RESUMO
This study investigated hepatic oxidative damage in rats following long-term manganese (Mn) exposure and clarified the underlying mechanisms. Forty-eight rats (SPF, male) were randomly assigned to receive low (10 mg/kg, n = 16) or high doses of Mn (50 mg/kg, n = 16) or sterilized distilled water (control group, n = 16). Rats were euthanized after 12 months, and liver Mn levels and histopathological changes were determined. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver malondialdehyde (MDA), glutathione peroxidase (GSH-PX), nuclear factor E2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinine oxidoreductase-1 (NQO1) levels were also determined. The Mn concentration and relative liver weights were significantly higher in the high-dose Mn group than in the control and low-dose Mn exposure groups. Low-dose Mn exposure resulted in mild expansion of hepatic sinuses and intact nuclei, whereas high-dose exposure led to pathological alterations in hepatocytes. High-dose Mn treatment significantly increased AST, ALT, and MDA activities and decreased GSH-PX activity. Additionally, liver Nrf2, HO-1, and NQO1 protein expression were markedly reduced by Mn exposure. Under the study conditions, long-term low-dose Mn exposure resulted in slight pathological changes in liver structure, but high-dose Mn exposure affected both liver structure and function, which might be related to the inhibition of Nrf2 expression, suppression of the transcription of its underlying antioxidant genes, and down regulation of the corresponding proteins. Consequently, the antioxidant capacity in the rat liver was weakened.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Manganês/sangue , Manganês/toxicidade , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Relação Dose-Resposta a Droga , Glutationa Peroxidase/sangue , Heme Oxigenase-1/sangue , Masculino , Malondialdeído/sangue , NAD(P)H Desidrogenase (Quinona)/sangue , Ratos , Ratos Sprague-DawleyRESUMO
Necrotizing soft-tissue infection (NSTI) is a rare, severe, and fast-progressing bacterial infection associated with a high risk of developing sepsis or septic shock. Increasing evidence indicates that oxidative stress is crucial in the development and progression of sepsis, but its role in NSTI specifically has not been investigated. Some patients with NSTI receive hyperbaric oxygen (HBO2) treatment as the restoration of oxidative stress balance is considered an important mechanism of action, which HBO2 facilitates. However, a gap in knowledge exists regarding the effect of HBO2 treatment on oxidative stress in patients with NSTI. In the present observational study, we aimed to investigate HBO2 treatment effects on known markers of oxidative stress in patients with NSTI. We measured plasma myeloperoxidase (MPO), superoxide dismutase (SOD), heme oxygenase-1 (HO-1) and nitrite+nitrate in 80 patients with NSTI immediately before and after their first HBO2 treatment, and on the following day. We found that HBO2 treatment was associated with a significant increase in MPO and SOD by a median of 3.4 and 8.8 ng/mL, respectively. Moreover, we observed an HBO2 treatment-associated increase in HO-1 in patients presenting with septic shock (n=39) by a median of 301.3 pg/mL. All markers were significantly higher in patients presenting with septic shock compared to patients without shock, and all markers correlated with disease severity. High baseline SOD was associated with 90-day mortality. In conclusion, HBO2 treatment was associated with an increase in MPO and SOD in patients with NSTI, and oxidative stress was more pronounced in patients with septic shock.
Assuntos
Oxigenoterapia Hiperbárica , Estresse Oxidativo , Choque Séptico , Infecções dos Tecidos Moles , Biomarcadores , Heme Oxigenase-1/sangue , Humanos , Necrose , Oxigênio , Peroxidase/sangue , Choque Séptico/terapia , Infecções dos Tecidos Moles/terapia , Superóxido Dismutase/sangueRESUMO
BACKGROUND AND OBJECTIVES: Oxidative stress is a hallmark and mediator of CKD. Diminished antioxidant defenses are thought to be partly responsible. However, there is currently no way to prospectively assess antioxidant defenses in humans. Tin protoporphyrin (SnPP) induces mild, transient oxidant stress in mice, triggering increased expression of select antioxidant proteins (e.g., heme oxygenase 1 [HO-1], NAD[P]H dehydrogenase [quinone] 1 [NQO1], ferritin, p21). Hence, we tested the hypothesis that SnPP can also variably increase these proteins in humans and can thus serve as a pharmacologic "stress test" for gauging gene responsiveness and antioxidant reserves. DESIGN: , setting, participants, & measurementsA total of 18 healthy volunteers and 24 participants with stage 3 CKD (n=12; eGFR 30-59 ml/min per 1.73 m2) or stage 4 CKD (n=12; eGFR 15-29 ml/min per 1.73 m2) were injected once with SnPP (9, 27, or 90 mg). Plasma and/or urinary antioxidant proteins were measured at baseline and for up to 4 days post-SnPP dosing. Kidney safety was gauged by serial measurements of BUN, creatinine, eGFR, albuminuria, and four urinary AKI biomarkers (kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, cystatin C, and N-acetyl glucosaminidase). RESULTS: Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (r=-0.85 to -0.95). All four proteins manifested statistically significant dose- and time-dependent elevations after SnPP injection. However, marked intersubject differences were observed. p21 responses to high-dose SnPP and HO-1 responses to low-dose SnPP were significantly suppressed in participants with CKD versus healthy volunteers. SnPP was well tolerated by all participants, and no evidence of nephrotoxicity was observed. CONCLUSIONS: SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.
Assuntos
Testes de Função Renal , Metaloporfirinas/administração & dosagem , Estresse Oxidativo , Protoporfirinas/administração & dosagem , Insuficiência Renal Crônica/diagnóstico , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Estudos de Casos e Controles , Inibidor de Quinase Dependente de Ciclina p21/sangue , Inibidor de Quinase Dependente de Ciclina p21/urina , Feminino , Ferritinas/sangue , Ferritinas/urina , Taxa de Filtração Glomerular , Heme Oxigenase-1/sangue , Heme Oxigenase-1/urina , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/sangue , NAD(P)H Desidrogenase (Quinona)/urina , Valor Preditivo dos Testes , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/urinaRESUMO
Psoriasis is an autoimmune skin disease characterized by hyperproliferation of keratinocytes due to interplay between keratinocytes and immune cells. Iron status plays an important role in modifying the function of the immune system. Heme oxygenase (HO), heme-degrading enzyme, plays important role in protective response to oxidative cellular stress. We aimed in this study to map the iron status and HO levels and declare the role HO enzyme in iron homeostasis and immune-modulation in psoriasis. Fifty-one patients with psoriasis and 50 age- and sex-matched healthy controls were enrolled in this study. 5 mL blood sample was withdrawn from each subject. Hepcidin, iron soluble transferring receptor (sTfR), and total iron binding capacity (TIBC) were estimated using ELISA technique and, HO-1 gene level was detected using RT-PCR (reverse transcription-polymerase chain reaction). Iron levels, TIBC, and hepcidin were significantly lower in cases compared to controls. On the contrary, sTfR and HO-1 were significantly over-expressed in cases compared to controls (p < 0.05 in all). HO-1 expression negatively correlated with PASI score and disease extent (%) (r = - 0.614-, p = 0.001; r = - 0.807-, p = 0.001 respectively). There were no significant associations between HO-1 expression and iron, TIBC, hepcidin, sTfR levels (p > 0.05 in all). Iron supplements for the patients with psoriasis are important to maintain haematopoiesis. The induction of HO-1 might have be a promising approach for the treatment of psoriasis through antioxidant ability, immunomodulatory role as well as its role in heme synthesis.
Assuntos
Exossomos/enzimologia , Heme Oxigenase-1/sangue , Ferro/sangue , Psoríase/enzimologia , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Heme Oxigenase-1/genética , Hepcidinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/sangue , Psoríase/diagnóstico , Psoríase/genética , Receptores da Transferrina/sangue , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Umbilical cord blood (UCB) is in contact with all the fetal tissues and can reflect the state of fetus and UCB can be compared with maternal blood. Inflammatory, metabolic and immunological disorders during pregnancy can affect the environment in which the fetus is developing and may produce various alterations. OBJECTIVE: To analyze different biochemical parameters in maternal venous blood and new born umbilical cord blood from healthy normotensive pregnant and preeclamptic women. MATERIALS AND METHODS: Homocysteine, folate, B12, heme oxygenase-1 (HO-1), endoglin, leptin, cholinesterase, IGF-1, Apo A, lipoproteins, TSH, fT3, fT4 were analyzed in maternal sera and venous umbilical cord sera of newborns of twenty five preeclamptics (group II) and twenty five normotensive pregnant women (group I). Homocysteine, folic acid, vitamin B12, Apo A I & II, TSH, fT3, fT4 levels were estimated by competitive immunoassay using direct chemiluminiscence technology. Heme oxygenase-1 (HO-1), endoglin, leptin, cholinesterase, IGF-1 were analyzed by ELISA. RESULTS: Maternal and cord blood levels of homocysteine, folic acid, lipid profile (namely, total cholesterol, triglycerides, LDL-C, VLDL-C and HDL-C), TSH, heme oxygenase 1, were higher in preeclamptic women as compared to normotensive pregnant women. Endoglin levels were significantly lower in cord blood of preeclamptic mother as compared to normotensive mothers. Serum and cord blood vitamin B12, Apo A-I and Apo B l, cholinesterase, leptin levels, IGF-I were lower in preeclamptic women as compared to normotensive pregnant. CONCLUSION: Findings of the present study suggest that biochemical alterations occur in mothers and fetuses and modifications of uterine environment (in terms of thyroxine and folate and vitamin B12 supplementation) can be of help.
Assuntos
Sangue Fetal/química , Pré-Eclâmpsia/sangue , Apoproteína(a)/sangue , Biomarcadores/sangue , Feminino , Ácido Fólico/sangue , Heme Oxigenase-1/sangue , Homocisteína/sangue , Humanos , Recém-Nascido , Lipídeos/sangue , Gravidez , Hormônios Tireóideos/sangue , Tireotropina/sangue , Vitamina B 12/sangueRESUMO
Reseda odorata L. has long been used in traditional Asian medicine for the treatment of diseases associated with oxidative injury and acute inflammation, such as endotoxemia, acute lung injury, acute myocardial infarction and hepatitis. Luteolin, the main component of Reseda odorata L., which is also widely found in many natural herbs and vege-tables, has been shown to induce heme oxygenase-1 (HO-1) expression to exert anti-inflammatory and antioxidant effects. In this study, we aimed to examine the effects of luteolin on mice with severe acute pancreatitis (SAP), and to explore the underlying mechanisms. Cerulein and lipopolysaccharide were used to induce SAP in male Institute of Cancer Research (ICR) mice in the SAP group. The SAP group was divided into 4 subgroups, as follows: the vehicle, luteolin, zinc protoporphyrin (ZnPP) only, and luteolin (Lut) + ZnPP (luteolin plus zinc protoporphyrin treatment) groups. The wet/dry weight ratios, hematoxylin and eosin staining and pathological scores of pancreatic tissues were assessed and compared to those of the control mice. Amylase, lipase, nuclear factor-κB (NF-κB) and myeloperoxidase activities, and malondialdehyde, tumor necrosis factor α (TNFα), interleukin (IL)-6, IL-10 and HO-1 levels, as well as the expression of HO-1 were determined in serum and/or pancreatic tissue samples. SAP was successfully induced in male mice compared to normal control mice. The wet/dry weight ratios, pathological scores, and amylase and lipase activity, as well as the levels of TNFα and IL-6 were significantly reduced in the pancreatic tissues of the mice in the Lut group compared with those of the mice in the vehicle group. The Lut group exhibited a significant increase in HO-1 expression in the pancreas and enhanced serum HO-1 and IL-10 levels compared with the vehicle group. The suppression of HO-1 activity in the ZnPP group significantly abolished the protective effects of luteolin. NF-κB expression in the pancreatic tissues from the mice in the Lut + ZnPP group was significantly increased following the suppression of HO-1 activity. On the whole, our findings demonstrate that luteolin protects mice from SAP by inducing HO-1-mediated anti-inflammatory and antioxidant activities, in association with the suppression of the activation of the NF-κB pathway.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Heme Oxigenase-1/metabolismo , Luteolina/uso terapêutico , Pancreatite/tratamento farmacológico , Pancreatite/enzimologia , Substâncias Protetoras/uso terapêutico , Doença Aguda , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Ceruletídeo , Cromatografia Líquida de Alta Pressão , Citocinas/sangue , Citocinas/metabolismo , Heme Oxigenase-1/sangue , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Luteolina/farmacologia , Masculino , Camundongos Endogâmicos ICR , Modelos Biológicos , NF-kappa B/metabolismo , Necrose , Pâncreas/efeitos dos fármacos , Pâncreas/enzimologia , Pâncreas/patologia , Pancreatite/sangue , Substâncias Protetoras/farmacologia , Protoporfirinas/farmacologia , Protoporfirinas/uso terapêuticoRESUMO
High blood pressure is the most powerful contributor to the cardiovascular morbidity and mortality, and inverse correlation between consumption of polyphenol-rich foods or beverages and incidence of cardiovascular diseases gains more importance. Reactive oxygen species plays an important role in the development of hypertension. We found that wild thyme (a spice plant, rich in polyphenolic compounds) induced a significant decrease of blood pressure and vascular resistance in hypertensive rats. The inverse correlation between vascular resistance and plasma heme oxygenase-1 suggests that endogenous vasodilator carbon monoxide generated by heme oxidation could account for this normalization of blood pressure. Next product of heme oxidation, bilirubin (a chain-breaking antioxidant that acts as a lipid peroxyl radical scavenger), becomes significantly increased after wild thyme treatment and induces the reduction of plasma lipid peroxidation in hypertensive, but not in normotensive rats. The obtained results promote wild thyme as useful supplement for cardiovascular interventions.
Assuntos
Heme Oxigenase-1/sangue , Hipertensão/prevenção & controle , Thymus (Planta)/química , Animais , Antioxidantes/química , Bilirrubina/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Catalase/metabolismo , Ensaio de Imunoadsorção Enzimática , Eritrócitos/enzimologia , Eritrócitos/metabolismo , Glutationa Peroxidase/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Heme Oxigenase-1/análise , Hemodinâmica/efeitos dos fármacos , Hipertensão/metabolismo , Rim/enzimologia , Rim/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Endogâmicos SHR , Superóxido Dismutase/metabolismo , Thymus (Planta)/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
The incidence of liver cancer is higher in men than in women. This sex difference is also observed in murine tumor induction models that result in the appearance of liver tumors in adult mice following their exposure on postnatal days 8 and/or 15 to carcinogens such as 4-aminobiphenyl (ABP) or diethylnitrosamine (DEN). Previous studies performed in adult mice showed that acute hepatotoxic and inflammatory responses to high-dose DEN exposure were greater in males than in females, leading to the suggestion that these responses could account for the sex difference in tumor development. We also recently observed that female but not male mice exposed postnatally to ABP had slightly increased expression of the antioxidant defense genes Nqo1 and Ggt1, which are regulated by the oxidative stress response protein nuclear factor erythroid 2-related factor 2 (NRF2), while expression of Hmox1 was increased in both sexes. The goal of the present study was therefore to compare selected acute hepatotoxic, inflammatory and oxidative stress defense responses to ABP, DEN, or the prototype hepatotoxicant carbon tetrachloride (CCl4), in male and female mice exposed to these chemicals either postnatally or as adults. Exposure of adult mice to ABP, DEN or CCl4 produced a 2-fold greater acute elevation in serum levels of the hepatotoxicity biomarker alanine aminotransferase (ALT) in males than in females, while levels of the inflammatory biomarker interleukin-6 (IL-6) showed no sex difference. However, treatment of immature mice with either ABP or DEN using standard tumor-inducing postnatal exposure protocols produced no increase in serum ALT or IL-6 levels in either males or females, while CCl4 produced a 40-fold ALT elevation but with no sex difference. Basal expression of the NRF2-responsive gene Nqo1 was higher in adult females than in males, but there was no sex difference in basal expression of Ggt1 or Hmox1. Sexually immature animals showed no sex difference in basal expression of any of the three genes. Postnatal DEN exposure modestly increased the expression of Ggt1 only in male mice and Nqo1 in both sexes, while CCl4 slightly increased expression of Ggt1 in both males and females and Nqo1 only in females. Taken together, our results make it unlikely that acute hepatotoxic, inflammatory or NRF2-activated gene responses account for the male predominance in liver tumor growth following postnatal carcinogen exposure in mice. Our findings also suggest that acute toxicity studies performed in adult mice should be interpreted with caution when extrapolating potential mechanisms to liver carcinogenesis models that commonly use postnatally exposed mice.
Assuntos
Carcinógenos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Envelhecimento/fisiologia , Alanina Transaminase/sangue , Compostos de Aminobifenil/toxicidade , Animais , Animais Recém-Nascidos , Tetracloreto de Carbono/toxicidade , Dano ao DNA/efeitos dos fármacos , Dietilnitrosamina/toxicidade , Feminino , Heme Oxigenase-1/sangue , Interleucina-6/sangue , Masculino , Proteínas de Membrana/sangue , Camundongos , Camundongos Endogâmicos C57BL , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Caracteres SexuaisRESUMO
In the present study, we investigated the effects of sour cherry seed extract (SCSE) on a variety of systemic processes that contribute to general health and viability of human subjects. The experiments were conducted according to a double-blind protocol in which six healthy individuals were administered 250-mg/day SCSE for 14 days, while four were treated with placebo. Peripheral blood was collected before and after the treatment period. Samples were analyzed for levels of selected cells, enzymes, or metabolites. Subjects that received SCSE showed increases in the values of mean cell volume, serum transferrin, mean peroxidase index, and representation of peripheral blood lymphocytes. On the other hand, decreases were observed in circulating neutrophils and ferritin levels. Changes observed in the present study do not fit into a clear pattern that might yield additional in-depth understanding of SCSE-mediated alterations in physiologic responses. The most encouraging result of the present study is the absence of any indication of toxicity by subjects consuming the extract.
Assuntos
Extratos Vegetais/farmacologia , Prunus/química , Sementes/química , Adulto , Tamanho Celular , Método Duplo-Cego , Feminino , Ferritinas/sangue , Voluntários Saudáveis , Testes Hematológicos , Heme Oxigenase-1/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Peroxidase/química , Transferrina/químicaRESUMO
SCOPE: Sulforaphane (SFN), an isothiocyanate derived from crucifers, has numerous health benefits. SFN bioavailability from dietary sources is a critical determinant of its efficacy in humans. A key factor in SFN absorption is the release of SFN from its glucosinolate precursor, glucoraphanin, by myrosinase. Dietary supplements are used in clinical trials to deliver consistent SFN doses, but myrosinase is often inactivated in available supplements. We evaluated SFN absorption from a myrosinase-treated broccoli sprout extract (BSE) and are the first to report effects of twice daily, oral dosing on SFN exposure in healthy adults. METHODS AND RESULTS: Subjects consumed fresh broccoli sprouts or the BSE, each providing 200 µmol SFN daily, as a single dose and as two 100-µmol doses taken 12 h apart. Using HPLC-MS/MS, we detected â¼3 x higher SFN metabolite levels in plasma and urine of sprout consumers, indicating enhanced SFN absorption from sprouts. Twelve-hour dosing retained higher plasma SFN metabolite levels at later time points than 24-hour dosing. No dose responses were observed for molecular targets of SFN (i.e. heme oxygenase-1, histone deacetylase activity, p21). CONCLUSION: We conclude that the dietary form and dosing schedule of SFN may impact SFN absorption and efficacy in human trials.
Assuntos
Anticarcinógenos/farmacologia , Brassica/química , Glicosídeo Hidrolases/química , Isotiocianatos/farmacologia , Adulto , Anticarcinógenos/farmacocinética , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/sangue , Heme Oxigenase-1/genética , Histona Desacetilases/sangue , Humanos , Absorção Intestinal , Isotiocianatos/administração & dosagem , Isotiocianatos/farmacocinética , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Extratos Vegetais/farmacologia , Sulfóxidos , Adulto JovemRESUMO
BACKGROUND: Heme oxygenase-1 (HO-1) has been shown to have antioxidant and anti-apoptotic properties. The present study transduced HO-1 protein into intestinal tissues using PEP-1, a cell-penetrating peptide, and investigated its potentiality in prevention against intestinal ischemia/reperfusion (I/R) injury. MATERIALS AND METHODS: PEP-1-HO-1 fusion protein was administered intravenously to explore the time and dose characteristics through measuring serum HO-1 levels. Twenty-four male Sprague-Dawley rats were randomly divided into three groups: sham, intestinal I/R (II/R), II/R + PEP-1-HO-1 fusion protein (HO). The model was established by occluding the superior mesenteric artery for 45 min followed by 120 min reperfusion. In HO group, PEP-1-HO-1 was administered intravenously 30 min before ischemia, whereas animals in sham and II/R groups received the equal volume of physiological saline. After the experiment, the intestines were harvested for determination of histologic injury, wet/dry ratio, enzyme activity, apoptosis, and His-probe protein (one part of PEP-1-HO-1). RESULTS: Levels of serum HO-1 were dose- and time-dependent manner after intravenous injection of PEP-1-HO-1. I/R caused deterioration of histologic characteristics and increases in histologic injury scoring, wet/dry ratio, myeloperoxidase activity, malondialdehyde, and intestinal apoptosis. These changes were also accompanied by a decrease in superoxide dismutase activity (P < 0.05). PEP-1-HO-1 treatment significantly reversed these changes (P < 0.05). Furthermore, His-probe protein expression was only detected in PEP-1-HO-1-treated animals. CONCLUSION: Treatment of PEP-1-HO-1 attenuates intestinal I/R injury, which might be attributable to its antioxidant and anti-apoptotic roles of HO-1.
Assuntos
Heme Oxigenase-1/sangue , Heme Oxigenase-1/genética , Intestinos/irrigação sanguínea , Proteínas Recombinantes de Fusão/sangue , Proteínas Recombinantes de Fusão/genética , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Injeções Intravenosas , Intestinos/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Tamanho do Órgão , Peroxidase/metabolismo , Fenóis/sangue , Extratos Vegetais/sangue , Extratos Vegetais/genética , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologiaRESUMO
BACKGROUND: A previous case study showed that Guasha, an ancient manual therapeutic technique, could exert hepatoprotective effect in a human chronic active hepatitis B carrier (active-CHB) by modulating the liver enzymes, cytokines, and heme oxygenase-1 (HO-1). The present study serves as a control to the aforementioned case report. The controls were chronic inactive carriers (inactive-CHB) and noncarriers of hepatitis B (NCs). Besides showing a difference in biochemical markers between controls and the previously reported active-CHB case, the asymptomatic condition in both inactive- and active-CHB offers an excellent control for the patient's expectation about Guasha's efficacy. The purpose of this case study was to investigate whether hepatoprotective biochemical markers previously measured in active-CHB in response to Guasha were also present in controls. PARTICIPANTS AND METHODS: Four inactive-CHB and nine NC participants were included. Each participant received a 15-minute Guasha treatment. Blood samples were obtained immediately before Guasha (day 0) and after Guasha (days 2, 5, and 7). Biochemistry values for liver function, HO-1, and T-helper (Th) cytokines were determined from blood tests. Neither the participants nor the investigator who administered Guasha were aware of the blood test results until after all data were collected for all participants. RESULTS: In both inactive-CHB and NC participants, liver function, serum HO-1, and Th1/Th2 cytokines did not significantly differ before and after Guasha. CONCLUSIONS: In contrast to results in active-CHB patients, Guasha did not induce any significant modulation of liver enzymes, HO-1, or cytokines in inactive-CHB and NC participants. The current results suggest that a Guasha-induced hepatoprotective effect depends on the inflammatory event or clinical stage of chronic hepatitis B. Because both active and inactive carriers were completely unaware of their liver status at the time of receiving Guasha, the research protocol is effective in discounting the model that attributes the Guasha therapeutic efficacy to a placebo effect due to participants' expectations.
Assuntos
Hepatite B Crônica/terapia , Medicina Tradicional Chinesa , Manipulações Musculoesqueléticas/métodos , Biomarcadores/sangue , Portador Sadio , Citocinas/sangue , Feminino , Heme Oxigenase-1/sangue , Humanos , Testes de Função Hepática , Masculino , Resultado do TratamentoRESUMO
Oxidative stress is involved in the chronic pathological vascular remodelling of both abdominal aortic aneurysm and occlusive atherosclerosis. Red blood cells (RBCs), leukocytes and platelets present in both, aneurysmal intraluminal thrombus and intraplaque haemorraghes, could be involved in the redox imbalance inside diseased arterial tissues. RBCs haemolysis may release the pro-oxidant haemoglobin (Hb), which transfers heme to tissue and low-density lipoproteins. Heme-iron potentiates molecular, cell and tissue toxicity mediated by leukocytes and other sources of reactive oxygen species (ROS). Polymorphonuclear neutrophils release myeloperoxidase and, along with activated platelets, produce superoxide mediated by NADPH oxidase, causing oxidative damage. In response to this pro-oxidant milieu, several antioxidant molecules of plasma or cell origin can prevent ROS production. Free Hb binds to haptoglobin (Hp) and once Hp-Hb complex is endocytosed by CD163, liberated heme is converted into less toxic compounds by heme oxygenase-1. Iron homeostasis is mainly regulated by transferrin, which transports ferric ions to other cells. Transferrin-bound iron is internalised via endocytosis mediated by transferrin receptor. Once inside the cell, iron is mainly stored by ferritin. Other non hemo-iron related antioxidant enzymes (e.g. superoxide dismutase, catalase, thioredoxin and peroxiredoxin) are also involved in redox modulation in vascular remodelling. Oxidative stress is a main determinant of chronic pathological remodelling of the arterial wall, partially linked to the presence of RBCs, leukocytes, platelets and oxidised fibrin within tissue and to the imbalance between pro-/anti-oxidant molecules. Understanding the complex mechanisms underlying redox imbalance could help to define novel potential targets to decrease atherothrombotic risk.
Assuntos
Plaquetas/metabolismo , Eritrócitos/metabolismo , Leucócitos/metabolismo , Estresse Oxidativo , Animais , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Antioxidantes/uso terapêutico , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Catalase/sangue , Terapia por Quelação , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Haptoglobinas/metabolismo , Heme/metabolismo , Heme Oxigenase-1/sangue , Humanos , Ferro/sangue , Peroxidase/sangue , Peroxirredoxinas/sangue , Ativação Plaquetária , Espécies Reativas de Oxigênio/metabolismo , Receptores de Superfície Celular/sangue , Explosão Respiratória , Superóxido Dismutase/sangue , Tiorredoxinas/sangueRESUMO
Rhabdomyolysis (RM) caused by severe burn releases extracellular myoglobin (Mb) that accumulates in the kidney. Extracellular Mb is a pro-oxidant. This study tested whether supplementation with tert-butyl-bisphenol (BP) or vitamin E (Vit E, as α-tocopherol) at 0.12% w/w in the diet inhibits acute renal failure (ARF) in an animal model of RM. After RM-induction in rats, creatinine clearance decreased (p < 0.01), proteinuria increased (p < 0.001) and renal-tubule damage was detected. Accompanying ARF, biomarkers of oxidative stress (lipid oxidation and hemeoxygenase-1 (HO-1) gene and protein activity) increased in the kidney (p < 0.05). Supplemented BP or Vit E decreased lipid oxidation (p < 0.05) and HO-1 gene/activity and restored aortic cyclic guanylyl monophosphate in control animals (p < 0.001), yet ARF was unaffected. Antioxidant supplementation inhibited oxidative stress, yet was unable to ameliorate ARF in this animal model indicating that oxidative stress in kidney and vascular cells may not be causally related to renal dysfunction elicited by RM.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Antioxidantes/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Fenóis/uso terapêutico , Rabdomiólise/tratamento farmacológico , alfa-Tocoferol/uso terapêutico , Injúria Renal Aguda/enzimologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/genética , Animais , Creatinina/sangue , Modelos Animais de Doenças , Heme Oxigenase-1/sangue , Peroxidação de Lipídeos , Masculino , Mioglobina/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/sangue , Espécies Reativas de Oxigênio/metabolismo , Rabdomiólise/complicaçõesRESUMO
OBJECTIVE: To explore the pharmacological mechanism of Realgar by the way of studying the effects of Realgar and the prescription containing Realgar named Niuhuang Jiedu Tablet on stress response proteins (heat shock protein 70, HSP70 and heme oxygenase-1, HO-1), inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha), activities of nitric oxide synthetase (NOS) and its isoenzyme (inducible nitric oxide synthetase, iNOS), and complements C3, CA under pathologic status (fever model). METHODS: SD rats were randomly divided into four groups, 15 rats in each: untreated normal group, fever model group, Realgar (90 mg/kg) group and Niuhuang Jiedu Tablet (NJT, 1.404 g/kg) group. Each group was divided into three subgroups (5 rats/subgroup). Blood samples of the rats in subgroups were collected at 1 h, 2 h and 4 h after administration, respectively. ELISA method was used to determine HSP70, IL-1beta, IL-6, and TNF-alpha levels in serum. Dual wavelength spectrophotometry was used to determine activity of HO-1 in serum. Spectrophotometry was used to test activities of nitric oxide synthetase (NOS) and its isoenzyme (inducible nitric oxide synthetase, iNOS) in serum. Immunonephelometery method was used to test complements C3, C4 in serum. RESULTS: Realgar and NJT significantly increased the level of HSP70 in rat serum as compared with the fever model group. Realgar and NJT significantly enhanced the activity of HO-1 in rat serum as compared with the fever model group. The increase ranges of HO-1 activities at different time post administration changed with the arsenic concentration in rat serum. Realgar and NJT significantly decreased the level of IL-1beta in rat serum as compared with fever model group, and the level of IL-lbeta recovered normaly at 4 h after administration. NJT significantly inhibited activities of NOS and iNOS in rat serum as compared with the fever model group at 2 h after administration. CONCLUSION: Realgar as contained in certain prescriptions, at certain specific levels, assists in removal of internal toxins by inducing stress protein (HSP70, HO-1) to improve the positive stress level in the body and inhibiting some over-releasing inflammatory mediators (IL-1beta) to reduce the inflammatory reactions under pathologic status.