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Kaempferia parviflora (KP), a health-promoting herb, has been traditionally used for treating a variety of diseases. Pharmacological studies have claimed the various benefits from KP and its main effective methoxyflavones, including cellular metabolism-regulating activity, anticancer activity, vascular relaxation and cardioprotective activity, sexual enhancing activity, neuroprotective activity, antiallergic, anti-inflammatory, and antioxidative activity, antiosteoarthritis activity, antimicroorganism activity, and transdermal permeable activity. These might be associated with increased mitochondrial functions and activated cGMP-NO signaling pathway. However, the underlying molecular mechanisms of KP and its methoxyflavones are still under investigation. The clinical applications of KP and its methoxyflavones may be limited due to their low bioavailability. But promising strategies are on the way. This review will comprehensively discuss the biological activities of KP and its methoxyflavones. [ABSTRACT FROM AUTHOR]

Abstract: Our recent studies showed that total body irradiation (TBI) induces long-term bone marrow (BM) suppression in part by induction of hematopoietic stem cell (HSC) senescence through reactive oxygen species (ROS). In this study, we examined if Mn(III) meso-tetrakis-(N-ethylpyridinium-2-yl) porphyrin (MnTE), a superoxide dismutase mimetic and potent antioxidant, can mitigate TBI-induced long-term BM injury in a mouse model. Our results showed that post-TBI treatment with MnTE significantly inhibited the increases in ROS production and DNA damage in HSCs and the reduction in HSC frequency and clonogenic function induced by TBI. In fact, the clonogenic function of HSCs from irradiated mice after MnTE treatment was comparable to that of HSCs from normal controls on a per-HSC basis, suggesting that MnTE treatment inhibited the induction of HSC senescence by TBI. This suggestion is supported by the finding that MnTE treatment also reduced the expression of p16Ink4a (p16) mRNA in HSCs induced by TBI and improved the long-term and multilineage engraftment of irradiated HSCs after transplantation. Therefore, the results from this study demonstrate that MnTE has the potential to be used as a therapeutic agent to mitigate TBI-induced long-term BM suppression by inhibiting ionizing radiation-induced HSC senescence through the ROS–p16 pathway. [Copyright &y& Elsevier]

Ionising radiation (IR) is a known carcinogen and poses a significant risk to the haematopoietic system for the development of leukaemia in part by induction of genomic instability. Induction of chronic oxidative stress has been assumed to play an important role in mediating the effect of IR on the haematopoietic system. However, there was no direct evidence to support this hypothesis prior to our studies. In our recent studies, we showed that exposure of mice to total body irradiation (TBI) induces persistent oxidative stress selectively in haematopoietic stem cells (HSCs) at least in part via up-regulation of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 4. Now, we found that post-TBI treatment with diphenylene iodonium (DPI), a pan NOX inhibitor, not only significantly reduces TBI-induced increases in reactive oxygen species (ROS) production, oxidative DNA damage and DNA double-strand breaks in HSCs but also dramatically decreases the number of cells with unstable chromosomal aberrations in the clonal progeny of irradiated HSCs. The effects of DPI are comparable to Mn (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin, a superoxide dismutase mimetic and a potent antioxidant. These findings demonstrate that increased production of ROS by NOX in HSCs mediates the induction of haematopoietic genomic instability by IR and that NOX may represent a novel molecular target to inhibit TBI-induced genomic instability. [ABSTRACT FROM PUBLISHER]

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common disease worldwide in an era of rapid economic growth. NAFLD is a multifactorial disease, involving multiple genetic, metabolic, and environmental factors, and is closely associated with metabolic syndrome, obesity, and cardiovascular disease. NAFLD can be classified into nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH), which can both progress to cirrhosis and even hepatocellular carcinoma (HCC). Due to the enormous burden of NAFLD and its complications, no FDA-approved drugs for the treatment of NAFLD are on the market, and therapeutic targets and drug therapies are being actively investigated. In view of the various pathological mechanisms of NAFLD, numbers of preclinical studies and clinical trials have made rapid progress. This review mainly summarizes the most recently characterized mechanisms and therapeutic targets in each mechanism of NAFLD, focusing on the mechanism and application potential. [ABSTRACT FROM AUTHOR]

Metabolic cardiomyopathy is an emerging cause of heart failure in patients with obesity, insulin resistance, and diabetes. It is characterized by impaired myocardial metabolic flexibility, intramyocardial triglyceride accumulation, and lipotoxic damage in association with structural and functional alterations of the heart, unrelated to hypertension, coronary artery disease, and other cardiovascular diseases. Oxidative stress plays an important role in the development and progression of metabolic cardiomyopathy. Mitochondria are the most significant sources of reactive oxygen species (ROS) in cardiomyocytes. Disturbances in myocardial substrate metabolism induce mitochondrial adaptation and dysfunction, manifested as a mismatch between mitochondrial fatty acid oxidation and the electron transport chain (ETC) activity, which facilitates ROS production within the ETC components. In addition, non-ETC sources of mitochondrial ROS, such as β-oxidation of fatty acids, may also produce a considerable quantity of ROS in metabolic cardiomyopathy. Augmented ROS production in cardiomyocytes can induce a variety of effects, including the programming of myocardial energy substrate metabolism, modulation of metabolic inflammation, redox modification of ion channels and transporters, and cardiomyocyte apoptosis, ultimately leading to the structural and functional alterations of the heart. Based on the above mechanistic views, the present review summarizes the current understanding of the mechanisms underlying metabolic cardiomyopathy, focusing on the role of oxidative stress. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide and is strongly associated with the presence of oxidative stress. Disturbances in lipid metabolism lead to hepatic lipid accumulation, which affects different reactive oxygen species (ROS) generators, including mitochondria, endoplasmic reticulum, and NADPH oxidase. Mitochondrial function adapts to NAFLD mainly through the downregulation of the electron transport chain (ETC) and the preserved or enhanced capacity of mitochondrial fatty acid oxidation, which stimulates ROS overproduction within different ETC components upstream of cytochrome c oxidase. However, non-ETC sources of ROS, in particular, fatty acid β-oxidation, appear to produce more ROS in hepatic metabolic diseases. Endoplasmic reticulum stress and NADPH oxidase alterations are also associated with NAFLD, but the degree of their contribution to oxidative stress in NAFLD remains unclear. Increased ROS generation induces changes in insulin sensitivity and in the expression and activity of key enzymes involved in lipid metabolism. Moreover, the interaction between redox signaling and innate immune signaling forms a complex network that regulates inflammatory responses. Based on the mechanistic view described above, this review summarizes the mechanisms that may account for the excessive production of ROS, the potential mechanistic roles of ROS that drive NAFLD progression, and therapeutic interventions that are related to oxidative stress. Image 1 • Oxidative stress plays a central role in the pathogenesis of NAFLD. • Mechanisms for ROS production include alterations in the mitochondria, ER, and NOX. • Non-ETC sources, especially β-oxidation, are important sources of mitochondrial ROS. • ROS signaling modulates lipid metabolism, insulin signaling, and inflammation. • Targeting hepatic oxidative stress is a promising strategy to treat NAFLD. [ABSTRACT FROM AUTHOR]

Humans are exposed to disinfection by-products through oral, inhalation, and dermal routes, during bathing and swimming, potentially causing skin lesions, asthma, and bladder cancer. Nuclear factor E2-related factor 2 (NRF2) is a master regulator of the adaptive antioxidant response via the antioxidant reaction elements (ARE) orchestrating the transcription of a large group of antioxidant and detoxification genes. Here we used an immortalized human keratinocyte model HaCaT cells to investigate NRF2-ARE as a responder and protector in the acute cytotoxicity of seven haloacetonitriles (HANs), including chloroacetonitrile (CAN), bromoacetonitrile (BAN), iodoacetonitrile (IAN), bromochloroacetonitrile (BCAN), dichloroacetonitrile (DCAN), dibromoacetonitrile (DBAN), and trichloroacetonitrile (TCAN) found in drinking water and swimming pools. The rank order of cytotoxicity among the HANs tested was IAN ≈ BAN ˃ DBAN ˃ BCAN ˃ CAN ˃ TCAN ˃ DCAN based on their LC 50. The HANs induced intracellular reactive oxygen species accumulation and activated cellular antioxidant responses in concentration- and time-dependent fashions, showing elevated NRF2 protein levels and ARE activity, induction of antioxidant genes, and increased glutathione levels. Additionally, knockdown of NRF2 by lentiviral shRNAs sensitized the HaCaT cells to HANs-induced cytotoxicity, emphasizing a protective role of NRF2 against the cytotoxicity of HANs. These results indicate that HANs cause oxidative stress and activate NRF2-ARE-mediated antioxidant response, which in turn protects the cells from HANs-induced cytotoxicity, highlighting that NRF2-ARE activity could be a sensitive indicator to identify and characterize the oxidative stress induced by HANs and other environmental pollutants. [Display omitted] • Haloacetonitriles cause acute cytotoxicity and oxidative stress in HaCaT cells. • Haloacetonitriles induce NRF2-ARE-mediated antioxidant response in HaCaT cells. • NRF2 protects human keratinocytes from HANs-induced acute cell damage. • NRF2-ARE activity is an indicator for the oxidative stress caused by haloacetonitriles. [ABSTRACT FROM AUTHOR]

Interferon regulatory factor 3 ( IRF3) is a transcription factor that plays a central role in the innate immune response, apoptosis, and oncogenesis. Previous studies have shown that endogenous IRF3 does not affect stroke in mice; however, paradoxically, elevated IRF3 expression was observed in the rat brains following cerebral ischemia/reperfusion (I/R) injury, indicating that IRF3 may have different functions during stroke in rats than in mice. A clear and comprehensive study of the effect of IRF3 on stroke in rats has been hampered by the lack of an IRF3-knockout rat strain. In this study, a novel IRF3 knockout rat strain and a transgenic rat strain with neuronal-specific IRF3 over-expression ( IRF3- TG) were created. Subsequently, the generated IRF3-knockout rats, the neuronal-specific IRF3 over-expressing rats and their corresponding controls were subjected to transient middle cerebral artery occlusion and followed by reperfusion, to investigate the exact role of IRF3 in cerebral I/R in rats. In contrast to the results in mice, IRF3 deficiency in rats provided significant protection against cerebral I/R injury and inhibited neuronal apoptosis, inflammation, and oxidative stress after cerebral I/R injury; the opposite patterns were observed in neuronal-specific IRF3 over-expressing rats. Taken together, these data demonstrate that IRF3 plays a negative regulatory role in cerebral I/R in rats, and IRF3 may be an attractive therapeutic target for preventing stroke. [ABSTRACT FROM AUTHOR]

Interferon regulatory factor 8 (IRF8), a transcriptional regulator in the IRF family, has been implicated in innate immunity, immune cell differentiation and tumour cell apoptosis. In the present study, we found that IRF8 is constitutively expressed in the brain and suppressed after cerebral ischaemia in a time-dependent manner. IRF8 knockout (IRF8-KO) mice, wild type (WT) mice, neuron-specific IRF8 transgenic (TG) mice and non-transgenic mice were used in a transient cerebral ischaemic model. The IRF8 knockout mice exhibited aggravated apoptosis, inflammation and oxidative injury in the ischaemic brain, eventually leading to poorer stroke outcomes, whereas neuron-specific IRF8 transgenic mice showed a marked inhibition of apoptosis and improved stroke outcomes. To model ischaemia/reperfusion conditions in vitro, primary cortical neurons were cultured and subjected to transient oxygen and glucose deprivation for 60 min. Similar to the in vivo study, IRF8 knockdown by Ad-shIRF8 resulted in increased apoptosis, whereas IRF8 over-expression by Ad-IRF8 significantly decreased neuronal apoptosis. These data indicate that IRF8 is strongly protective in ischaemic stroke by regulating neuronal apoptosis, the inflammatory response and oxidative stress. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2012) 122, 834-843. Abstract Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), also known as Signal-regulatory protein alpha (SIRPα) or SIRPA is a transmembrane protein that is predominantly expressed in neurons, dendritic cells, and macrophages. This study was conducted to investigate the role of SHPS-1 in the oxidative stress and brain damage induced by acute focal cerebral ischemia. Wild-type (WT) and SHPS-1 mutant (MT) mice were subjected to middle cerebral artery occlusion (60 min) followed by reperfusion. SHPS-1 MT mice had significantly reduced infarct volumes and improved neurological function after brain ischemia. In addition, neural injury and oxidative stress were inhibited in SHPS-1 MT mice. The mRNA and protein levels of the antioxidant genes nuclear factor-E2-related factor 2 (Nrf2) and heme oxygenase 1 were up-regulated in SHPS-1 MT mice. The SHPS-1 mutation suppressed the phosphorylation of SHP-1 and SHP-2 and increased the phosphorylation of Akt and GSK3β. These results provide the first demonstration that SHPS-1 plays an important role in the oxidative stress and brain injury induced by acute cerebral ischemia. The activation of Akt signaling and the up-regulation of Nrf2 and heme oxygenase 1 likely account for the protective effects that were observed in the SHPS-1 MT mice. [ABSTRACT FROM AUTHOR]

Aims While a wealth of data has uncovered distinct microRNA (miR) expression alterations in hypertrophic and ischaemic/reperfused (I/R) hearts, little is known about miR regulation and response to ischaemic preconditioning (IPC). Methods and results We analysed miRs in murine hearts preconditioned with six cycles of 4 min ischaemia via coronary artery occlusion, followed by 4 min reperfusion in vivo. Both miRs within the miR-144/451 cluster were the most elevated among a cohort of 21 dysregulated miRs in preconditioned hearts, compared with shams. To investigate the significance of this finding, we examined IPC-mediated cardioprotection within a miR-144/451-knockout (KO) mouse model. Wild-type (WT) hearts exposed to IPC followed by I/R (30 min/24 h) showed a smaller infarction size compared with mice treated with I/R alone. In contrast, IPC failed to protect miR-144/451-KO hearts against infarct caused by I/R treatment. Thus, the miR-144/451 cluster is required for IPC-elicited cardioprotection. Rac-1, a key component of NADPH oxidase, was mostly up-regulated in KO hearts among three bona fide targets (Rac-1, 14-3-3ζ, and CUGBP2) for both miR-144 and miR-451. Accordingly, reactive oxygen species (ROS) levels were markedly increased in KO hearts upon IPC, compared with IPC-WT hearts. Pre-treatment of KO hearts with a Rac-1 inhibitor NSC23766 (20 mg/kg, ip) reduced IPC-triggered ROS levels and restored IPC-elicited cardioprotection. Using antagomiRs, we showed that miR-451 was largely responsible for IPC-mediated cardioprotection. Conclusion Loss of the miR-144/451 cluster limits IPC cardioprotection by up-regulating Rac-1-mediated oxidative stress signalling. [ABSTRACT FROM PUBLISHER]

Abstract: Increased oxidative stress has been associated with the pathogenesis of chronic cardiac hypertrophy and heart failure. Since allicin suppresses oxidative stress in vitro and in vivo, we hypothesized that allicin would inhibit cardiac hypertrophy through blocking oxidative stress-dependent signaling. We examined this hypothesis using primary cultured cardiac myocytes and fibroblasts and one well-established animal model of cardiac hypertrophy. Our results showed that allicin markedly inhibited hypertrophic responses induced by Ang II or pressure overload. The increased reactive oxygen species (ROS) generation and NADPH oxidase activity were significantly suppressed by allicin. Our further investigation revealed this inhibitory effect on cardiac hypertrophy was mediated by blocking the activation of ROS-dependent ERK1/2, JNK1/2 and AKT signaling pathways. Additional experiments demonstrated allicin abrogated inflammation and fibrosis by blocking the activation of nuclear factor-κB and Smad 2/3 signaling, respectively. The combination of these effects resulted in preserved cardiac function in response to cardiac stimuli. Consequently, these findings indicated that allicin protected cardiac function and prevented the development of cardiac hypertrophy through ROS-dependent mechanism involving multiple intracellular signaling. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress has been implicated in several steps leading to the development of diabetic vascular complications. The purpose of this study was to determine the efficacy and the possible mechanism of puerarin on high-glucose (HG; 25 mM)-induced proliferation of cultured rat vascular smooth muscle cells (VSMCs) and neointimal formation in a carotid arterial balloon injury model of obese Zucker rats. Our data demonstrated that puerarin significantly inhibited rat VSMC proliferation as well as reactive oxygen species (ROS) generation and NADPH oxidase activity induced by HG treatment. Further studies revealed that HG treatment resulted in phosphorylation and membrane translocation of PKCβ2 as well as Rac1, p47phox, and p67phox subunits, leading to NADPH oxidase activation. Puerarin treatment remarkably disrupted the phosphorylation and membrane translocation of PKCβ2 as well as Rac1, p47phox, and p67phox subunits. Blocking PKCβ2 by infection with AdDNPKCβ2 also abolished HG-induced phosphorylation and membrane translocation of Rac1, p47phox, and p67phox subunits as well as ROS production and NADPH oxidase activation in VSMCs. In vivo neointimal formation of obese Zucker rats evoked by balloon injury was evidently attenuated by the administration of puerarin. These results demonstrate that puerarin may exert inhibitory effects on HG-induced VSMC proliferation via interfering with PKCβ2/Rac1-dependent ROS pathways, thus resulting in the attenuation of neointimal formation in the context of hyperglycemia in diabetes mellitus. [Copyright &y& Elsevier]

Abstract: Ionizing radiation (IR) and/or chemotherapy causes not only acute tissue damage but also late effects including long-term (or residual) bone marrow (BM) injury. The induction of residual BM injury is primarily attributable to the induction of hematopoietic stem cell (HSC) senescence. However, the molecular mechanisms by which IR and/or chemotherapy induces HSC senescence have not been clearly defined, nor has an effective treatment been developed to ameliorate the injury. Thus, we investigated these mechanisms in this study. The results from this study show that exposure of mice to a sublethal dose of total body irradiation (TBI) induced a persistent increase in reactive oxygen species (ROS) production in HSCs only. The induction of chronic oxidative stress in HSCs was associated with sustained increases in oxidative DNA damage, DNA double-strand breaks (DSBs), inhibition of HSC clonogenic function, and induction of HSC senescence but not apoptosis. Treatment of the irradiated mice with N-acetylcysteine after TBI significantly attenuated IR-induced inhibition of HSC clonogenic function and reduction of HSC long-term engraftment after transplantation. The induction of chronic oxidative stress in HSCs by TBI is probably attributable to the up-regulation of NADPH oxidase 4 (NOX4), because irradiated HSCs expressed an increased level of NOX4, and inhibition of NOX activity with diphenylene iodonium but not apocynin significantly reduced TBI-induced increases in ROS production, oxidative DNA damage, and DNA DSBs in HSCs and dramatically improved HSC clonogenic function. These findings provide the foremost direct evidence demonstrating that TBI selectively induces chronic oxidative stress in HSCs at least in part via up-regulation of NOX4, which leads to the induction of HSC senescence and residual BM injury. [Copyright &y& Elsevier]