RESUMEN
The clinical use of doxorubicin (DOX) is limited by its cardiotoxicity, which is closely associated with oxidative stress. Xinmailong (XML) is a bioactive peptide extracted from American cockroaches, which has been mainly applied to treat chronic heart failure in China. Our previous study showed that XML attenuates DOX-induced oxidative stress. However, the mechanism of XML in DOX-induced cardiotoxicity remains unclear. Heme oxygenase-1 (HO-1), an enzyme that is ubiquitously expressed in all cell types, has been found to take antioxidant effects in many cardiovascular diseases, and its expression is protectively upregulated under DOX treatment. Lysosome and autophagy are closely involved in oxidative stress as well. It is still unknown whether XML could attenuate doxorubicin-induced lysosomal dysfunction and oxidative stress in H9c2 cells via HO-1. Thus, this study was aimed at investigating the involvement of HO-1-mediated lysosomal function and autophagy flux in DOX-induced oxidative stress and cardiotoxicity in H9c2 cells. Our results showed that XML treatment markedly increased cell proliferation and SOD activity, improved lysosomal function, and ameliorated autophagy flux block in DOX-treated H9c2 cells. Furthermore, XML significantly increased HO-1 expression following DOX treatment. Importantly, HO-1-specific inhibitor (Znpp) or HO-1 siRNA could significantly attenuate the protective effects of XML against DOX-induced cell injury, oxidative stress, lysosomal dysfunction, and autophagy flux block. These results suggest that XML protects against DOX-induced cardiotoxicity through HO-1-mediated recovery of lysosomal function and autophagy flux and decreases oxidative stress, providing a novel mechanism responsible for the protection of XML against DOX-induced cardiomyopathy.
Asunto(s)
Doxorrubicina/farmacología , Medicamentos Herbarios Chinos/farmacología , Hemo Oxigenasa (Desciclizante)/metabolismo , Lisosomas/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/farmacología , Línea Celular , Doxorrubicina/efectos adversos , Interacciones Farmacológicas , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Lisosomas/enzimología , Miocitos Cardíacos/enzimología , RatasRESUMEN
Following renal ischemia-reperfusion injury (RIRI), because of the decrease in oxygen supply to the kidney, a large amount of oxygen-free radicals is generated, and in severe cases, tissue cells will undergo apoptosis or even die. Normobaric hyperoxia (NBHO) is a very common clinical adjuvant treatment. It restores the oxygen supply after renal ischemia and combats oxidative stress in tissues, thus playing a protective role. In this study, our aim is to elucidate the protective mechanism of NBHO inhalation in a rat RIRI model. We performed a surgical excision of the left kidney of the rat and established a right kidney solitary kidney model. Later, the right renal pedicle of the rat was clamped using a non-invasive vascular clamp for 45 min. After the vascular clamp was released and reperfused for 24 h, the rat was placed in a closed oxygen chamber. It was subjected to inhalation of high-concentration oxygen (50%-55%), 2 h daily, for 7 days.RIRI induces postoperative weight loss, impaired renal function, increased oxygen free radicals, reduced antioxidant substances, increased histopathological damage, and increased levels of apoptosis. These effects were significantly improved after treatment with NBHO. At the same time, NBHO significantly increased the expression levels of Nrf2 and HO-1 in the tissues after RIRI. To verify whether HO-1 induced by Nrf2 is involved in the resistance to oxidative stress, after the rat RIRI and before inhaling NBHO, we intraperitoneally injected HO-1 specific inhibitor zinc protoporphyrin (ZnPP) (45 µmol/Kg). However, we found that ZnPP reversed the protective effect of NBHO on RIRI in rats. Combining all the results, we have demonstrated the protective effect of NBHO on RIRI, which can be at least partially attributed to the activation of the Nrf2/HO-1 antioxidative stress pathway.
Asunto(s)
Hemo Oxigenasa (Desciclizante)/metabolismo , Hiperoxia/metabolismo , Riñón/lesiones , Riñón/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Animales , Antioxidantes/metabolismo , Apoptosis , Presión Atmosférica , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Masculino , Estrés Oxidativo , Protoporfirinas/farmacología , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/patología , Transducción de SeñalRESUMEN
Epigallocatechin 3-gallate (EGCG) is a polyphenol that has been shown to have antioxidant and anti-inflammatory effects. In this study, collagen-induced arthritis (CIA) model, in Wistar albino rats, was used to elucidate the effect of EGCG on pathogenetic pathways in inflammatory arthritis. The levels of serum TNF-α, IL-17, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx); the expression levels of tissue heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2); histopathologically, perisynovial inflammation and cartilage-bone destruction were examined. In the sham group, serum TNF-α, IL-17, and MDA levels increased, while SOD, CAT, GPx levels, and the expressions of Nrf2 and HO-1 decreased. On the other hand, in the EGCG administered groups, serum TNF-α, IL-17, and MDA levels improved, while SOD, CAT, GPx levels and the expressions of Nrf2 and HO-1 increased. Moreover, histopathological analysis has shown that perisynovial inflammation and cartilage-bone destruction decreased in the EGCG administered groups. These results suggest that EGCG has an antiarthritic effect by regulating the oxidative-antioxidant balance and cytokine levels in the CIA model, which is a surrogate experimental model of rheumatoid arthritis.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Catequina/análogos & derivados , Citocinas/antagonistas & inhibidores , Modelos Animales de Enfermedad , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/metabolismo , Catequina/farmacología , Colágeno Tipo II , Citocinas/biosíntesis , Femenino , Hemo Oxigenasa (Desciclizante)/biosíntesis , Factor 2 Relacionado con NF-E2/biosíntesis , Ratas , Ratas WistarRESUMEN
OBJECTIVES: This study aimed to investigate the pharmacological function and underlying regulation mechanisms of Ginsenoside-Rb3 (G-Rb3) in cardioprotection. METHODS: Cultured H9C2 cells were pre-treated with gradient concentrations of G-Rb3, and subsequently challenged with hypoxia/reoxygenation (H/R) treatment. The generation of intracellular reactive oxygen species (ROS) and cellular antioxidatant capacity were quantified. Cell apoptosis was measured by flow cytometry. Myocardial ischemia reperfusion injury (MIRI) rat models constructed by coronary artery ligation surgery were orally administrated with G-Rb3 for 5 consecutive days, and then infarction area, apoptosis ratio and total antioxidant capacity (T-AOC) of myocardial tissues were measured. PERK phosphorylation inhibitor GSK2656157 and Nrf2 translocation inhibitor ML385 were co-treated with G-Rb3 to further verify the signaling pathway mediated by G-Rb3. RESULTS: H/R treatment induced prominent ROS deposition and elevated cell apoptosis ratio in H9C2 cells. G-Rb3 pretreatment suppressed intracellular ROS accumulation and enhanced T-AOC, partially rescuing cardiomyocytes from oxidative stress and apoptosis induced by H/R. In vivo, the cardiac infarction area of MIRI model rats was reduced by G-Rb3 treatment via improved total antioxidant levels. In the further functional and mechanistic studies, G-Rb3 was found to induce PERK phosphorylation and nuclear translocation of transcriptional factor Nrf2, promoting the expression of antioxidative genes such as HMOX1. Inhibitors GSK2656157 and ML385 reversed the effects of G-Rb3. CONCLUSION: Our studies revealed a novel mechanism of G-Rb3 to attenuates oxidative stress via activating the antioxidation signaling pathway of PERK/Nrf2/HMOX1 in vivo and in vitro, which may help us to enrich the theoretical knewledge of Ginsenoside-Rb3 in cardiopretection.
Asunto(s)
Cardiotónicos/farmacología , Ginsenósidos/farmacología , Hemo Oxigenasa (Desciclizante)/metabolismo , Miocitos Cardíacos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , eIF-2 Quinasa/metabolismo , Adenina/análogos & derivados , Adenina/farmacología , Animales , Antioxidantes/metabolismo , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/fisiología , Línea Celular , Relación Dosis-Respuesta a Droga , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Indoles/farmacología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Panax , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , eIF-2 Quinasa/antagonistas & inhibidoresRESUMEN
One of the worldwide metabolic health dilemma is nonalcoholic fatty liver diseases (NAFLD). Researchers are searching effective drug to manage NAFLD patients. One of the best way to manage the metabolic imperfection is through natural principal isolated from different sources. Butein, a natural compound known to have numerous pharmacological application. In the current study we assessed the therapeutic effect of butein administration on liver function tests, oxidative stress, antioxidants, lipid abnormalities, serum inflammatory cytokines, and mitochondrial reactive oxygen species levels, in rats with methionine-choline deficient (MCD) diet induced NAFLD. Male Wistar rats were treated with MCD diet with/without butein (200 mg/kg body wt. orally) for 6 weeks. The protective effect of butein, were evident from decreased transaminase activities, restoration of albumin, globulin, albumin/globulin ratio, and oxidants in serum (P < 0.01), further it improved liver antioxidant status (P < 0.01). Butein significantly lowered lipid profile parameters (P < 0.01), suppressed inflammatory cytokines (P < 0.01), and improved liver histology. Further to understand the possible mechanism behind the hepatoprotective and lipid lowering effect of butein, the activities of heme oxygenase (HO1), myeloperoxidase (MPO), and mitochondrial reactive oxygen species (ROS) were measured. We found that butein supplementation significantly decreased the activity of HO1 (P < 0.001), and increased the activity of MPO (P < 0.001). Furthermore butein attenuated mitochondrial ROS produced in NAFLD condition. Present study shows that butein supplementation restore liver function by altering liver oxidative stress, inflammatory markers, vital defensive enzyme activities, and mitochondrial ROS. In summary, butein has remarkable potential to develop effective hepato-protective drug. © 2018 BioFactors, 44(3):289-298, 2018.
Asunto(s)
Chalconas/farmacología , Deficiencia de Colina/tratamiento farmacológico , Dieta/efectos adversos , Hipolipemiantes/farmacología , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Administración Oral , Albúminas/metabolismo , Animales , Colina/metabolismo , Deficiencia de Colina/etiología , Deficiencia de Colina/metabolismo , Deficiencia de Colina/patología , Globulinas/metabolismo , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hemo Oxigenasa (Desciclizante)/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Metionina/deficiencia , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Peroxidasa/antagonistas & inhibidores , Peroxidasa/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Transaminasas/antagonistas & inhibidores , Transaminasas/metabolismoRESUMEN
BACKGROUND: As an indispensable clinical inhalation anesthetic, sevoflurane is widely used for peri-operative sedation. The neuroprotective effect of sevoflurane pre-conditioning against cerebral ischemia/reperfusion has been gradually realized, but the underlying mechanism during the early reperfusion period has not been established. METHOD: Primary cultured cortical neurons were treated with 2% sevoflurane pre-conditioning for 30min, exposed to oxygen-glucose deprivation for 90min, and followed by 60min of reperfusion (OGD/R). Additionally, neuronal cells were treated with an inhibitor of extracellular signal-related kinases 1 and 2 (Erk1/2) phosphorylation (PD98059), a mPTP opener (atractyloside), or a mPTP opening inhibitor (cyclosporine A) before sevoflurane pre-conditioning. RESULT: Sevoflurane pre-conditioning decreased neuronal apoptosis (assessed by TUNEL), oxidative stress (assessed by malondialdehyde [MDA], superoxide dismutase [SOD], and heme oxygenase [HO]-1), and opening of mitochondrial permeability transition pores [mPTPs] (assessed by calcein-cobalt), but increased neuronal viability (assessed by MTT) and mitochondrial membrane potential (assessed by JC-1) after OGD/R exposure compared with OGD/R treatment alone. Pre-treatment with the mPTP opener and inhibitor of Erk1/2 phosphorylation abolished the protective effect induced by sevoflurane pre-conditioning. Pre-treatment with the mPTP opener attenuated the phosphorylation of Erk1/2 in mitochondria of neuronal cultures exposed to OGD/R induced by sevoflurane pre-conditioning. The mPTP opening inhibitor, like sevoflurane pre-conditioning, increased phosphorylation of Erk1/2 after OGD/R exposure, while PD98059 failed to reverse inhibition of mPTP opening in cultures exposed to OGD/R induced by sevoflurane pre-conditioning. CONCLUSION: The neuroprotective mechanism of sevoflurane pre-conditioning might be associated with increased Erk1/2 phosphorylation in mitochondria via inhibition of mPTP opening in the early reperfusion period.
Asunto(s)
Hemo Oxigenasa (Desciclizante)/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Éteres Metílicos/farmacología , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Atractilósido/farmacología , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/fisiología , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Ciclosporina/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Glucosa/deficiencia , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Ratas Sprague-Dawley , SevofluranoRESUMEN
The present study has been designed and carried out to explore the role of grape seed proanthocyanidins (GSP) in the pancreas of cadmium (Cd)-induced cellular oxidative stress-mediated toxicity in rats. Four groups of healthy rats were given oral doses of Cd (5-mg/kg BW) and to identify the possible mechanism of action of GSP 100-mg/kg BW was selected and was given 90 min before Cd intoxication. The causative molecular and cellular mechanism of Cd was determined using various biochemical assays, histology, western blotting and ELISA. Cd intoxication revealed increased levels of proinflammatory cytokines (TNF-α, IL1ß and IFN-γ), reduced levels of cellular defense proteins (Nrf-2 and HO-1) and glucose transporter (GLUT-2 and GLUT-4) along with the enhanced levels of signaling molecules of apoptosis (cleaved Caspase-12/9/8/3) in the pancreas of Cd-intoxicated rats. Results suggested that the treatment with GSP reduced blood glucose level, increased plasma insulin and mitigated oxidative stress-related markers. GSP protects pancreatic tissue by attenuated inflammatory responses and inhibited apoptosis. This uniqueness and absence of any detectable adverse effect of GSP proposes the possibility of using it as an effective protector in the oxidative stress-mediated pancreatic dysfunction in rats.
Asunto(s)
Antioxidantes/uso terapéutico , Intoxicación por Cadmio/dietoterapia , Suplementos Dietéticos , Extracto de Semillas de Uva/uso terapéutico , Estrés Oxidativo , Páncreas/metabolismo , Pancreatitis/prevención & control , Proantocianidinas/uso terapéutico , Animales , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Apoptosis/efectos de los fármacos , Biomarcadores/sangre , Biomarcadores/metabolismo , Cloruro de Cadmio/administración & dosificación , Intoxicación por Cadmio/metabolismo , Intoxicación por Cadmio/patología , Intoxicación por Cadmio/fisiopatología , Citocinas/agonistas , Citocinas/antagonistas & inhibidores , Citocinas/sangre , Citocinas/metabolismo , Suplementos Dietéticos/efectos adversos , Transportador de Glucosa de Tipo 2/agonistas , Transportador de Glucosa de Tipo 2/antagonistas & inhibidores , Transportador de Glucosa de Tipo 2/metabolismo , Transportador de Glucosa de Tipo 4/agonistas , Transportador de Glucosa de Tipo 4/antagonistas & inhibidores , Transportador de Glucosa de Tipo 4/metabolismo , Extracto de Semillas de Uva/administración & dosificación , Extracto de Semillas de Uva/efectos adversos , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hemo Oxigenasa (Desciclizante)/química , Hemo Oxigenasa (Desciclizante)/metabolismo , Hiperglucemia/etiología , Hiperglucemia/prevención & control , Masculino , Factor 2 Relacionado con NF-E2/agonistas , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Páncreas/efectos de los fármacos , Páncreas/inmunología , Páncreas/patología , Pancreatitis/etiología , Pancreatitis/inmunología , Proantocianidinas/administración & dosificación , Proantocianidinas/efectos adversos , Distribución Aleatoria , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVE: To assess the efficacy of the heme oxygenase inhibitor, tin mesoporphyrin (SnMP), to reduce total bilirubin (TB) levels. STUDY DESIGN: Masked, SnMP (4.5 mg kg(-1)), placebo-controlled, multicenter trial of single intramuscular injection to newborns ⩾35 weeks gestational age whose predischarge screening transcutaneous bilirubin (TcB) was >75th percentile. RESULTS: Two hundred and thirteen newborns (median age 30 h) were randomized to treatment with SnMP (n=87) or 'sham' (n=89). We found that the duration of phototherapy was halved. Within 12 h of SnMP administration, the natural TB trajectory was reversed. At age 3 to 5 days, TB in the SnMP-treated group was +8% but sixfold lower than the 47% increase in the sham-treated group (P<0.001). At age 7 to 10 days, mean TB declined 18% (P<0.001) compared with a 7.1% increase among controls. No short-term adverse events from SnMP treatment were noted other than photoreactivity due to inadvertent exposure to white light phototherapy. CONCLUSION: Early, predischarge SnMP administration decreased the duration of phototherapy, reversed TB trajectory and reduced the severity of subsequent hyperbilirubinemia.
Asunto(s)
Bilirrubina/sangre , Hemo Oxigenasa (Desciclizante)/administración & dosificación , Hiperbilirrubinemia Neonatal/terapia , Recien Nacido Prematuro/sangre , Metaloporfirinas/administración & dosificación , Femenino , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal/métodos , Fototerapia/métodos , Estados UnidosRESUMEN
Triptolide is a bioactive component of Chinese herbal plant Tripterygium wilfordii Hook F that has recently been noted to attenuate hepatic and cerebral ischemia/reperfusion (I/R) injuries in rodents. To investigate whether triptolide could protect against myocardial I/R injuries, triptolide (25, 50 or 100 µg/kg) was administrated in Wistar rats that underwent left anterior descending coronary artery ligation in this study. Our data showed that triptolide pretreatment could attenuate myocardial infarction, increase the fractional shortening and left ventricular systolic pressure and decrease the left ventricular end-diastolic pressure in ischemic rats. Also, triptolide was noted to inhibit the activities of lactate dehydrogenase and creatine kinase in I/R rats. Moreover, triptolide administration suppressed macrophage infiltration, inhibited the overproduction of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6 and malondialdehyde (MDA) in reperfused myocardium tissues and upregulated the activities of antioxidative superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GPx). In addition, nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the activity of its downstream target Heme oxygenase-1 (HO-1) in ischemic myocardium tissues were enhanced by triptolide pretreatment. In addition, the HO-1 inhibitor, zinc protoporphyrin-IX, abrograted the cardiac protection mediated by triptolide. Our study reveals a novel cardioprotective effect of triptolide in rats with I/R injuries, wherein the activation of Nrf2/HO-1 signaling was involved.
Asunto(s)
Cardiotónicos/farmacología , Diterpenos/farmacología , Hemo Oxigenasa (Desciclizante)/metabolismo , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/enzimología , Factor 2 Relacionado con NF-E2/metabolismo , Fenantrenos/farmacología , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Biomarcadores/metabolismo , Citocinas/metabolismo , Citoprotección , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Compuestos Epoxi/farmacología , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Contracción Miocárdica/efectos de los fármacos , Infarto del Miocardio/enzimología , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Harpagophytum procumbens (H. procumbens), also known as Devil's Claw, has been used to treat a wide range of pathological conditions, including pain, arthritis and inflammation. Inflammatory mediators, released at the site of injury, can sensitize nociceptive terminals and are responsible for allodynia and hyperalgesia. Carbon monoxide (CO), produced in a reaction catalyzed by the enzyme heme oxygenase (HO), may play a role in nociceptive processing and has also been recognized to act as a neurotransmitter or neuromodulator in the nervous system. This study was designed to investigate whether the HO/CO pathway is involved in the analgesic response of H. procumbens in carrageenan-induced hyperalgesia in rats. Mechanical allodynia and thermal hyperalgesia were evaluated by using von Frey filaments and the plantar test, respectively. The results of our experiments showed that pretreatment with the HO inhibitor ZnPP IX significantly decreased the antihyperalgesic effect produced by H. procumbens (800 mg/kg, i.p.) in carrageenan-injected rats. Consistently, the pretreatment with hemin, a HO-1 substrate, or CORM-3, a CO releasing molecule, before a low dose of H. procumbens (300 mg/kg, i.p.) induced a clear antiallodynic response in carrageenan injected rats. These results suggest the involvement of HO-1/CO system in the antiallodynic and antihyperalgesic effect of H. procumbens in carrageenan-induced inflammatory pain.
Asunto(s)
Analgésicos/farmacología , Harpagophytum/química , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Animales , Monóxido de Carbono/metabolismo , Carragenina/toxicidad , Hiperalgesia/inducido químicamente , Inflamación/inducido químicamente , Masculino , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Insufficient production of neurotrophic factors is implicated in the pathogenesis of various neurodegenerative disorders. The aim of the present study was to evaluate the potential of N-propargyl caffeate amide (PACA) to enhance nerve growth factor (NGF)-induced neurite outgrowth and the underlying mechanisms. We discovered that PACA not only potentiated NGF-induced neurite outgrowth but also attenuated 6-hydroxydopamine (6-OHDA) neurotoxicity in dopaminergic PC12 cells and primary rat midbrain neurons. To identify the PACA-binding proteins, we introduced a biotin tag to the covalent PACA-protein adducts via "click chemistry" alkyne-azido cycloaddition. As a result, kelch-like ECH-associated protein 1 (Keap1) was isolated as the predominant protein from PACA treated PC12 cells. We demonstrated that the formation of PACA-Keap1 conjugates induced the nuclear translocation of transcription factor Nrf2 and the expression of antioxidant heme oxygenase-1 (HO-1). Importantly, specific HO-1 inhibitor SnPP diminished the neuroprotective and neuritogenic activities of PACA. Moreover, PACA attenuated 6-OHDA-induced production of neurotoxic reactive oxygen species and reactive nitrogen species. PACA also preserved mitochondrial membrane integrity and enhanced the cellular resistance against 6-OHDA neurotoxicity. These results suggest that PACA may exhibit neuroprotective and neuritogenic activities via activating the Nrf2/HO-1 antioxidant pathway.
Asunto(s)
Ácidos Cafeicos/farmacología , Hemo Oxigenasa (Desciclizante)/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Neuritas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Transporte Activo de Núcleo Celular/efectos de los fármacos , Transporte Activo de Núcleo Celular/fisiología , Animales , Ácidos Cafeicos/síntesis química , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patología , Dopamina/metabolismo , Evaluación Preclínica de Medicamentos , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Mesencéfalo/efectos de los fármacos , Mesencéfalo/patología , Mesencéfalo/fisiopatología , Neuritas/patología , Neuritas/fisiología , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/fisiología , Fármacos Neuroprotectores/síntesis química , Óxido Nítrico/metabolismo , Oxidopamina/toxicidad , Células PC12 , Ratas , Superóxidos/metabolismoRESUMEN
Hyperoxic acute lung injury (HALI) is a clinical syndrome as a result of prolonged supplement of high concentrations of oxygen. Previous studies have shown hyperbaric oxygen preconditioning (HBO-PC) had a protective effect on oxidative injury. In the present study, we investigated the effect of HBO-PC on HALI in rats. The results demonstrated that HBO-PC ameliorated the lung biochemical and histological alterations induced by hyperoxia, decreased oxidative products but increased antioxidant enzymes. Furthermore, HBO-PC up-regulated heme oxygenase-1 (HO-1) mRNA and activity in lung tissues. The administration of HO-1 inhibitor, Zinc protoporphyrin IX, abolished its protective effects. The data showed that HBO-PC could protect rats against HALI and the anti-oxidative effect may be related to the up-regulation of HO-1.
Asunto(s)
Lesión Pulmonar Aguda/prevención & control , Hemo Oxigenasa (Desciclizante)/biosíntesis , Oxigenoterapia Hiperbárica/métodos , Hiperoxia/prevención & control , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , Lesión Pulmonar Aguda/patología , Animales , Inhibidores Enzimáticos/administración & dosificación , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hiperoxia/patología , L-Lactato Deshidrogenasa/metabolismo , Masculino , Protoporfirinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Lesión Pulmonar Inducida por Ventilación Mecánica/patologíaRESUMEN
We recently reported that chronic nicotine impairs reflex chronotropic activity in female rats. Here, we sought evidence to implicate nitric oxide synthase (NOS) and/or heme oxygenase (HO) in the nicotine-baroreflex interaction. Baroreflex curves relating changes in heart rate to increases (phenylephrine) or decreases (sodium nitroprusside) in blood pressure were generated in conscious female rats treated with nicotine or saline in absence and presence of pharmacological modulators of NOS or HO activity. Compared with saline-treated rats, nicotine (2 mg/kg/day i.p., for 14 days) significantly reduced the slopes of baroreflex curves, a measure of baroreflex sensitivity (BRS). Findings that favor the involvement of NOS inhibition in the nicotine effect were (i) NOS inhibition (Nω-Nitro-L-arginine methyl ester, L-NAME) reduced BRS in control rats but failed to do so in nicotine-treated rats, (ii) L-arginine, NO donor, reversed the BRS inhibitory effect of nicotine. Alternatively, HO inhibition (zinc protoporphyrin IX, ZnPP) had no effect on BRS in nicotine- or control rats and failed to reverse the beneficial effect of L-arginine on nicotine-BRS interaction. Similar to female rats, BRS was reduced by L-NAME, but not ZnPP, in male rats and the L-NAME effect was not accentuated after concomitant administration of nicotine. Baroreflex dysfunction caused by nicotine in female rats was blunted after supplementation with hemin (HO inducer) but not tricarbonyldichlororuthenium(II) dimer (CORM-2), a carbon monoxide (CO) releasing molecule, or bilirubin, the breakdown product of heme catabolism. The facilitatory effect of hemin was abolished upon simultaneous treatment with L-NAME or 1H-[1], [2], [4] oxadiazolo[4,3-a] quinoxalin-1-one (inhibitor of soluble guanylate cyclase, sGC). The activities of HO and NOS in brainstem tissues were also significantly increased by hemin. Thus, the inhibition of NOS, but not HO, accounts for the baroreflex depressant of chronic nicotine. Further, hemin alleviates the nicotine effect through a mechanism that is NOS/sGC but not CO or bilirubin-dependent.
Asunto(s)
Barorreflejo/fisiología , Hemo Oxigenasa (Desciclizante)/metabolismo , Nicotina/toxicidad , Óxido Nítrico Sintasa/metabolismo , Análisis de Varianza , Animales , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Tronco Encefálico/metabolismo , Femenino , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hemina , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/genética , Nitroprusiato/farmacología , Compuestos Organometálicos , Fenilefrina/farmacología , Protoporfirinas/farmacología , Ratas , Factores SexualesRESUMEN
We have shown previously that inhibition of sEH (soluble epoxide hydrolase) increased EETs (epoxyeicosatrienoic acids) levels and reduced renal injury in diabetic mice and these changes were associated with induction of HO (haem oxygenase)-1. The present study determines whether the inhibition of HO negates the renoprotective effect of sEH inhibition in diabetic SHR (spontaneously hypertensive rats). After 6 weeks of induction of diabetes with streptozotocin, SHR were divided into the following groups: untreated, treated with the sEH inhibitor t-AUCB {trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid}, treated with the HO inhibitor SnMP (stannous mesoporphyrin), and treated with both inhibitors for 4 more weeks; non-diabetic SHR served as a control group. Induction of diabetes significantly increased renal sEH expression and decreased the renal EETs/DHETEs (dihydroxyeicosatrienoic acid) ratio without affecting HO-1 activity or expression in SHR. Inhibition of sEH with t-AUCB increased the renal EETs/DHETEs ratio and HO-1 activity in diabetic SHR; however, it did not significantly alter systolic blood pressure. Treatment of diabetic SHR with t-AUCB significantly reduced the elevation in urinary albumin and nephrin excretion, whereas co-administration of the HO inhibitor SnMP with t-AUCB prevented these changes. Immunohistochemical analysis revealed elevations in renal fibrosis as indicated by increased renal TGF-ß (transforming growth factor ß) levels and fibronectin expression in diabetic SHR and these changes were reduced with sEH inhibition. Co-administration of SnMP with t-AUCB prevented its ability to reduce renal fibrosis in diabetic SHR. In addition, SnMP treatment also prevented t-AUCB-induced decreases in renal macrophage infiltration, IL-17 expression and MCP-1 levels in diabetic SHR. These findings suggest that HO-1 induction is involved in the protective effect of sEH inhibition against diabetic renal injury.
Asunto(s)
Benzoatos/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Epóxido Hidrolasas/antagonistas & inhibidores , Hemo Oxigenasa (Desciclizante)/fisiología , Urea/análogos & derivados , Actinas/metabolismo , Albuminuria/prevención & control , Animales , Benzoatos/antagonistas & inhibidores , Benzoatos/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Creatinina/orina , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/fisiopatología , Nefropatías Diabéticas/enzimología , Nefropatías Diabéticas/metabolismo , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Epóxido Hidrolasas/metabolismo , Epóxido Hidrolasas/fisiología , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hemo Oxigenasa (Desciclizante)/metabolismo , Hemo-Oxigenasa 1/antagonistas & inhibidores , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/fisiología , Corteza Renal/metabolismo , Masculino , Proteínas de la Membrana/orina , Metaloporfirinas/farmacología , Ratas , Ratas Endogámicas SHR , Urea/antagonistas & inhibidores , Urea/farmacología , Urea/uso terapéuticoRESUMEN
We describe the use of tin-mesoporphyrin (SnMP) in the treatment of an infant with Rh hemolytic disease. The infant's hyperbilirubinemia responded to phototherapy but every time the phototherapy was discontinued, the serum bilirubin rebounded and repeat phototherapy was necessary. A single intramuscular dose of SnMP on day 18 eliminated the need for further phototherapy and allowed us to discharge this infant.
Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Eritroblastosis Fetal/tratamiento farmacológico , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Metaloporfirinas/uso terapéutico , Adulto , Terapia Combinada , Humanos , Hiperbilirrubinemia , Masculino , RetratamientoRESUMEN
BACKGROUND: Neonatal hyperbilirubinemia arises from increased bilirubin production and decreased bilirubin elimination. Although phototherapy safely and effectively reduces bilirubin levels, recent evidence shows that it has adverse effects. Therefore, alternative treatments are warranted. Metalloporphyrins, competitive inhibitors of heme oxygenase (HO), the rate-limiting enzyme in bilirubin production, effectively reduce bilirubin formation; however, many are photoreactive. Here, we investigated possible photosensitizing effects of chromium mesoporphyrin (CrMP) and zinc deuteroporphyrin bis-glycol (ZnBG). METHODS AND RESULTS: Administration of CrMP or ZnBG to 3-d-old mouse pups (3.75-30.0 µmol/kg intraperitoneally) and exposure to cool white (F20T12CW) and blue (TL20W/52) fluorescent lights (+L) for 3 h, resulted in a dose-dependent mortality (50% lethal dose (LD50) = 21.5 and 19.5 µmol/kg, respectively). In contrast to ZnBG, there was no significant difference in survival between the CrMP+L and CrMP groups. Following 30 µmol/kg ZnBG+L, we found significant weight loss, decreased liver antioxidant capacities, and increased aspartate aminotransaminase levels. At 6-d post-light exposure, ZnBG+L-treated pups showed gross and histologic skin changes at doses >7.5 µmol/kg. No lethality was observed following treatment with 30 µmol ZnBG/kg plus exposure to blue light-emitting diodes. Phototoxicity of ZnBG was dependent on light source, emission spectrum, and irradiance. CONCLUSION: Low doses of ZnBG (<3.75 µmol/kg) retained maximal HO inhibitory potency without photosensitizing effects, and therefore are potentially useful in treating neonatal hyperbilirubinemia.
Asunto(s)
Animales Recién Nacidos , Deuteroporfirinas/farmacología , Hiperbilirrubinemia Neonatal/tratamiento farmacológico , Luz , Mesoporfirinas/toxicidad , Fármacos Fotosensibilizantes/toxicidad , Animales , Bilirrubina/biosíntesis , Deuteroporfirinas/administración & dosificación , Relación Dosis-Respuesta a Droga , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Dosificación Letal Mediana , Mesoporfirinas/administración & dosificación , Ratones , Fármacos Fotosensibilizantes/administración & dosificación , Análisis de SupervivenciaRESUMEN
Age-related changes in joint tissues lead to osteoarthritis (OA). Detection of early changes in OA patients may help to initiate treatments before the establishment of irreversible joint destruction. STR/ort mice develop with age a severe degenerative joint disease that resembles human OA thus allowing the investigation of biochemical markers as well as new treatments in an accelerated time frame. We have analyzed the changes in serum levels of different mediators during the early phases of idiopathic OA in STR/ort mice. Serum levels of matrix metalloproteinase-3 (MMP-3) but not those of tumor necrosis factor-α, interleukin(IL)-1ß, IL-17 or prostaglandin E(2) correlated with histopathological changes in knees of STR/ort mice at 9 weeks. Treatment of animals with tin protoporphyrin IX (SnPP, 12 mg/kg/dayi.p.) for 4 weeks significantly reduced the progression of OA. Our data suggest that MMP-3 is a sensitive biomarker to detect early OA alterations and that SnPP could be a protective agent in OA.
Asunto(s)
Artritis Experimental/diagnóstico , Inhibidores Enzimáticos/uso terapéutico , Metaloporfirinas/uso terapéutico , Osteoartritis/diagnóstico , Protoporfirinas/uso terapéutico , Animales , Artritis Experimental/sangre , Artritis Experimental/patología , Artritis Experimental/prevención & control , Biomarcadores/sangre , Pruebas Enzimáticas Clínicas/métodos , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Diagnóstico Precoz , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Masculino , Metaloproteinasa 3 de la Matriz/sangre , Ratones , Ratones Endogámicos , Osteoartritis/sangre , Osteoartritis/patología , Osteoartritis/prevención & controlRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum cassia Blume has been used as a traditional Chinese herbal medicine for alleviation of fever, inflammation, chronic bronchitis, and to improve blood circulation. AIM OF THE STUDY: We addressed whether 2-methoxycinnamaldehyde (2-MCA), one of active ingredients of Cinnamomum cassia, reduces vascular cell adhesion molecule-1 (VCAM-1) expression in tumor necrosis factor-alpha (TNF-α)-activated endothelial cells and protects ischemia/reperfusion (I/R)-injury due to heme oxygenase (HO)-1 induction. MATERIALS AND METHODS: Adult male rats were subjected to 30 min of ischemia by occlusion of the left anterior descending coronary artery followed by 24h of reperfusion. Rats were randomized to receive vehicle or 2-MCA (i.v.) 10 min before reperfusion. RESULTS: Administration of 2-MCA significantly improved I/R-induced myocardial dysfunction by increasing the values of the first derivative (±dp/dt) of left ventricular pressure and decreased infarct size. In addition, 2-MCA reduced the expression of high mobility group box 1 (HMGB1), an activator of the inflammatory cascade when released into the extracellular space, and VCAM-1 in I/R myocardium along with increase of HO-1 induction. The reduced injury was accompanied by significantly reduction of neutrophils infiltration and increased SOD activity in ischemic tissues and reduced serum level of cardiac troponin I (cTnI). Furthermore, 2-MCA significantly increased HO-1 induction by translocation of Nrf-2 from cytosol to nucleus in endothelial cells. Inhibition of VCAM-1 expression by 2-MCA was reversed both by SnPPIX, a HO-1 inhibitor and siHO-1 RNA trasfection in TNF-α-activated cells. In addition, 2-MCA significantly inhibited NF-κB luciferase activity in TNF-α-activated endothelial cells. As expected, 2-MCA significantly inhibited monocyte (U937) adhesion to endothelial cells. CONCLUSION: We concluded that 2-MCA protects of myocardial I/R-injury due to antioxidant and anti-inflammatory action possibly by HO-1 induction which can be explained why Cinnamomum cassia has been used in inflammatory disorders.
Asunto(s)
Acroleína/análogos & derivados , Cardiotónicos/farmacología , Cinnamomum aromaticum , Hemo Oxigenasa (Desciclizante)/biosíntesis , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/enzimología , Extractos Vegetales/farmacología , Acroleína/aislamiento & purificación , Acroleína/farmacología , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Cardiotónicos/aislamiento & purificación , Cinnamomum aromaticum/química , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inducción Enzimática , Inhibidores Enzimáticos/farmacología , Proteína HMGB1/metabolismo , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hemo Oxigenasa (Desciclizante)/genética , Hemo-Oxigenasa 1/biosíntesis , Hemodinámica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/enzimología , Células Endoteliales de la Vena Umbilical Humana/inmunología , Humanos , Masculino , Infarto del Miocardio/enzimología , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/patología , FN-kappa B/genética , FN-kappa B/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Interferencia de ARN , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Factores de Tiempo , Transfección , Troponina I/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Células U937 , Molécula 1 de Adhesión Celular Vascular/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Presión Ventricular/efectos de los fármacosRESUMEN
Infants with hemolytic diseases frequently develop hyperbilirubinemia and are treated with phototherapy, which only eliminates bilirubin after its production. A better strategy might be to directly inhibit heme oxygenase (HO), the rate-limiting enzyme in bilirubin production. Metalloporphyrins (Mps) are heme analogs that competitively inhibit HO activity in vitro and in vivo and suppress plasma bilirubin levels in vivo. A promising Mp, zinc deuteroporphyrin bis glycol (ZnBG), is orally absorbed and effectively inhibits HO activity at relatively low doses. We determined the I(50) (the dose needed to inhibit HO activity by 50%) of orally administered ZnBG in vivo and then evaluated ZnBG's effects on in vivo bilirubin production, HO activity, HO protein levels, and HO-1 gene expression in newborn mice after heme loading, a model analogous to a hemolytic infant. The I(50) of ZnBG was found to be 4.0 µmol/kg body weight (BW). At a dose of 15 µmol/kg BW, ZnBG reduced in vivo bilirubin production, inhibited heme-induced liver HO activity and spleen HO activity to and below baseline, respectively, transiently induced liver and spleen HO-1 gene transcription, and induced liver and spleen HO-1 protein levels. We conclude that ZnBG may be an attractive compound for treating severe neonatal hyperbilirubinemia caused by hemolytic disease.
Asunto(s)
Deuteroporfirinas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hiperbilirrubinemia Neonatal/prevención & control , Animales , Animales Recién Nacidos , Bilirrubina/sangre , Western Blotting , Monóxido de Carbono/análisis , Cromatografía de Gases , Relación Dosis-Respuesta a Droga , Hemo Oxigenasa (Desciclizante)/genética , Hemo Oxigenasa (Desciclizante)/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Reacción en Cadena en Tiempo Real de la Polimerasa , Bazo/efectos de los fármacos , Bazo/metabolismoRESUMEN
We previously showed that cyclosporine (CSA) impairs renal vasodilations caused by ß-adrenoceptor activation. This study investigated whether the peroxisome proliferator-activated receptor gamma (PPARγ) and related nitric oxide synthase (NOS)/heme oxygenase (HO) signaling mediates the CSA-ß-adrenoceptor interaction. The vasodilatory response elicited by a bolus injection of isoprenaline (1 µmole) in phenylephrine-preconstricted perfused kidneys of rats was reduced after prior infusion of zinc protoporphyrin IX (ZnPP, HO inhibitor) or GW9662 (PPARγ antagonist), suggesting the involvement of PPARγ and HO-derived CO in the isoprenaline response. In contrast, the inhibition of NOS activity by N-nitro-l-arginine methyl ester had no effect on isoprenaline responses. CSA (5 µM) significantly attenuated isoprenaline vasodilations, an effect that was abolished in the presence of GW9662 and accentuated by ZnPP. Also, supplementation with the PPARγ agonist pioglitazone or with l-arginine or hemin, substrates for NOS and HO, respectively, eliminated the unfavorable effect of CSA on isoprenaline vasodilations. The protection conferred by pioglitazone against CSA-evoked attenuation of isoprenaline vasodilations was maintained in N-nitro-l-arginine methyl ester-treated kidneys and disappeared after treatment with ZnPP or GW9662. In conclusion, the activation of the HO/CO/PPARγ cascade is probably the cellular mechanism that underlies the beneficial effect of pioglitazone on the CSA-isoprenaline interaction. Further, the facilitation of the HO/CO or NOS/NO pathway seems to offset this harmful effect of CSA.