RESUMO
Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.
Assuntos
Carcinoma Hepatocelular , Animais , Camundongos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Espécies Reativas de Oxigênio , Carcinogênese/genéticaRESUMO
The pathogenesis of malignant mesothelioma (MM) has been extensively investigated, focusing on stress derived from reactive oxygen species. We aimed to identify diagnostic biomarkers of MM by analyzing proteins in formalin-fixed paraffin-embedded specimens using liquid chromatography-mass spectrometry. We extracted proteins from formalin-fixed paraffin-embedded sections of MM tissues (n = 7) and compared their profiles with those of benign mesothelial tissues (n = 4) and alveolar tissue (n = 1). Proteomic data were statistically assessed and profiled using principal component analysis. We were successful in the classification of MM and healthy tissue. The levels of superoxide dismutase 2 (SOD2), an enzyme that converts superoxide anion into oxygen and hydrogen peroxide, and thioredoxin (TXN), which plays a crucial role in reducing disulfide bonds in proteins, primarily contributed to the classification. Other redox-related proteins, such as pyruvate dehydrogenase subunit X, and ceruloplasmin also contributed to the classification. Protein-protein interaction analysis demonstrated that these proteins play essential roles in MM pathogenesis. Immunohistochemistry revealed that TXN levels were significantly lower, whereas SOD2 levels were significantly higher in MM and lung cancer tissues than in controls. Proteomic profiling suggested that MM tissues experienced increased exposure to hydrogen peroxide and other reactive oxygen species. Combining immunohistochemistry for TXN and SOD2 allows for differentiation among MM, lung cancer, and control tissues; hence, TXN and SOD2 may be promising MM biomarkers and therapeutic targets.
Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Superóxido Dismutase , Humanos , Imuno-Histoquímica , Proteômica/métodos , Formaldeído/química , Inclusão em Parafina/métodos , Peróxido de Hidrogênio , Espécies Reativas de Oxigênio , Biomarcadores , Tiorredoxinas , Neoplasias Pulmonares/diagnósticoRESUMO
Diabetic kidney disease (DKD) is a major contributor to chronic kidney disease. Hydrogen sulfide (H2S) serves as an endogenous gaseous signaling molecule capable of safeguarding renal function within the context of DKD. However, the underlying mechanisms need to be elucidated. This study was undertaken to unveil the mechanisms by which H2S counteracts against DKD. Utilizing mice and human renal tubular epithelial (HK-2) cells, we demonstrated a reduction in cystathionine-γ-lyase/H2S levels within renal tissues of db/db mice and in HK-2 cells subjected to hyperglycemic and hyperlipidemic environments. Notably, we observed that sodium hydrosulfide (NaHS) supplementation could serve as an exogenous source of H2S. Exogenous H2S exhibited the capacity to mitigate the accumulation of reactive oxygen species and attenuate the degradation of superoxide dismutase 2 (SOD2) by Lon protease homolog 1 induced by hyperglycemia and hyperlipidemia, thus affording cellular protection against mitochondrial apoptosis. Consequently, NaHS treatment led to decreased serum levels of blood urea nitrogen and serum creatinine, reflecting alleviated renal damage and thereby preserving renal function in db/db mice. Based on these findings, we propose that exogenous H2S exerts a protective role against DKD by inhibiting SOD2 degradation.
Assuntos
Nefropatias Diabéticas , Sulfeto de Hidrogênio , Superóxido Dismutase , Animais , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Camundongos , Humanos , Superóxido Dismutase/metabolismo , Masculino , Rim/metabolismo , Rim/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológicoRESUMO
Skeletal fluorosis is a chronic metabolic bone disease caused by long-term excessive fluoride intake. Abnormal differentiation of osteoblasts plays an important role in disease progression. Research on the mechanism of fluoride-mediated bone differentiation is necessary for the prevention and treatment of skeletal fluorosis. In the present study, a rat model of fluorosis was established by exposing it to drinking water containing 50 mg/L F-. We found that fluoride promoted Runt-related transcription factor 2 (RUNX2) as well as superoxide dismutase 2 (SOD2) and sirtuin 3 (SIRT3) expression in osteoblasts of rat bone tissue. In vitro, we also found that 4 mg/L sodium fluoride promoted osteogenesis-related indicators as well as SOD2 and SIRT3 expression in MG-63 and Saos-2 cells. In addition, we unexpectedly discovered that fluoride suppressed the levels of reactive oxygen species (ROS) and mitochondrial reactive oxygen species (mtROS) in osteoblasts. When SOD2 or SIRT3 was inhibited in MG-63 cells, fluoride-decreased ROS and mtROS were alleviated, which in turn inhibited fluoride-promoted osteogenic differentiation. In conclusion, our results suggest that SIRT3/SOD2 mediates fluoride-promoted osteoblastic differentiation by down-regulating reactive oxygen species.
RESUMO
Pancreatic adenocarcinoma (PDAC) is one of the most lethal malignant tumors with an urgent need for precision medicine strategies. The present study seeks to assess the antitumor effects of fisetin, and characterize its impact on PDAC. Multi-omic approaches include proteomic, transcriptomic, and metabolomic analyses. Further validation includes the assessment of mitochondria-derived reactive oxygen species (mtROS), mitochondrial membrane potential, as well as ATP generation. Molecular docking, immunoprecipitation, and proximity ligation assay were used to detect the interactions among fiseitn, superoxide dismutase 2 (SOD2), and sirtuin 2 (SIRT2). We showed that fisetin disrupted mitochondrial homeostasis and induced SOD2 acetylation in PDAC. Further, we produced site mutants to determine that fisetin-induced mtROS were dependent on SOD2 acetylation. Fisetin inhibited SIRT2 expression, thus blocking SOD2 deacetylation. SIRT2 overexpression could impede fisetin-induced SOD2 acetylation. Additionally, untargeted metabolomic analysis revealed an acceleration of folate metabolism with fisetin. Collectively, our findings suggest that fisetin disrupts mitochondrial homeostasis, eliciting an important cancer-suppressive role; thus, fisetin may serve as a promising therapeutic for PDAC.
RESUMO
Elevated oxidative stress can play a pivotal role in autoimmune diseases by exacerbating inflammatory responses and tissue damage. In Sjögren's disease (SjD), the contribution of oxidative stress in the disease pathogenesis remains unclear. To address this question, we created mice with a tamoxifen-inducible conditional knockout (KO) of a critical antioxidant enzyme, superoxide dismutase 2 (Sod2), in the salivary glands (i-sg-Sod2 KO mice). Following tamoxifen treatment, Sod2 deletion occurred primarily in the ductal epithelium, and the salivary glands showed a significant downregulation of Sod2 expression. At twelve weeks post-treatment, salivary glands from the i-sg-Sod2 KO mice exhibited increased 3-Nitrotyrosine staining. Bulk RNA-seq revealed alterations in gene expression pathways related to ribosome biogenesis, mitochondrial function, and oxidative phosphorylation. Significant changes were noted in genes characteristic of salivary gland ionocytes. The i-sg-Sod2 KO mice developed reversible glandular hypofunction. However, this functional loss was not accompanied by glandular lymphocytic foci or circulating anti-nuclear antibodies. These data demonstrate that although localized oxidative stress in salivary gland ductal cells was insufficient for SjD development, it induced glandular dysfunction. The i-sg-Sod2 KO mouse resembles patients classified as non-Sjögren's sicca and will be a valuable model for deciphering oxidative-stress-mediated glandular dysfunction and recovery mechanisms.
Assuntos
Células Epiteliais , Camundongos Knockout , Mitocôndrias , Estresse Oxidativo , Glândulas Salivares , Síndrome de Sjogren , Superóxido Dismutase , Animais , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Glândulas Salivares/patologia , Glândulas Salivares/metabolismo , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Síndrome de Sjogren/genética , Camundongos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Mitocôndrias/metabolismo , Modelos Animais de DoençasRESUMO
Gα13 and Gα12, encoded by the GNA13 and GNA12 genes, respectively, are members of the G12 family of Gα proteins that, along with their associated Gßγ subunits, mediate signaling from specific G protein-coupled receptors (GPCRs). Advanced prostate cancers have increased expression of GPCRs such as CXC Motif Chemokine Receptor 4 (CXCR4), lysophosphatidic acid receptor (LPAR), and protease activated receptor 1 (PAR-1). These GPCRs signal through either the G12 family, or through Gα13 exclusively, often in addition to other G proteins. The effect of Gα13 can be distinct from that of Gα12, and the role of Gα13 in prostate cancer initiation and progression is largely unexplored. The oncogenic effect of Gα13 on cell migration and invasion in prostate cancer has been characterized, but little is known about other biological processes such as mitochondrial function and oxidative stress. Current knowledge on the link between Gα13 and oxidative stress is based on animal studies in which GPCR-Gα13 signaling decreased superoxide levels, and the overexpression of constitutively active Gα13 promoted antioxidant gene activation. In human samples, mitochondrial superoxide dismutase 2 (SOD2) correlates with prostate cancer risk and prognostic Gleason grade. However, overexpression of SOD2 in prostate cancer cells yielded conflicting results on cell growth and survival under basal versus oxidative stress conditions. Hence, it is necessary to explore the effect of Gα13 on prostate cancer tumorigenesis, as well as the effect of Gα13 on SOD2 in prostate cancer cell growth under oxidative stress conditions.
Assuntos
Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP , Mitocôndrias , Estresse Oxidativo , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Mitocôndrias/metabolismo , Mitocôndrias/genética , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/genética , Animais , Transdução de Sinais , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genéticaRESUMO
The sirtuin 6 (SIRT6) participates in regulating glucose and lipid homeostasis. However, the function of SIRT6 in the process of cardiac pathogenesis caused by obesity-associated lipotoxicity remains to be unveiled. This study was designed to elucidate the role of SIRT6 in the pathogenesis of cardiac injury due to nutrition overload-induced obesity and explore the downstream signaling pathways affecting oxidative stress in the heart. In this study, we used Sirt6 cardiac-specific knockout murine models treated with a high-fat diet (HFD) feeding to explore the function and mechanism of SIRT6 in the heart tissue during HFD-induced obesity. We also took advantage of neonatal cardiomyocytes to study the role and downstream molecules of SIRT6 during HFD-induced injury in vitro, in which intracellular oxidative stress and mitochondrial content were assessed. We observed that during HFD-induced obesity, Sirt6 loss-of-function aggravated cardiac injury including left ventricular hypertrophy and lipid accumulation. Our results evidenced that upon increased fatty acid uptake, SIRT6 positively regulated the expression of endonuclease G (ENDOG), which is a mitochondrial-resident molecule that plays an important role in mitochondrial biogenesis and redox homeostasis. Our results also showed that SIRT6 positively regulated superoxide dismutase 2 (SOD2) expression post-transcriptionally via ENDOG. Our study gives a new sight into SIRT6 beneficial role in mitochondrial biogenesis of cardiomyocytes. Our data also show that SIRT6 is required to reduce intracellular oxidative stress in the heart triggered by high-fat diet-induced obesity, involving the control of ENDOG/SOD2.
Assuntos
Estresse Oxidativo , Sirtuínas , Camundongos , Animais , Estresse Oxidativo/fisiologia , Sirtuínas/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , LipídeosRESUMO
PURPOSE: Ultraviolet-induced skin photoaging was involved in DNA oxidative damage. Specnuezhenide, one of the secoiridoids extracted from Ligustri Lucidi Fructus, possesses antioxidant and anti-inflammatory effects. Whether specnuezhenide ameliorates skin photoaging remains unclear. This study aimed to investigate the effect of specnuezhenide on skin photoaging induced by ultraviolet and explore the underlying mechanism. METHODS: Mice were employed to treat with ultraviolet to induce skin photoaging, then administrated 10 and 20 mg/kg of specnuezhenide. Histological analysis, protein expression, network pharmacology, and autodock analysis were conducted. RESULTS: Specnuezhenide ameliorated ultraviolet-induced skin photoaging in mice via the increase in collagen contents, and decrease in epidermal thickness, malondialdehyde content, and ß-galactosidase expression in the skin. Specnuezhenide reduced cutaneous apoptosis and inflammation in mice with skin photoaging. In addition, network pharmacology data indicated that specnuezhenide possessed potential targets on the NOD-like receptor signaling pathway. Validation experiment found that specnuezhenide inhibited the expression of NOD-like receptor family pyrin domain-containing 3, gasdermin D-C1, and Caspase 1. Furthermore, the expression of 8-Oxoguanine DNA glycosylase (OGG1), sirtuin 3 (SIRT3), and superoxide dismutase 2 was increased in specnuezhenide-treated mice with photoaging. CONCLUSION: Specnuezhenide protected against ultraviolet-induced skin photoaging in mice via a probable activation of SIRT3/OGG1 signal.
Assuntos
Sirtuína 3 , Envelhecimento da Pele , Camundongos , Animais , Sirtuína 3/metabolismo , Sirtuína 3/farmacologia , Pele/patologia , Raios Ultravioleta/efeitos adversosRESUMO
Microglia are immune cells in the brain that can respond to endogenous and exogenous substrates to elicit inflammatory reactions. The transcription factor nuclear factor kappa-light-chain-enhancer of activated B induces proinflammatory gene expression in response to foreign matter via pattern recognition receptors; thus, nuclear factor kappa-light-chain-enhancer of activated B is a master regulator of inflammation. During the inflammatory process, very large amounts of reactive oxygen species are generated and promote the onset and progression of inflammation. Interestingly, nuclear factor kappa-light-chain-enhancer of activated B drives the transcription of superoxide dismutase 2 in many types of cells, including microglia. Superoxide dismutase 2 is an antioxidative enzyme that catalyzes the dismutation of superoxide anions into molecular oxygen and hydrogen peroxide. Of note, nuclear factor kappa-light-chain-enhancer of activated B can initiate inflammation to elicit proinflammatory gene expression, while its transcription product superoxide dismutase 2 can suppress inflammation. In this review, we use recent knowledge to describe the interaction between oxidative stress and nuclear factor kappa-light-chain-enhancer of activated B and discuss the complicated role of microglial superoxide dismutase 2 in inflammation.
RESUMO
It is becoming increasingly evident that oxidative stress has a supporting role in pathophysiology and progression of primary open angle glaucoma (POAG). The aim of our study was to assess the association between polymorphisms in genes encoding enzymes involved in redox homeostasis, mitochondrial superoxide dismutase (SOD2), glutathione peroxidase (GPX1) and glutathione transferases (GSTs) with susceptibility to POAG. Single nucleotide polymorphisms in GST omega (GSTO1rs4925, GSTO2 rs156697), pi 1 (GSTP1 rs1695), as well as GPX1 (rs1050450) and SOD2 (rs4880) were determined by quantitative polymerase chain reaction (qPCR) in 102 POAG patients and 302 respective controls. The risk for POAG development was noted in carriers of both GSTO2*GG and GSTO1*AA variant genotypes (OR = 8.21, p = 0.002). Individuals who carried GPX1*TT and SOD2*CC genotypes had also an increased risk of POAG development but without significance after Bonferroni multiple test correction (OR = 6.66, p = 0.005). The present study supports the hypothesis that in combination, GSTO1/GSTO2, modulate the risk of primary open angle glaucoma.
Assuntos
Glaucoma de Ângulo Aberto/genética , Glutationa Peroxidase/genética , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Polimorfismo de Nucleotídeo Único/genética , Superóxido Dismutase/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Glaucoma de Ângulo Aberto/diagnóstico , Humanos , Pressão Intraocular/fisiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Glutationa Peroxidase GPX1RESUMO
BACKGROUND: Prenatal exposure to heavy metals is implicated in the etiology of birth defects. We investigated whether concentrations of cadmium (Cd) and lead (Pb) in umbilical cord tissue are associated with risk for neural tube defects (NTDs) and whether selected genetic variants of the fetus modify their associations. METHODS: This study included 166 cases of NTD fetuses/newborns and 166 newborns without congenital malformations. Umbilical cord tissue was collected at birth or elective pregnancy termination. Cd and Pb concentrations were assessed by inductively coupled plasma-mass spectrometry, and 20 single-nucleotide polymorphisms (SNPs) in 9 genes were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the risk for NTDs in association with metal concentrations or genotype using logistic regression. Multiplicative-scale interactions between the metals and genotypes on NTD risk were assessed with logistic regression, and additive-scale interactions were estimated with a non-linear mixed effects model. RESULTS: Higher concentrations of Cd were observed in the NTD group than in the control group, but no difference was found for Pb. Concentrations of Cd above the median level showed a risk effect, while the association between Pb and NTD risk was not significant in univariate analyses. The association of Cd was attenuated after adjusting for periconceptional folic acid supplementation. Fetuses with the AG and GG genotypes of rs4880 in SOD2 (superoxide dismutase 2) tended to have a lower risk, but fetuses with the CT and TT genotypes of rs1801133 in MTHFR (5,10-methylenetetrahydrofolatereductase) have a higher risk for NTDs when compared to their respective wild-type. rs4880 and Cd exhibited a multiplicative-scale interaction on NTD risk: the association between higher Cd and the risk for NTDs was increased by over fourfold in fetuses carrying the G allele [OR 4.43 (1.30-15.07)] compared to fetuses with the wild-type genotype. rs1801133 and Cd exposure showed an additive interaction, with a significant relative excess risk of interaction [RERI 0.64 (0.02-1.25)]. CONCLUSIONS: Prenatal exposure to Cd may be a risk factor for NTDs, and the risk effect may be enhanced in fetuses who carry the G allele of rs4880 in SOD2 and T allele of rs1801133 in MTHFR.
Assuntos
Cádmio/efeitos adversos , Poluentes Ambientais/efeitos adversos , Exposição Materna/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Defeitos do Tubo Neural/genética , Superóxido Dismutase/genética , Adulto , Cádmio/análise , Estudos de Casos e Controles , China/epidemiologia , Poluentes Ambientais/análise , Feminino , Feto , Genótipo , Humanos , Recém-Nascido , Chumbo/análise , Troca Materno-Fetal , Defeitos do Tubo Neural/epidemiologia , Polimorfismo de Nucleotídeo Único , GravidezRESUMO
Inflammasomes are powerful cytosolic sensors of environmental stressors and are critical for triggering interleukin-1 (IL-1)-mediated inflammatory responses. However, dysregulation of inflammasome activation may lead to pathological conditions, and the identification of negative regulators for therapeutic purposes is increasingly being recognized. Anakinra, the recombinant form of the IL-1 receptor antagonist, proved effective by preventing the binding of IL-1 to its receptor, IL-1R1, thus restoring autophagy and dampening NLR family pyrin domain containing 3 (NLRP3) activity. As the generation of mitochondrial reactive oxidative species (ROS) is a critical upstream event in the activation of NLRP3, we investigated whether anakinra would regulate mitochondrial ROS production. By profiling the activation of transcription factors induced in murine alveolar macrophages, we found a mitochondrial antioxidative pathway induced by anakinra involving the manganese-dependent superoxide dismutase (MnSOD) or SOD2. Molecularly, anakinra promotes the binding of SOD2 with the deubiquitinase Ubiquitin Specific Peptidase 36 (USP36) and Constitutive photomorphogenesis 9 (COP9) signalosome, thus increasing SOD2 protein longevity. Functionally, anakinra and SOD2 protects mice from pulmonary oxidative inflammation and infection. On a preclinical level, anakinra upregulates SOD2 in murine models of chronic granulomatous disease (CGD) and cystic fibrosis (CF). These data suggest that protection from mitochondrial oxidative stress may represent an additional mechanism underlying the clinical benefit of anakinra and identifies SOD2 as a potential therapeutic target.
Assuntos
Inflamassomos/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteínas Recombinantes/farmacologia , Superóxido Dismutase/metabolismo , Animais , Células Cultivadas , Fibrose Cística/etiologia , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Modelos Animais de Doenças , Doença Granulomatosa Crônica/etiologia , Doença Granulomatosa Crônica/metabolismo , Doença Granulomatosa Crônica/patologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Oxirredução , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Accurate prediction of the prognosis of RCC using a single biomarker is challenging due to the genetic heterogeneity of the disease. However, it is essential to develop an accurate system to allow better patient selection for optimal treatment strategies. ARL4C, ECT2, SOD2, and STEAP3 are novel molecular biomarkers identified in earlier studies as survival-related genes by comprehensive analyses of 43 primary RCC tissues and RCC cell lines. METHODS: To develop a prognostic model based on these multiple biomarkers, the expression of four biomarkers ARL4C, ECT2, SOD2, and STEAP3 in primary RCC tissue were semi-quantitatively investigated by immunohistochemical analysis in an independent cohort of 97 patients who underwent nephrectomy, and the clinical significance of these biomarkers were analyzed by survival analysis using Kaplan-Meier curves. The prognostic model was constructed by calculation of the contribution score to prognosis of each biomarker on Cox regression analysis, and its prognostic performance was validated. RESULTS: Patients whose tumors had high expression of the individual biomarkers had shorter cancer-specific survival (CSS) from the time of primary nephrectomy. The prognostic model based on four biomarkers segregated the patients into a high- and low-risk scored group according to defined cut-off value. This approach was more robust in predicting CSS compared to each single biomarker alone in the total of 97 patients with RCC. Especially in the 36 metastatic RCC patients, our prognostic model could more accurately predict early events within 2 years of diagnosis of metastasis. In addition, high risk-scored patients with particular strong SOD2 expression had a much worse prognosis in 25 patients with metastatic RCC who were treated with molecular targeting agents. CONCLUSIONS: Our findings indicate that a prognostic model based on four novel biomarkers provides valuable data for prediction of clinical prognosis and useful information for considering the follow-up conditions and therapeutic strategies for patients with primary and metastatic RCC.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Neoplasias Renais , Fatores de Ribosilação do ADP , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/cirurgia , Proteínas de Ciclo Celular , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/cirurgia , Nefrectomia , Oxirredutases , Prognóstico , Proteínas Proto-Oncogênicas , Medição de Risco , Superóxido DismutaseRESUMO
It is now accepted that nutrient abundance in the blood, especially glucose, leads to the generation of reactive oxygen species (ROS), ultimately leading to increased oxidative stress in a variety of tissues. In the absence of an appropriate compensatory response from antioxidant mechanisms, the cell, or indeed the tissue, becomes overwhelmed by oxidative stress, leading to the activation of intracellular stress-associated pathways. Activation of the same or similar pathways also appears to play a role in mediating insulin resistance, impaired insulin secretion, and late diabetic complications. The ability of antioxidants to protect against the oxidative stress induced by hyperglycemia and elevated free fatty acid (FFA) levels in vitro suggests a causative role of oxidative stress in mediating the latter clinical conditions. In this review, we describe common biochemical processes associated with oxidative stress driven by hyperglycemia and/or elevated FFA and the resulting clinical outcomes: ß-cell dysfunction and peripheral tissue insulin resistance.
Assuntos
Metabolismo Energético/fisiologia , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Estresse Oxidativo/fisiologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Impaired autophagy and oxidative stress are implicated in the development of many diseases. This study aimed to investigate the involvement of autophagy represented by autophagy-related gene 7 (Atg7) and oxidative stress represented by superoxide dismutase 2 (SOD2) gene expression and enzyme activity in the pathogenesis of osteoporosis. Atg7 and SOD2 gene relative expression were evaluated by SYBR green quantitative real-time-polymerase chain reaction in the osteoporotic group (n = 26) versus the osteoporosis free group (n = 14). SOD2 enzyme activity was evaluated by colorimetric method in both study groups. Both Atg7 and SOD2 relative expression showed highly significant decrease (P < 0.01) between both groups. However, SOD2 enzyme activity showed no significant difference between the two groups. There was a significant direct correlation between Atg7 and SOD2 gene expression in both study groups. Atg7 relative expression showed significant ( P < 0.01) direct correlation with vitamin D serum levels and body mass index in osteoporotic group. In conclusion, both genes are involved in the pathogenesis of osteoporosis and this could be amenable to future therapeutic intervention.
RESUMO
Toll-like receptors (TLRs) play critical roles in host defense after recognition of conserved microbial- and host-derived components, and their dysregulation is a common feature of various inflammation-associated cancers, including gastric cancer (GC). Despite the recent recognition that metabolic reprogramming is a hallmark of cancer, the molecular effectors of altered metabolism during tumorigenesis remain unclear. Here, using bioenergetics function assays on human GC cells, we reveal that ligand-induced activation of TLR2, predominantly through TLR1/2 heterodimer, augments both oxidative phosphorylation (OXPHOS) and glycolysis, with a bias toward glycolytic activity. Notably, DNA microarray-based expression profiling of human cancer cells stimulated with TLR2 ligands demonstrated significant enrichment of gene-sets for oncogenic pathways previously implicated in metabolic regulation, including reactive oxygen species (ROS), p53 and Myc. Moreover, the redox gene encoding the manganese-dependent mitochondrial enzyme, superoxide dismutase (SOD)2, was strongly induced at the mRNA and protein levels by multiple signaling pathways downstream of TLR2, namely JAK-STAT3, JNK MAPK and NF-κB. Furthermore, siRNA-mediated suppression of SOD2 ameliorated the TLR2-induced metabolic shift in human GC cancer cells. Importantly, patient-derived tissue microarrays and bioinformatics interrogation of clinical datasets indicated that upregulated expression of TLR2 and SOD2 were significantly correlated in human GC, and the TLR2-SOD2 axis was associated with multiple clinical parameters of advanced stage disease, including distant metastasis, microvascular invasion and stage, as well as poor survival. Collectively, our findings reveal a novel TLR2-SOD2 axis as a potential biomarker for therapy and prognosis in cancer.
Assuntos
Neoplasias Gástricas/metabolismo , Superóxido Dismutase/metabolismo , Receptor 2 Toll-Like/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Reprogramação Celular/fisiologia , Metabolismo Energético , Indução Enzimática , Glicólise , Humanos , Imuno-Histoquímica , Fosforilação Oxidativa , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologia , Análise Serial de Tecidos , Regulação para CimaRESUMO
PURPOSE: To investigate the relationship between superoxide dismutase 2 (SOD2) A16V and paraoxonase 2 (PON2) S311C gene variants and the risk of polycystic ovary syndrome (PCOS) and evaluate the effects of the genotypes on clinical, hormonal, metabolic and oxidative stress indexes in Chinese women. METHODS: This is a cross-sectional study of 932 patients with PCOS and 745 control women. For the clinical and metabolic association study of genotypes, 631 patients and 492 controls were included after excluding the subjects with interferential factors. Genotypes were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis. Serum total oxidant status, total antioxidant capacity (T-AOC), oxidative stress index and malondialdehyde (MDA) levels, and clinical and metabolic parameters were also analyzed. RESULTS: The prevalence of the A allele of SOD2 A16V polymorphism was significantly greater in patients with PCOS than in control subjects. Genotype (AA + AV) remained a significant predictor for PCOS in prognostic models including age, body mass index, insulin resistance index, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TGs) as covariates. Patients carrying the A allele had significantly higher serum luteinizing hormone (LH) levels, and the ratio of LH to follicle-stimulating hormone compared with patients with the VV genotype. We also showed that patients carrying the C allele of the PON2 S311C polymorphism had lower T-AOC compared with patients carrying the SS genotype. However, no significant differences were observed in the frequencies of the S311C genotypes and alleles of the PON2 gene between PCOS and control groups. CONCLUSION: The SOD2 A16V, but not PON2 S311C, polymorphism may be one of the genetic determinants for PCOS in Chinese women.
Assuntos
Arildialquilfosfatase/genética , Povo Asiático/genética , Biomarcadores/análise , Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único , Superóxido Dismutase/genética , Adolescente , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , China/epidemiologia , Estudos Transversais , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Resistência à Insulina , Síndrome do Ovário Policístico/epidemiologia , Síndrome do Ovário Policístico/patologia , Prognóstico , Adulto JovemRESUMO
Hyperoxia-induced oxidative stress contributes to the pathogenesis of bronchopulmonary dysplasia (BPD), the most common respiratory morbidity of preterm infants. Importantly, the disease lack specific therapies and is associated with long-term cardio-pulmonary and neurodevelopmental morbidities, signifying the need to discover novel therapies and decrease the disease burden. We and others have demonstrated that leflunomide, a food and drug administration approved drug to treat humans with rheumatoid arthritis, increases the expression of the anti-oxidant enzymes, NAD(P)H quinone dehydrogenase 1 (NQO1), catalase, and superoxide dismutase (SOD). However, whether this drug can decrease oxidative stress in fetal human pulmonary arterial endothelial cells (HPAECs) is unknown. Therefore, we tested the hypothesis that leflunomide will decrease hyperoxia-induced oxidative stress by upregulating these anti-oxidant enzymes in HPAECs. Leflunomide decreased hydrogen peroxide (H2O2) levels and increased the mRNA and protein levels of catalase, NQO1, and SOD2 in HPAECs at basal conditions. Further, leflunomide-treated cells continued to have decreased H2O2 and increased SOD2 levels upon hyperoxia exposure. Leflunomide did not affect the expression of other anti-oxidant enzymes, including hemoxygenase-1 and SOD1. AhR-knockdown experiments suggested that leflunomide regulated NQO1 levels via AhR-dependent mechanisms and H2O2, catalase, and SOD2 levels via AhR-independent mechanisms. Collectively, the results support the hypothesis that leflunomide decreases oxidative stress in HPAECs via SOD2-and catalase-dependent, but AhR- and NQO1-independent mechanisms. Our findings indicate that leflunomide is a potential drug for the management of BPD in preterm infants.
Assuntos
Catalase/metabolismo , Células Endoteliais/efeitos dos fármacos , Feto/citologia , Leflunomida/farmacologia , Pulmão/citologia , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Humanos , Peróxido de Hidrogênio/análise , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Intravenous administration of bone marrow-derived mesenchymal stem cells (BM-MSCs) has been shown to promote nerve cell regeneration following traumatic brain injury (TBI). As the anti-oxidant defense systems in neuronal tissue including superoxide dismutase 2 (SOD2) are crucial to defend cell against oxidative stress. We proposed a new stratege to increase the therapeutic effect of MSCs by preventing cells death from oxidative stress. We overexpressed SOD2 in BM-MSCs, transplanted these MSCs into TBI model mice, assessed the protective effect of SOD2 against oxidation-induced apoptosis in BM-MSCs both in vitro and in vivo, evaluated brain functional recovery by the rotarod behavioral test, and tested the oxidation status of TBI mice brain after BM-MSCs transplantation by monitoring the superoxide dismutase, glutathione and malonaldehyde level. We found over-expression of SOD2 protected BM-MSCs from H2O2-induced cell apoptosis. Injection of SOD2 over-expressed BM-MSCs attenuated neuro-inflammation in the ipsilateral cortex of TBI mice, and protected TBI mice against loss of blood-brain barrier integrity. Furthermore, the rotarod behavioral test showed functional recovery of TBI mice after MSC treatment. Our experiments indicated that SOD2-over-expressed BM-MSCs have an improved therapeutic effect on brain injury treatment in TBI mice.