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1.
Life Sci ; 269: 119031, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33453244

RESUMO

AIMS: Cadmium (Cd) is a prevalent environmental contaminant that incurs deleterious health effects, including testicular impairment. Sitagliptin, a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated marked cardio-, hepato-, and reno-protective actions, however, its impact on Cd-triggered testicular dysfunction has not been formerly investigated. Hence, the present study aimed to explore the probable beneficial impact of sitagliptin against Cd-evoked testicular impairment which may add to its potential clinical utility. The underlying mechanisms pertaining to the balance between testicular autophagy and apoptosis were explored, including the AMPK/mTOR and Nrf2/HO-1 pathways. MATERIALS AND METHODS: The testicular tissues were examined using histopathology, immunohistochemistry, Western blotting, and ELISA. Sitagliptin (10 mg/kg/day, by gavage) was administered for 4 consecutive weeks. KEY FINDINGS: Sitagliptin attenuated the testicular impairment via improvement of the relative testicular weight, sperm count/motility, sperm abnormalities, and serum testosterone. Additionally, sitagliptin counteracted Cd-induced histologic aberrations/disrupted spermatogenesis. Interestingly, sitagliptin augmented the defective autophagy as demonstrated by upregulating Beclin 1 protein expression and lowering p62 SQSTM1 protein accumulation. These effects were mediated via the activation of testicular AMPK/mTOR pathway as proven by increasing p-AMPK (Ser485, Ser491)/total AMPK and diminishing p-mTOR (Ser2448)/total mTOR protein expression. Additionally, sitagliptin suppressed the testicular apoptotic events via downregulating Bax and upregulating Bcl-2 protein expression. In tandem, sitagliptin suppressed the oxidative stress through lowering lipid peroxides and activating Nrf2/HO-1 pathway via upregulating the protein expression of Nrf2, and the downstream effectors HO-1 and GPx. SIGNIFICANCE: Sitagliptin attenuated Cd-induced testicular injury via boosting the autophagy/apoptosis ratio through activation of AMPK/mTOR and Nrf2/HO-1 pathways.


Assuntos
Autofagia , Cádmio/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Doenças Testiculares/tratamento farmacológico , Testículo/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Doenças Testiculares/induzido quimicamente , Doenças Testiculares/metabolismo , Doenças Testiculares/patologia , Testículo/metabolismo , Testículo/patologia
2.
Biomed Pharmacother ; 134: 111130, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33348309

RESUMO

OBJECTIVE: Dimethyl fumarate (DMFU), a known Nrf2 activator, has proven its positive effect in different organs against ischemia/reperfusion (Is/Re) injury. Nevertheless, its possible impact to modulate intestinal Is/Re-induced injury has not been previously demonstrated before. Hence, this study aimed to investigate DMFU mechanistic maneuver against intestinal Is/Re. METHODS: To accomplish this goal, Wistar rats were allocated into four groups; Sham-operated (SOP), intestinal Is/Re (1 h/6 h), and 14 days pre-treated DMFU (15 and 25 mg/kg/day, p.o). RESULTS: The mechanistic maneuver divulged that DMFU safeguarded the intestine partly via amplifying the expression/content of Nrf2 along with enhancing its downstream, HO-1 expression/content. In addition, DMFU lessened GSK-3ß expression/content accompanied by enriching ß-catenin expression/content. The antioxidant action was affirmed by enhancing total antioxidant capacity, besides reducing MDA, iNOS, and its by-product, NOx. The DMFU action entailed anti-inflammatory character manifested by down-regulation of expression/content NF-κB with subsequent rebating the contents of TNF-α, IL-1ß, and P-selectin, as well as MPO activity. Moreover, DMFU had anti-apoptotic nature demonstrated through enriching Bcl-2 level and diminishing that of caspase-3. CONCLUSION: DMFU purveyed tenable novel protective mechanisms and mitigated events associated with intestinal Is/Re mischief either in the lower or the high dose partly by amending of oxidative stress and inflammation through the modulation of Nrf2/HO-1, GSK-3ß, and Wnt/ß-catenin pathways.


Assuntos
Anti-Inflamatórios/farmacologia , Fumarato de Dimetilo/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Enteropatias/prevenção & controle , Intestinos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/genética , Heme Oxigenase (Desciclizante)/genética , Enteropatias/enzimologia , Enteropatias/genética , Enteropatias/patologia , Intestinos/enzimologia , Intestinos/patologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Estresse Nitrosativo/efeitos dos fármacos , Ratos Wistar , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
3.
Mol Med Rep ; 23(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33300078

RESUMO

Inflammation of alveolar macrophages is the primary pathological factor leading to acute lung injury (ALI), and NF­κB activation and HO­1 inhibition are widely involved in inflammation. Salusin­ß has been reported to contribute to the progression of the inflammatory response, but whether salusin­ß could regulate inflammation in lipopolysaccharide (LPS)­induced ALI remains unknown. The present study aimed to investigate the role of salusin­ß in LPS­induced ALI and to uncover the potential underlying mechanisms. Sprague­Dawley rats were subjected to LPS administration, and then pathological manifestations of lung tissues, inflammatory cytokines levels in bronchoalveolar lavage fluid (BALF) and expression of salusin­ß in macrophages of lung tissues were assessed. NR8383 cells with or without salusin­ß knockdown were treated with LPS, and then the concentration of inflammatory cytokines, and the expression of high mobility group box­1 (HMGB1), NF­κB signaling molecules and heme oxygenase­1 (HO­1) levels were detected. The results showed that LPS caused injury of lung tissues, increased the levels of proinflammatory cytokines in BALF, and led to higher expression of salusin­ß or macrophages in lung tissues of rats. In vitro experiments, LPS also upregulated salusin­ß expression in NR8383 cells. Knockdown of salusin­ß using short hairpin (sh)RNA inhibited the LPS­induced generation of inflammatory cytokines. LPS also enhanced HMGB1, phosphorylated (p)­IκB and p­p65 expression, but reduced HO­1 expression in both lung tissues and NR8383 cells, which were instead inhibited by the transfection of sh­salusin­ß. In addition, knockdown of HO­1 using shRNA reversed the inhibitory effect of sh­salusin­ß on the LPS­induced generation of inflammatory cytokines, activation of NF­κB signaling and inactivation of HO­1. In conclusion, this study suggested that knockdown of salusin­ß may inhibit LPS­induced inflammation in alveolar macrophages by blocking NF­κB signaling and upregulating HO­1 expression.


Assuntos
Heme Oxigenase (Desciclizante)/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Lipopolissacarídeos/toxicidade , Macrófagos Alveolares/metabolismo , NF-kappa B/metabolismo , Animais , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Técnicas de Silenciamento de Genes , Heme Oxigenase (Desciclizante)/genética , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos Alveolares/patologia , Masculino , NF-kappa B/genética , Ratos , Ratos Sprague-Dawley
4.
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
5.
Inflamm Res ; 69(2): 217-231, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31897506

RESUMO

OBJECTIVE: The objective of the study was to test the hypothesis that nicotine guards against endotoxemia-associated renal inflammation and vasoconstrictor dysfunction via the activation of α7-nicotinic acetylcholine receptors (α7-nAChRs)/heme oxygenase-1 (HO-1) cascade. MATERIALS: 91 male and female rats were included in the study. TREATMENTS: Lipopolysaccharide (LPS, 5 mg kg-1), nicotine (0.5-2 mg kg-1), pentoxifylline (PTX, TNFα inhibitor, 3 mg kg-1), methyllycaconitine (MLA, α7-nAChR blocker), zinc protoporphyrin (ZnPP, HO-1 inhibitor), hemin (HO-1 inducer), tricarbonyldichlororuthenium (carbon monoxide-releasing molecule, CORM-2) or bilirubin was administered before LPS. METHODS: Isolated perfused kidney was used to evaluate renal vasoconstriction and immunohistochemistry to assess inflammatory cytokines. RESULTS: LPS reduced renal vasoconstrictions induced by phenylephrine or vasopressin in perfused kidneys of male, but not female, rats. Higher elevations in serum interleukin-1ß and renal expressions of inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB) were observed in LPS-treated male rats, whereas greater HO-1 expression was evident in endotoxic female rats. LPS effects were reversed by nicotine or PTX. Further, the favorable nicotine actions were (i) diminished by MLA or ZnPP and (ii) replicated by hemin or CORM-2, but not bilirubin, and (iii) associated with exaggerated and MLA-sensitive increases in HO-1 expression. CONCLUSIONS: α7-nAChR/HO-1/CO signaling mediates nicotine protection against renal inflammation and vasoconstrictor hyporeactivity in endotoxic male rats.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Monóxido de Carbono/metabolismo , Endotoxemia/genética , Endotoxemia/fisiopatologia , Heme Oxigenase (Desciclizante)/genética , Inflamação/genética , Inflamação/fisiopatologia , Nicotina/farmacologia , Receptores Nicotínicos/genética , Transdução de Sinais/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Feminino , Técnicas In Vitro , Interleucina-1beta/sangue , Rim/efeitos dos fármacos , Rim/metabolismo , Lipopolissacarídeos , Masculino , Perfusão , Ratos , Ratos Wistar
6.
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
7.
Exp Neurol ; 326: 113203, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31954682

RESUMO

INTRODUCTION: Disruption of the blood brain barrier (BBB) and subsequent cerebral edema formation is one of the major adverse effects of brain surgery, leading to postoperative neurological dysfunction. Recently, Mfsd2a has been shown to have a crucial role for the maintenance of BBB functions. In this study, we aimed to evaluate the role of Mfsd2a on BBB disruption following surgical brain injury (SBI) in rats. MATERIALS AND METHODS: Rats were subjected to SBI by partial resection of the right frontal lobe. To evaluate the effect of Mfsd2a on BBB permeability and neurobehavior outcome following SBI, Mfsd2a was either overexpressed or downregulated in the brain by administering Mfsd2a CRISPR activation or knockout plasmids, respectively. The potential mechanism of Mfsd2a-mediated BBB protection through the cav-1/Nrf-2/HO-1 signaling pathway was evaluated. RESULTS: Mfsd2a levels were significantly decreased while cav-1, Nrf-2 and HO-1 levels were increased in the right frontal perisurgical area following SBI. When overexpressed, Mfsd2a attenuated brain edema and abolished neurologic impairment caused by SBI while downregulation of Mfsd2a expression further deteriorated BBB functions and worsened neurologic performance following SBI. The beneficial effect of Mfsd2a overexpression on BBB functions was associated with diminished expression of cav-1, increased Keap-1/Nrf-2 dissociation and further augmented levels of Nrf-2 and HO-1 in the right frontal perisurgical area, leading to enhanced levels of tight junction proteins following SBI. The BBB protective effect of Mfsd2a was blocked by selective inhibitors of Nrf-2 and HO-1. CONCLUSIONS: Mfsd2a attenuates BBB disruption through cav-1/Nrf-2/HO-1 signaling pathway in rats subjected to experimental SBI.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Lesões Encefálicas/fisiopatologia , Transdução de Sinais/genética , Animais , Comportamento Animal , Água Corporal/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/terapia , Caveolina 1/genética , Lobo Frontal/lesões , Terapia Genética , Heme Oxigenase (Desciclizante)/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Masculino , Fator 2 Relacionado a NF-E2/genética , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
8.
Exp Eye Res ; 190: 107870, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31705898

RESUMO

The eye is a very important organ in the human body which is affected by various external factors. One of these factors is the sunlight which can cause the visual impairment and as well as the increase in the oxidative stress. The heme oxygenase I (HO-1) plays a very important role in the fight against the oxidative stress. The HO enzyme catalyses the degradation of the heme to the ferrous iron, the biliverdin and the carbon monoxide (CO). The HO-2 is the isoform HO-1 and is mainly constitutively expressed. We have studied the changes in the HO-1 and the HO-2 in the retina on the level of the RNA and the protein in the summer and in the winter season (the biggest difference is in the length of the day light). The retina of the eye was obtained from the breeding pigs in concern (Sus scrofa f. domestica) posthumously. The expression of the HO-1 genes in the retina cells is higher in the winter and the amount of protein decreases. However, the HO enzyme concentration definitely increases in the summer, when the production of the free radicals (the oxidative stress) related to the exposition to the sunlight is greater. The obtained results suggest that various factors have the influence on the protein synthesis. One of the factors, can be the miRNA which blocks the synthesis of the HO. Another factors, influencing the HO are the biological clock, the sunlight and the UV radiation associated with it.


Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase-1/genética , Retina/enzimologia , Estações do Ano , Animais , Western Blotting , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Sus scrofa
9.
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
10.
Biosci Rep ; 39(12)2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31729530

RESUMO

The present study was designed to investigate the protective effect of moracin on primary culture of nucleus pulposus cells in intervertebral disc and explore the underlying mechanism. Moracin treatment significantly inhibited the LPS-induced inflammatory cytokine accumulation (IL-1ß, IL-6 and TNF-α) in nucleus pulposus cells. And moracin also dramatically decreased MDA activity, and increased the levels of SOD and CAT induced by LPS challenge. Moreover, the expressions of Nrf-2 and HO-1 were decreased and the protein levels of p-NF-κBp65, p-IκBα, p-smad-3 and TGF-ß were increased by LPS challenge, which were significantly reversed after moracin treatments. Moracin treatments also decreased the levels of matrix degradation enzymes (MMP-3, MMP-13) as indicated by RT-PCR analysis. However, Nrf-2 knockdown abolished these protective effects of moracin. Together, our results demonstrated the ability of moracin to antagonize LPS-mediated inflammation in primary culture of nucleus pulposus in intervertebral disc by partly regulating the Nrf2/HO-1 and NF-κB/TGF-ß pathway in nucleus pulposus cells.


Assuntos
Benzofuranos/farmacologia , Heme Oxigenase (Desciclizante)/genética , Inflamação/tratamento farmacológico , Fator 2 Relacionado a NF-E2/genética , Estilbenos/farmacologia , Fator de Crescimento Transformador beta/genética , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , NF-kappa B/genética , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/metabolismo
11.
Artif Cells Nanomed Biotechnol ; 47(1): 3823-3831, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31556325

RESUMO

Cardiovascular complications are the leading cause of mortality and morbidity in type 2 diabetes patients. Diabetes greatly increases the risk of heart disease; therefore, the management of diabetes often involves the prevention of heart disease. DPP-4 inhibitors have been proven to be the effective therapeutic agents of glycaemic control. Recent studies have shown that certain types of DPP-4 inhibitors could also have cardiovascular benefits. In this study, we examined the protective role of the newly developed DPP-4 inhibitor anagliptin in cultured cardiac myocytic cell line H9C2 cells. Our data show that exposure of H9C2 cells to hypoxic conditions induced higher expression of DPP-4, indicating that DPP-4 is a hypoxia-inducible factor. The inhibition of DPP-4 by anagliptin ameliorates hypoxia-induced cytotoxicity and induction of the pro-inflammatory cytokines IL-6 and MCP-1. Anagliptin also suppresses hypoxia-induced oxidative stress as revealed by the detected levels of cellular ROS and reduced GSH. Moreover, anagliptin protects myocytes from hypoxia-associated reduced mitochondrial membrane potential. Mechanistically, we show that anagliptin promotes hypoxia-induced NFR2/HO1 induction but suppresses HMGB1 and MyD88 generation. Collectively, our data indicate that anagliptin-mediated DPP-4 inhibition is a protective mechanism in cardiomyocytes and imply that the DDP-4 inhibitor anagliptin plays dual roles by lowering glucose and protecting cardiomyocytes.


Assuntos
Citoproteção/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Pirimidinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL2/biossíntese , Dipeptidil Peptidase 4/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Proteína HMGB1/genética , Heme Oxigenase (Desciclizante)/genética , Interleucina-6/biossíntese , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos
12.
Sci Rep ; 9(1): 13726, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551499

RESUMO

Heme oxygenase (HO) is a ubiquitous enzyme responsible for heme breakdown, which yields carbon monoxide (CO), biliverdin (BV) and ferrous ion. Here we show that the Aedes aegypti heme oxygenase gene (AeHO - AAEL008136) is expressed in different developmental stages and tissues. AeHO expression increases after a blood meal in the midgut, and its maximal transcription levels overlaps with the maximal rate of the further modified A. aegypti biglutaminyl-biliverdin (AeBV) pigment production. HO is a classical component of stress response in eukaryotic cells, being activated under oxidative stress or increased heme levels. Indeed, the final product of HO activity in the mosquito midgut, AeBV, exerts a protective antioxidant activity. AeHO, however, does not seem to be under a classical redox-sensitive transcriptional regulation, being unresponsive to heme itself, and even down regulated when insects face a pro-oxidant insult. In contrast, AeHO gene expression responds to nutrient sensing mechanisms, through the target of rapamycin (TOR) pathway. This unusual transcriptional control of AeHO, together with the antioxidant properties of AeBV, suggests that heme degradation by HO, in addition to its important role in protection of Aedes aegypti against heme exposure, also acts as a digestive feature, being an essential adaptation to blood feeding.


Assuntos
Heme Oxigenase (Desciclizante)/genética , Transcrição Genética/genética , Aedes , Animais , Antioxidantes/metabolismo , Biliverdina/genética , Monóxido de Carbono/metabolismo , Regulação para Baixo/genética , Regulação da Expressão Gênica/genética , Heme/genética , Estresse Oxidativo/genética
13.
Arch Biochem Biophys ; 672: 108066, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31398314

RESUMO

Acinetobacter baumannii is an opportunistic pathogen that causes serious infections in critically ill and immune compromised patients. The ability to acquire iron from the hosts iron and heme containing proteins is critical to their survival and virulence. The majority of A. baumannii hypervirulent strains encode a heme uptake system that includes a putative heme oxygenase (hemO). Despite reports indicating A. baumannii can grow on heme direct evidence of extracellular heme uptake and metabolism has not been shown. Through isotopic labeling (13C-heme) we show the hypervirulent A. baumannii LAC-4 metabolizes heme to biliverdin IXα (BVIXα), whereas ATC 17978 that lacks the hemO gene cluster cannot efficiently utilize heme. Expression and purification of the protein encoded by the A. baumannii LAC-4 hemO gene confirmed catalytic conversion of heme to BVIX. We further show inhibition of abHemO with previously characterized P. aeruginosa HemO inhibitors in a fluorescence based assay that couples HemO catalytic activity to the BVIXα binding phytochrome IFP1.4. Furthermore, the hemO gene cluster encodes genes with homology to heme-dependent extra cytoplasmic function (ECF) σ factor systems. The hemophore-dependent ECF system in Pseudomonas aeruginosa has been shown to play a critical role in heme sensing and virulence within the host. The prevalence of a hemO gene cluster in A. baumannii LAC4 and other hypervirulent strains suggests it is required within the host to adapt and utilize heme and is a major contributor to virulence.


Assuntos
Acinetobacter baumannii/metabolismo , Proteínas de Bactérias/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Heme/metabolismo , Fatores de Virulência/metabolismo , Acinetobacter baumannii/enzimologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/isolamento & purificação , Ferro/metabolismo , Família Multigênica , Fatores de Virulência/genética , Fatores de Virulência/isolamento & purificação
14.
Food Funct ; 10(8): 4593-4607, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31289794

RESUMO

Drug-induced nephrotoxicity contributes to acute kidney injury (AKI) and represents a major problem in the clinical setting. We investigated the possible involvement of NLRP3 inflammasome activation in methotrexate (MTX)-induced nephrotoxicity and the protective potential of ferulic acid (FA), pointing out the role of PPARγ and Nrf2/HO-1 signaling. Rats that received MTX showed a significant increase in circulating creatinine and urea, and kidney Kim-1 levels along with multiple histological alterations. Reactive oxygen species (ROS), malondialdehyde and nitric oxide levels showed a significant increase in the kidney of rats that received MTX, while antioxidant defenses were diminished. FA ameliorated kidney function markers, prevented histological alterations, suppressed ROS production and enhanced antioxidant defenses. FA inhibited MTX-induced inflammasome activation as showed by the decreased phosphorylation of NF-κB, and expression of NLRP3, caspase-1 and IL-1ß. MTX caused apoptosis marked by increased expression of BAX, cytochrome c and caspase-3, and suppressed Bcl-2, effects that were significantly reversed in FA-treated groups. In addition, FA up-regulated Nrf2/ARE/HO-1 signaling and PPARγ expression in the kidney of MTX-induced rats. In conclusion, activation of NLRP3 inflammasome may represent a new mechanism for MTX nephrotoxicity. FA up-regulated PPARγ and Nrf2 signaling, prevented overproduction of ROS, and suppressed NF-κB/NLRP3 inflammasome axis and apoptosis in the kidney of MTX-induced rats.


Assuntos
Lesão Renal Aguda/prevenção & controle , Ácidos Cumáricos/administração & dosagem , Heme Oxigenase (Desciclizante)/metabolismo , Inflamassomos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PPAR gama/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/genética , Lesão Renal Aguda/metabolismo , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/genética , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Metotrexato/efeitos adversos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , PPAR gama/genética , Substâncias Protetoras/administração & dosagem , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Int Immunopharmacol ; 75: 105746, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325725

RESUMO

Neuropathic pain is evoked by aberrant sensory processing in the peripheral or central nervous system, which is characterized by persistent pain, tactile allodynia, or hyperalgesia. Neuroinflammation is associated with the initiation and maintenance of persistent pain in both the peripheral and central nervous systems. Hydrogen sulfide plays important regulatory roles in different physiological and pathological conditions. Therefore, we investigated the effect of hydrogen sulfide on allodynia, hyperalgesia and cytokine release in rats with neuropathic pain and the related regulatory mechanism. Neuropathic pain was established by chronic constriction injury (CCI) of the sciatic nerve in rats. Nuclear factor erythroid-2 (NF-E2)-related factor 2 (Nrf2) siRNA, hemin, Sn-protoporphyrin (SnPP)-IX and/or NaHS were administered to rats with neuropathic pain, and the spinal cord was collected to detect the expression of Nrf2, hemeoxygenase-1 (HO-1), nuclear factor-kappa B (NF-κb) and the cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 and high mobility group box (HMGB)-1 by Western blot (WB) analysis, reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence or enzyme-linked immunosorbent assay (ELISA). Mechanical allodynia, thermal hyperalgesia and the number of paw lifts were measured at different time points after operation. In the present research, neuropathic pain induced Nrf2 and HO-1 expression in the microglial cells of the spinal cord; Nrf2 and HO-1 were necessary to alleviate the hyperalgesia of CCI-induced rats; NaHS mitigated the hyperalgesia and allodynia induced by the CCI operation; and NaHS mitigated the excessive release of the cytokines TNF-α, IL-1ß, IL-6 and HMGB1 via the Nrf2/HO-1 pathway in the microglial cells of the spinal cord. These results indicated that NaHS exhibited antinociceptive and anti-inflammatory effects that were associated with the activation of the Nrf2/HO-1 pathway in the spinal cord of rats with neuropathic pain.


Assuntos
Heme Oxigenase (Desciclizante)/metabolismo , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Hiperalgesia/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Neuralgia/tratamento farmacológico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Animais , Citocinas/metabolismo , Heme Oxigenase (Desciclizante)/genética , Hiperalgesia/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/genética , Neuralgia/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
16.
Oxid Med Cell Longev ; 2019: 1245749, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360293

RESUMO

The present study focuses on the investigation of the oxidized cell-free DNA (cfDNA) properties in several experimental models, including cultured cerebellum cells, peripheral blood lymphocytes (PBL), plasma, and hippocampus under an acute and chronic unpredictable stress model in rats. Firstly, our study shows that Spectrum Green fluorescence-labeled oxidized cfDNA fragments were transferred into the cytoplasm of 80% of the cerebellum culture cells; meanwhile, the nonoxidized cfDNA fragments do not pass into the cells. Oxidized cfDNA stimulates the antioxidant mechanisms and induction of transcription factor NRF2 expression, followed by an activation of NRF2 signaling pathway genes-rise of Nrf2 and Hmox1 gene expression and consequently NRF2 protein synthesis. Secondly, we showed that stress increases plasma cfDNA concentration in rats corresponding with the duration of the stress exposure. At the same time, our study did not reveal any significant changes of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) level in PBL of rats under acute or chronic stress, probably due to the significantly increased Nrf2 expression, that we found in such conditions. 8-oxodG is one of the most reliable markers of DNA oxidation. We also found an increased level of 8-oxodG in the hippocampal homogenates and hippocampal dentate gyrus in rats subjected to acute and chronic stress. Taken together, our data shows that oxidized cfDNA may play a significant role in systemic and neuronal physiological mechanisms of stress and adaptation.


Assuntos
Antioxidantes/metabolismo , Ácidos Nucleicos Livres/metabolismo , Estresse Oxidativo , 8-Hidroxi-2'-Desoxiguanosina/análise , Animais , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/química , Células Cultivadas , Cerebelo/citologia , Cerebelo/metabolismo , Citoplasma/metabolismo , Regulação da Expressão Gênica , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Hipocampo/metabolismo , Linfócitos/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais
17.
Biofactors ; 45(4): 598-606, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31336028

RESUMO

Liver diseases are one of the fatal disorders due to the vital role of the liver. Carbon tetrachloride (CCl4 ) is the most perceived chemical substance utilized in developing models of hepatic damage. Metformin (Met) is a potent antidiabetic and redox modulatory agent that has shown anticancer and protective effects on various organs. Therefore, addition of therapy with natural antioxidative agents or herbal extracts shows defensive impacts against different injuries inside the body. Luteolin (Lut) can be found in several customary Chinese remedies. It has been reported for various pharmacological actions such as antitumor, antioxidative, and anti-inflammatory impacts. Here, the liver injury rat model was established using CCl4 (1.00 mL/kg body weight) in vivo. The protective roles of Met and Lut separately or in combination were observed in hepatotoxicity induced by CCl4 . The result was shown that both Met and Lut, while individually used, were normally active in diminishing CCl4 -caused hepatotoxicity. The combination of two drugs performed synergistically to improve liver damage caused by CCl4 , as shown by the considerably improved liver dysfunction. Met and Lut showed highly antioxidative effects on CCl4 -treated rats moderately by increasing the activities and expression of the antioxidant enzymes. Along with this, a combination of Met and Lut significantly suppressed inflammatory responses, which is evidenced by the reduced level of inflammatory cytokines together with interleukin 1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6). Additionally, CCl4 -agitated apoptosis was intensely reduced by Met and Lut through reducing cleaved caspase-3 and Bax (pro-apoptotic factor) while increasing Bcl-2 (antiapoptotic factor) signaling pathways. Cotreatments of Met and Lut upregulated nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) expression in the CCl4 -intoxicated rat's liver. The above result recommended that combination of Met and Lut may have a substantial potential and synergizing impact against CCl4 -induced hepatotoxicity.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Heme Oxigenase (Desciclizante)/genética , Luteolina/farmacologia , Metformina/farmacologia , Fator 2 Relacionado a NF-E2/genética , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono/administração & dosagem , Caspase 3/genética , Caspase 3/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Combinação de Medicamentos , Sinergismo Farmacológico , Regulação da Expressão Gênica , Heme Oxigenase (Desciclizante)/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
18.
Arch Biochem Biophys ; 671: 185-195, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31326516

RESUMO

Variations in Nrf-2 and NF-κB expression profiles have been reported in ulcerative colitis (UC), in which an interplay between these two critical pathways has been identified. The therapeutic potential of angiotensin receptor blockers (ARBs) for oxidative damage and inflammation has recently received considerable attention. Dextran sodium sulfate (DSS)-induced colitis in rats closely resembles human UC and is associated with oxidative damage and the production of pro-inflammatory mediators. Therefore, we aimed to investigate the effect of orally administered telmisartan (TEL) (1.75, 3.5 and 7 mg/kg) in a rat model of DSS-induced colitis. Our study revealed that TEL, particularly at 7 mg/kg, alleviated tissue injury and inflammatory signs upon histological analysis and enhanced survival and recovery during DSS-induced colitis. The levels of colonic IL-1ß, IL-6, TNF-α and serum C-reactive protein (CRP) were downregulated, while the level of colonic IL-10 was upregulated. TEL repressed DSS-induced neutrophil infiltration and improved the colonic antioxidant defence machinery. TEL inhibited apoptotic signalling as indicated by lower caspase 3 expression, increased CD36 gene expression and exhibited PPARγ agonistic activity. In addition, TEL downregulated gene expression and inhibited phosphorylation of the NF-κB p65 subunit. On the other hand, TEL upregulated the gene expression of Nrf-2 and HO-1. We concluded that TEL, besides its PPARγ agonistic activity, acted as a modulator of Nrf-2/NF-κB interactions and exhibited anti-apoptotic activity after tissue damage and that PPARγ and CD36 might play a critical role in the pathogenesis of murine colitis. Therefore, our findings suggest that further investigations on human IBDs are warranted.


Assuntos
Colite Ulcerativa/tratamento farmacológico , PPAR gama/agonistas , Transdução de Sinais/efeitos dos fármacos , Telmisartan/uso terapêutico , Fator de Transcrição RelA/metabolismo , Animais , Antígenos CD36/genética , Colite Ulcerativa/induzido quimicamente , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Heme Oxigenase (Desciclizante)/genética , Masculino , Fator 2 Relacionado a NF-E2/genética , Peroxidase/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/metabolismo
19.
Am J Physiol Renal Physiol ; 317(3): F695-F704, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31215802

RESUMO

Heme oxygenase (HO) activity is exhibited by inducible (HO-1) and constitutive (HO-2) proteins. HO-1 protects against ischemic and nephrotoxic acute kidney injury (AKI). We have previously demonstrated that HO-2 protects against heme protein-induced AKI. The present study examined whether HO-2 is protective in ischemic AKI. Renal ischemia was imposed on young and aged HO-2+/+ and HO-2-/- mice. On days 1 and 2 after renal ischemia, there were no significant differences in renal function between young male HO-2+/+ and HO-2-/- mice, between young female HO-2+/+ and HO-2-/- mice, or between aged female HO-2+/+ and HO-2-/- mice. However, in aged male mice, HO-2 deficiency worsened renal function on days 1 and 2 after ischemic AKI, and, on day 2 after ischemia, such deficiency augmented upregulation of injury-related genes and worsened histological injury. Renal HO activity was markedly decreased in unstressed aged male HO-2-/- mice and remained so after ischemia, despite exaggerated HO-1 induction in HO-2-/- mice after ischemia. Such exacerbation of deficiency of HO-2 protein and HO activity may reflect phosphorylated STAT3, as activation of this proinflammatory transcription factor was accentuated early after ischemia in aged male HO-2-/- mice. This exacerbation may not reflect impaired induction of nephroprotectant genes, since the induction of HO-1, sirtuin 1, and ß-catenin was accentuated in aged male HO-2-/- mice after ischemia. We conclude that aged male mice are hypersensitive to ischemic AKI and that HO-2 mitigates such sensitivity. We speculate that this protective effect of HO-2 may be mediated, at least in part, by suppression of phosphorylated STAT3-dependent signaling.


Assuntos
Lesão Renal Aguda/prevenção & controle , Heme Oxigenase (Desciclizante)/metabolismo , Rim/enzimologia , Traumatismo por Reperfusão/prevenção & controle , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/patologia , Lesão Renal Aguda/fisiopatologia , Fatores Etários , Animais , Modelos Animais de Doenças , Feminino , Heme Oxigenase (Desciclizante)/deficiência , Heme Oxigenase (Desciclizante)/genética , Rim/patologia , Rim/fisiopatologia , Masculino , Camundongos Knockout , Fosforilação , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Fator de Transcrição STAT3/metabolismo , Fatores Sexuais , Transdução de Sinais
20.
Environ Toxicol Pharmacol ; 70: 103198, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154273

RESUMO

Cadmium (Cd) is a highly toxic heavy metal with several harmful effects including cardiotoxicity. For the first time, we aimed to evaluate the possible cardioprotective effect of carvedilol (CAR) in Cd induced cardiotoxicity and study the mechanisms involved in such protection including endothelial nitric oxide synthase (eNOS) and HO1/Nrf2 pathway. CAR (1,10 mg/kg/d) was administered orally for 4 weeks with Cd induced cardiac injury (3 mg/kg/d) orally for 4 weeks. We measured cardiac enzymes, mean arterial pressure changes, heme oxygenase-1 (HO1) and total antioxidant capacity (TAC). Moreover; cardiac tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), western blotting of caspase3 and eNOS levels and histopathology were evaluated. Immunoexpression of eNOS in cardiac tissue, gene expression changes of HO1, and nuclear factor erythroid 2-related factor 2 (Nrf2) using real time polymerase chain reactions (rtPCR) were detected. Our results showed that CAR could significantly decrease Cd induced cardiotoxicity.


Assuntos
Cádmio/toxicidade , Cardiotônicos/farmacologia , Cardiotoxicidade/metabolismo , Carvedilol/farmacologia , Animais , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/genética , Carvedilol/uso terapêutico , Heme Oxigenase (Desciclizante)/genética , Masculino , Malondialdeído/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
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