RESUMO
Administration of Chemotherapeutics, especially doxorubicin (DOX) and cyclophosphamide (CPS), is commonly associated with adverse effects such as myelosuppression and cardiotoxicity. At this time, few approved therapeutic options are currently available for the management of chemotherapy-associated cardiotoxicity. Thus, identification of novel therapeutics with potent cardioprotective properties and minimal adverse effects are pertinent in treating Doxorubicin and Cyclophosphamide-induced cardiotoxicity. Oroxylum indicum extract (OIE, Sabroxy®) is a natural product known to possess several beneficial biological functions including antioxidant, anti-inflammatory and cytoprotective effects. We therefore set to investigate the cardioprotective effects of OIE against Doxorubicin and Cyclophosphamide-induced cardiotoxicity and explore the potential cardioprotective mechanisms involved. Adult male mice were treated with DOX and CPS in combination, OIE alone, or a combination of OIE and DOX & CPS. Swimming test was performed to assess cardiac function. Markers of oxidative stress were assessed by levels of reactive oxygen species (ROS), nitrite, hydrogen peroxide, catalase, and glutathione content. The activity of interleukin converting enzyme and cyclooxygenase was determined as markers of inflammation. Mitochondrial function was assessed by measuring Complex-I activity. Apoptosis was assessed by Caspase-3 and protease activity. Mice treated with DOX and CPS exhibited reduced swim rate, increased oxidative stress, increased inflammation, and apoptosis in the heart tissue. These cardiotoxic effects were significantly reduced by co-administration of OIE. Furthermore, computational molecular docking studies revealed potential binding of DOX and CPS to tyrosine hydroxylase which validated our in vivo findings regarding the inhibition of tyrosine hydroxylase activity. Our current findings indicated that OIE counteracts Doxorubicin and Cyclophosphamide-induced cardiotoxicity-through inhibition of ROS-mediated apoptosis and by blocking the effect on tyrosine hydroxylase. Taken together, our findings suggested that OIE possesses cardioprotective effects to counteract potentially fatal cardiac complications associated with chemotherapy treatment.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Bignoniaceae , Cardiopatias/prevenção & controle , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Bignoniaceae/química , Cardiotoxicidade , Ciclofosfamida , Modelos Animais de Doenças , Doxorrubicina , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
The goal of this work aimed to evaluate the protective effects of pea (Pisum sativum) peels extract versus doxorubicin-induced oxidative myocardial injury in male mice. The mice were divided into seven groups (n = 7): (I) control group; (II) P. sativum 250 group; (III) P. sativum 500 group; (IV) DOX (3 times alternately of 2.5 mg/kg/week, i.p. for a continuous two-week period) group; (V) Vit. E 100 + DOX group; (VI) P. sativum 250 + DOX group, and (VII) P. sativum 500 + DOX group). Twenty polyphenolic compounds, mainly flavonoid glycosides such as quercetin, kaempferol apigenin, and phenolics compounds were characterized by LC-MS/MS analysis in the examined extract. DOX administration elevated the activities of serum biomarkers of myocardial dysfunction (ALT, AST, ALP, LDH, troponin, CPK, and CK-MB), lipid profile, and proinflammatory cytokines. Also, it decreased cardiac antioxidants (GSH, SOD, GPX, CAT) and increased myocardial markers of oxidative stress (NO and MDA) and inflammatory marker (MPO). As well as it downregulated and upregulated the Bcl-2 (anti-apoptotic gene) and the Bax (pro-apoptotic gene) expressions, respectively. Pre-treatment of DOX-exposed mice with P. sativum or vitamin E (as a reference protective antioxidant) alleviated the changes dose-dependently via DOX-induced cardiotoxicity. These data show that P. sativum has a cardio-protective impact against DOX-induced cardiomyocyte damage in mice via boosting endogenous antioxidants, decreasing inflammation, and regulating BcL-2 and Bax apoptosis pathway, which might be related to the presence of flavonoid glycosides. P. sativum peels are a by-product that could be suggested for further screening as a possible new candidate for therapeutic use.
Assuntos
Antioxidantes/farmacologia , Cardiopatias/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Pisum sativum , Extratos Vegetais/farmacologia , Animais , Antioxidantes/isolamento & purificação , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Cardiotoxicidade , Modelos Animais de Doenças , Doxorrubicina , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Pisum sativum/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Metabolismo Secundário , Sementes , Transdução de SinaisRESUMO
BACKGROUND: According to WHO statistics, cardiovascular disease are the leading causes of death in the world. One of the main factors which is causing heart failure, systolic and diastolic dysfunction, and arrythmias is a condition named cardiac fibrosis. This condition is defined by the accumulation of fibroblast-produced ECM in myocardium layer of the heart. OBJECTIVE: Accordingly, the current review aims to depict the role of curcumin in the regulation of different signaling pathways that are involved in cardiac fibrosis. RESULTS: A great number of cellular and molecular mechanisms such as oxidative stress, inflammation, and mechanical stress are acknowledged to be involved in cardiac fibrosis. Despite the available therapeutic procedures which are designed to target these mechanisms in order to prevent cardiac fibrosis, still, effective therapeutic methods are needed. Curcumin is a natural Chinese medicine which currently has been declared to have therapeutic properties such as anti-oxidant and immunomodulatory activities. In this review, we have gathered several experimental studies in order to represent diverse impacts of this turmeric derivative on pathogenic factors of cardiac fibrosis. CONCLUSION: Curcumin might open new avenues in the field of cardiovascular treatment.
Assuntos
Antioxidantes/uso terapêutico , Curcumina/uso terapêutico , Cardiopatias/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Miocárdio/metabolismo , Animais , Fibrose , Cardiopatias/metabolismo , Cardiopatias/patologia , Humanos , Medicina Tradicional Chinesa , Miocárdio/patologiaRESUMO
Background It is known that dietary intake of polyunsaturated fatty acids may improve cardiac function. However, relatively high daily doses are required to achieve sufficient cardiac concentrations of beneficial omega-3 fatty acids. The liver X receptor (LXR) is a nuclear hormone receptor and a crucial regulator of lipid homeostasis in mammals. LXR activation has been shown to endogenously reprogram cellular lipid profiles toward increased polyunsaturated fatty acids levels. Here we studied whether LXR lipid reprogramming occurs in cardiac tissue and exerts cardioprotective actions. Methods and Results Male 129SV mice were treated with the LXR agonist AZ876 (20 µmol/kg per day) for 11 days. From day 6, the mice were injected with the nonselective ß-agonist isoproterenol for 4 consecutive days to induce diastolic dysfunction and subendocardial fibrosis while maintaining systolic function. Treatment with isoproterenol led to a marked impairment of global longitudinal strain and the E/e' ratio of transmitral flow to mitral annular velocity, which were both significantly improved by the LXR agonist. Histological examination showed a significant reduction in isoproterenol-induced subendocardial fibrosis by AZ876. Analysis of the cardiac lipid composition by liquid chromatography-high resolution mass spectrometry revealed a significant increase in cardiac polyunsaturated fatty acids levels and a significant reduction in saturated fatty acids by AZ876. Conclusions The present study provides evidence that the LXR agonist AZ876 prevents subendocardial damage, improves global longitudinal strain and E/e' in a mouse model of isoproterenol-induced cardiac damage, accompanied by an upregulation of cardiac polyunsaturated fatty acids levels. Cardiac LXR activation and beneficial endogenous cardiac lipid reprogramming may provide a new therapeutic strategy in cardiac disease with diastolic dysfunction.
Assuntos
Compostos de Anilina/farmacologia , Ácidos Graxos/metabolismo , Cardiopatias/prevenção & controle , Isoproterenol , Miocárdio/metabolismo , Tiazóis/farmacologia , Animais , Reprogramação Celular , Modelos Animais de Doenças , Fibrose , Cardiopatias/induzido quimicamente , Cardiopatias/patologia , Receptores X do Fígado/agonistas , Masculino , Camundongos , Camundongos da Linhagem 129 , Miocárdio/patologiaRESUMO
Heart failure (HF) is the advanced heart disease with high morbidity and mortality. Compound DanShen Dripping Pill (CDDP) is a widely used Traditional Chinese Medicine for cardiovascular disease treatment. Herein, we investigated if CDDP can protect mice against doxorubicin (DOX) or isoprenaline (ISO)-induced HF. After 3 days feeding of normal chow containing CDDP, mice were started DOX or ISO treatment for 4 weeks or 18 days. At the end of treatment, mice were conducted electrocardiogram and echocardiographic test. Blood and heart samples were determined biochemical parameters, myocardial structure and expression of the related molecules. CDDP normalized DOX/ISO-induced heart weight changes, HF parameters and fibrogenesis. The DOX/ISO-impaired left ventricular ejection fraction and fractional shortening were restored by CDDP. Mechanistically, CDDP blocked DOX/ISO-inhibited expression of antioxidant enzymes and DOX/ISO-induced expression of pro-fibrotic molecules, inflammation and cell apoptosis. Additional DOX/ISO-impaired targets in cardiac function but protected by CDDP were identified by RNAseq, qRT-PCR and Western blot. In addition, CDDP protected cardiomyocytes against oxygen-glucose deprivation-induced injuries. Taken together, our study shows that CDDP can protect against myocardial injuries in different models, suggesting its potential application for HF treatment.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Cardiopatias/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Canfanos , Cardiotoxicidade , Linhagem Celular , Modelos Animais de Doenças , Doxorrubicina , Fibrose , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Mediadores da Inflamação/metabolismo , Isoproterenol , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Panax notoginseng , Ratos , Salvia miltiorrhiza , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
To evaluate whether lowering plasma homocysteine (Hcy) levels at different doses of folic acid (FA) could reduce cardiac fibrosis and diastolic dysfunction in spontaneously hypertensive rats (SHRs) with hyperhomocysteinemia (Hhcy) and investigate the possible mechanism of action.We randomly divided 32 male SHRs into control, Hhcy, Hhcy + low-dose FA (LFA), and Hhcy + high-dose FA (HFA) groups. Echocardiography and Masson staining of cardiac tissue were used to assess diastolic function and cardiac fibrosis. Blood pressure (BP) and Hcy levels were measured during the experiment. We also measured the indicators of oxidative stress (OS) and examined the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) genes and proteins using real-time polymerase chain reaction (PCR), immunohistochemistry, and western blotting to explore the possible mechanism of action.FA treatment reversed SHR cardiomyocyte interstitial and perivascular collagen deposition and diastolic dysfunction exacerbated by Hhcy. These effects were associated with promoting the translocation of Nrf2 from the cytoplasm to the nucleus, activating HO-1 expression and inhibiting OS. However, HFA did not show any additional benefit from LFA in reducing cardiac injury.Even at a low dose, FA can ameliorate Hhcy-induced cardiac fibrosis and diastolic dysfunction in SHRs by activating Nrf2/HO-1 pathway and inhibiting OS, independent of BP, providing evidence for the efficacy of LFA in the treatment of hypertension associated with Hhcy.
Assuntos
Ácido Fólico/uso terapêutico , Cardiopatias/prevenção & controle , Hematínicos/uso terapêutico , Hiper-Homocisteinemia/complicações , Hipertensão/complicações , Animais , Diástole , Avaliação Pré-Clínica de Medicamentos , Fibrose , Coração/fisiopatologia , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Masculino , Miocárdio/patologia , Distribuição Aleatória , Ratos Endogâmicos SHRRESUMO
Coronary artery diseases are the major causes of disabilities and death worldwide. Evidence from the literature has demonstrated that Origanum majorana L. (marjoram) acts as an antioxidant, anti-inflammatory, antiplatelet, and assists in hormonal regulation. However, there is limited scientific evidence describing the signaling pathways associated with the marjoram's positive effect on cardiac injury. Therefore, we aimed to understand the mechanistic protective effects of marjoram on isoproterenol (ISO)-induced myocardial injury in rats. Sprague Dawley rats were randomly assigned into six groups. Marjoram was administrated by oral gavage and isoproterenol was administrated subcutaneously (ISO; 85 mg/kg). Heart weight, cardiac enzymes, inflammatory, and oxidative stress biomarkers were measured. The ISO-induced cardiac injury was confirmed by the significant increase in the levels of cardiac enzymes (P value < 0.05), whereas pre-treatment with marjoram normalized these cardiac injury parameters. We also determined that marjoram had a protective effect against ISO-induced increase in C-reactive protein (CRP), IL-6, IL-13, and TNF-α. Additionally, marjoram significantly decreased cardiac thiobarbituric acid reactive substances (TBARS) levels (P value < 0.05) and protected against ISO-induced oxidative stress. We have demonstrated that marjoram decreased both cardiac oxidative stress and inflammation, thus establishing the beneficial effects of marjoram on ISO-induced cardiac injury in rats.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cardiopatias/prevenção & controle , Mediadores da Inflamação/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Origanum , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Biomarcadores/metabolismo , Cardiotoxicidade , Modelos Animais de Doenças , Fibrose , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Isoproterenol , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Origanum/química , Extratos Vegetais/isolamento & purificação , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
Offspring born to diabetic or obese mothers have a higher lifetime risk of heart disease. Previously, we found that rat offspring exposed to late-gestational diabetes mellitus (LGDM) and maternal high-fat (HF) diet develop mitochondrial dysfunction, impaired cardiomyocyte bioenergetics, and cardiac dysfunction at birth and again during aging. Here, we compared echocardiography, cardiomyocyte bioenergetics, oxidative damage, and mitochondria-mediated cell death among control, pregestational diabetes mellitus (PGDM)-exposed, HF-diet-exposed, and combination-exposed newborn offspring. We hypothesized that PGDM exposure, similar to LGDM, causes mitochondrial dysfunction to play a central, pathogenic role in neonatal cardiomyopathy. We found that PGDM-exposed offspring, similar to LGDM-exposed offspring, have cardiac dysfunction at birth, but their isolated cardiomyocytes have seemingly less bioenergetics impairment. This finding was due to confounding by impaired viability related to poorer ATP generation, more lipid peroxidation, and faster apoptosis under metabolic stress. To mechanistically isolate and test the role of mitochondria, we transferred mitochondria from normal rat myocardium to control and exposed neonatal rat cardiomyocytes. As expected, transfer provides a respiratory boost to cardiomyocytes from all groups. They also reduce apoptosis in PGDM-exposed males, but not in females. Findings highlight sex-specific differences in mitochondria-mediated mechanisms of developmentally programmed heart disease and underscore potential caveats of therapeutic mitochondrial transfer.
Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Gestacional/fisiopatologia , Metabolismo Energético , Cardiopatias/prevenção & controle , Mitocôndrias/transplante , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Cardiopatias/etiologia , Cardiopatias/patologia , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Ratos , Ratos Sprague-Dawley , Fatores SexuaisRESUMO
The cardiotoxicity of chemotherapeutic drugs as cisplatin has become a major issue in recent years. The present study investigates the efficacy of curcumin nanoparticles against the cardiotoxic effects of cisplatin by assessment of oxidative stress parameters, Na+,K+-ATPase, acetylcholinesterase (AchE) and tumor necrosis factor-alpha (TNF-α) in cardiac tissue in addition to serum lactate dehydrogenase (LDH). Rats were divided into three groups: control rats that received saline for 14 days; cisplatin-treated rats that received a single intraperitoneal (i.p.) injection of cisplatin (12 mg/kg) followed by a daily oral administration of saline (0.9%) for 14 days and rats treated with a single i.p. injection of cisplatin (12 mg/kg) followed by a daily oral administration of curcumin nanoparticles (50 mg/kg) for 14 days. Cisplatin resulted in a significant increase in lipid peroxidation, nitric oxide (NO), and TNF-α and a significant decrease in reduced glutathione (GSH) levels and Na+, K+- ATPase activity. Moreover, significant increases in cardiac AchE and serum lactate dehydrogenase activities were recorded. Treatment of cisplatin-injected animals with curcumin nanoparticles ameliorated all the alterations induced by cisplatin in the heart of rats. This suggests that curcumin nanoparticles can be used as an important therapeutic adjuvant in chemotherapeutic and other toxicities mediated by oxidative stress and inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Curcumina/farmacologia , Cardiopatias/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Nanopartículas , Acetilcolinesterase/metabolismo , Animais , Cisplatino , Modelos Animais de Doenças , Proteínas Ligadas por GPI/metabolismo , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Pain is the commonest symptom of a disease and the percentage of persons manifesting one form of pain is growing globally. Aframomum melegueta (AM) is commonly used by traditional doctors as medication for many ailments such as body pains and rheumatism because it possesses anti-inflammatory, anti-allergenic, antiviral, anti-ageing and anti-tumour phytochemical agents. AIM OF THE STUDY: Traditionally a botanical remedy in the management of pain was assessed. A common tropical plant Aframomum melegueta (AM) was evaluated for the amelioration of pain. For further pharmacologic understanding sensitive marker were used to assess the effect of the extract on the organ as a multifaceted approach to the evaluation of safety and analgesic efficacy. MATERIALS AND METHOD: Sensitive biomarkers such as troponin-T (CTnT), cardiac troponin-I (CTnI), interleukin-beta (IL-ß), interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF-α) were evaluated using the enzyme-linked immunosorbent assay (ELISA) method and electrocardiographic parameters were also evaluated. The dynamics of concentrations of the various subfamilies of cytochrome were also assessed using ELISA in the evaluation of thirty-day oral AM, while histopathological changes of organs were also observed. RESULTS: Thirty-day oral AM doses 40 mg/kg and 80 mg/kg showed analgesic potential but influenced IL-6 level, IL-1ß, TNF-α and P-LCR. Electrocardiographic parameters showed the extract had arrhythmogenic effects the other cardiac parameters influenced was CTnT. The testicular alfa-fetoprotein and prostate specific antigen were also influenced. There were also some histopathological changes. CONCLUSIONS: The extract showed analgesic, anti-oxidant and anti-inflammatory potential with possible adverse effects consistent with testicular and prostate cancers, cardiovascular complication, hepatic congestion and cholestasis.
Assuntos
Analgésicos/toxicidade , Citocromo P-450 CYP1B1/metabolismo , Fígado/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Dor/prevenção & controle , Extratos Vegetais/toxicidade , Testículo/efeitos dos fármacos , Troponina T/sangue , Zingiberaceae , alfa-Fetoproteínas/metabolismo , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios/toxicidade , Antioxidantes/toxicidade , Biomarcadores/sangue , Cardiotoxicidade , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Cardiopatias/sangue , Cardiopatias/induzido quimicamente , Cardiopatias/patologia , Fígado/enzimologia , Fígado/patologia , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Dor/etiologia , Dor/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Ratos Wistar , Testículo/metabolismo , Zingiberaceae/químicaRESUMO
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by mutations in the IDUA gene, that codifies the alpha-L-iduronidase enzyme, which deficiency leads to storage of glycosaminoglycans, with multiple clinical manifestations. One of the leading causes of death in MPS I patients are cardiac complications such as cardiac valve thickening, conduction abnormalities, myocardial dysfunction, and cardiac hypertrophy. The mechanism leading to cardiac dysfunction in MPS I is not entirely understood. In a previous study, we have demonstrated that losartan and propranolol improved the cardiac function in MPS I mice. Thus, we aimed to investigate whether the pathways influenced by these drugs may modulate the cardiac remodeling process in MPS I mice. According to our previous observation, losartan and propranolol restore the heart function, without altering valve thickness. MPS I mice presented reduced activation of AKT and ERK1/2, increased activity of cathepsins, but no alteration in metalloproteinase activity was observed. Animals treated with losartan showed a reduction in cathepsin activity and restored ERK1/2 activation. While both losartan and propranolol improved heart function, no mechanistic evidence was found for propranolol so far. Our results suggest that losartan or propranolol could be used to ameliorate the cardiac disease in MPS I and could be considered as adjuvant treatment candidates for therapy optimization.
Assuntos
Cardiopatias/patologia , Losartan/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mucopolissacaridose I/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Ecocardiografia , Feminino , Cardiopatias/tratamento farmacológico , Cardiopatias/genética , Iduronidase/genética , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucopolissacaridose I/genética , Mucopolissacaridose I/patologia , MutaçãoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The Fructus (Alpinia oxyphylla MIQ) known as Yi Zhi Ren in Chinese medicine has been used as a food and herbal medicinal substance in China for centuries; in the year 2015 Chinese Pharmacopoeia Commission reported water extracts of Alpinia oxyphyllae Fructus (AoF) as a popular medication for aging-related diseases in the form of tonic, aphrodisiac, and health-care food in south China. AIM OF THE STUDY: Adipose mesenchymal stem cells are physiologically and therapeutically associated with healthy vascular function and cardiac health. However aging conditions hinder stem cell function and increases the vulnerability to cardiovascular diseases. In this study, the effect of the anti-aging herbal medicine AoF to enhance the cardiac restorative function of adipose-derived mesenchymal stem cells (ADMSCs) in aging condition was investigated. MATERIALS AND METHODS: Low dose (0.1 µM) Doxorubicin and D-galactose (150 mg/kg/day for 8 weeks) were used to respectively induce aging in vitro and in vivo. For In vivo studies, 20 week old WKY rats were divided into Control, Aging induced (AI), AI + AoF, AI + ADMSC, AI + AoF Oral + ADMSC, and AI + AoF treated ADMSC groups. AoF (100 mg/kg/day) was administered orally and ADMSCs (1 × 106 cells) were injected (IV). RESULTS: AoF preconditioned ADMSC showed reduction in low dose Dox induced mitochondrial apoptosis and improved DNA replication in H9c2 cardiomyoblasts. In vivo experiments confirmed that both a combined treatment with AoF-ADMSCs and with AoF preconditioned ADMSCs reduced aging associated cardiac damages which was correlated with reduction in apoptosis and expression of senescence markers (P21 and ß-gal). Survival and longevity markers were upregulated up on combined administration of AoF and ADMSCs. The cardiac performance of the aging-induced rats was improved significantly in the treatment groups. AoF along with ADMSCs might activate paracrine factors to restore the performance of an aging heart. CONCLUSION: Hence, we propose that ADMSCs combined with AoF have promising therapeutic properties in the treatment of healthy aging heart.
Assuntos
Tecido Adiposo/transplante , Envelhecimento/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais/métodos , Miócitos Cardíacos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Alpinia , Animais , Apoptose/fisiologia , Linhagem Celular , Terapia Combinada/métodos , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/terapia , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Mitocôndrias , Modelos Animais , Miócitos Cardíacos/fisiologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Ratos , Ratos Endogâmicos WKYRESUMO
Regorafenib (RGF) has a great success in the treatment of colorectal cancer, gastrointestinal stromal tumours and hepatocellular carcinoma by inhibiting angiogenic, stromal and oncogenic kinases. However, RGF can induce life-threatening cardiotoxicity including hypertension and cardiac ischemia/infarction. The molecular mechanism of the adverse effects has not been elucidated. Mitochondrial dysfunction is one of the major causes of cardiac diseases since cardiac cells highly need ATP for their contractility. Therefore, we aimed to investigate molecular mechanisms of RGF-induced cardiac adverse effects using H9c2 cell model by focusing on mitochondria. Cells were treated with 0-20 µM RGF for 48 and 72 h. According to our results, RGF inhibited cell proliferation and decreased the ATP content of the cells depending on the exposure time and concentration. Loss of mitochondrial membrane potential was also observed at high dose. Mitochondrial fusion/fission genes and antioxidant SOD2 (superoxide dismutase) gene expression levels increased at high doses in both treatments. Mitochondrial DNA content decreased as exposure time and concentration increased. Also, protein expression levels of mitochondrial complex I and V have reduced and stress protein HSP70 level has increased following RGF treatment. Structural abnormalities in mitochondria was seen with transmission electron microscopy at the applied higher doses. Our findings suggest that RGF-induced cardiotoxicity may be associated with mitochondrial damage in cardiac cells.
Assuntos
Antineoplásicos/toxicidade , Cardiopatias/induzido quimicamente , Mitocôndrias Cardíacas/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Compostos de Fenilureia/toxicidade , Piridinas/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Cardiotoxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico HSP70/metabolismo , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Fatores de TempoRESUMO
Obesity is growing at an alarming rate, which is characterized by increased adipose tissue. It increases the probability of many health complications, such as diabetes, arthritis, cardiac disease, and cancer. In modern society, with a growing population of obese patients, several individuals have increased insulin resistance. Herbal medicines are known as the oldest method of health care treatment for obesity-related secondary health issues. Several traditional medicinal plants and their effective phytoconstituents have shown anti-diabetic and anti-adipogenic activity. Adipose tissue is a major site for lipid accumulation as well as the whole-body insulin sensitivity region. 3T3-L1 cell line model can achieve adipogenesis. Adipocyte characteristics features such as expression of adipocyte markers and aggregation of lipids are chemically induced in the 3T3-L1 fibroblast cell line. Differentiation of 3T3-L1 is an efficient and convenient way to obtain adipocyte like cells in experimental studies. Peroxisome proliferation activated receptor γ (PPARγ) and Cytosine-Cytosine-Adenosine-Adenosine-Thymidine/Enhancer-binding protein α (CCAAT/Enhancer-binding protein α or C/EBPα) are considered to be regulating adipogenesis at the early stage, while adiponectin and fatty acid synthase (FAS) is responsible for the mature adipocyte formation. Excess accumulation of these adipose tissues and lipids leads to obesity. Thus, investigating adipose tissue development and the underlying molecular mechanism is important in the therapeutical approach. This review describes the cellular mechanism of 3T3-L1 fibroblast cells on potential anti-adipogenic herbal bioactive compounds.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Artrite/prevenção & controle , Diabetes Mellitus/prevenção & controle , Cardiopatias/prevenção & controle , Neoplasias/prevenção & controle , Obesidade/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Fármacos Antiobesidade/química , Artrite/etiologia , Artrite/genética , Artrite/patologia , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diabetes Mellitus/etiologia , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Regulação da Expressão Gênica , Cardiopatias/etiologia , Cardiopatias/genética , Cardiopatias/patologia , Humanos , Resistência à Insulina , Camundongos , Neoplasias/etiologia , Neoplasias/genética , Neoplasias/patologia , Obesidade/complicações , Obesidade/genética , Obesidade/patologia , PPAR gama/genética , PPAR gama/metabolismo , Compostos Fitoquímicos/químicaRESUMO
: Over the years, numerous groups have employed human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) as a superb human-compatible model for investigating the function and dysfunction of cardiomyocytes, drug screening and toxicity, disease modeling and for the development of novel drugs for heart diseases. In this review, we discuss the broad use of iPSC-CMs for drug development and disease modeling, in two related themes. In the first theme-drug development, adverse drug reactions, mechanisms of cardiotoxicity and the need for efficient drug screening protocols-we discuss the critical need to screen old and new drugs, the process of drug development, marketing and Adverse Drug reactions (ADRs), drug-induced cardiotoxicity, safety screening during drug development, drug development and patient-specific effect and different mechanisms of ADRs. In the second theme-using iPSC-CMs for disease modeling and developing novel drugs for heart diseases-we discuss the rationale for using iPSC-CMs and modeling acquired and inherited heart diseases with iPSC-CMs.
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Cardiotoxicidade/diagnóstico , Cardiopatias/tratamento farmacológico , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Cardiotoxicidade/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Cardiopatias/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologiaRESUMO
BACKGROUND/AIMS: Considering the importance of inflammation on obesity-related disorders pathogenesis, including cardiac dysfunction, the interest in natural anti-inflammatory therapeutic strategies has emerged. The lycopene is a carotenoid presents in tomato and red fruits that displays anti-inflammatory properties. In this sense, we will evaluate the anti-inflamma-tory effect of tomato-oleoresin supplementation on obesity- related cardiac dysfunction by modulating myocardial calcium kinetic. METHODS: Male Wistar rats were initially randomized into 2 experimental groups: (Control, n= 20) or high sugar- fat diet (HSF, n=20) for 20 weeks. At week 20th, once detected the cardiac dysfunction (cardiac remodeling, systolic and diastolic dysfunction) by echocardiography in HSF group, animals were randomly divided to begin the treatment with tomato-oleoresin, performing 4 groups: Control (n= 10); Control + tomato tomato-oleoresin supplementation (Control + Ly, n= 10); HSF (n= 10) or HSF + tomato tomato-oleoresin supplementation (HSF + Ly, n= 10). Tomato oleoresin was mixed with maize oil equivalent to 10mg lycopene/kg body weight (BW) per day and given orally, by gavage, every morning for a 10-week period. It was analyzed cardiac inflammatory parameters by the enzyme-linked immunosorbent assay (ELISA) and in vivo (echocardiography) and in vitro (studying isolated papillary muscles from the left ventricle) cardiac function. The groups were compared by Two-Way analysis of variance (ANOVA). RESULTS: The HSF diet induced cardiac dysfunction (FS(%) C: 60.4±1.3; C+Ly: 60.9±1.3; HSF: 51.7±1.3; HSF+Ly: 59.4±1.4) and inflammation (TNF-α: C:1.88±0.41; C+Ly: 1.93±1.01; HSF: 4.58±1.99; HSF+Ly: 2.03±0.55; IL-6: C:0.58±0.16; C+Ly: 0.40±0.16; HSF: 2.00±0.45; HSF+Ly: 0.53±0.26; MCP-1: C:0.31±0.08; C+Ly: 0.43±0.22; HSF: 1.54±0.32; HSF+Ly: 0.50±0.16). Tomato-oleoresin supplementation improved cardiac remodeling and dysfunction, cardiac inflammation and myocardial calcium kinetic. CONCLUSION: the anti-inflammatory effect of tomato-oleoresin supplementation treated the obesity-induced cardiac dysfunction by modulating myocardial calcium handling.
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Anti-Inflamatórios/farmacologia , Cálcio/metabolismo , Dieta Hiperlipídica , Cardiopatias/tratamento farmacológico , Inflamação/prevenção & controle , Obesidade/complicações , Extratos Vegetais/farmacologia , Animais , Cardiopatias/etiologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Solanum lycopersicum , Masculino , Ratos , Ratos Wistar , Recuperação de Função FisiológicaRESUMO
Cardiac dysfunction is a critical manifestation of sepsis-induced multiorgan failure and results in the high mortality of sepsis. Our previous study demonstrated that a traditional Chinese medicine formula, Qiang-Xin 1 (QX1), ameliorates cardiac tissue damage in septic mice; however, the underlying pharmacology mechanism remains to be elucidated. The present study was aimed at clarifying the protective mechanism of the QX1 formula on sepsis-induced cardiac dysfunction. The moderate sepsis model of mice was established by cecal ligation and puncture surgery. Treatment with the QX1 formula improved the 7-day survival outcome, attenuated cardiac dysfunction, and ameliorated the disruption of myocardial structure in septic mice. Subsequent systems pharmacology analysis found that 63 bioactive compounds and the related 79 candidate target proteins were screened from the QX1 formula. The network analysis showed that the QX1 active components quercetin, formononetin, kaempferol, taxifolin, cryptotanshinone, and tanshinone IIA had a good binding activity with screened targets. The integrating pathway analysis indicated the calcium, PI3K/AKT, MAPK, and Toll-like receptor signaling pathways may be involved in the protective effect of the QX1 formula on sepsis-induced cardiac dysfunction. Further, experimental validation showed that the QX1 formula inhibited the activity of calcium/calmodulin-dependent protein kinase II (CaMKII), MAPK (P38, ERK1/2, and JNK), and TLR4/NF-κB signaling pathways but promoted the activation of the PI3K/AKT pathway. A cytokine array found that the QX1 formula attenuated sepsis-induced upregulated levels of serum IFN-γ, IL-1ß, IL-3, IL-6, IL-17, IL-4, IL-10, and TNF-α. Our data suggested that QX1 may represent a novel therapeutic strategy for sepsis by suppressing the activity of calcium, MAPK, and TLR4/NF-κB pathways, but promoting the activation of AKT, thus controlling cytokine storm and regulating immune balance. The present study demonstrated the multicomponent, multitarget, and multipathway characteristics of the QX1 formula and provided a novel understanding of the QX1 formula in the clinical application on cardiac dysfunction-related diseases.
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Medicamentos de Ervas Chinesas/farmacologia , Coração/fisiopatologia , Sepse/complicações , Animais , Citocinas/sangue , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Coração/efeitos dos fármacos , Cardiopatias/sangue , Cardiopatias/tratamento farmacológico , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Masculino , Camundongos Endogâmicos BALB C , Distribuição Tecidual/efeitos dos fármacosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Shenfu injection (SFI) is a well-known Chinese herbal medicine widely used in the treatment of septic shock in China. AIMS: The aims of this study are to investigate the protective effects of SFI on sepsis-induced myocardial injury in mice and to identify the underlying mechanism of action. MATERIALS AND METHODS: Seventy-two male C57/B6J mice (5-6 weeks old) were randomly divided into five groups: control (NC), sham sepsis (sham), sepsis (Lipopolysaccharide- LPS), sepsis treated with a low dose SFI, and sepsis treated with a high dose SFI. Sepsis was induced in mice by intraperitoneal injection of LPS. Myocardial tissue samples were collected from different groups at 6 h, 12 h, and 24 h post-LPS injection. Myocardial injury was examined using hematoxylin-eosin (H&E) and TUNEL staining. Western-blot analysis was performed to determine the protein expression of B-cell lymphoma 2 (Bcl-2), BH3 interacting-domain death agonist (Bid), truncated-Bid (t-Bid) and caspase-9 in all the groups. Moreover, the structural changes in the mitochondria of cardiomyocytes were also observed by transmission electron microscopy. RESULTS: H&E staining revealed structural damage, local necrosis, interstitial edema, inflammatory cell infiltration and vacuolar changes in the myocardial tissue in the sepsis (LPS) group; almost intact myocardial tissue was observed in the high dose SFI group with improvements in interstitial edema and inflammatory cell infiltration. We observed that LPS-induced cardiomyocyte apoptosis was significantly improved with high dose SFI as compared with sepsis (LPS) group (P Ë 0.05). LPS was found to decrease the protein expression of Bcl-2 and increase the level of Bid, t-Bid and caspase-9. Treatment with SFI significantly increased the Bcl-2 protein expression (P Ë 0.05) and decreased the protein expression of Bid, t-Bid and caspase-9 as compared with LPS group (P Ë 0.05). Markedly swollen myocardial mitochondria with partial vacuolation were observed in LPS treated mice while SFI treatment was found to significantly improve the LPS-induced morphological damage of the mitochondria. CONCLUSION: In conclusion, we demonstrate that SFI protects against sepsis-induced myocardial injury in mice through the suppression of myocardial apoptosis. It upregulates the protein expression of Bcl-2 and downregulates the protein expression of Bid, t-Bid and caspase-9, and alleviates sepsis-induced mitochondrial damage.
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Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Cardiopatias/prevenção & controle , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Modelos Animais de Doenças , Cardiopatias/etiologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/ultraestrutura , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Sepse/complicações , Transdução de SinaisRESUMO
Phytomedicine has shown a promising potential for the prevention of cardiovascular system diseases and disorders. This study aimed to evaluate protective effect of ergosterol (ER) on isoproterenol (ISO)-induced myocardial cardiotoxicity. We found that pretreatment with ER significantly decreased levels of myocardial CK-MB and LDH, and alleviated myocardial damage induced by ISO in rat model. In addition, ER restored Nrf2 and HO-1 expression and inhibited apoptosis through upregulating Bcl-2 and downregulating Bax, cytochrome c, cleaved caspase-3, caspase-9, and PARP in rat hearts. Hypoxia-reoxygenation model in H9C2 cells confirmed the cardioprotective effects of ER. In conclusion, we provide both in vitro and in vivo evidence that ER significantly enhances Nrf2-mediated anti-oxidative activities, and exerts a protective effect on cardiomyocyte apoptosis. ER could be considered as a potential therapeutic agent to prevent myocardial injury.
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Antioxidantes/farmacologia , Ergosterol/farmacologia , Cardiopatias/prevenção & controle , Isoproterenol , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Cardiotoxicidade , Linhagem Celular , Modelos Animais de Doenças , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Heme Oxigenase (Desciclizante)/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
BACKGROUND: Elective percutaneous coronary interventions (PCI) are difficult to discriminate from non-elective PCI in administrative data due to non-specific encounter codes, limiting the ability to track outcomes, ensure appropriate medical management, and/or perform research on patients who undergo elective PCI. The objective of this study was to assess the abilities of several algorithms to identify elective PCI procedures using administrative data containing diagnostic, utilization, and/or procedural codes. METHODS AND RESULTS: For this retrospective study, administrative databases in an integrated healthcare delivery system were queried between 1/1/2015 and 6/31/2016 to identify patients who had an encounter for a PCI. Using clinical criteria, each encounter was classified via chart review as a valid PCI, then as elective or non-elective. Cases were tested against nine pre-determined algorithms. Performance statistics (sensitivity, specificity, positive predictive value, and negative predictive value) and associated 95% confidence intervals (CI) were calculated. Of 521 PCI encounters reviewed, 497 were valid PCI, 93 of which were elective. An algorithm that excluded emergency room visit events had the highest sensitivity (97.9%, 95%CI 92.5%-99.7%) while an algorithm that included events occurring within 90 days of a cardiologist visit and coronary angiogram or stress test had the highest positive predictive value (62.2%, 95%CI 50.8%-72.7%). CONCLUSIONS: Without an encounter code specific for elective PCI, an algorithm excluding procedures associated with an emergency room visit had the highest sensitivity to identify elective PCI. This offers a reasonable approach to identify elective PCI from administrative data.