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Myocardial ischemia/reperfusion (I/R) injury is marked by rapid increase in inflammation and not only results in myocardial apoptosis but also compromises the myocardial function. Dunaliella salina (D. salina), a halophilic unicellular microalga, has been used as a provitamin A carotenoid supplement and color additive. Several studies have reported that D. salina extract could attenuate lipopolysaccharides-induced inflammatory effects and regulate the virus-induced inflammatory response in macrophages. However, the effects of D. salina on myocardial I/R injury remain unknown. Therefore, we aimed to investigate the cardioprotection of D. salina extract in rats subjected to myocardial I/R injury that was induced by occlusion of the left anterior descending coronary artery for 1 h followed by 3 h of reperfusion. Compared with the vehicle group, the myocardial infarct size significantly decreased in rats that were pre-treated with D. salina. D. salina significantly attenuated the expressions of TLR4, COX-2 and the activity of STAT1, JAK2, IκB, NF-κB. Furthermore, D. salina significantly inhibited the activation of caspase-3 and the levels of Beclin-1, p62, LC3-I/II. This study is the first to report that the cardioprotective effects of D. salina may mediate anti-inflammatory and anti-apoptotic activities and decrease autophagy through the TLR4-mediated signaling pathway to antagonize myocardial I/R injury.
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Chlorophyta , Daño por Reperfusión Miocárdica , Receptor Toll-Like 4 , Animales , Ratas , Apoptosis , Daño por Reperfusión Miocárdica/prevención & control , FN-kappa B/metabolismo , Ratas Sprague-Dawley , Transducción de Señal , Receptor Toll-Like 4/metabolismoRESUMEN
Background: Resveratrol, a natural antioxidant polyphenol, has the functions of anti-inflammation, anti-cancer, liver protection and cardioprotection. Microorganism biotransformation-produced resveratrol (MBR) product shows higher purity than the natural source of resveratrol and costs less than the chemically synthesized resveratrol. The aim of the present study was to investigate the protective effects of MBR in hamsters treated with a high-fat diet (HFD). Methods: MBR was obtained by the fermentative process of piceid. Hamsters were randomly divided into four groups: HFD plus oral administration of MBR 0 (C), 5 (L), 20 (M) or 50 mg/kg (H), respectively. After six-week of treatment, hamsters were sacrificed, and tissues were collected for further analysis. Results: MBR at these three dosages did not influence the appetite or growth of the hamsters. Liver enzymes, blood glucose, total cholesterol, triglyceride, and liver weight were significantly reduced in the MBR groups than in the control group. Additionally, high-density lipoprotein-cholesterol (HDL-C) was also elevated in all MBR groups. On the other hand, serum low-density lipoprotein-cholesterol (LDL-C) was decreased in the MBR groups. Triglyceride (TG) in liver tissue and fatty liver level were lower in group H. Memory-associated proteins, phosphorylation of calmodulin-dependent protein kinase II (p-CaMK II) and synaptophysin (SYP), were increased in the brains of MBR groups. Conclusion: The high yield- and short procedure-produced MBR has the potential to protect animals fed with HFD from hyperlipidemia, hepatic steatosis, hyperglycemia, and synaptic impairment, which might be beneficial for patients with these types of diseases.
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Hígado Graso , Hiperlipidemias , Animales , Antioxidantes/farmacología , Biotransformación , Glucemia/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/farmacología , HDL-Colesterol , LDL-Colesterol , Cricetinae , Dieta Alta en Grasa/efectos adversos , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Hígado Graso/metabolismo , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/etiología , Hígado , Polifenoles/metabolismo , Polifenoles/farmacología , Resveratrol/farmacología , Sinaptofisina/metabolismo , TriglicéridosRESUMEN
Ischemic stroke is characterized by the loss of cerebral blood flow, which frequently leads to neurological deficits. Tissue plasminogen activator is the only therapeutic agent approved to treat ischemic stroke but increases the risk of intracranial hemorrhage and mortality. The fibrinogen-depleting agent lumbrokinase has been used to improve myocardial perfusion in symptomatic stable angina and to prevent secondary ischemic stroke. Lumbrokinase is highly fibrin-specific and only active in the presence of fibrin. Therefore, lumbrokinase has a low risk of hemorrhage due to excessive fibrinolysis. In this study, we aimed to clarify the neuroprotection of lumbrokinase in mice subjected to permanent middle cerebral artery occlusion. Lumbrokinase significantly attenuated infarct volume and improved neurological dysfunction. Lumbrokinase dramatically decreased the expressions of the endoplasmic reticulum (ER) transmembrane receptor protein inositol-requiring enzyme-1 (IRE1) and its downstream transcription factor, XBP-1, caspase-12, and NF-κB activity, thereby significantly inhibiting apoptosis and autophagy and decreasing the NLRP3 inflammasome. Our evidence indicates that post-stroke treatment with lumbrokinase protects against ischemic stroke, thereby regulating ER stress through the collective inhibitory effect of the IRE1 signaling pathways to decrease apoptosis, autophagy, and inflammatory responses. We suggest that lumbrokinase is potential as an adjuvant treatment for ischemic stroke.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Animales , Ratones , Activador de Tejido Plasminógeno/uso terapéutico , Estrés del Retículo Endoplásmico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas , Apoptosis , Proteínas de la Membrana/metabolismo , Fibrina/farmacología , Fibrina/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismoRESUMEN
Systemic growth differentiation factor 11 (GDF11) treatment improves the vasculature in the hippocampus and cortex in mice in recent studies. However, systemic application of recombinant GDF11 (rGDF11) cannot cross the brain blood barrier (BBB). Thus, large doses and long-term administration are required, while systemically applied high-dose rGDF11 is associated with deleterious effects, such as severe cachexia. This study tested whether in situ low dosage rGDF11 (1 µg/kg) protects the brain against ischemic stroke and it investigated the underlying mechanisms. Fibrin glue mixed with rGDF11 was applied to the surgical cortex for the slow release of rGDF11 in mice after permanent middle cerebral artery occlusion (MCAO). In situ rGDF11 improved cerebral infarction and sensorimotor function by upregulating Smad2/3 and downregulating FOXO3 expression. In situ rGDF11 was associated with reductions in protein and lipid oxidation, Wnt5a, iNOS and COX2 expression, at 24 h after injury. In situ rGDF11 protected hippocampal neurons and subventricular neural progenitor cells against MCAO injury, and increased newborn neurogenesis in the peri-infarct cortex. Systematic profiling and qPCR analysis revealed that Pax5, Sox3, Th, and Cdk5rap2, genes associated with neurogenesis, were increased by in situ rGDF11 treatment. In addition, greater numbers of newborn neurons in the peri-infarct cortex were observed with in situ rGDF11 than with systemic application. Our evidence indicates that in situ rGDF11 effectively decreases the extent of damage after ischemic stroke via antioxidative, anti-inflammatory and proneurogenic activities. We suggest that in situ slow-release rGDF11 with fibrin glue is a potential therapeutic approach against ischemic stroke.
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Antiinflamatorios/administración & dosificación , Antioxidantes/administración & dosificación , Encéfalo/efectos de los fármacos , Factores de Diferenciación de Crecimiento/administración & dosificación , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Administración Tópica , Animales , Antiinflamatorios/química , Antioxidantes/química , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Composición de Medicamentos , Regulación de la Expresión Génica , Factores de Diferenciación de Crecimiento/química , Fuerza de la Mano , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/fisiopatología , Mediadores de Inflamación/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Accidente Cerebrovascular Isquémico/fisiopatología , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Proteínas Recombinantes/farmacología , Vía de Señalización WntRESUMEN
BACKGROUND/AIM: Triple negative breast cancer (TNBC) is characterized by increased recurrence and poor survival. Mounting evidence suggests that interleukin-10 (IL-10) plays a role in carcinogenesis, however, little is known about the contribution of IL-10 to TNBC. The study evaluated the contribution of IL-10 promoter A-1082G (rs1800896), T-819C (rs3021097), A-592C (rs1800872) genotypes to the risk of TNBC. MATERIALS AND METHODS: IL-10 genotypes were examined among 1,232 breast cancer patients and 1,232 controls and evaluated. RESULTS: The percentages of AG and GG for IL-10 A-1082G genotypes were higher in the breast cancer patient group than in the control group. The GG genotype carriers were of higher risk for breast cancer [odds ratio (OR)=2.02, 95% confidence interval (CI)=1.28-3.21, p=0.0021]. Interestingly, G allele carriers were of higher risk of TNBC (OR=1.25, 95%CI=1.07-1.46, p=0.0050). CONCLUSION: The G allele of IL-10 A-1082G genotype may serve as a predictor for TNBC risk. The finding should be validated in other populations.
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Carcinogénesis/genética , Predisposición Genética a la Enfermedad , Interleucina-10/genética , Neoplasias de la Mama Triple Negativas/genética , Adulto , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Persona de Mediana Edad , Factores de Riesgo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
The DNA repair capacity plays a critical role in maintaining the genomic stability and gatekeeping for individual cancer risk. In this study, we aim at evaluation the role of the Asp148Glu (rs1130409) variant at apurinic/apyrimidinic endonuclease (APE) gene in renal cell carcinoma (RCC) risk and the contribution of different genotypes to its transcriptional mRNA levels. In the case-control study, 92 RCC patients and 580 cancer-free patients matched by age and gender were recruited. The apurinic/APE genotyping work was conducted with typical restriction fragment length polymorphism methodology after polymerase chain reaction. At the meanwhile, thirty renal tissue samples with variant genotypes were examined for their apurinic/APE mRNA and protein expressions by real-time quantitative reverse transcription method and Western blotting. The results showed that compared with the wild-type TT genotype, the people with TG and GG genotypes of apurinic/APE Asp148Glu had 0.88- and 1.09-fold risk of RCC, respectively. We have also examined the in vivo transcriptional (RNA) and translational (protein) levels with renal tissues of various apurinic/APE Asp148Glu genotypes, revealing that the apurinic/APE mRNA and protein were of similar levels among people of TT, TG, or GG genotypes. There was no joint gene-environment effect of apurinic/APE Asp148Glu genotype and smoking habit on RCC risk. The evidence indicated that apurinic/APE Asp148Glu genotypic variants did not alter its mRNA and protein expression among RCC patients. The genotype of apurinic/APE Asp148Glu may not serve as a proper predictive marker for RCC risk in Taiwan.
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Carcinoma de Células Renales , Neoplasias Renales , Estudios de Casos y Controles , Reparación del ADN , ADN-(Sitio Apurínico o Apirimidínico) Liasa , Endonucleasas , Genotipo , Humanos , Fenotipo , TaiwánRESUMEN
INTRODUCTION: DNA repair systems play essential roles in genomic stability and carcinogenesis. Therefore, genotypes at DNA repair loci may contribute to the determination of personal susceptibility to cancers. The contribution of human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) genotypes to renal cell carcinoma (RCC) is largely unknown. This study aimed to evaluate the contributions of hOGG1 rs1052133 genotypes to the RCC risk. METHODS: We evaluated the contribution of hOGG1 rs1052133 (G/C) genotypes among 118 cases and 590 controls and analyzed the interactions of hOGG1 genotypes with smoking, alcohol drinking, hypertension, and diabetes status. RESULTS: The hOGG1 rs1052133 CC genotype was significantly associated with a decreased RCC risk compared with that of the GG genotype (odds ratio [OR] = 0.25, 95% confidence interval [CI] = 0.09-0.72, p = 0.0049). The frequency of the rs1052133 C allele was significantly low in the RCC group (22.5% vs 31.2%; OR = 0.64; 95% CI = 0.46-0.89, p = 0.0074). Stratifying the analysis according to smoking, alcohol drinking, and diabetes status revealed no difference in the rs1052133 genotype distribution among these subgroups. A significant differential distribution of rs1052133 genotypes was observed among subjects with hypertension. CONCLUSION: The CC genotype of rs1052133 may play a role in determining RCC susceptibility among Taiwanese people and may serve as a biomarker of RCC, particularly in patients with hypertension.
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Many studies have shown that crosstalk exists between apoptosis and autophagy, despite differences in mechanisms between these processes. Paeonol, a major phenolic compound isolated from Moutan Cortex Radicis, the root bark of Paeonia × suffruticosa Andrews (Paeoniaceae), is widely used in traditional Chinese medicine as an antipyretic, analgesic and anti-inflammatory agent. In this study, we investigated the detailed molecular mechanisms of the crosstalk between apoptosis and autophagy underlying the cardioprotective effects of paeonol in rats subjected to myocardial ischemia/reperfusion (I/R) injury. Myocardial I/R injury was induced by occlusion of the left anterior descending coronary artery (LAD) for 1 h followed by 3 h of reperfusion. Paeonol was intravenously administered 15 min before LAD ligation. We found that paeonol significantly improved cardiac function after myocardial I/R injury and significantly decreased myocardial I/R-induced arrhythmia and mortality. Paeonol also significantly decreased myocardial infarction and plasma LDH activity and Troponin-I levels in carotid blood after I/R. Compared with vehicle treatment, paeonol significantly upregulated Bcl-2 protein expression and significantly downregulated the cleaved forms of caspase-8, caspase-9, caspase-3 and PARP protein expression in the I/R injured myocardium. Myocardial I/R-induced autophagy, including the increase of Beclin-1, p62, LC3-I, and LC3-II protein expression in the myocardium was significantly reversed by paeonol treatment. Paeonol also significantly increased the Bcl-2/Bax and Bcl-2/Beclin-1 ratios in the myocardium after I/R injury. The cardioprotective role of paeonol during I/R injury may be due to its mediation of crosstalk between apoptotic and autophagic signaling pathways, which inhibits apoptosis and autophagic cell death.
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Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor beta 1 (TGF-ß1) superfamily that reverses age-related cardiac hypertrophy, improves muscle regeneration and angiogenesis, and maintains progenitor cells in injured tissue. Recently, targeted myocardial delivery of the GDF11 gene in aged mice was found to reduce heart failure and enhance the proliferation of cardiac progenitor cells after myocardial ischemia-reperfusion (I-R). No investigations have as yet explored the cardioprotective effect of exogenous recombinant GDF11 in acute I-R injury, despite the convenience of its clinical application. We sought to determine whether exogenous recombinant GDF11 protects against acute myocardial I-R injury and investigate the underlying mechanism in Sprague-Dawley rats. We found that GDF11 reduced arrhythmia severity and successfully attenuated myocardial infarction; GDF11 also increased cardiac function after I-R, enhanced HO-1 expression and decreased oxidative damage. GDF11 activated the canonical TGF-ß signaling pathway and inactivated the non-canonical pathways, ERK and JNK signaling pathways. Moreover, administration of GDF11 prior to reperfusion protected the heart from reperfusion damage. Notably, pretreatment with the activin-binding protein, follistatin (FST), inhibited the cardioprotective effects of GDF11 by blocking its activation of Smad2/3 signaling and its inactivation of detrimental TGF-ß signaling. Our data suggest that exogenous GDF11 has cardioprotective effects and may have morphologic and functional recovery in the early stage of myocardial I-R injury. GDF11 may be an innovative therapeutic approach for reducing myocardial I-R injury.
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Factores de Diferenciación de Crecimiento/uso terapéutico , Corazón/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Daño por Reperfusión Miocárdica/prevención & control , Factor de Crecimiento Transformador beta/metabolismo , Animales , Apoptosis/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Proteína Forkhead Box O3/metabolismo , Factores de Diferenciación de Crecimiento/farmacología , Hemo Oxigenasa (Desciclizante)/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Proteínas Smad Reguladas por Receptores/metabolismoRESUMEN
Cisplatin induces anorexia, weight loss, loss of adipose tissue, skeletal muscle atrophy, and serious adverse effects that can cause premature termination of chemotherapy. The aim of this study was to use an animal model to assess cisplatin therapy (3 cycles) with and without d-methionine to investigate its protective effects on cisplatin-induced anorexia and skeletal muscle wasting. Wistar rats were divided into 3 groups and treated as follows: saline as control (group 1), intraperitoneal cisplatin once a week for 3 weeks (group 2), and intraperitoneal cisplatin once a week for 3 weeks plus oral administration of d-methionine (group 3). Tissue somatic index (TSI), gastric emptying index (GEI), and feeding efficiency were measured. Both hepatic lipid metabolism and muscle atrophy-related gene expressions and C2C12 myotubes were determined by polymerase chain reaction. Micro-computed tomography (micro-CT) was used to conduct assessment of bone microarchitecture indices. Pathological changes of the gastric mucosa were assessed by hematoxylin and eosin staining after euthanizing the animals. d-Methionine increased food intake, weight gain, gastric emptying, and feeding efficiency, as well as decrease stomach contents, after cisplatin injections. Cisplatin caused shortening of myofibers. Cisplatin-induced muscle mass wasting was mediated by the elevation of mRNA expressions of MAFbx and MuRF-1 in ubiquitin ligases in muscle tissue homogenate. The mRNA expressions of MyoD and myogenin, markers of muscle differentiation, declined following cisplatin administration. The administration of d-methionine not only led to significant improvements in myofiber diameter and cross-sectional fiber areas but also reversed muscle atrophy-related gene expression. However, there were no significant changes in stomach histology or microarchitecture of trabecular bone among the study groups. The results indicate that d-methionine has an appetite-enhancing effect and ameliorates cisplatin-induced adipose and muscle tissue loss during cisplatin-based chemotherapy.
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Cisplatino/efectos adversos , Cisplatino/farmacología , Metionina/farmacología , Músculo Esquelético/efectos de los fármacos , Atrofia Muscular/inducido químicamente , Atrofia Muscular/tratamiento farmacológico , Animales , Anorexia/inducido químicamente , Anorexia/tratamiento farmacológico , Línea Celular , Masculino , Ratones , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Pérdida de Peso/efectos de los fármacosRESUMEN
BACKGROUND: There are close links between chemotherapy-induced intestinal mucositis and microbiota dysbiosis. Previous studies indicated that D-methionine was an excellent candidate for a chemopreventive agent. Here, we investigated the effects of D-methionine on cisplatin-induced mucositis. MATERIALS AND METHODS: Male Wistar rats (176-200 g, 6 weeks old) were given cisplatin (5 mg/kg) and treated with D-methionine (300 mg/kg). Histopathological, digestive enzymes activity, oxidative/antioxidant status, proinflammatory/anti-inflammatory cytokines in intestinal tissues were measured. Next-generation sequencing technologies were also performed to investigate the gut microbial ecology. RESULTS: D-methionine administration increased villus length and crypt depth and improved digestive enzyme (leucine aminopeptidase, sucrose and alkaline phosphatase) activities in the brush-border membrane of cisplatin-treated rats (p < 0.05). Furthermore, D-methionine significantly attenuated oxidative stress and inflammatory reaction and increased interleukin-10 levels in cisplatin-induced intestinal mucositis (p < 0.05). Cisplatin administration resulted in high relative abundances of Deferribacteres and Proteobacteria and a low diversity of the microbiota when compared with control groups, D-methionine only and cisplatin plus D-methionine. Cisplatin markedly increased comparative abundances of Bacteroides caccae, Escherichia coli, Mucispirillum schaedleri, Bacteroides uniformis and Desulfovibrio C21-c20, while Lactobacillus was almost completely depleted, compared with the control group. There were higher abundances of Lactobacillus, Lachnospiraceae, and Clostridium butyrium in cisplatin plus D-methionine rats than in cisplatin rats. D-methionine treatment alone significantly increased the number of Lactobacillus reuteri. CONCLUSION: D-methionine protects against cisplatin-induced intestinal damage through antioxidative and anti-inflammatory effects. By enhancing growth of beneficial bacteria (Lachnospiraceae and Lactobacillus), D-methionine attenuates gut microbiome imbalance caused by cisplatin and maintains gut homeostasis.
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The incidence of myocardial ischemia-reperfusion (IR) injury is rapidly increasing around the world and this disease is a major contributor to global morbidity and mortality. It is known that regulation of programmed cell death including apoptosis and autophagy reduces the impact of myocardial IR injury. In this study, the cardioprotective effects and underlying mechanisms of Phellinus linteus (Berk. and Curt.) Teng, Hymenochaetaceae (PL), a type of medicinal mushroom, were examined in rats subjected to myocardial IR injury. The left main coronary artery of rats was ligated for 1 h and reperfused for 3 h. The arrhythmia levels were monitored during the entire process and the infarct size was evaluated after myocardial IR injury. Furthermore, the expression levels of proteins in apoptotic and autophagic pathways were observed. Pretreatment with PL mycelium (PLM) significantly reduced ventricular arrhythmia and mortality due to myocardial IR injury. PLM also significantly decreased myocardial infarct size and plasma lactate dehydrogenase level after myocardial IR injury. Moreover, PLM administration resulted in decreased caspase 3 and caspase 9 activation and increased Bcl-2/Bax ratio. Phosphorylation level of AMPK was elevated while mTOR level was reduced. Becline-1 and p62 levels decreased. These findings suggest that PLM is effective in protecting the myocardium against IR injury. The mechanism involves mediation through suppressed pro-apoptotic signaling and regulation of autophagic signaling, including stimulation of AMPK-dependent pathway and inhibition of beclin-1-dependent pathway, resulting in enhancement of protective autophagy and inhibition of excessive autophagy.
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Lumbrokinase, a novel antithrombotic agent, purified from the earthworm Lumbricus rubellus, has been clinically used to treat stroke and cardiovascular diseases. However, inflammatory responses associated with the cardioprotective effect of lumbrokinase remain unknown. In this study, the signaling pathways involved in lumbrokinase-inhibited expressions of inflammation mediators were investigated in rats subjected to myocardial ischemia-reperfusion (I-R) injury. The left main coronary artery of anesthetized rats was subjected to 1h occlusion and 3h reperfusion. The animals were treated with/without lumbrokinase and the severities of I-R-induced arrhythmias and infarction were compared. Lumbrokinase inhibited I-R-induced arrhythmias and reduced mortality, as well as decreased the lactate dehydrogenase levels in carotid blood. Lumbrokinase also inhibited the enhancement of I-R induced expressions of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), and matrix metalloproteinase (MMP)-9 through toll-like receptor 4 (TLR4) signaling pathway. Moreover, our results demonstrated that stimulation with lumbrokinase decreases the phosphorylation of JNK, IκB, and NF-κB. These findings suggested that lumbrokinase is a potent cardioprotective drug in rats with I-R injury. The cardioprotective effects of lumbrokinase may be correlated with its inhibitory effect on the I-R-induced expressions of COX-2, iNOS and MMP-9, mediated by TLR4 signaling through JNK and NF-κB pathways.
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Productos Biológicos/farmacología , Endopeptidasas/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Animales , Biomarcadores , Ciclooxigenasa 2/metabolismo , Electrocardiografía , Frecuencia Cardíaca , Hemodinámica , Masculino , Metaloproteinasas de la Matriz/metabolismo , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/diagnóstico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Óxido Nítrico Sintasa/metabolismo , Peroxidasa/metabolismo , Ratas , Receptor Toll-Like 2/metabolismoRESUMEN
Risk factors for prostate cancer (PCa) include age, hormones, race, family history and diet. Recently, epidemiologic evidence has indicated that history of diabetes mellitus (DM) is inversely associated with risk of PCa. However, epidemiological investigations have yielded inconsistent results. Hence, the exact mechanism of DM-induced reduction in the incidence of PCa has yet to be fully elucidated. The aim of this study was to investigate the effects of DM factors, including glucose, insulin and insulin-like growth factor-1 (IGF-1), on the proliferation of PCa cell lines in vitro. Cell proliferation and expression of hormone receptors was examined in MTT assay and Western blot analysis, respectively. The results showed that DM factors did not affect the viability of androgen receptor (AR)-expressing PCa cell lines. However, cell proliferation increased after treatment with DM factors in androgen-independent PCa cell lines. On PCa tissue arrays, intensities of total AR and nuclear IGF-1R were higher in malignant tissues than in normal prostate glands. In terms of hormonal receptors, androgen-dependent LNCaP cells treated with insulin and IGF-1 in a low-serum medium showed decreased expression of insulin receptor beta (IRß) and elevated expression of IGF-1 receptor beta (IGF-1Rß). Moreover, expression of AR was upregulated after insulin and IGF-1 treatment in LNCaP cells, but not in the other PCa cell lines. Most of the studied antidiabetic drugs promoted the viability of PCa cells. However, metformin decreased the viability of AR-expressing PCa cells. These results suggest that diabetic factors modify the expression of AR, IR and IGF-1R to increase cancer cell proliferation. Moreover, the growth suppressing effects of metformin on PCa may be via the regulation of the AR signaling pathway.
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Diabetes Mellitus/fisiopatología , Hipoglucemiantes/farmacología , Neoplasias de la Próstata/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Glucosa/farmacología , Humanos , Inmunohistoquímica , Insulina/farmacología , Factor I del Crecimiento Similar a la Insulina/farmacología , Masculino , Neoplasias de la Próstata/fisiopatología , Receptor IGF Tipo 1/biosíntesis , Receptor IGF Tipo 1/efectos de los fármacos , Receptor de Insulina/biosíntesis , Receptor de Insulina/efectos de los fármacos , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: The functions of free radicals on the effects of insulin that result in protection against cerebral ischemic insult in diabetes remain undefined. This present study aims to explain the contradiction among nitric oxide (NO)/superoxide/peroxynitrite of insulin in amelioration of focal cerebral ischemia-reperfusion (FC I/R) injury in streptozotocin (STZ)-diabetic rats and to delineate the underlying mechanisms. Long-Evans male rats were divided into three groups (age-matched controls, diabetic, and diabetic treated with insulin) with or without being subjected to FC I/R injury. RESULTS: Hyperglycemia exacerbated microvascular functions, increased cerebral NO production, and aggravated FC I/R-induced cerebral infarction and neurological deficits. Parallel with hypoglycemic effects, insulin improved microvascular functions and attenuated FC I/R injury in STZ-diabetic rats. Diabetes decreased the efficacy of NO and superoxide production, but NO and superoxide easily formed peroxynitrite in diabetic rats after FC I/R injury. Insulin treatment significantly rescued the phenomenon. CONCLUSIONS: These results suggest that insulin renders diabetic rats resistant to acute ischemic stroke by arresting NO reaction with superoxide to form peroxynitrite.
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Isquemia Encefálica/prevención & control , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Insulina/farmacología , Óxido Nítrico/metabolismo , Ácido Peroxinitroso/metabolismo , Accidente Cerebrovascular/prevención & control , Superóxidos/metabolismo , Enfermedad Aguda , Animales , Isquemia Encefálica/inducido químicamente , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Masculino , Ratas , Ratas Long-Evans , Accidente Cerebrovascular/inducido químicamente , Accidente Cerebrovascular/metabolismoRESUMEN
D-galactose is known to cause oxidative stress and induce aging-related diseases. Our previous study demonstrated that diosgenin can prevent osteoporosis in menopausal rats. The aim of the present study was to determine the effects of oral administration of diosgenin on bone loss in a D-galactose-induced aging rat model. Three groups of twelve-week-old male Wistar rats received a daily injection of D-galactose (150 mg/kg/day, i.p.) and orally administered diosgenin (0, 10, or 50 mg/kg/day) for eight weeks, while a control group received saline injection (1 ml/kg/day, i.p.), then the femurs were taken to measure mechanical and morphological properties. The results showed that frame volume and femur volume decreased and porosity and frame density increased in the D-galactose-induced aging rats compared to controls and that these effects were prevented by co-administration of diosgenin. This suggests that diosgenin might prevent bone loss during aging and provide beneficial effects in osteoporosis in the elderly.
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Dioscorea/química , Diosgenina/farmacología , Galactosa/toxicidad , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Envejecimiento , Animales , Modelos Animales de Enfermedad , Fémur/efectos de los fármacos , Fémur/patología , Osteoporosis/patología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
BACKGROUND: Hypothalamic neuropeptide Y (NPY) and two immediate early genes, c-fos and c-jun, have been found to be involved in regulating the appetite-suppressing effect of amphetamine (AMPH). The present study investigated whether cerebral catecholamine (CA) might regulate NPY and POMC expression and whether NPY Y1 receptor (Y1R) participated in activator protein-1 (AP-1)-mediated feeding. METHODS: Rats were given AMPH daily for 4 days. Changes in the expression of NPY, Y1R, c-Fos, c-Jun, and AP-1 were assessed and compared. RESULTS: Decreased CA could modulate NPY and melanocortin receptor 4 (MC4R) expressions. NPY and food intake decreased the most on Day 2, but Y1R, c-Fos, and c-Jun increased by approximately 350%, 280%, and 300%, respectively, on Day 2. Similarly, AP-1/DNA binding activity was increased by about 180% on Day 2. The expression patterns in Y1R, c-Fos, c-Jun, and AP-1/DNA binding were opposite to those in NPY during AMPH treatment. Y1R knockdown was found to modulate the opposite regulation between NPY and AP-1, revealing an involvement of Y1R in regulating NPY/AP-1-mediated feeding. CONCLUSIONS: These results point to a molecular mechanism of CA/NPY/Y1R/AP-1 signaling in the control of AMPH-mediated anorexia and may advance the medical research of anorectic and anti-obesity drugs.
Asunto(s)
Anfetamina/farmacología , Conducta Alimentaria/efectos de los fármacos , Receptores de Neuropéptido Y/metabolismo , Factor de Transcripción AP-1/metabolismo , Anfetamina/administración & dosificación , Animales , Apetito/efectos de los fármacos , Arginina/análogos & derivados , Arginina/farmacología , Inmunoprecipitación de Cromatina , Técnicas de Silenciamiento del Gen , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Masculino , Neuropéptido Y/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Ratas , Ratas Wistar , Receptor de Melanocortina Tipo 4/metabolismo , alfa-Metiltirosina/administración & dosificación , alfa-Metiltirosina/farmacologíaRESUMEN
Neuropeptide Y (NPY) and nuclear factor-kappa B (NF-κB) are involved in regulating anorexia elicited by phenylpropanolamine (PPA), a sympathomimetic drug. This study explored whether NPY Y1 receptor (Y1R) is involved in this process, and a potential role for the proopiomelanocortin system was identified. Rats were given PPA once a day for 4days. Changes in the hypothalamic expression of the NPY, Y1R, NF-κB, and melanocortin receptor 4 (MC4R) levels were assessed and compared. The results indicated that food intake and NPY expression decreased, with the largest reductions observed on Day 2 (approximately 50% and 45%, respectively), whereas NF-κB, MC4R, and Y1R increased, achieving maximums on Day 2 (160%, 200%, and 280%, respectively). To determine the role of Y1R, rats were pretreated with Y1R antisense or a Y1R antagonist via intracerebroventricular injection 1h before the daily PPA dose. Y1R knockdown and inhibition reduced PPA anorexia and partially restored the normal expression of NPY, MC4R, and NF-κB. The data suggest that hypothalamic Y1R participates in the appetite-suppression from PPA by regulating MC4R and NF-κB. The results of this study increase our understanding of the molecular mechanisms in PPA-induced anorexia.
Asunto(s)
Depresores del Apetito/farmacología , Conducta Alimentaria/efectos de los fármacos , FN-kappa B/efectos de los fármacos , Fenilpropanolamina/farmacología , Receptores de Melanocortina/efectos de los fármacos , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Elementos sin Sentido (Genética) , Western Blotting , Peso Corporal/fisiología , Cateterismo , Ventrículos Cerebrales/fisiología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Colículos Inferiores , Inyecciones , Masculino , FN-kappa B/biosíntesis , Ratas , Ratas Wistar , Receptor de Melanocortina Tipo 4/biosíntesis , Receptores de Melanocortina/biosíntesis , Receptores de Neuropéptido Y/biosíntesis , Receptores de Neuropéptido Y/genéticaRESUMEN
This study was performed to define the roles of actin-binding proteins in the regulation of actin filament assembly associated with cellular signal transduction pathways in stromal cell proliferation. Genistein, a tyrosine protein kinase inhibitor, decreased the intracellular Ca(2+) and attenuated cell proliferation and DNA synthesis through the beta-catenin and cyclin D1 pathway in human umbilical CD105-positive cells. Immunoprecipitation studies using anti-beta-actin antibody revealed that several actin-binding proteins implicated in cells include formin-2 (FMN-2), caldesmon (CaD), tropomyosin (Tm), and profilin. Protein levels of these proteins in whole cell lysates were not significantly changed by genistein. Three Tm isoforms, Tm-1, Tm-2, and Tm-4, were found to be present in cells. Genistein caused a reduction in levels of mRNAs coding for Tm-1 and Tm-4, but had no significant effect on Tm-2 mRNA levels. Immunofluorescence confocal scanning microscopy indicated that changes in the subcellular distribution of Tm and CaD, in which the diffuse cytosolic staining was shifted to show colocalization with actin stress fibers. In contrast, genistein-induced accumulation of FMN-2 and profilin in the peri-nuclear area. Silencing of FMN-2 by small interfering RNA resulted in increases of intracellular Ca(2+) and rendered genistein resistance in decreasing intracellular Ca(2+) in cells. These results provide the novel findings that genistein acts by modulating the cellular distribution of actin-binding proteins in association with alterations of cellular signal transduction pathways in human stromal cell proliferation.
Asunto(s)
Genisteína/farmacología , Proteínas de Microfilamentos/efectos de los fármacos , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , beta Catenina/efectos de los fármacos , Antígenos CD/análisis , Antígenos CD/metabolismo , Biomarcadores/análisis , Biomarcadores/metabolismo , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Proteínas de Unión a Calmodulina/efectos de los fármacos , Proteínas de Unión a Calmodulina/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Ciclina D1/efectos de los fármacos , Ciclina D1/metabolismo , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Endoglina , Humanos , Recién Nacido , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas del Tejido Nervioso/efectos de los fármacos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Profilinas/efectos de los fármacos , Profilinas/metabolismo , Isoformas de Proteínas/efectos de los fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores de Superficie Celular/análisis , Receptores de Superficie Celular/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Células del Estroma/citología , Tropomiosina/efectos de los fármacos , Tropomiosina/genética , Tropomiosina/metabolismo , Cordón Umbilical , beta Catenina/metabolismoRESUMEN
We investigated the participation of cyclin-dependent kinase-5 (Cdk5)-mediated N-methyl-D-aspartate receptor (NMDAR) NR2B subunit phosphorylation in cross-organ reflex sensitization caused by colon irritation. The external urethral sphincter electromyogram (EUSE) reflex activity evoked by the pelvic afferent nerve test stimulation (TS, 1 stimulation/30s) and protein expression in the spinal cord and dorsal root ganglion tissue (T13-L2 and L6-S2 ipsilateral to the stimulation) in response to colon mustard oil (MO) instillation were tested in anesthetized rats. When compared with a baseline reflex activity with a single action potential evoked by the TS before the administration of test agents, MO instillation into the descending colon sensitized the evoked activity characterized by elongated firing in the reflex activity in association with increased protein levels of Cdk5, PSD95, and phosphorylated NR2B (pNR2B) but not of total NR2B (tNR2B) in the spinal cord tissue. Both cross-organ reflex sensitization and increments in protein expression were reversed by intra-colonic pretreatments with ruthenium red (a non-selective transient receptor potential vanilloid, TRPV, antagonist), capsaizepine (a TRPV1-selective antagonist), lidocaine (a nerve conduction blocker) as well as by the intra-thecal pretreatment with APV (a NRMDR antagonist) Co-101244 (a NR2B-selective antagonist) and roscovitine (a Cdk5 antagonist). Moreover, compared with the control group, both the increase in pNR2B and the cross-organ reflex sensitization were attenuated in the si-RNA of NR2B rats. All these results suggested that Cdk-dependent NMDAR NR2B subunit phosphorylation mediates the development of cross-organ pelvic-urethra reflex sensitization caused by acute colon irritation which could possibly underlie the high concurrence of pelvic pain syndrome with irritable bowel syndrome.