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1.
Nat Commun ; 11(1): 3273, 2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32601301

RESUMO

Restoration of coronary blood flow after a heart attack can cause reperfusion injury potentially leading to impaired cardiac function, adverse tissue remodeling and heart failure. Iron is an essential biometal that may have a pathologic role in this process. There is a clinical need for a precise noninvasive method to detect iron for risk stratification of patients and therapy evaluation. Here, we report that magnetic susceptibility imaging in a large animal model shows an infarct paramagnetic shift associated with duration of coronary artery occlusion and the presence of iron. Iron validation techniques used include histology, immunohistochemistry, spectrometry and spectroscopy. Further mRNA analysis shows upregulation of ferritin and heme oxygenase. While conventional imaging corroborates the findings of iron deposition, magnetic susceptibility imaging has improved sensitivity to iron and mitigates confounding factors such as edema and fibrosis. Myocardial infarction patients receiving reperfusion therapy show magnetic susceptibility changes associated with hypokinetic myocardial wall motion and microvascular obstruction, demonstrating potential for clinical translation.


Assuntos
Ferro/análise , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Idoso , Animais , Estudos Transversais , Feminino , Ferritinas/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/patologia , Cicatrização
2.
Vasc Med ; 25(4): 295-301, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32469270

RESUMO

Preeclampsia is a life-threatening multiorgan systemic disease with manifestations including gestational hypertension, oxidative stress, and vascular dysfunction. We aimed to evaluate the therapeutic effects of melatonin on an L-NAME (NLG-nitro-l-arginine methyl ester)-induced rat preeclampsia model. During gestation, L-NAME was added to drinking water at 50 mg/kg/day from gestation day (GD) 8. Rats received the combination of L-NAME with melatonin (10 mg/kg/day), or aspirin (1.5 mg/kg/day), and rats that received only L-NAME or no treatments were used as controls. Aspirin was mixed with rodent chow and melatonin was administered intraperitoneally. Blood pressure and urine protein content were monitored every 3 days. On GD19, blood samples were collected for biochemical analysis. Compared to untreated L-NAME rats, melatonin led to markedly lowered blood pressure and urine protein content, and recovery in the fetus alive ratio, fetal weight, and the fetal weight/placental weight ratio. Compared to untreated L-NAME rats, plasma antioxidant capacity and plasma malondialdehyde were increased and decreased by melatonin, respectively, in L-NAME rats. Melatonin treatment also reduced sFlt-1, increased PlGF, and decreased the sFlt-1/PlGF ratio. In the placenta, melatonin also reduced sFlt-1 levels and increased Nrf2, PlGF, and HO-1 levels. We have demonstrated in a rat model of preeclampsia that melatonin exerts significant protective effects through lowering blood pressure and reducing oxidative stress.


Assuntos
Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão Induzida pela Gravidez/prevenção & controle , Melatonina/farmacologia , NG-Nitroarginina Metil Éster , Estresse Oxidativo/efeitos dos fármacos , Placenta/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Heme Oxigenase (Desciclizante)/metabolismo , Hipertensão Induzida pela Gravidez/induzido quimicamente , Hipertensão Induzida pela Gravidez/metabolismo , Hipertensão Induzida pela Gravidez/fisiopatologia , Fator 2 Relacionado a NF-E2/metabolismo , Placenta/metabolismo , Placenta/fisiopatologia , Fator de Crescimento Placentário/metabolismo , Gravidez , Proteinúria/induzido quimicamente , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Proteinúria/prevenção & controle , Ratos Sprague-Dawley , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
3.
Phys Chem Chem Phys ; 22(16): 8817-8826, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32285865

RESUMO

The oxygen-dependent heme utilization degrading enzyme in Mycobacterium tuberculosis (MhuD) uniquely integrates monooxygenase and dioxygenase functions in a single active site. It cannot convert heme to biliverdin as canonical heme oxygenases but generates mycobilin without releasing carbon monoxide. Herein, by employing ONIOM calculations, we investigated the heme degradation mechanism of MhuD. Our calculations revealed that MhuD firstly follows a canonical monooxygenation mechanism to hydroxylate heme on the δ-meso carbon guided by the asparagine residue Asn7, which experiences a 21.2 kcal mol-1 energy barrier in the O-O cleavage rate-limiting step during the conversion process from ferric heme-hydroperoxy species to mycobilin. In the second degradation step, the ruffled conformation of oxoheme (oxoheme is the ferrous π radical complex formed by hydroxyheme experiencing deprotonation in the hydroxyl group and intramolecular electron transfer) imposed by the hydrophobic environment of the enzyme not only inhibits the continuing conversion of oxoheme to biliverdin but also endows the meso-carbons with radical characteristics, which turns the second degradation step to a dioxygenation reaction with 20.4 kcal mol-1 energy barrier. We further analysed the electronic structure change along the reaction process. Our calculation discovered that the ruffled structure of oxoheme is critical to the regiospecificity and even atom location selectivity, as well as the reaction mechanism of the degradation process.


Assuntos
Heme/química , Proteólise , Heme/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Mycobacterium tuberculosis/efeitos dos fármacos
4.
Arch Biochem Biophys ; 687: 108387, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32348741

RESUMO

Although acetaminophen (APAP) is a commonly used analgesic antipyretic drug, hepatotoxicity and nephrotoxicity are common after the overdose. The main mechanism of APAP toxicity is oxidative stress based. Stress may induce the production of heme oxygenase 1 (HO)-1 which is regulated by interleukin (IL)-10 and inhibit the production of tumor necrosis factor-alpha (TNF-α). HO-1 expression is further regulated by nuclear factor erythroid 2-related factor 2 (Nrf2) and the transcription factor BTB and CNC homology 1 (BACH1). Drug-induced toxicity can be relieved by several natural products, which are preferred due to their dietary nature and less adverse reactions. Of these natural products, omega-3 (ω-3) fatty acids are known for anti-inflammatory and antioxidant actions. However, effects of ω-3fatty acids on APAP-induced hepatic and renal toxicity are not well addressed. We designed this study to test the potential protecting actions of ω-3 fatty acids (270 mg/kg Eicosapentaenoic acid and 180 mg/kg docosahexaenoic acid, orally, for 7 days) in hepatotoxicity and nephrotoxicity induced by APAP (2 g/kg, once orally on day 7) in rats. Moreover, we focused on the molecular mechanism underlying APAP hepatotoxicity and nephrotoxicity. Pre-treatment with ω-3 fatty acids enhanced liver and kidney functions indicated by decreased serum aminotransferases activities and serum creatinine and urea concentrations. These results were further confirmed by histopathological examination. Moreover, ω-3 fatty acids showed antioxidant properties confirmed by decreased malondialdehyde level and increased total antioxidant capacity. Antioxidant Nrf2, its regulators (HO-1 and BACH1) and the anti-inflammatory cytokine (IL-10) were up-regulated by APAP administration as a compensatory mechanism and they were normalized by ω-3 fatty acids. ω-3 fatty acids showed anti-inflammatory actions through down-regulating nuclear factor kappa B (NF-ĸB) and its downstream TNF-α. Moreover, Western blot analysis showed that ω-3 fatty acids promoted Nrf2 translocation to the nucleus; BACH1 exit from the nucleus and inhibited NF-ĸB nuclear translocation. These findings suggested the protecting actions of ω-3 fatty acids against APAP-induced hepatic and renal toxicity through regulation of antioxidant Nrf2 and inflammatory NF-ĸB pathways.


Assuntos
Anti-Inflamatórios/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ácidos Graxos Ômega-3/farmacologia , Nefropatias/prevenção & controle , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Acetaminofen , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Núcleo Celular/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Regulação para Baixo , Heme Oxigenase (Desciclizante)/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Fígado/patologia , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Proteínas Repressoras/metabolismo , Fator de Crescimento Transformador alfa/metabolismo
5.
Chin J Integr Med ; 26(3): 197-204, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32180149

RESUMO

OBJECTIVE: To investigate protective effects of hirudin on oxidative stress and apoptosis of spinal dorsal root ganglion cells in high-glucose rats at the cellular and molecular level. METHODS: Dorsal root ganglion neurons (DRGn) were harvested from embryonic day in 15 SD rats, purified and identificated after primary culture. They were divided into the normal control group, high-glucose (HG) group, positive control (alpha-lipoic acid, ALA) group, low-dose hirudin group (H1), medium-dose hirudin group (H2) and high-dose hirudin group (H3). The control group was cultured by neuron specific culture medium, while the HG group was cultured by neuron specific culture medium and 20 mmol/L glucose (HG medium). The hirudin groups were cultured by HG medium+0.25 IU/mL hirudin (H1), HG medium+0.5 IU/mL hirudin (H2) and HG medium+1 IU/mL hirudin (H3). The ALA group was cultured by HG medium+100 µ mol/L ALA. 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenylt etrazolium bromide (MTT) assay was used to explore the optimum concentration and intervention time. Flow cytometry assay was used to detect the level of reactive oxygen series (ROS). Western blot and quantificational realtime polymerase chain reaction (qRT-PCR) were used to detect the expression of protein and mRNA of nuclear factor erythroid 2-related factor 2 (Nrf-2), hemeoxygence-1 (HO-1), nuclear factor-κ B (NF-κ B) and Caspase-3. TUNEL assay was used to test the apoptosis rate of different groups. RESULTS: After 24 h of culture, the cell activity of hirudin and ALA groups were higher than that of HG group, and there was a statistical difference between the H1 group and HG group (P<0.05). In hirudin groups, the apoptosis rate of cells, the expression of activated Caspase-3 protein and Caspase-3 mRNA were lower than those of HG group (P<0.01), higher than those of ALA group (P<0.01 or P<0.05). The ROS level of hirudin groups was higher than that of ALA group (P<0.01), lower than that of HG group (P<0.01 or P<0.05). The expression of NF-κ B (P65) protein in H3 group were lower than those of HG group (P<0.05). The expression of Nrf-2 protein in hirudin groups was higher than that of HG group (P<0.01), lower than that of ALA group (P<0.01 or P<0.05). The expression of HO-1 protein in hirudin groups was lower than that of ALA group (P<0.01 or P<0.05), higher than that of HG group (P<0.01 or P<0.05). CONCLUSIONS: The activity of DRGn cells can be promoted by hirudin under HG conditions. The effects of hirudin on the inhibition of HG on DRGn cells damage mainly include scavenging ROS, up-regulating Nrf-2/HO-1 pathway, inhibiting activation of NF-κ B pathway, down-regulating the expression of and Caspase-3 and reducing DRGn cell apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Gânglios Espinais/efeitos dos fármacos , Hirudinas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Caspase 3/metabolismo , China , Modelos Animais de Doenças , Heme Oxigenase (Desciclizante)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo
6.
Chem Biol Interact ; 318: 108973, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32035862

RESUMO

Carbon monoxide (CO) is an inorganic chemical compound that can bind with hemoglobin with highly toxic effects. In living organisms, it is produced endogenously during the degradation of heme by oxygenase, which occurs in three isoforms: HO-1, HO-2 and HO-3. CO can play an important role in the regulation of many physiological functions. Carbon Oxide Releasing Molecules (CORMs) are a novel group of chemical compounds capable of controlled CO release directly in tissues or organs. This release depends on concentration, pH, solvent type and temperature. The biological role and the therapeutic potential of different CORMs is not always well demonstrated. However, this mini review summarizes the various function of these compounds.


Assuntos
Monóxido de Carbono/química , Monóxido de Carbono/metabolismo , Animais , Monóxido de Carbono/toxicidade , Heme/química , Heme/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Isoenzimas
8.
Oxid Med Cell Longev ; 2020: 6325378, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32064027

RESUMO

In addition to the lung, the liver is considered another major target for paraquat (PQ) poisoning. Hydrogen sulfide (H2S) has been demonstrated to be effective in the inhibition of oxidative stress and inflammation. The aim of this study was to investigate the protective effect of exogenous H2S against PQ-induced acute liver injury. The acute liver injury model was established by a single intraperitoneal injection of PQ, evidenced by histological alteration and elevated serum aminotransferase levels. Different doses of NaHS were administered intraperitoneally one hour before exposure to PQ. Analysis of the data shows that exogenous H2S attenuated the PQ-induced liver injury and oxidative stress in a dose-dependent manner. H2S significantly suppressed reactive oxygen species (ROS) generation and the elevation of malondialdehyde content while it increased the ratio of GSH/GSSG and levels of antioxidant enzymes including SOD, GSH-Px, HO-1, and NQO-1. When hepatocytes were subjected to PQ-induced oxidative stress, H2S markedly enhanced nuclear translocation of Nrf2 via S-sulfhydration of Keap1 and resulted in the increase in IDH2 activity by regulating S-sulfhydration of SIRT3. In addition, H2S significantly suppressed NLRP3 inflammasome activation and subsequent IL-1ß excretion in PQ-induced acute liver injury. Moreover, H2S cannot reverse the decrease in SIRT3 and activation of the NLRP3 inflammasome caused by PQ in Nrf2-knockdown hepatocytes. In summary, H2S attenuated the PQ-induced acute liver injury by enhancing antioxidative capability, regulating mitochondrial function, and suppressing ROS-induced NLRP3 inflammasome activation. The antioxidative effect of H2S in PQ-induced liver injury can at least partly be attributed to the promotion of Nrf2-driven antioxidant enzymes via Keap1 S-sulfhydration and regulation of SIRT3/IDH2 signaling via Nrf2-dependent SIRT3 gene transcription as well as SIRT3 S-sulfhydration. Thus, H2S supplementation can form the basis for a promising novel therapeutic strategy for PQ-induced acute liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Inflamação/metabolismo , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Paraquat/toxicidade , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Glutationa/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Isocitrato Desidrogenase/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Mitocôndrias/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/genética , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Sirtuínas/metabolismo , Sulfetos/administração & dosagem , Superóxido Dismutase-1/metabolismo , Transaminases/metabolismo
9.
Life Sci ; 244: 117331, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972209

RESUMO

AIM: Drug-induced liver and kidney injuries are worldwide problems that cause restrictions in the use of drugs. The injury is highly mediated by oxidative stress and inflammation pathways. So, demonstrating the role of the natural compound (Vit.D) on the prevention of acetaminophen (APAP) overdose toxicity and the molecular mechanism through NrF2/BACH1/HO-1 pathway is promising. EXPERIMENTAL: Male Sprague Dawley rats (40 rats) were divided randomly into 4 groups: Normal, APAP, APAP+Vit.D (500 IU/kg) and APAP+Vit.D (1000 IU/kg). The APAP toxicity caused by 2 g/kg (orally) on day 7. KEY FINDINGS: Vit D decreased significantly liver and kidney functions: serum ALT and AST activities (P < 0.0005); creatinine and urea (P < 0.0005) concentrations; liver and kidney histopathological scores. Furthermore, Vit.D ameliorated APAP-caused oxidative stress through the liver malondialdehyde concentration's decrease and the total antioxidant capacity's increase (P < 0.0005). The molecular mechanism of Vit.D may include the prevention of high deteriorating increase of oxidative stress mediators: hepatic and renal NrF2 and BACH1 tissue expression in addition to serum HO-1 (P < 0.0005); the increase of inflammatory mediators; hepatic and renal NF-κB tissue expression, serum interleukin-10 (P < 0.0005) and TNF-α (P < 0.05). The 500 IU/kg Vit.D administration caused better protection results especially on the histopathological and immunohistochemical results than the 1000 IU/kg Vit.D administration. SIGNIFICANCE: Vit.D ameliorates APAP-induced liver and kidney injury that may be attributed to its ability to moderately increase antioxidant status to counteract the toxicity without the massive destructive increase in the anti-oxidant pathway (NrF2/HO-1/BACH1). So, this work represents a great prophylactic role of Vit.D against drug-induced liver and kidney injury.


Assuntos
Acetaminofen/toxicidade , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Heme Oxigenase (Desciclizante)/metabolismo , Rim/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Repressoras/metabolismo , Vitamina D/administração & dosagem , Doença Aguda , Analgésicos não Entorpecentes/toxicidade , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/genética , Rim/metabolismo , Rim/patologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Ratos , Ratos Sprague-Dawley , Proteínas Repressoras/genética , Vitaminas/administração & dosagem
10.
Life Sci ; 242: 117248, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31899224

RESUMO

Diabetic nephropathy is the most common long-term complication of diabetes mellitus. The Methylglyoxal (MGO) production is mainly by metabolic pathways, such as lipolysis and glycolysis, its increases in the DM enhances oxidative stress and plays a crucial role in the diabetic nephrotic pathogenesis. Phosphocreatine (PCr) can improve lipopolysaccharide, ox-LDL-induced atherosclerosis, and alleviate vascular endothelial cell injury in diabetes. The aim of our present study is to examine the potential role of phosphocreatine (PCr) as a molecule protects against diabetes-induced Kidney Injury in-vitro and in-vivo through ERK/Nrf2/HO-1 signaling pathway. NRK-52E cells treatment with PCr obviously suppressed MGO-induced change of viability, apoptosis, coupled with decreased Bax/Bcl-2ratio, casapse-9 and caspase-3expressions. We determined the generation of reactive oxygen species (ROS) using membrane permeable fluorescent probe DCFH-DA as well as intracellular calcium by flow cytometry. ERK, Nrf2 and HO-1 expressions were determined by Western blot. PCr pretreatment significantly returned the oxidative stress enzymes to normal condition in-vitro and in-vivo. PCr pretreatment significantly reduced apoptosis, calcium and ROS production, induced by MGO, in NRK-52E cells. Moreover, pretreatment with PCr significantly inhibited cleaved caspase-3, cleaved caspase-9 and p-ERK expressions, while increased Nrf-2 and HO-1 expressions. Furthermore, PCr pretreatment significantly decreased p-ERK expression of MGO-induced injury in NRK-52E cells transfected with p-ERK cDNA. In conclusion, the renal protective effect of PCr in-vitro and in-vivo depends on suppressing apoptosis and ROS generation through ERK mediated Nrf-2/HO-1 pathway, suggesting that PCr may be a novel therapeutic candidate for the diabetic nephropathy treatment.


Assuntos
Nefropatias Diabéticas/prevenção & controle , Heme Oxigenase (Desciclizante)/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fosfocreatina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Cálcio/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/complicações , Citometria de Fluxo , Imunofluorescência , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
11.
Biochem J ; 477(3): 601-614, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31913441

RESUMO

The pro-oxidant effect of free heme (Fe2+-protoporphyrin IX) is neutralized by phylogenetically-conserved heme oxygenases (HMOX) that generate carbon monoxide, free ferrous iron, and biliverdin (BV) tetrapyrrole(s), with downstream BV reduction by non-redundant NADPH-dependent BV reductases (BLVRA and BLVRB) that retain isomer-restricted functional activity for bilirubin (BR) generation. Regioselectivity for the heme α-meso carbon resulting in predominant BV IXα generation is a defining characteristic of canonical HMOXs, thereby limiting generation and availability of BVs IXß, IXδ, and IXγ as BLVRB substrates. We have now exploited the unique capacity of the Pseudomonas aeruginosa (P. aeruginosa) hemO/pigA gene for focused generation of isomeric BVs (IXß and IXδ). A scalable system followed by isomeric separation yielded highly pure samples with predicted hydrogen-bonded structure(s) as documented by 1H NMR spectroscopy. Detailed kinetic studies established near-identical activity of BV IXß and BV IXδ as BLVRB-selective substrates, with confirmation of an ordered sequential mechanism of BR/NADP+ dissociation. Halogenated xanthene-based compounds previously identified as BLVRB-targeted flavin reductase inhibitors displayed comparable inhibition parameters using BV IXß as substrate, documenting common structural features of the cofactor/substrate-binding pocket. These data provide further insights into structure/activity mechanisms of isomeric BVs as BLVRB substrates, with potential applicability to further dissect redox-regulated functions in cytoprotection and hematopoiesis.


Assuntos
Biliverdina , Heme Oxigenase (Desciclizante) , Heme/metabolismo , Pseudomonas aeruginosa/metabolismo , Biliverdina/química , Biliverdina/metabolismo , Genes Bacterianos/fisiologia , Heme Oxigenase (Desciclizante)/química , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Cinética , Oxirredução , Oxirredutases/metabolismo , Pseudomonas aeruginosa/genética
12.
J Biochem Mol Toxicol ; 34(2): e22427, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31777137

RESUMO

The study aimed to examine the effects of nobiletin on the toxicity model induced with acetaminophen (APAP). For this purpose, 24 adult male rats were equally divided into four groups. The groups were the control group (group 1); dimethyl sulfoxide only, the APAP group (group 2) received a single dose of APAP 1000 mg/kg on the 10th day of experiment; the Nobiletin group (group 3), nobiletin (10 mg/kg) for 10 days; and the APAP + Nobiletin group (group 4), nobiletin (10 mg/kg) for 10 days with a single dose of APAP (1000 mg/kg) administered on the 10th day and the experiment ended after 48 hours. At the end of the study, a significant increase in malondialdehyde, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels and a significant decrease in glutathione levels, glutathione peroxidase activities and nuclear factor erythroid-derived 2-like 2 (Nrf-2) and heme oxygenase-1 (HO-1) expressions were observed with APAP application in liver and kidney tissues. Serum aspartate transaminase (AST), alanine transaminase (ALT), urea, and creatinine levels were also significantly increased in the APAP group. However, nobiletin treatment in group 4 reversed oxidative stress and inflammatory and histopathological signs caused by APAP. It is concluded that nobiletin may be a beneficial substance that confers hepatorenal protection to APAP-induced toxicity via antioxidant and anti-inflammatory mechanisms.


Assuntos
Acetaminofen/efeitos adversos , Acetaminofen/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Flavonas/farmacologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Creatinina/sangue , Citocinas/metabolismo , Flavonas/uso terapêutico , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Ureia/sangue
13.
Life Sci ; 242: 117151, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31843526

RESUMO

AIMS: Anaesthesia-related neurotoxicity in the developing brain is a controversial issue that has recently attracted much attention. Hemin plays a protective role in hypoxic and ischemic brain damage; however, its effects on sevoflurane-induced neurotoxicity remain unclear. Our aim was to investigate the mechanisms of sevoflurane neurotoxicity and potential neuroprotective roles of hemin upon sevoflurane exposure. MAIN METHODS: Hippocampi were harvested 18 h after sevoflurane exposure. Haem oxygenase 1 (HMOX1), superoxide dismutase 2 (SOD2), discs large MAGUK scaffold protein 4 (DLG4), phosphorylated Akt, Akt, cleaved caspase 3, and neuroglobin were detected by western blotting. A water maze test was used to assess learning and memory ability in P30 rats. KEY FINDINGS: Sevoflurane inhalation increased cleaved caspase 3 levels. Hemin treatment enhanced the antioxidant defence response, protecting rats from oxidative stress injury. Hemin plays its neuroprotective role via phosphoinositide 3-kinase (PI3K)/Akt signalling. A single inhalation of sevoflurane did not affect DLG4 expression, while hemin treatment did. Platform crossing increased in rats treated with hemin as well, which may be related to increased DLG4. Neuroglobin expression was not affected, suggesting that it may act upstream of PI3K/Akt signalling. SIGNIFICANCE: Our study demonstrates that hemin plays a protective role in anaesthesia-induced neurotoxicity by both inhibiting apoptosis via the PI3K/Akt pathway and increasing the expression of antioxidant enzymes, reducing oxidative damage. The results provide mechanistic insight into the effects of sevoflurane anaesthesia on the developing brain and suggest that hemin could help avoid these effects.


Assuntos
Anestésicos Inalatórios/toxicidade , Encéfalo/efeitos dos fármacos , Hemina/farmacologia , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sevoflurano/toxicidade , Transdução de Sinais/efeitos dos fármacos , Administração por Inalação , Animais , Animais Recém-Nascidos , Western Blotting , Caspase 3/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hipocampo/química , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Aprendizagem em Labirinto/efeitos dos fármacos , Neuroglobina/metabolismo , Ratos , Ratos Sprague-Dawley , Sevoflurano/antagonistas & inibidores , Superóxido Dismutase/metabolismo
14.
Phytomedicine ; 67: 153140, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31884405

RESUMO

BACKGROUND: Hedansanqi Tiaozhi Tang extract (HTT) consists of Notoginseng, Danshen, Hawthorn and Lotus leaf from traditional Chinese medicine, which has significant therapeutic effects on hyperlipidemia in patients with non-alcoholic fatty liver disease (NAFLD). PURPOSE: This study sought to evaluate the pharmacological effects and molecular mechanism of HTT for the treatment of hyperlipidemia in adipocytes and animal model with NAFLD. METHODS: Quantitative phytochemical analysis of HTT was performed by HPLC. Antioxidant activity and the adipogenesis in 3T3-L1 cells were assessed. In the rat model induced by high-fat diet, lipid-related and antioxidant markers in serum and liver were detected. Moreover, the organ weights, non-alcoholic steatohepatitis (NASH) score and the levels of Nrf2 and HO-1 in liver sections were analyzed by tissue pathological techniques. RESULTS: 8 constituents were identified in HTT including saponins, flavonoids, alkaloids and others. HTT treatment enhanced antioxidant activities and promoted lipolysis in 3T3-L1 adipocytes. We also found that HTT inhibited weight gain, reduced the lipid profiles and improved the liver function and pathological characteristics induced by high-fat diet. In addition, HTT activated the Nrf2/HO-1 antioxidant pathway in the liver. CONCLUSION: HTT has protective effect against NAFLD in vitro and in vivo by activating the Nrf2/HO-1 antioxidant pathway.


Assuntos
Antioxidantes/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Células 3T3-L1 , Animais , Crataegus/química , Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/química , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Compostos Fitoquímicos/análise , Ratos Sprague-Dawley
15.
J Cardiovasc Pharmacol ; 75(3): 259-267, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31868825

RESUMO

ur preclinical findings replicated women's hypersensitivity to type-2 diabetes mellitus (T2DM)-evoked cardiac dysfunction along with demonstrating estrogen (E2)-dependent disruption of the cardiac adiponectin (APN)-connexin43 (Cx43) signaling. Whether the latter molecular anomaly underlies this women's cardiovascular health problem remains unknown. We hypothesized that restoration of the disrupted APN-Cx43 signaling alleviates this sex/E2-dependent cardiac dysfunction in diabetic female rats. To test this hypothesis, we administered the adiponectin receptor 1 (AdipoR1) agonist AdipoRon (30 mg/kg/d for 10 days) to female sham operated (SO) and ovariectomized (OVX) rats, which exhibited and lacked the T2DM left ventricular (LV) dysfunction, respectively, when fed high-fat diet and received low dose streptozotocin regimen; nondiabetic control SO and OVX rats received control diet and vehicle for streptozotocin. In T2DM SO rats, LV dysfunction, AdipoRon mitigated: (1) LV hypertrophy, (2) reductions in fractional shortening, LV developed pressure, dP/dtmax, dP/dtmin, and Tau. In LV tissues of the same rats, AdipoRon reversed reduction in Cx43 and elevations in TNFα, heme-oxygenase 1 (HO-1), and circulating cardiovascular risk factor asymmetric dimethylarginine. The findings also revealed ovarian hormones independent effects of AdipoRon, which included dampening of the pro-oxidant enzyme HO-1. These novel findings yield new insight into a causal role for compromised APN-Cx43 signaling in the E2-dependent hypersensitivity to T2DM-evoked cardiac inflammation and dysfunction. Equally important, the findings identify restoration of Cx43 signaling as a viable therapeutic modality for alleviating this women's cardiovascular health-related problem.


Assuntos
Adiponectina/metabolismo , Conexina 43/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Hipertrofia Ventricular Esquerda/prevenção & controle , Piperidinas/farmacologia , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Arginina/análogos & derivados , Arginina/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Heme Oxigenase (Desciclizante)/metabolismo , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Ovariectomia , Ratos Wistar , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular/efeitos dos fármacos
16.
Oxid Med Cell Longev ; 2019: 9605980, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827712

RESUMO

Acute lung injury (ALI) is a life-threatening disease that is characterised by the rapid onset of inflammatory responses. Lipopolysaccharide (LPS) is an endotoxin that plays an important role in triggering ALI via pneumonia and sepsis. However, no effective therapeutic strategies are currently available to treat ALI. Nerolidol is an aliphatic sesquiterpene alcohol that is found in the essential oils of many flowers as well as floral plants. It has been shown to exhibit anti-inflammatory, antioxidant, and anticancer properties. Herein, we show that nerolidol pretreatment counteracted the histopathological hallmarks in LPS-induced ALI mice. Indeed, nerolidol pretreatment inhibited LPS-induced alveolar-capillary barrier disruption, lung edema, and lipid peroxidation. Moreover, nerolidol pretreatment prevented the LPS from decreasing the enzymatic activities of superoxide dismutase, catalase, and glutathione peroxidase. Importantly, nerolidol treatment enhanced phosphorylation of AMP-activated protein kinase (AMPK) and expression of nuclear factor erythroid-derived 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1). Taken together, our study reveals the novel protective effects of nerolidol in LPS-induced ALI via the induction of antioxidant responses and activation of the AMPK/Nrf-2/HO-1 signalling pathway.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Lipopolissacarídeos/toxicidade , Pneumonia/prevenção & controle , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pneumonia/metabolismo , Pneumonia/patologia
17.
J Toxicol Sci ; 44(12): 833-843, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31813902

RESUMO

Drug-induced liver injury is not readily detectable using conventional animal studies during pre-clinical drug development. To address this problem, other researchers have proposed the use of co-administration of lipopolysaccharide (LPS), an endotoxin produced by gram-negative bacteria, and a drug. Using this approach, liver injury that is otherwise not detected following drug administration alone can be successfully identified. Previous studies have demonstrated that such injury is suppressed by heparin; therefore, the mechanism may involve coagulation-dependent ischemia. However, it has not been established how LPS-induced ischemia might sensitize hepatocytes to a potentially hepatotoxic drug. In the present study, we aimed to determine the effect of LPS-induced ischemia on liver mitochondrial function and downstream toxicologic responses. Consistent with previous findings, plasma alanine transaminase (ALT) activity was higher in rats co-administered with LPS (1 mg/kg) and diclofenac (100 mg/kg), but reduced by heparin. Liver mRNA expression of Hmox1, encoding heme oxygenase-1, an oxidative stress indicator, was three times higher at 2 hr after LPS administration. Furthermore, respiratory activity via mitochondrial complex II, lipid peroxidation in mitochondria, and the susceptibility to mitochondrial permeability transition pore opening in response to diclofenac administration were significantly increased by LPS administration. The increase in plasma ALT activity and the sensitization to mitochondrial permeability transition pore opening were reduced by the co-administration of heparin. In conclusion, LPS-induced transient ischemia disrupts respiratory chain complex activities, enhances reactive oxygen species production, especially in mitochondria, and sensitizes mitochondria to permeability transition pore opening when testing a potentially hepatotoxic drug in vivo.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Diclofenaco/toxicidade , Modelos Animais de Doenças , Endotoxinas/toxicidade , Fígado/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Animais , Sinergismo Farmacológico , Heme Oxigenase (Desciclizante)/metabolismo , Isquemia/induzido quimicamente , Isquemia/metabolismo , Fígado/irrigação sanguínea , Fígado/metabolismo , Testes de Função Hepática , Masculino , Mitocôndrias Hepáticas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
18.
Int J Mol Sci ; 20(24)2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31817701

RESUMO

To elucidate the effect of rice protein (RP) on the depression of inflammation, growing and adult rats were fed with caseins and RP for 2 weeks. Compared with casein, RP reduced hepatic accumulations of reactive oxygen species (ROS) and nitro oxide (NO), and plasma activities of alanine transaminase (ALT) and aspartate transaminase (AST) in growing and adult rats. Intake of RP led to increased mRNA levels, and protein expressions of phosphoinositide 3 kinase (PI3K), protein kinase B (Akt), nuclear factor-κB 1 (NF-αB1), reticuloendotheliosis viral oncogene homolog A (RelA), tumor necrotic factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and monocyte chemoattractant protein-1 (MCP-1) were decreased, whereas hepatic expressions of interleukin-10 (IL-10) and heme oxygenase 1 (HO-1) were increased by RP. The activation of NF-κB was suppressed by RP through upregulation of inhibitory κB α (IκBα), resulting in decreased translocation of nuclear factor-κB 1 (p50) and RelA (p65) to the nucleus in RP groups. The present study demonstrates that RP exerts an anti-inflammatory effect to inhibit ROS-derived inflammation through suppression of the NF-κB pathway in growing and adult rats. Results suggest that the anti-inflammatory capacity of RP is independent of age.


Assuntos
Anti-Inflamatórios/farmacologia , NF-kappa B/metabolismo , Oryza/química , Proteínas de Plantas/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Interleucina-6/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Wistar
19.
Curr Med Sci ; 39(6): 938-946, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31845225

RESUMO

Diabetic cardiomyopathy (DCM) is one of the major heart complications of diabetic patients. Hydrogen sulfide (H2S) is now recognized as an important signaling molecule and has been shown to attenuate the development of diabetic cardiomyopathy. However, the underlying mechanisms linking H2S and the development of DCM have not been fully elucidated. In the present study, we therefore sought to explore the role and mechanism of H2S in the pathogenesis of DCM by establishing high glucose-induced injury model in neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. Using cystathionine gamma-lyase (CSE) overexpression and CSE interference vectors transfection, the cell viability, cell apoptosis. and oxidative stress were determined and compared between the treatment of high glucose induction and exgenous NaHS administration. Meanwhile, the relationship between the CSE/H2S system and Wnt/beta-catenin pathway was analyzed and discussed in the high glucose-induced cardiomyocytes. Our results indicated that H2S played an important protective role in high glucose-induced apoptosis and oxidative stress in cardiomyocytes, as shown by the decreased reactive oxygen species and malondialdehyde levels, and the increased activities of superoxide dismutase, catalase and glutathione peroxidase. Moreover, H2S could attenuate the Wnt/ß-catenin signalling pathway and up-regulate the expression of haem oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) in the diabetic myocardium cells. Together, these results demonstrated that H2S could attenuate high glucose-induced myocardial injury in rat cardiomyocytes by suppressing Wnt/ß-catenin pathway.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , Glucose/efeitos adversos , Sulfeto de Hidrogênio/administração & dosagem , Miócitos Cardíacos/citologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Cardiomiopatias Diabéticas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Sulfeto de Hidrogênio/farmacologia , Modelos Biológicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos
20.
Oxid Med Cell Longev ; 2019: 5416728, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885801

RESUMO

Ultraviolet (UV) irradiation can be considered as a double-edged sword: not only is it a crucial environmental factor that can cause skin-related disorders but it can also be used for phototherapy of skin diseases. Inducible heme oxygenase-1 (HO-1) in response to a variety of stimuli, including UV exposure, is vital to maintain cell homeostasis. Heme oxygenase-2 (HO-2), another member of the heme oxygenase family, is constitutively expressed. In this review, we discuss how heme oxygenase (HO), a vital rate-limiting enzyme, participates in heme catabolism and cytoprotection. Phylogenetic analysis showed that there may exist a functional differentiation between HO-1 and HO-2 during evolution. Furthermore, depending on functions in immunomodulation and antioxidation, HO-1 participates in disease progression, especially in pathogenesis of skin diseases, such as vitiligo and psoriasis. To further investigate the particular role of HO-1 in diseases, we summarized the profile of the HO enzyme system and its related signaling pathways, such as Nrf2 and endoplasmic reticulum crucial signaling, both known to regulate HO-1 expression. Furthermore, we report on a C-terminal truncation of HO-1, which is generally considered as a signal molecule. Also, a newly identified alternative splice isoform of HO-1 not only provides us a novel perspective on comprehensive HO-1 alternative splicing but also offers us a basis to clarify the relationship between HO-1 transcripts and oxidative diseases. To conclude, the HO system is not only involved in heme catabolism but also involved in biological processes related to the pathogenesis of certain diseases, even though the mechanism of disease progression still remains sketchy. Further understanding the role of the HO system and its relationship to UV is helpful for revealing the HO-related signaling networks and the pathogenesis of many diseases.


Assuntos
Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Heme/metabolismo , Vitiligo/metabolismo , Animais , Citoproteção , Homeostase , Humanos , Estresse Oxidativo , Filogenia , Transdução de Sinais , Raios Ultravioleta/efeitos adversos
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