Wogonin alleviates liver injury in sepsis through Nrf2-mediated NF-κB signalling suppression

Sepsis is a life-threatening organ dysfunction syndrome, and liver is a susceptible target organ in sepsis, because the activation of inflammatory pathways contributes to septic liver injury. Oxidative stress has been documented to participate in septic liver injury, because it not only directly induces oxidative genotoxicity, but also exacerbates inflammatory pathways to potentiate damage of liver. Therefore, to ameliorate oxidative stress is promising for protecting liver in sepsis. Wogonin is the compound extracted from the medicinal plant Scutellaria baicalensis Geogi and was found to exert therapeutic effects in multiple inflammatory diseases via alleviation of oxidative stress. However, whether wogonin is able to mitigate septic liver injury remains unknown. Herein, we firstly proved that wogonin treatment could improve survival of mice with lipopolysaccharide (LPS)- or caecal ligation and puncture (CLP)-induced sepsis, together with restoration of reduced body temperature and respiratory rate, and suppression of several pro-inflammatory cytokines in circulation. Then, we found that wogonin effectively alleviated liver injury via potentiation of the anti-oxidative capacity. To be specific, wogonin activated Nrf2 thereby promoting expressions of anti-oxidative enzymes including NQO-1, GST, HO-1, SOD1 and SOD2 in hepatocytes. Moreover, wogonin-induced Nrf2 activation could suppress NF-κB-regulated up-regulation of pro-inflammatory cytokines. Ultimately, we provided in vivo evidence that wogonin activated Nrf2 signalling, potentiated anti-oxidative enzymes and inhibited NF-κB-regulated pro-inflammatory signalling. Taken together, this study demonstrates that wogonin can be the potential therapeutic agent for alleviating liver injury in sepsis by simultaneously ameliorating oxidative stress and inflammatory response through the activation of Nrf2.     

The role of oxidative stress in adult critical care

Oxidative stress defines an imbalance in production of oxidizing chemical species and their effective removal by protective antioxidants and scavenger enzymes. Evidence of massive oxidative stress is well established in adult critical illnesses characterized by tissue ischemia-reperfusion injury and by an intense systemic inflammatory response such as during sepsis and acute respiratory distress syndrome. Oxidative stress could exacerbate organ injury and thus overall clinical outcome. We searched MEDLINE databases (January 1966 to June 2005). For interventional studies, we accepted only randomized trials. Several small clinical trials have been performed in order to reduce oxidative stress by supplementation of antioxidants alone or in combination with standard therapies. These studies have reported controversial results. Newer large multicenter trials with antioxidant supplementation should be performed, considering administration at an early stage of illness and a wider population of critically ill patients.     

Study on oxidative stress in patients with abdominal trauma

Reactive oxygen species have been implicated in the etiology of multiple organ dyspepsia syndrome and infection's complications in patients with trauma. But the oxidative stress and antioxidants levels in abdominal trauma have not yet been studied. Therefore, this study was planned to measure lipid peroxidation for oxidative stress and reduced glutathione, catalase and superoxide dismutase (SOD) for antioxidant levels in plasma & heamolysate of 30 patients with abdominal trauma and 30 controls. From this study we can summarize that there was an increase in oxidative stress and decrease in antioxidant levels (causing oxidative stress) on day zero in patients with abdominal trauma. This oxidative stress on day zero was not related to the development of complications. There was no significant difference in oxidative stress between patients with solitary and multiple abdominal organ injury and also between patients with hollow viscus injury and solid organ injury on day zero. From this study, we conclude that in patients with abdominal trauma there was increase in oxidative stress and decrease in antioxidant levels on day zero.     

Acrolein scavenging: a potential novel mechanism of attenuating oxidative stress following spinal cord injury

It has long been established that oxidative stress plays a critical role in the pathophysiology of spinal cord injury, and represents an important target of therapeutic intervention following the initial trauma. However, free radical scavengers have been largely ineffective in clinical trials, and as such a novel target to attenuate oxidative stress is highly warranted. In addition to free radicals, peroxidation of lipid membranes following spinal cord injury (SCI) produces reactive aldehydes such as acrolein. Acrolein is capable of depleting endogenous antioxidants such as glutathione, generating free radicals, promoting oxidative stress, and damaging proteins and DNA. Acrolein has a significantly longer half‐life than the transient free radicals, and thus may represent a potentially better target of therapeutic intervention to attenuate oxidative stress. There is growing evidence, from our lab and others, to suggest that reactive aldehydes such as acrolein play a critical role in oxidative stress and SCI. The focus of this review is to summarize the cellular and biochemical mechanisms of acrolein‐induced membrane damage, mitochondrial injury, oxidative stress, cell death, and functional loss. Evidence will also be presented to suggest that acrolein scavenging may be a novel means of therapeutic intervention to attenuate oxidative stress and improve recovery following traumatic SCI.     

Mitophagy and mitochondrial integrity in cardiac ischemia-reperfusion injury

Ischemia-reperfusion injury (IR injury), produced by initial interruption and subsequent restoration of organ blood flow, is an important clinical dilemma accompanied by various cardiac reperfusion strategies following acute myocardial infarction (AMI). Although the restored blood flow is necessary for oxygen and nutrient supply, reperfusion often results in pathological sequelae leading to elevated ischemic damage. Among various theories postulated for IR injury including vascular leakage, oxidative stress, leukocyte entrapment, inflammation and apoptosis, mitochondrial dysfunction plays an essential role in mediating pathophysiological processes with recent evidence depicting a pivotal role for impaired mitophagy in mitochondrial injury. Given the critical role for mitophagy in mitochondrial quality control and the recent reports supporting a tie between mitophagy and IR injury, this review will revisit the contemporary understanding of mitophagy in the regulation of cardiac homeostasis and update recent progresses with regards to mitophagy and cardiac IR injury. We hope to establish a role for mitophagy as a potential therapeutic target in the management of IR injury.     

In vivo stress preconditioning

The heat shock or stress protein response is a highly conserved defense mechanism. Activation of the stress protein response by mild hyperthermia or by pharmacological agents allows cells to withstand a subsequent metabolic insult that would otherwise be lethal, a phenomenon referred as "thermotolerance" or "preconditioning." Heat shock response is characterized by increased expression of stress proteins that provide cellular protection, e.g., via increased chaperoning activity in all organisms, from bacteria to animals and humans. Indeed, there is experimental evidence that overexpression of specific heat shock proteins or heat shock factors produce protective effects similar to those observed after stress preconditioning. The purpose of this review is first to discuss the methods used to induce in vivo thermotolerance with mild hyperthermia or pharmacological agents. Then, as an example of the organ protection provided by in vivo stress preconditioning, the second part of this paper will examine how the induction of thermotolerance modulates the lung inflammatory response associated with acute lung injury, thus providing broad organ and tissue protection against oxidative stress associated this syndrome.     

Activation of the CaR-CSE/H2S pathway confers cardioprotection against ischemia-reperfusion injury

Ischemia-reperfusion (I/R) injury is a multifactorial process triggered when an organ is subjected to transiently reduced blood supply. The result is a cascade of pathological complications and organ damage due to the production of reactive oxygen species following reperfusion. The present study aims to evaluate the role of activated calcium-sensing receptor (CaR)-cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway in I/R injury. Firstly, an I/R rat model with CSE knockout was constructed. Transthoracic echocardiography, TTC and HE staining were performed to determine the cardiac function of rats following I/R Injury, followed by TUNEL staining observation on apoptosis. Besides, with the attempt to better elucidate how CaR-CSE/H2S affects I/R, in-vitro culture of human coronary artery endothelial cells (HCAECs) was conducted with gadolinium chloride (GdCl3, a CaR agonist), H₂O₂, siRNA against CSE (siCSE), or W7 (a CaM inhibitor). The interaction between CSE and CaM was subsequently detected. Plasma oxidative stress indexes, H2S and CSE, and apoptosis-related proteins were all analyzed following cell apoptosis. We found that H2S elevation led to the improvement whereas CSE knockdown decreased cardiac function in rats with I/R injury. Moreover, oxidative stress injury in I/R rats with CSE knockout was aggravated, while the increased expression of H2S and CSE in the aortic tissues resulted in alleviated the oxidative stress injury. Moreover, increased H2S and CSE levels were found to inhibit cell apoptotic ability in the aortic tissues after I/R injury, thus attenuating oxidative stress injury, accompanied by inhibited expression of apoptosis-related proteins. In HCAECs following oxidative stress treatment, siCSE and CaM inhibitor were observed to reverse the protection of CaR agonist. Coimmunoprecipitation assay revealed the interaction between CSE and CaM. Taken together, all above-mentioned data provides evidence that activation of the CaR-CSE/H2S pathway may confer a potent protective effect in cardiac I/R injury.     

An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations

Aging is an inherently complex process that is manifested within an organism at genetic, molecular, cellular, organ, and system levels. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward reactive oxygen species (ROS) as one of the primary determinants of aging. The "oxidative stress theory" holds that a progressive and irreversible accumulation of oxidative damage caused by ROS impacts on critical aspects of the aging process and contributes to impaired physiological function, increased incidence of disease, and a reduction in life span. While compelling correlative data have been generated to support the oxidative stress theory, a direct cause-and-effect relationship between the accumulation of oxidatively mediated damage and aging has not been strongly established. The goal of this minireview is to broadly describe mechanisms of in vivo ROS generation, examine the potential impact of ROS and oxidative damage on cellular function, and evaluate how these responses change with aging in physiologically relevant situations. In addition, the mounting genetic evidence that links oxidative stress to aging is discussed, as well as the potential challenges and benefits associated with the development of anti-aging interventions and therapies.     

microRNA-340-5p inhibits hypoxia/reoxygenation-induced apoptosis and oxidative stress in cardiomyocytes by regulating the Act1/NF-κB pathway

MicroRNAs (miRNAs) have been reported to play critical roles in the occurrence, progression, and treatment of many cardiovascular diseases. However, the molecular mechanism by which miRNA regulates target gene expression in ischemia-reperfusion (I/R) injury in acute myocardial infarction (AMI) is not entirely clear. MiR-340-5p was reported to be downregulated in acute ischemic stroke. However, it still remains unknown whether miR-340-5p is mediated in the pathogenesis process of I/R injury after AMI. In the present study, male C57BL/6 J mice and H9C2 cardiomyocytes were used as experimental models. Real-time polymerase chain reaction analysis, Western blot analysis, and the terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling immunofluorescence staining assay were conducted to examine related indicators in the study. We confirmed that the expression of miR-340-5p is downregulated after I/R in AMI mice and hypoxia/reperfusion (H/R)-induced cardiomyocytes. miR-340-5p could inhibit apoptosis and oxidative stress in H/R-induced H9C2 cells via downregulating activator 1 (Act1). The inhibiting action of miR-340-5p on H/R-induced apoptosis and oxidative stress in cardiomyocytes was partially reversed after Act1 overexpression. Moreover, the results showed that the NF-κB pathway may be mediated in the role of miR-340-5p on H/R-induced cardiomyocyte apoptosis and oxidative stress. We demonstrated that upregulation of miR-340-5p suppresses apoptosis and oxidative stress induced by H/R in H9C2 cells by inhibiting Act1. Therapeutic strategies that target miR-340-5p, Act1, and the NF-κB pathway could be beneficial for the treatment of I/R injury after AMI.     

中性粒细胞NADPH氧化酶与组织缺血再灌注关系的研究进展

缺血再灌注损伤为心肌梗死,器官移植,肠道灌注不足,脑中风等疾病或手术的常见并发症,是导致危重病人死亡的重要因素,然而至今临床上仍未有十分理想的治疗方法。在组织缺血再灌注过程中,中性粒细胞通过NADPH(Nicotinamide-adenine dinucleotide phosphate)氧化酶的活化产生大量活性氧(Reactive oxygen species,ROS),一方面参与氧化应激,另一方面进一步招募中性粒细胞,扩大炎症反应,造成组织损伤。本文综述了国外期刊报道的中性粒细胞NADPH氧化酶与组织缺血再灌注损伤的相关研究进展,以期为心脑血管等重大疾病防治提供一定线索。     

Congenital DNA repair deficiency results in protection against renal ischemia reperfusion injury in mice

Cockayne syndrome and other segmental progerias with inborn defects in DNA repair mechanisms are thought to be due in part to hypersensitivity to endogenous oxidative DNA damage. The accelerated aging-like symptoms of this disorder include dysmyelination within the central nervous system, progressive sensineuronal hearing loss and retinal degeneration. We tested the effects of congenital nucleotide excision DNA repair deficiency on acute oxidative stress sensitivity in vivo . Surprisingly, we found mouse models of Cockayne syndrome less susceptible than wild type animals to surgically induced renal ischemia reperfusion injury, a multifactorial injury mediated in part by oxidative damage. Renal failure-related mortality was significantly reduced in Csb^−/– mice, kidney function was improved and proliferation was significantly higher in the regenerative phase following ischemic injury. Protection from ischemic damage correlated with improved baseline glucose tolerance and insulin sensitivity and a reduced inflammatory response following injury. Protection was further associated with genetic ablation of a different Cockayne syndrome-associated gene, Csa . Our data provide the first functional in vivo evidence that congenital DNA repair deficiency can induce protection from acute stress in at least one organ. This suggests that while specific types of unrepaired endogenous DNA damage may lead to detrimental effects in certain tissues, they may at the same time elicit beneficial adaptive changes in others and thus contribute to the tissue specificity of disease symptoms.     

The neurobiology of isoprostanes and Alzheimer's disease

In its sporadic form Alzheimer's disease (AD) results from a combination of genetic and environmental risk factors with abnormal oxidative reactions, which result in free radical mediated injury of the brain. Isoprostanes are oxidized lipids formed by a free radical mediated mechanism, which in recent years have emerged as a reliable and sensitive marker of lipid peroxidation and oxidative stress. Consistent data show that they are increased in the brain of human AD as well as AD animal models. Besides their role as biomarkers, isoprostanes possess important biological effects, functioning as mediators of the cellular response to oxidative stress within the CNS. Recent evidence indicates that these lipid oxidation products, by activating the thromboxane receptor system, mediate the pro-amyloidotic neuronal response to oxidative stress in an experimental model of AD. This novel observation has important clinical implication, since pharmacologic modulation of the TP receptor system by selective antagonists, some of which are already available, could represent a novel therapeutic opportunity for AD as disease-modifying agents.     

Diabetes, metallothionein, and zinc interactions: a review

Epidemiological evidence, associating diabetes with zinc (Zn) deficiencies, has resulted in numerous research studies describing the effects of Zn and associated metallothionein (MT), on reducing diabetic complications associated with oxidative stress. MT has been found to have a profound effect on the reduction of oxidative stress induced by the diabetic condition. Over expression of MT in various metabolic organs has also been shown to reduce hyperglycaemia-induced oxidative stress, organ specific diabetic complications, and DNA damage in diabetic experimental animals, which have been further substantiated by the results from MT-knockout mice. Additionally, supplementation with Zn has been shown to induce in vivo MT synthesis in experimental animals and to reduce diabetes related complications in both humans and animal models. Although the results are promising, some caution regarding this topic is however necessary, due to the fact that the majority of the studies done have been animal based. Hence more human intervention trials are needed regarding the positive effects of MT and Zn before firm conclusions can be made regarding their use in the treatment of diabetes.     

Molecular mechanisms of acrolein-mediated myelin destruction in CNS trauma and disease

Abstract

Myelin is a critical component of the nervous system facilitating efficient propagation of electrical signals and thus communication between the central and peripheral nervous systems and the organ systems that they innervate throughout the body. In instances of neurotrauma and neurodegenerative disease, injury to myelin is a prominent pathological feature responsible for conduction deficits, and leaves axons vulnerable to damage from noxious compounds. Although the pathological mechanisms underlying myelin loss have yet to be fully characterized, oxidative stress (OS) appears to play a prominent role. Specifically, acrolein, a neurotoxic aldehyde that is both a product and an instigator of OS, has been observed in studies to elicit demyelination through calcium-independent and -dependent mechanisms and also by affecting glutamate uptake and promoting excitotoxicity. Furthermore, pharmacological scavenging of acrolein has demonstrated a neuroprotective effect in animal disease models, by conserving myelin's structural integrity and alleviating functional deficits. This evidence indicates that acrolein may be a key culprit of myelin damage while acrolein scavenging could potentially be a promising therapeutic approach for patients suffering from nervous system trauma and disease.     

Protective effects of molecular hydrogen on lung injury from lung transplantation

Lung grafts may experience multiple injuries during lung transplantation, such as warm ischaemia, cold ischaemia, and reperfusion injury. These injuries all contribute to primary graft dysfunction, which is a major cause of morbidity and mortality after lung transplantation. As a potential selective antioxidant, hydrogen molecule (H₂) protects against post-transplant complications in animal models of multiple organ transplantation. Herein, the authors review the current literature regarding the effects of H₂ on lung injury from lung transplantation. The reviewed studies showed that H₂ improved the outcomes of lung transplantation by decreasing oxidative stress and inflammation at the donor and recipient phases. H₂ is primarily administered via inhalation, drinking hydrogen-rich water, hydrogen-rich saline injection, or a hydrogen-rich water bath. H₂ favorably modulates signal transduction and gene expression, resulting in the suppression of pro-inflammatory cytokines and excess reactive oxygen species production. Although H₂ appears to be a physiological regulatory molecule with antioxidant, anti-inflammatory and anti-apoptotic properties, its exact mechanisms of action remain elusive. Taken together, accumulating experimental evidence indicates that H₂ can significantly alleviate transplantation-related lung injury, mainly via inhibition of inflammatory cytokine secretion and reduction in oxidative stress through several underlying mechanisms. Further animal experiments and preliminary human clinical trials will lay the foundation for the use of H₂ as a treatment in the clinic.     

Protective Effects of Anthocyanins from Coreopsis tinctoria against Oxidative Stress Induced by Hydrogen Peroxide in MIN6 Cells

Anthocyanins (AC) from Coreopsis tinctoria possesses strong antioxidant properties, while the effects of AC on cells damage induced by reactive oxygen species (ROS) in diabetes mellitus diseases progression have not been reported. The present study was carried out to evaluate the protective property of AC against cellular oxidative stress with an experimental model, H₂O₂‐exposed MIN6 cells. AC could reverse the decrease of cell viability induced by H₂O₂ and efficiently suppressed cellular ROS production and cell apoptosis. In addition, Real‐time PCR and Western blot analyses indicated that AC could protect MIN6 cells against oxidative injury through increasing the translocation of Nrf2 into nuclear, decreasing the phosphorylation level of p38 and up‐regulating the protein expression of antioxidant enzyme (SOD1, SOD2 and CAT). Thus, this study provides evidence to support the beneficial effect of AC in inhibiting MIN6 cells from H₂O₂‐induced oxidative injury.     

Induction of acute respiratory distress syndrome in rats by lipopolysaccharide and its effect on oxidative stress and antioxidant status in lung

Acute lung injury (ALI) or its severe form, acute respiratory distress syndrome (ARDS) is an important cause of mortality in the human population. Despite significant advances made, the mortality associated with ALI remains unchanged. The objective of the present study was to evaluate the role of oxidative stress, alveolar antioxidant status and multiple organ injury in ARDS induced by lipopolysaccharide (LPS) in rats. Rats were divided into 4 groups, group I control rats were given saline intraperitoneally, whereas groups II, III and IV (LPS-treated) rats received an intraperitoneal injection of LPS (10 mg/kg body weight) and sacrificed after various time intervals. In LPS-treated rats, we observed increased levels of oxidative products, decreased levels of antioxidants in lung tissues and increased levels of serum marker enzymes, suggesting multiple organ injury. Bronchoalveolar lavage fluid (BALF) neutrophil content and protein concentration in LPS-treated rats were significantly elevated in a time-dependent manner. Histological studies revealed neutrophil influx and diffused alveolar damage in LPS-administered rats. These results clearly suggested that increased oxidant levels led to oxidative stress, antioxidant deficiency attenuating lung inflammation and tissue damage. LPS administration resulted in multiple organ failure, leading to increased mortality.     

Reactive oxygen species in vascular biology: implications in hypertension

Reactive oxygen species (ROS), including superoxide (·O₂^–), hydrogen peroxide (H₂O₂), and hydroxyl anion (OH-), and reactive nitrogen species, such as nitric oxide (NO) and peroxynitrite (ONOO^–), are biologically important O₂ derivatives that are increasingly recognized to be important in vascular biology through their oxidation/reduction (redox) potential. All vascular cell types (endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts) produce ROS, primarily via cell membrane-associated NAD(P)H oxidase. Reactive oxygen species regulate vascular function by modulating cell growth, apoptosis/anoikis, migration, inflammation, secretion, and extracellular matrix protein production. An imbalance in redox state where pro-oxidants overwhelm anti-oxidant capacity results in oxidative stress. Oxidative stress and associated oxidative damage are mediators of vascular injury and inflammation in many cardiovascular diseases, including hypertension, hyperlipidemia, and diabetes. Increased generation of ROS has been demonstrated in experimental and human hypertension. Anti-oxidants and agents that interrupt NAD(P)H oxidase-driven ·O₂^– production regress vascular remodeling, improve endothelial function, reduce inflammation, and decrease blood pressure in hypertensive models. This experimental evidence has evoked considerable interest because of the possibilities that therapies targeted against reactive oxygen intermediates, by decreasing generation of ROS and/or by increasing availability of antioxidants, may be useful in minimizing vascular injury and hypertensive end organ damage. The present chapter focuses on the importance of ROS in vascular biology and discusses the role of oxidative stress in vascular damage in hypertension.     

Renal damage mediated by oxidative stress: a hypothesis of protective effects of red wine

Over the last decade, oxidative stress has been implicated in the pathogenesis of a wide variety of seemingly unrelated renal diseases. Epidemiological studies have documented an association of moderate wine consumption with a decreased risk of cardiovascular and neurological diseases; however, similar studies in the kidney are still lacking. The kidney is an organ highly vulnerable to damage caused by reactive oxygen species (ROS), likely due to the abundance of polyunsaturated fatty acids in the composition of renal lipids. ROS are involved in the pathogenic mechanism of conditions such as glomerulosclerosis and tubulointerstitial fibrosis. The health benefits of moderate consumption of red wine can be partly attributed to its antioxidant properties. Indeed, the kidney antioxidant defense system is enhanced after chronic exposure to moderate amounts of wine, a response arising from the combined effects of ethanol and the nonalcoholic components, mainly polyphenols. Polyphenols behave as potent ROS scavengers and metal chelators; ethanol, in turn, modulates the activity of antioxidant enzymes. Therefore, a hypothesis that red wine causes a decreased vulnerability of the kidney to the oxidative challenges could be proposed. This view is partly supported by direct evidences indicating that wine and antioxidants isolated from red wine, as well as other antioxidants, significantly attenuate or prevent the oxidative damage to the kidney. The present hypothesis paper provides a collective body of evidence suggesting a protective role of moderate wine consumption against the production and progression of renal diseases, based on the existing concepts on the pathophysiology of kidney injury mediated by oxidative stress.