, S. Yang, I. H. Chaudry, and R. Raju, “Resveratrol improves cardiac contractility following trauma-hemorrhage by modulating Sirt1,” Molecular Medicine, vol. 18, no. 2, pp. 209–214, 2012. View at: Publisher Site | Google Scholar
  173. J. T. Hsu, H. C. Yeh, T. H. Chen et al., “Role of Akt/HO-1 pathway in estrogen-mediated attenuation of trauma-hemorrhage-induced lung injury,” Journal of Surgical Research, vol. 182, no. 2, pp. 319–325, 2013. View at: Publisher Site | Google Scholar
  174. J.-T. Hsu, W.-H. Kan, C.-H. Hsieh et al., “Mechanism of estrogen-mediated intestinal protection following trauma-hemorrhage: p38 MAPK-dependent upregulation of HO-1,” The American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 294, no. 6, pp. R1825–R1831, 2008. View at: Publisher Site | Google Scholar
  175. J.-T. Hsu, W.-H. Kan, C.-H. Hsieh, M. A. Choudhry, K. I. Bland, and I. H. Chaudry, “Mechanism of salutary effects of estrogen on cardiac function following trauma-hemorrhage: Akt-dependent HO-1 up-regulation,” Critical Care Medicine, vol. 37, no. 8, pp. 2338–2344, 2009. View at: Publisher Site | Google Scholar
  176. H. P. Yu, M. A. Choudhry, T. Shimizu et al., “Mechanism of the salutary effects of flutamide on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of estrogen receptor-β-dependent HO-1,” Journal of Leukocyte Biology, vol. 79, no. 2, pp. 277–284, 2006. View at: Publisher Site | Google Scholar
  177. D. He, X. Liu, Y. Pang, and L. Liu, “Inhibitory effect of resveratol on ischemia reperfusion-induced cardiocyte apoptosis and its relationship with PI3K-Akt signaling pathway,” Zhongguo Zhong Yao Za Zhi, vol. 37, no. 15, pp. 2323–2326, 2012. View at: Publisher Site | Google Scholar
  178. Y.-F. Tsai, F.-C. Liu, Y.-T. Lau, and H.-P. Yu, “Role of Akt-dependent pathway in resveratrol-mediated cardioprotection after trauma-hemorrhage,” Journal of Surgical Research, vol. 176, no. 1, pp. 171–177, 2012. View at: Publisher Site | Google Scholar
  179. H.-P. Yu, S.-C. Yang, Y.-T. Lau, and T.-L. Hwang, “Role of Akt-dependent up-regulation of hemeoxygenase-1 in resveratrol-mediated attenuation of hepatic injury after trauma hemorrhage,” Surgery, vol. 148, no. 1, pp. 103–109, 2010. View at: Publisher Site | Google Scholar
  180. F. C. Liu, Y. J. Day, C. H. Liao, J. T. Liou, C. C. Mao, and H. P. Yu, “Hemeoxygenase-1 upregulation is critical for sirtinol-mediated attenuation of lung injury after trauma-hemorrhage in a rodent model,” Anesthesia and Analgesia, vol. 108, no. 6, pp. 1855–1861, 2009. View at: Publisher Site | Google Scholar

Copyright © 2015 Fu-Chao Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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