RESUMO
This study aimed to clarify the therapeutic effects of exercise training on neural BDNF/TrkB signaling and apoptotic pathways in diabetic cerebral cortex. Thirty-six male C57BL/6JNarl mice were randomly divided into three groups: control (CON-G), diabetic group (DM-G, 100 mg/kg streptozotocin, i.p.), and diabetic with exercise training group (DMEX-G, Swim training for 30 min/day, 5 days/week). After 12 weeks, H&E staining, TUNEL staining, and Western blotting were performed to detect the morphological changes, neural apoptosis, and protein levels in the cerebral cortex. The Bcl2, BclxL, and pBad were significant decreased in DM-G compared with CON-G, whereas they (excluded the Ras and pRaf1) were increased in DMEX-G. In addition, interstitial space and TUNEL(+) apoptotic cells found increased in DM-G with increases in Fas/FasL-mediated (FasL, Fas, FADD, cleaved-caspase-8, and cleaved-caspase-3) and mitochondria-initiated (tBid, Bax/Bcl2, Bak/BclxL, Bad, Apaf1, cytochrome c, and cleaved-caspase-9) apoptotic pathways. However, diabetes-induced neural apoptosis was less in DMEX-G than DM-G with observed raises in the BDNF/TrkB signaling pathway as well as decreases in Fas/FasL-mediated and mitochondria-initiated pathways. In conclusion, exercise training provided neuroprotective effects via enhanced neural BDNF/TrkB signaling pathway and prevent Fas/FasL-mediated and mitochondria-initiated apoptotic pathways in diabetic cerebral cortex.
Assuntos
Diabetes Mellitus , Condicionamento Físico Animal , Animais , Masculino , Camundongos , Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de SinaisRESUMO
The aim of this study was to investigate the effects of longan flower (LF) water extract on cardiac apoptotic and survival pathways in rat models of fructose-induced metabolic syndrome. The study findings revealed that the levels of glucose, insulin, triglyceride, and cholesterol and TUNEL-positive apoptotic cells were significantly increased in the HF group compared with the control group; whereas, the levels were decreased in the HFLF group. The expressions of Fas, FADD, and activated caspases 8 and 3, as well as the expressions of Bax, Bak, Bax/Bcl-2, Bak/Bcl-xL, cytosolic cytochrome c, and activated caspases 9 and 3 were increased in the HF group were significantly reversed in HFLF administrated group. Furthermore, LF extract increased IGF-1R, p-PI3K, p-Akt, Bcl-2, and Bcl-xL expression compared to HF group. Taken together, the present findings help identify LF as a potential cardioprotective agent that can be effectively used in treating fructose-induced metabolic syndrome.
Assuntos
Síndrome Metabólica , Animais , Apoptose , Flores , Frutose/toxicidade , Síndrome Metabólica/induzido quimicamente , Miocárdio , Proteínas Proto-Oncogênicas c-bcl-2 , Ratos , Sapindaceae , Proteína X Associada a bcl-2 , Receptor fasRESUMO
It has been increasingly recognized that accelerated atherosclerosis is a major cause of morbidity and mortality in patients with systemic lupus erythematosus, a multisystem autoimmune disease. In this study, we investigated the anti-apoptotic effects of heat-killed Lactobacillus reuteri GMNL-263 on the cardiac tissue of NZB/W F1 mice. The myocardial architecture of the mice heart was observed and evaluated using different staining techniques such as hematoxylin and eosin, TUNEL assay, Masson's trichrome, and fluorescent immunohistochemistry. Additionally, the probiotics-related pathway proteins were analyzed via western blot analysis. Our results showed prevention of enlarged interstitial spaces and abnormal myocardial structures in the hearts of NZB/W F1 mice with L. reuteri GMNL-263 feeding. Significant reduction in TUNEL-positive cells, Fas death receptor-related components, and apoptosis was also detected in the cardiac tissues of the NZB/W F1 mice after L. reuteri GMNL-263 feeding compared with the control group. These findings are the first to reveal the protective effects of L. reuteri GMNL-263 against cardiac abnormalities in NZB/W F1 mice and suggest the potential clinical applications of L. reuteri GMNL-263 in the treatment of SLE-related cardiovascular diseases.
Assuntos
Cardiomiopatias , Temperatura Alta , Limosilactobacillus reuteri , Lúpus Eritematoso Sistêmico , Probióticos/farmacologia , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/prevenção & controle , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/terapia , CamundongosRESUMO
INTRODUCTION: Insulin-like growth factor-I receptor (IGF1R) mediated survival signaling is a crucial mechanism for cellular endurance and a potential indicator of recuperation in deteriorating hearts. OBJECTIVE: This study evaluates the impact of long-term exercise training in enhancing cardiac survival mechanism in D-galactose-induced toxicity associated aging rats. METHODS: Forty-eight male SD-rats were segregated into 4 groups (n=9) and were named as control, exercise training groups, aging group and aging group with exercise training. Aging was induced by intraperitoneal (IP) D-galactose (150 mL/kg) injection for 8 weeks and for exercise training, the rats were left to swim in warm water for 60 min every day and 5 times/week. Western blotting of proteins from the left ventricles was performed to identify the modulations in the survival signaling. Tissue sections were analyzed to determine the extent of fibrosis and apoptosis. RESULTS: Western-blot analysis performed on the excised left ventricles (LV) showed that proteins of the cardiac survival pathway including IGF1R and Akt and the pro-survival Bcl-2 showed significant decrease in the aging group, whereas the levels were restored in the aging rats subjected to exercise training. In addition, aging groups showed increased interstitial space and collagen accumulation. Further, TUNEL assay showed higher number of apoptotic cells in the LV of aging group, which was correlated with increase in the proteins involved in FAS-FADD-dependent apoptosis. However, these aging associated effects were ameliorated upon exercise training in the D-galactose-induced aging rats that showed elevated IGF1R/Akt signaling. CONCLUSION: The results suggest that IGFIR survival signaling cascadeis elevated in following long-term exercise training and thereby provide cardio-protective benefits in D-galactose induced aging rats.
RESUMO
The purpose of this study was to evaluate the effects of diosgenin on the D-galactose-induced cerebral cortical widely dispersed apoptosis. Male 12-week-old Wistar rats were divided into four groups: Control (1mg/kg/day of saline, i.p.), DD0 (150mg/kg/day of D-galactose, i.p.), DD10, and DD50 (D-galactose+10 or 50mg/kg/day of diosgenin orally). After eight weeks, histopathological analysis, positive TUNEL and Western blotting assays were performed on the excised cerebral cortex from all four groups. The TUNEL-positive apoptotic cells, the components of Fas pathway (Fas, FADD, active caspase-8 and active caspase-3), and mitochondria pathway (t-Bid, Bax, cytochrome c, active caspase-9 and active caspase-3) were increased in the DD0 group compared with the control group, whereas they were decreased in the DD50 group. The components of survival pathway (p-Bad, Bcl-2, Bcl-xL, IGF-1, p-PI3K and p-AKT) were increased in the DD50 group compared to the control group, whereas the levels of Bcl-xL, p-PI3K, and p-AKT were also compensatorily increased in the DD0 group compared to the control group. Taken together, diosgenin suppressed D-galactose-induced neuronal Fas-dependent and mitochondria-dependent apoptotic pathways and enhanced the Bcl-2 family associated pro-survival and IGF-1-PI3K-AKT survival pathways, which might provide neuroprotective effects of diosgenin for prevention of the D-galactose-induced aging brain.
Assuntos
Envelhecimento , Apoptose/efeitos dos fármacos , Diosgenina/farmacologia , Fármacos Neuroprotetores , Animais , Encéfalo/metabolismo , Caspase 3/metabolismo , Caspase 8/metabolismo , Proteína de Domínio de Morte Associada a Fas/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Mitocôndrias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Receptor fas/metabolismoRESUMO
The medicinal plant Rhodiola crenulata grows at high altitudes in the Arctic and mountainous regions and is commonly used in phytotherapy in Eastern European and Asian countries. In the present study, we investigated the anti-apoptotic effect of Rhodiola crenulata and its neuroprotective mechanism of action in a rat model of D-galactose-induced aging. Two groups of twelve-week-old male Wistar rats received a daily injection of D-galactose (150mg/kg/day, i.p.) and orally administered Rhodiola crenulata (0, 248mg/kg/day) for eight weeks, while a control group received a saline injection (1ml/kg/day, i.p.). We examined apoptosis in the cortex and hippocampus of three groups of rats based on a terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling (TUNEL) positive assay. The expression levels of apoptotic and anti-apoptotic proteins in excised brains were analyzed by Western blotting. Our findings indicated that D-galactose caused marked neuronal apoptosis via activation of both extrinsic-dependent and mitochondrial-dependent apoptotic pathways. When compared to the control group, the protein levels of Fas receptor, Fas ligand, Fas-associated death domain (FADD), and activated caspase-8 (Fas-dependent apoptotic pathways), as well as those of t-Bid, Bax, cytochrome c, activated caspase-9, and activated caspase-3 (mitochondrial-dependent apoptotic pathways), were significantly increased in the D-galactose treated group. In addition, D-galactose impaired the phosphorylation of PI3K/Akt, an important survival signaling event in neurons. Rhodiola crenulata, however, protected against all these neurotoxicities in aging brains. The present study suggests that neuronal survival promoted by Rhodiola crenulata may be a potentially effective method to enhance the resistance of neurons to age-related disorders.
Assuntos
Envelhecimento , Apoptose/efeitos dos fármacos , Galactose , Fármacos Neuroprotetores , Extratos Vegetais/farmacologia , Rhodiola/química , Administração Oral , Animais , Encéfalo/metabolismo , Caspase 8/metabolismo , Córtex Cerebral/patologia , Proteína Ligante Fas/metabolismo , Hipocampo/patologia , Masculino , Modelos Animais , Fosfatidilinositol 3-Quinases/metabolismo , Fitoterapia , Extratos Vegetais/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Receptor fas/metabolismoRESUMO
Dilated cardiomyopathy (DCM) is the most common form of non-ischemic cardiomyopathy. It is characterized by ventricular chamber dilation, and myocyte hypertrophy. Human tumorous imaginal disc 1 (Tid1), a chaperone protein and response to regulate number of signaling molecules in the mitochondria or cytosol. Tid1 also plays a major role in preventing DCM; however, the role of Tid1 in isoproterenol (ISO)-induced cardiac apoptosis and hypertrophy remains unclear. H9c2 cells were pretreated Tid1 before ISO-induced hypertrophy and apoptosis and then evaluated by IHC, TUNEL assay, IFC, Co-IP, and Western blot. From the IHC experiment, we found that Tid1 proteins were increased in tissues from different stages of human myocardial infarction. Using H9c2 cardiomyoblast cells we found that Tid1 was decreased by ISO treatment. However, over-expression of Tid1S suppressed NFATc3, BNP and calcineurin protein expression and inhibited NFATc3 nuclear translocation in ISO induced cardiomyoblast cells. On the other hand, Tid1S over-expression activated survival proteins p-AKTser473 and decreased caspase-3 and cytochrome c expression. We also found that overexpression of Tid1 enhanced CHIP expression, and induced CHIP to ubiquitinate Gαs, resulting in increased Gαs degradation. Our study showed that Gαs is a novel substrate of CHIP, and we also found that the Tid1-CHIP complex plays an essential role in inhibiting ISO induced cardiomyoblast hypertrophy and apoptosis.
Assuntos
Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Isoproterenol/toxicidade , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas de Choque Térmico HSP40/genética , Humanos , Masculino , Ratos , Transdução de Sinais/efeitos dos fármacos , Análise Serial de Tecidos , Ubiquitina-Proteína Ligases/genéticaRESUMO
Hypertension-stimulated cardiac hypertrophy and apoptosis play critical roles in the progression of heart failure. Our previous study suggested that hypertensive angiotensin II (Ang II) enhanced insulin-like growth factor receptor II (IGF-IIR) expression and cardiomyocyte apoptosis, which are involved JNK activation, sirtuin1 (SIRT1) degradation, and heat-shock transcription factor 1 (HSF1) acetylation. Moreover, previous studies have implied that short-term hypoxia (STH) might exert cardioprotective effects. However, the effects of STH on Ang II-induced cardiomyocyte apoptosis remain unknown. In this study, we found that STH reduced myocardial apoptosis caused by Ang II via upregulation of the Mas receptor (MasR) to inhibit the AT1 R signaling pathway. STH activates MasR to counteract the Ang II pro-apoptotic signaling cascade by inhibiting IGF-IIR expression via downregulation of JNK activation and reduction of SIRT1 degradation. Hence, HSF could remain deacetylated, and repress IGF-IIR expression. These effects decrease the activation of downstream pro-apoptotic and hypertrophic cascades and protect cardiomyocytes from Ang II-induced injury. In addition, we also found that silencing MasR expression enhanced Ang II-induced cardiac hypertrophy and the apoptosis signaling pathway. These findings suggest a critical role for MasR in cardiomyocyte survival. Altogether, our findings indicate that STH protects cardiomyocytes from Ang II-stimulated apoptosis. The protective effects of STH are associated with the upregulation of MasR to inhibit AT1 R signaling. STH could be a potential therapeutic strategy for cardiac diseases in hypertensive patients.
Assuntos
Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/biossíntese , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Animais , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Miócitos Cardíacos/patologia , Proto-Oncogene Mas , RatosRESUMO
Hepatocellular carcinoma (HCC) metastasis is often associated with the activation of Wnt/ß-catenin signaling pathway. Zanthoxylum avicennae (Ying Bu Bo, YBB), a traditional herb with hepatoprotective effect, has been proven to inhibit human HCC in in vivo models however, the in vitro and in vivo effect of YBB on tumor metastasis is not clear yet. To determine whether YBB could inhibit HA22T human HCC cell by acting on ß-catenin metastatic signaling in vitro and in vivo, HA22T cells were treated with different concentrations of YBB extracts (YBBE) and analyzed by Immunofluorescence staining assay, western blot analysis, siRNA mediated gene knock-down assays and co-immunoprecipitation assay. Additionally, the HA22T-implanted xenograft nude mice were used to confirm the assessed cellular effects. Mice treated with YBBEs showed a strong increasing trend in PP2Acα, GSK-3ß, APC, and ß-TrCP/HOS levels, however the expression of ß-catenin, p-GSK-3ß, TBX 3, and IL8 proteins showed a decreasing trend. YBBE significantly downregulated the nuclear and cytosolic ß-catenin levels by facilitating the proteosomal degradation of ß-catenin. Moreover, as observed by co-immunoprecipitation assay, YBBE directly promoted the protein interactions between GSK-3ß, ß-TrCP, APC, PP2A, and ß-catenin. In conclusion, both in vitro and in vivo models clearly demonstrated that YBBE inhibits ß-catenin involved metastatic signaling in highly metastatic HA22T cells through PP2A activation.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Extratos Vegetais/farmacologia , Proteína Fosfatase 2/metabolismo , Zanthoxylum/química , beta Catenina/metabolismo , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Quinase 3 da Glicogênio Sintase/metabolismo , Xenoenxertos , Humanos , Neoplasias Hepáticas/patologia , Camundongos Nus , Metástase Neoplásica , Extratos Vegetais/uso terapêutico , Transdução de SinaisRESUMO
Food restriction and weight loss are known to prevent obesity-related heart diseases. This study investigates whether food restriction elicits anti-apoptotic and pro-survival effects on high-fat diet-induced obese hearts. Histopathological analysis, TUNEL assay, and Western blotting were performed on the excised hearts from three groups of Sprague-Dawley rats which were fed with regular chow diet (CON, 13.5 % fat), a high-fat ad libitum diet (HFa, 45 % fat), or a high-fat food-restricted diet (HFr, 45 % fat, maintaining the same weight as CON) for 12 weeks. Body weight, blood pressure, heart weight, triglycerides, insulin, HOMAIR, interstitial spaces, cardiac fibrosis, and cardiac TUNEL-positive apoptotic cells were increased in HFa relative to CON, whereas these parameters were decreased in HFr relative to HFa. The protein levels of cardiac Fas ligand, Fas receptors, Fas-associated death domain (FADD), activated caspase-8, and activated caspase-3 (Fas receptor-dependent apoptotic pathways), as well as t-Bid/Bid, Bax/Bcl-2, Bad/p-Bad, Cytochrome c, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptotic pathways) in HFr were lower than those in HFa. Moreover, the Bcl-xL and IGF-1-related components of IGF-1, p-PI3 K/PI3 K, p-Akt/Akt in HFr were higher than those in HFa. Our findings suggest that a restricted high-fat diet for maintaining weight control could diminish cardiac Fas receptor-dependent and mitochondria-dependent apoptotic pathways as well as might enhance IGF-1-related pro-survival pathways. In sum, food restriction for maintaining normal weight could elicit anti-apoptotic and pro-survival effects on high-fat diet-induced obese hearts.
Assuntos
Apoptose , Restrição Calórica , Dieta Hiperlipídica , Cardiopatias/dietoterapia , Miocárdio/patologia , Obesidade/dietoterapia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Sobrevivência Celular , Modelos Animais de Doenças , Fibrose , Cardiopatias/etiologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miocárdio/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Ratos Sprague-Dawley , Transdução de Sinais , Receptor fas/metabolismoRESUMO
The purpose of this study was to evaluate the effects of exercise training on cardiac Fas receptor-dependent and mitochondria-dependent apoptotic pathways in ovariectomized rats. Histopathological analysis, TUNEL assay, and Western blotting were performed on the excised hearts from three groups of Sprague-Dawley rats, which were divided into a sham-operated group, a bilaterally ovariectomized group (OVX), and a bilaterally ovariectomized group that underwent treadmill running exercise for 60 min/day, 5 sessions/wk, for 10 wk (OVX-EX). The abnormal myocardial architecture, cardiac trichome-stained fibrosis and cardiac TUNEL-positive apoptotic cells in ovariectomized rats improved after exercise training. The protein levels of tumor necrosis factor-α, tumor necrosis factor receptor 1, Fas ligand, Fas receptors, Fas-associated death domain, activated caspase-8 and activated caspase-3 (Fas receptor-dependent apoptotic pathways), as well as t-Bid, Bad, Bak, Bax, cytosolic cytochrome c, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptotic pathways) were decreased in the OVX-EX group compared with the OVX group. Exercise training suppressed ovariectomy-induced cardiac Fas receptor-dependent and mitochondria-dependent apoptotic pathways in ovariectomized rat models. These findings might indicate a new therapeutic effect for exercise training to prevent cardiac apoptosis in menopausal or bilaterally oophorectomized women.
Assuntos
Proteínas Reguladoras de Apoptose/imunologia , Apoptose/imunologia , Isquemia Miocárdica/imunologia , Miocárdio/imunologia , Ovariectomia/efeitos adversos , Condicionamento Físico Animal/métodos , Animais , Feminino , Mitocôndrias Cardíacas/imunologia , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/prevenção & controle , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
This study investigates the cardio-protective effect of Nos. 1 and 5 extracts from Taiwan Mingjian Oolong Tea on H9c2 cardiomyoblast cells treated with isoproterenol (ISO). Treatment with Nos. 1 and 5 extracts increased cell viability and blocked apoptosis in ISO exposed H9c2 cells. Moreover, Nos. 1 and 5 extracts blocked hypertrophy markers like G[Formula: see text]s, calcineurin, NFATc3, and BNP, thereby increasing cell proliferation markers -PI3K and AKT in a dose dependent manner. In contrast, apoptotic proteins, such as caspase-3 and cytochrome c were decreased in H9c2 cells treated with Nos. 1 and 5 extracts. We confirmed that the protective effect of No. 1 extract was partially mediated through the expression of ERK and p38, however, the No. 5 extract showed a protective effect via the ERK, JNK, and p38 pathways. This evidence provides new insights into the pharmacological role and therapeutic mechanism of Taiwan Mingjian Oolong Tea in heart diseases.
Assuntos
Apoptose/efeitos dos fármacos , Camellia sinensis/química , Cardiotônicos/farmacologia , Isoproterenol/efeitos adversos , Miócitos Cardíacos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Chá/química , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Hipertrofia , Sistema de Sinalização das MAP Quinases , Miócitos Cardíacos/citologia , Ratos , Taiwan , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
BACKGROUND: The goal of this study is to determine if Rhodiola Crenulata (RC) has protective effects on mice hearts with severe sleep apnea model. METHODS: Sixty-four C57BL/6 J mice 5-6 months old were distributed into 4 groups i.e. Control group (21% O2, 24 h per day, 8 weeks, n=16); Hypoxia group (Hypoxia: 7% O2 60 s, 20% O2 alternating 60 s, 8 h per day, 8 weeks, n=16); Hypoxia+90RC and Hypoxia+270RC group (Hypoxia for 1st 4 weeks and hypoxia pretreated 90 mg/Kg and 270 mg/Kg Rhodiola Crenulata by oral gavage per day for 2nd 4 weeks, each n=16). Excised hearts from 4 groups of mice were analyzed for heart weight index changes using H&E staining, TUNEL-positive assays and Western Blotting protein. RESULTS: Cardiac widely dispersed TUNEL-positive apoptotic cells in mice hearts were less in Hypoxia+RC90 and Hypoxia+RC270 than those in Hypoxia. Compared with Hypoxia, the protein levels of Fas ligand, Fas death receptors, Fas-Associated Death Domain (FADD), activated caspase 8, and activated caspase 3 (Fas dependent apoptotic pathways) were decreased in Hypoxia+RC90, Hypoxia+RC270. The protein levels of Bad, Bax, t-Bid, activated caspase 9, activated caspase 3 (mitochondria dependent apoptotic pathway) were less in Hypoxia+RC90, Hypoxia+RC270 than those in hypoxia. The protein levels of Bcl2, Bcl-xL, p-Bad (Bcl2-realted anti-apoptotic pathway) and VEGF, p-PI3k, p-AKT (VEGF-related pro-survival pathway) were higher in Hypoxia+RC90, Hypoxia+RC270 than those in hypoxia. CONCLUSIONS: Our findings suggest that Rhodiola Crenulata have protective effects on chronic intermittent hypoxia-induced cardiac widely dispersed apoptosis via Fas-dependent and mitochondria-dependent apoptotic and VEGF-related pro-survival pathway.
Assuntos
Apoptose/efeitos dos fármacos , Cardiopatias/patologia , Coração/efeitos dos fármacos , Miocárdio , Fitoterapia , Rhodiola , Síndromes da Apneia do Sono/patologia , Animais , Caspases/metabolismo , Proteína Ligante Fas/metabolismo , Proteína de Domínio de Morte Associada a Fas/metabolismo , Cardiopatias/etiologia , Cardiopatias/metabolismo , Cardiopatias/prevenção & controle , Hipóxia , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Síndromes da Apneia do Sono/complicações , Síndromes da Apneia do Sono/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor fas/metabolismoRESUMO
Obesity is often associated with the development of cardiac hypertrophy but the hypertrophy-related pathways in obesity remain unknown. The purpose of this study was to evaluate cardiac hypertrophy-related markers, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), tumor necrosis factor-alpha (TNFα) and hypertrophy-related pathways, interleukin (IL)-6-STAT3, IL-6-MEK5-ERK5 and calcineurin-nuclear factor of activated T-cells (NFAT)3 in the excised hearts from obese rats. Twelve obese Zucker rats were studied at 5-6 months of age and twelve age-matched lean Zucker rats served as the control group. The cardiac characteristics, myocardial architecture, ANP, BNP, TNFα levels, IL-6, STAT3, p-STAT3, MEK5, ERK-5, p-ERK-5, calcineurin and NFAT3 in the left ventricle from the rats were measured by heart weight index, echocardiography, vertical cross section, histological analysis, reverse transcription polymerase chain reaction and western blotting. Compared with the lean control, the whole heart weight, the left ventricule weight, the ratio of the whole heart weight to tibia length, echocardiographic interventricular septum, left ventricular posterior wall thickness, myocardial morphological changes and systolic blood pressure were found to increase in the obese rats. The protein levels of ANP, BNP, TNFα, IL-6, STAT3, p-STAT3, MEK-5, ERK-5, p-ERK 5, calcineurin and NFAT3 were also significantly increased in the hearts of the obese rats. The results showed that the hypertrophy-related markers, ANP, BNP and TNFα, the hypertrophy-related pathways IL-6-STAT3 and IL-6-MEK5-ERK5, and the calcineurin-NFAT3 hypertrophy-related pathways were more active in obese Zucker rats, which may provide possible hypertrophic mechanisms for developing cardiac hypertrophy and pathological changes in obesity.
Assuntos
Cardiomegalia/complicações , Cardiomegalia/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Obesidade Mórbida/complicações , Obesidade Mórbida/metabolismo , Animais , Fator Natriurético Atrial/metabolismo , Cardiomegalia/genética , Modelos Animais de Doenças , Interleucina-6/metabolismo , MAP Quinase Quinase 5/metabolismo , Masculino , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Obesidade Mórbida/genética , RNA Mensageiro/metabolismo , Ratos Zucker , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: The goal of this study is to determine if salidroside has protective effects on hypoxia-induced cardiac widely dispersed apoptosis in mice with severe sleep apnea model. METHODS: Sixty-four C57BL/6J mice 5-6 months of age were divided into four groups, i.e. Control group (21% O2, 24h per day, 8 weeks, n=16); Hypoxia group (Hypoxia: 7% O2 60s, 20% O2 alternating 60s, 8h per day, 8 weeks, n=16); and Hypoxia+S10 and Hypoxia+S 30 groups (Hypoxia for 1st 4 weeks, hypoxia pretreated 10mg/kg and 30 mg/kg salidroside by oral gavage per day for 2nd 4 weeks, n=16 and 16). The excised hearts from four groups were measured by the heart weight index, H&E staining, TUNEL-positive assays and Western blotting. RESULTS: TUNEL-positive apoptotic cells in mice heart were less in Hypoxia+S10 and Hypoxia+S30 than those in the Hypoxia group. Compared with Hypoxia, the protein levels of Fas ligand, Fas death receptors, Fas-Associated Death Domain (FADD), activated caspase 8, and activated caspase 3 (Fas pathways) were decreased in Hypoxia+S10 and Hypoxia+S30. In the mitochondria pathway, the protein levels of BcLx, Bcl2, and Bid (anti-apoptotic Bcl2 family) in Hypoxia+S10 and Hypoxia+S30 were more than those in Hypoxia. The protein levels of Bax, t-Bid, activated caspase 9, and activated caspase 3 were less in Hypoxia+S10 and Hypoxia+S30 than those in hypoxia. CONCLUSIONS: Our findings suggest that salidroside has protective effects on chronic intermittent hypoxia-induced Fas-dependent and mitochondria-dependent apoptotic pathways in mice hearts.
Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Glucosídeos/farmacologia , Coração/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Fenóis/farmacologia , Rhodiola , Animais , Apoptose/fisiologia , Cardiotônicos/uso terapêutico , Doença Crônica , Glucosídeos/uso terapêutico , Hipóxia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/patologia , Fenóis/uso terapêuticoRESUMO
Cordyceps sinensis (C. sinensis) has long been considered to be an herbal medicine and has been used in the treatment of various inflammatory diseases. The present study examined the cytoprotective properties of C. sinensis on D(+)-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice were randomly assigned into control, GalN/LPS, CS 20 mg and CS 40 mg groups (C. sinensis, oral gavage, five days/week, four weeks). After receiving saline or C. sinensis, mice were intraperitoneally given GalN (800 mg/kg)/LPS (10 µg/kg). The effects of C. sinensis on TNF-α, IL-10, AST, NO, SOD, and apoptoticrelated proteins after the onset of endotoxin intoxication were determined. Data demonstrated that GalN/LPS increased hepatocyte degeneration, circulating AST, TNF-α, IL-10, and hepatic apoptosis and caspase activity. C. sinensis pre-treatment reduced AST, TNF-α, and NO and increased IL-10 and SOD in GalN/LPS induced fulminant hepatic failure. C. sinensis attenuated the apoptosis of hepatocytes, as evidenced by the TUNEL and capase-3, 6 activity analyses. In summary, C. sinensis alleviates GalN/LPS-induced liver injury by modulating the cytokine response and inhibiting apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Cordyceps/química , Galactosamina/efeitos adversos , Lipopolissacarídeos/efeitos adversos , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/prevenção & controle , Fígado/citologia , Fígado/patologia , Fitoterapia , Extratos Vegetais/farmacologia , Animais , Aspartato Aminotransferases/metabolismo , Caspases/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Interleucina-10/metabolismo , Fígado/metabolismo , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Extratos Vegetais/uso terapêutico , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Consumption of fructose has been linked to the development of metabolic syndrome, whereas the cardiomyopathic changes and cardiac apoptosis of dietary high-fructose intake have not yet been clarified. The purpose of this study was to evaluate the effects of high-fructose on cardiac apoptotic and survival pathways. Thirty-two Wistar rats were randomly divided into a control group (CON), which received a standard chow diet, and a fructose-induced metabolic syndrome group (FIMS), which received a 50% fructose-content diet for 13 weeks. Histopathological analysis, TUNEL assays and Western blotting were performed on the excised hearts from both groups. The blood pressure, glucose, insulin, triglyceride and cholesterol levels were significantly increased in the FIMS group, compared with the CON group. The abnormal myocardial architecture, enlarged interstitial space and increased cardiac TUNEL-positive apoptotic cells were observed in the FIMS group. The TNF-α, TNF receptor 1, Fas ligand, Fas receptor, FADD, and activated caspase-3 and 8 protein levels (Fas pathway) and the Bax, Bak, Bax/Bcl-2, Bak/Bcl-xL, cytosolic cytochrome c, and activated caspase-3 and nine protein levels (mitochondria pathway) were increased in the FIMS group compared with those in the CON group. The IGFI, IGFI-R, p-PI3K, p-Akt, Bcl-2 and Bcl-xL protein levels (survival pathway) were all significantly decreased in the FIMS group compared with those in the CON group. High-fructose intake elevated blood pressure and glucose levels; moreover, high-fructose diet activated cardiac Fas-dependent and mitochondria-dependent apoptotic pathways and suppressed the survival pathway, which might provide one possible mechanism for developing heart failure in patients with metabolic syndrome.
Assuntos
Apoptose/efeitos dos fármacos , Frutose/efeitos adversos , Síndrome Metabólica/etiologia , Miocárdio/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Carboidratos da Dieta/efeitos adversos , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
BACKGROUND: Increased myocyte apoptosis in diabetic hearts has been previously reported. The purpose of this study was to evaluate the effects of exercise training on cardiac survival pathways in streptozotocin (STZ)-induced diabetic rats. METHODS: Forty-eight male Wistar rats were randomly divided into control group (Control), STZ-induced (65 mg/kg, i.p.) diabetes (DM), and DM rats with moderate aerobic exercise training (DM-EX) on a treadmill 60 min/day, 5 days/week, for 10 weeks. Histopathological analysis, positive TUNEL assays and Western blotting were performed on the excised cardiac left ventricles from all three groups. RESULTS: The components of cardiac survival pathway (insulin-like growth factor I (IGFI), IGFI-receptor (IGFI-R), phosphatidylinositol 3'-kinase (PI3K), and Akt) and the pro-survival Bcl-2 family proteins (Bcl-2, Bcl-xL, and p-BAD) were all significantly decreased in the DM group compared with the Control group whereas they were increased in the DM-EX group. In addition, the abnormal myocardial architecture, enlarged interstitial space and increased cardiac TUNEL-positive apoptotic cells were observed in the DM group, but they were reduced in the DM-EX group. The apoptotic key component, caspase-3, was significantly increased in the DM group relative to the Control group whereas it was decreased in the DM-EX group. CONCLUSIONS: Exercise training enhances cardiac IGFI-R/PI3K/Akt and Bcl-2 family associated pro-survival pathways, which provides one of the new beneficial effects for exercise training in diabetes.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Condicionamento Físico Animal/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Animais , Diabetes Mellitus Experimental/mortalidade , Diabetes Mellitus Experimental/terapia , Ventrículos do Coração/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Condicionamento Físico Animal/métodos , Distribuição Aleatória , Ratos , Ratos Wistar , Taxa de Sobrevida/tendênciasRESUMO
Rosiglitazone is a potent synthetic peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist which improves glucose control in the plasma and reduces ischemic brain injury. However, the pharmacokinetics of rosiglitazone in the brain is still unclear. In this study, a method using liquid chromatography-mass spectrometry coupled with microdialysis and an auto-blood sampling system was developed to determine rosiglitazone and glucose concentration in the brain and blood of gerbils subjected to treatment with rosiglitazone (3.0 mg kg(-1), i.p.). The results showed the limit of detection was 0.04 µg L(-1) and the correlation coefficient was 0.9997 for the determination of rosiglitazone in the brain. The mean parameters, maximum drug concentration (C(max)) and the area under the concentration-time curve from time zero to time infinity (AUC(inf)), following rosiglitazone administration were 1.06±0.28 µg L(-1) and 296.82±44.67 µg min L(-1), respectively. The time to peak concentration (C(max) or T(max)) of rosiglitazone occurred at 105±17.10 min, and the mean elimination half-life (t(1/2)) from brain was 190.81±85.18 min after administration of rosiglitazone. The brain glucose levels decreased to 71% of the basal levels in the rosiglitazone-treated group when compared with those in the control (p<0.01). Treatment with rosiglitazone decreased blood glucose levels to 80% at 1h after pretreatment of rosiglitazone (p<0.05). In addition, pretreatment with rosiglitazone significantly reduced the cerebral infarct volume compared with that of the control group. These findings suggest that this method may be useful for simultaneous and continuous determination of rosiglitazone and glucose concentrations in brain and plasma. Rosiglitazone was effective at penetrating the blood-brain barrier as evidenced by the rapid appearance of rosiglitazone in the brain, and rosiglitazone may contribute to a reduction in the extent of injuries related to cerebral ischemic stroke via its hypoglycemic effect.
Assuntos
Glicemia/análise , Isquemia Encefálica/sangue , Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Glucose/metabolismo , Hipoglicemiantes/farmacocinética , Tiazolidinedionas/farmacocinética , Animais , Automação Laboratorial , Encéfalo/efeitos dos fármacos , Infarto Encefálico/patologia , Gerbillinae , Meia-Vida , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Limite de Detecção , Masculino , Microdiálise , PPAR gama/agonistas , Distribuição Aleatória , Traumatismo por Reperfusão/prevenção & controle , Reprodutibilidade dos Testes , Rosiglitazona , Espectrometria de Massas em Tandem , Tiazolidinedionas/sangue , Tiazolidinedionas/química , Tiazolidinedionas/metabolismo , Distribuição TecidualRESUMO
The effect of magnesium supplementation on exercise performance remains controversial. In the present study, the effects of magnesium sulfate on exercise performance and blood glucose metabolism were examined. In order to provide a non-invasive measure of continuous exercise, we developed an auto-blood sampling system was coupled to a microdialysis analyzer to detect the dynamic changes in glucose metabolism in conscious and freely moving gerbils subjected to forced swimming. Gerbils were pretreated with saline or magnesium sulfate (90 mg kg(-1), ip) 30 min before exercise. The duration times were significantly increased by 71% in the magnesium sulfate-treated groups (p < 0.01) when compared with those in the control. Another group of gerbils were subjected to blood sampling assay. A catheter was implanted in the jugular vein of each gerbil for collecting blood samples by the computer-aided blood sampler. The basal levels of plasma glucose, lactate, and magnesium were 6,245 +/- 662, 1,067 +/- 309, and 590 +/- 50 microM, respectively, with no significant difference between groups. Plasma glucose, lactate, and magnesium levels increased to 134 and 204%, 369 and 220%, and 155 and 422% of basal levels during swimming in both the control and magnesium sulfate-treated groups, respectively (p < 0.05). Pretreatment with magnesium sulfate elevated glucose and magnesium levels to 175 and 302% of the basal levels (p < 0.05), respectively, whereas pretreatment with magnesium sulfate reduced the lactate levels 150% of the basal level (p < 0.05) during swimming. Furthermore, the magnesium levels increased to about 152-422% of basal levels during forced swimming and the recovery period (p < 0.05). The present study demonstrates that magnesium sulfate improved the duration time of forced swimming exercise. In addition, magnesium raised glucose levels and attenuated lactate levels during forced swimming. These results indicate that positive effects of magnesium supplementation may contribute to the enhancement of exercise performance in athletes.