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1.
Am J Chin Med ; : 1-17, 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38490806

RESUMO

Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug used to treat a wide spectrum of tumors. However, its clinical application is limited due to cardiotoxic side effects. Astragaloside IV (AS IV), one of the major compounds present in aqueous extracts of Astragalus membranaceus, possesses potent cardiovascular protective properties, but the underlying molecular mechanisms are unclear. Thus, the aim of this study was to investigate the effect of AS IV on DOX-induced cardiotoxicity (DIC). Our findings revealed that DOX induced pyroptosis through the caspase-1/gasdermin D (GSDMD) and caspase-3/gasdermin E (GSDME) pathways. AS IV treatment significantly improved the cardiac function and alleviated myocardial injury in DOX-exposed mice by regulating intestinal flora and inhibiting pyroptosis; markedly suppressed the levels of cleaved caspase-1, N-GSDMD, cleaved caspase-3, and N-GSDME; and reversed DOX-induced downregulation of silent information regulator 1 (SIRT1) and activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in mice. The SIRT1 inhibitor EX527 significantly blocked the protective effects of AS IV. Collectively, our results suggest that AS IV protects against DIC by inhibiting pyroptosis through the SIRT1/NLRP3 pathway.

2.
Mol Nutr Food Res ; 68(4): e2200771, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38356045

RESUMO

SCOPE: Early diabetic retinopathy (DR) is characterized by chronic inflammation, excessive oxidative stress, and retinal microvascular damage. Syringaresinol (SYR), as a natural polyphenolic compound, has been proved to inhibit many disease progression due to its antiinflammatory and antioxidant properties. The present study focuses on exploring the effect of SYR on hyperglycemia-induced early DR as well as the underlying mechanisms. METHODS AND RESULTS: Wild-type (WT) and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout C57BL/6 mice of type 1 diabetes and high glucose (HG)-induced RF/6A cells are used as in vivo and in vitro models, respectively. This study finds that SYR protects the retinal structure and function in diabetic mice and reduces the permeability and apoptosis of HG-treated RF/6A cells. Meanwhile, SYR distinctly mitigates inflammation and oxidative stress in vivo and vitro. The retinal microvascular damages are suppressed by SYR via downregulating hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. Whereas, SYR-provided protective effects are diminished in Nrf2-knockout mice, indicating that SYR improves DR progression by activating Nrf2. Similarly, SYR cannot exert protective effects against HG-induced oxidative stress and endothelial injury in small interfering RNA (siRNA)-Nrf2-transfected RF/6A cells. CONCLUSION: In summary, SYR suppresses oxidative stress via activating Nrf2 antioxidant pathway, which ameliorates retinal microvascular damage by downregulating HIF-1α/VEGF, thereby alleviating early DR progression.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Furanos , Lignanas , Camundongos , Animais , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Camundongos Endogâmicos C57BL , Inflamação , Estresse Oxidativo
3.
Cardiovasc Diabetol ; 23(1): 19, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-38195474

RESUMO

AIMS: Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms. METHODS AND RESULTS: We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B-/- mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes. CONCLUSIONS: These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Melatonina , Humanos , Camundongos , Ratos , Animais , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/prevenção & controle , Miócitos Cardíacos , Fator B de Crescimento do Endotélio Vascular , Melatonina/farmacologia , Chaperona BiP do Retículo Endoplasmático , Diabetes Mellitus Experimental/tratamento farmacológico , Transdução de Sinais , Autofagia , Glucose
4.
Oncoimmunology ; 12(1): 2219544, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37274296

RESUMO

We previously established a hepatocellular carcinoma (HCC) targeting system of conditionally replicative adenovirus (CRAd) delivered by human umbilical cord-derived mesenchymal stem cells (HUMSCs). However, this system needed to be developed further to enhance the antitumor effect and overcome the limitations caused by the alpha-fetoprotein (AFP) heterogeneity of HCC. In this study, a bispecific T cell engager (BiTE) targeting programmed death ligand 1 controlled by the human telomerase reverse transcriptase promoter was armed on the CRAd of the old system. It was demonstrated on orthotopic transplantation model mice that the new system had a better anti-tumor effect with no more damage to extrahepatic organs and less liver injury, and the infiltration and activation of T cells were significantly enhanced in the tumor tissues of the model mice treated with the new system. Importantly, we confirmed that the new system eliminated the AFP-negative cells on AFP heterogeneous tumor models efficiently. Conclusion: Compared with the old system, the new system provided a more effective and safer strategy against HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Células-Tronco Mesenquimais , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/metabolismo , Adenoviridae/genética , Linfócitos T , Vetores Genéticos/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia
5.
Front Pharmacol ; 13: 919202, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35833024

RESUMO

Coronary artery disease (CAD) and cardiac hypertrophy (CH) are two main causes of ischemic heart disease. Acute CAD may lead to left ventricular hypertrophy (LVH). Long-term and sustained CH is harmful and can gradually develop into cardiac insufficiency and heart failure. It is known that metformin (Met) can alleviate CH; however, the molecular mechanism is not fully understood. Herein, we used high-fat diet (HFD) rats and H9c2 cells to induce CH and clarify the potential mechanism of Met on CH. We found that Met treatment significantly decreased the cardiomyocyte size, reduced lactate dehydrogenase (LDH) release, and downregulated the expressions of hypertrophy markers ANP, VEGF-A, and GLUT1 either in vivo or in vitro. Meanwhile, the protein levels of HIF-1α and PPAR-γ were both decreased after Met treatment, and administrations of their agonists, deferoxamine (DFO) or rosiglitazone (Ros), markedly abolished the protective effect of Met on CH. In addition, DFO treatment upregulated the expression of PPAR-γ, whereas Ros treatment did not affect the expression of HIF-1α. In conclusion, Met attenuates CH via the HIF-1α/PPAR-γ signaling pathway.

6.
Front Cell Dev Biol ; 10: 809996, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35602605

RESUMO

Background: As an effective antitumor drug, doxorubicin (DOX) is primarily used to treat solid tumors and hematologic malignancies. However, increasing evidence has emerged indicating its cardiotoxicity, and few solutions have been proposed to counter this side effect. Higenamine (HG) is a natural compound widely found in many Chinese herbs and also serves as a component in many healthcare products. Several studies have demonstrated its cardioprotective effect in different models, but little is known about the underlying influences of HG against myocardial damage from DOX-induced chronic cardiotoxicity. Methods and Results: C57BL/6 mice and neonatal rat ventricular cardiomyocytes (NRVMs) were used to evaluate the cardioprotective effect of HG against DOX-induced myocardial damage. In mice, DOX (intraperitoneally injected 5 mg/kg every 3 days for 4 weeks) significantly increased cardiomyocyte apoptosis, cardiac atrophy, and cardiac dysfunction, which were significantly attenuated by HG (intragastrically administered with 10 mg/kg every day for 4 weeks). In NRVMs, DOX (3 µM for 24 h) significantly increased cell apoptosis and the level of reactive oxygen species while reducing the level of superoxide dismutase and mitochondrial membrane potential. Remarkably, HG can reverse these pathological changes caused by DOX. Interestingly, the protective effect of HG on DOX-induced cardiotoxicity was independent of the activation of the beta-2 adrenergic receptor (ß2-AR), known for mediating the effect of HG on antagonizing ischemia/reperfusion-induced cardiac apoptosis. Furthermore, HG attenuated the abnormal activation of phosphorylated adenosine-activated protein kinase (AMPK). Consistently, AMPK agonists (AICAR) can eliminate these pharmacological actions of HG. Conclusion: Collectively, our results suggested that HG alleviated DOX-induced chronic myocardial injury by suppressing AMPK activation and ROS production.

7.
Eur J Pharmacol ; 913: 174644, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34801532

RESUMO

The mortality of sepsis-induced cardiac dysfunction (SICD) is very high due to the complex pathophysiological mechanism. Syringaresinol (SYR) is a natural abstract which possesses anti-inflammatory property. The present study aims was to identify the protective impact of SYR on sepsis-induced cardiac dysfunction and investigate the specific mechanisms. We found that SYR improved the cardiac function and alleviated myocardial injury in mice that subjected to cecal ligation and puncture, in addition, SIRT1 expression was significantly elevated after SYR treatment compared to sepsis group both in vivo and in vitro, along with suppression of NLRP3 activation and proinflammatory cytokines release. However, SIRT1 inhibitor EX427 abolished the impact of SYR on LPS-induced pyroptosis in cardiomyocytes. Furthermore, molecular docking analysis predicted that there is high affinity between SYR and estrogen receptor (ER), ER inhibitor ICI182780, the specific ERß inhibitor PHTP and the specific ERαinhibitor AZD9496 were used to examine the role of ER in the protective effect of SYR against SICD, and the results suggested that ER activation was essential for the cardioprotective function of SYR. In conclusion, SYR ameliorates SICD via the ER/SIRT1/NLRP3/GSDMD pathway.


Assuntos
Cardiotônicos/farmacologia , Furanos/farmacologia , Cardiopatias/tratamento farmacológico , Lignanas/farmacologia , Receptores de Estrogênio/metabolismo , Sepse/complicações , Animais , Cardiotônicos/uso terapêutico , Cinamatos/farmacologia , Modelos Animais de Doenças , Fulvestranto/farmacologia , Furanos/uso terapêutico , Coração/efeitos dos fármacos , Cardiopatias/imunologia , Cardiopatias/patologia , Humanos , Indóis/farmacologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Lignanas/uso terapêutico , Masculino , Camundongos , Simulação de Acoplamento Molecular , Miocárdio/patologia , Piroptose/efeitos dos fármacos , Piroptose/imunologia , Receptores de Estrogênio/antagonistas & inibidores , Sepse/tratamento farmacológico , Sepse/imunologia , Sirtuína 1/metabolismo
8.
Front Cell Dev Biol ; 9: 723346, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34760885

RESUMO

Cancer is a complex disease extremely dependent on its microenvironment and is highly regulated by a variety of stimuli inside and outside the cell. Evidence suggests that active camel whey fraction (TR35) confer anti-tumor effects in non-small cell lung cancer (NSCLC). However, its exact mechanisms remain elusive. Here, we investigated the mechanisms underlying suppression of NSCLC cell growth and proliferation by TR35. Treatment of A549 and H1299 cells with TR35 suppressed their growth and enhanced apoptosis, as revealed by CCK-8, colony formation and flow cytometric analyses. We find that TR35 suppresses tumor growth in a xenograft nude mouse model without losses in body weight. RNA-seq and KEGG pathway analyses showed that the DEGs were enriched in mitogen-activated protein kinase (MAPK) and Jak-STAT signaling pathways. After test the key factors' activity associated with these pathways by Immunohistochemical (IHC) staining and western blotting, the activation of JNK phosphorylation and inhibition of p38 and STAT3 phosphorylation was observed both in TR35 treated lung cancer cell and tumor tissue. Taken together, these results showed that TR35 play a significant role in the NSCLC progression in the tumor microenvironment via MAPK and Jak-STAT signaling, highlighting TR35 as a potential therapeutic agent against lung cancer.

9.
J Cancer Res Clin Oncol ; 147(1): 93-103, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32897433

RESUMO

PURPOSE: In our previous study, we discovered that resveratrol (RSV) had potential tumor-promoting effect on pancreatic cancer (PaCa) via up-regulation of VEGF-B. Therefore, we assumed that a pharmacological inhibitor of VEGF-B should potentiate the anti-tumor effect of RSV on PaCa. METHODS: Real-time PCR and western blotting were used to examine VEGF-B mRNA and protein levels. Cell viability and cell apoptosis were assessed by CCK-8 assay and flow cytometry analysis, respectively. PaCa cell-bearing nude mice were used to evaluate the anti-cancer effects of single treatment or co-administration of RSV and gemcitabine (GEM). RESULTS: We found that treatment with GEM alone dramatically decreased VEGF-B expression in comparison with control group, indicating that GEM is a potential pharmacological inhibitor of VEGF-B in PaCa. The co-administration of RSV and GEM significantly lowered expression of VEGF-B and increased phosphorylation level of GSK3ß at Ser9 when compared to RSV alone treatment either in vitro or in vivo. Combination of RSV and GEM significantly increased cell death and apoptosis of PaCa cells in vitro and inhibited tumor growth in vivo in comparison with RSV or GEM alone treatment. Furthermore, we found that the anti-tumor effect in combination group was dramatically weakened after VEGF-B overexpressed in PaCa cells. CONCLUSION: These results suggest that VEGF-B signaling pathway plays an important role in the development of PaCa and combination of GEM and RSV would be a promising modality for clinical PaCa therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Fator B de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Resveratrol/administração & dosagem , Células Tumorais Cultivadas , Fator B de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
10.
Endocr J ; 67(4): 387-395, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31827053

RESUMO

Primary contents of dietary fat are three or four types of fatty acids, namely saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), n6-polyunsaturated fatty acid (n6PUFA) and, to less extent, n3-polyunsaturated fatty acid (n3PUFA). Previous studies suggest that increased SFA, MUFA, and n6PUFA in high fat diets (HFDs) stimulate the origination, growth, and liver metastasis of pancreatic cancer cells, whereas increased n3PUFA has the opposite effects. It is unclear whether the fatty acid-induced effects are based on changed fatty-acid composition of involved cells. Here, we investigated whether increased SFA, MUFA, n6PUFA, and n3PUFA in different HFDs determine the FA profiles of pancreatic cancer cells and their carrier's plasma, pancreas, and liver. We transplanted MiaPaCa2 human pancreatic cancer cells in athymic mice and fed them normal diet or four HFDs enriched with SFA, MUFA, n6PUFA, and n3PUFA, respectively. After 7 weeks, fatty acids were profiled in tumor, plasma, pancreas, and liver, using gas chromatography. When tumor carriers were fed four HFDs, the fatty acids that were increased dietarily were also increased in the plasma. When tumor carriers were fed MUFA-, n6PUFA-, and n3PUFA-enriched HFDs, the dietarily increased fatty acids were also increased in tumor, pancreas, and liver. When tumor-carriers were fed the SFA-enriched HFD featuring lauric and myristic acids (C12:0 and C14:0), tumor, pancreas, and liver showed an increase not in the same SFAs but palmitic acid (C16:0) and/or stearic acid (C18:0). In conclusion, predominant fatty acids in HFDs determine the fatty-acid profiles of pancreatic cancer cells and their murine carriers.


Assuntos
Gorduras na Dieta/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Fígado/metabolismo , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Linhagem Celular Tumoral , Dieta Hiperlipídica , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Ácidos Graxos Monoinsaturados/sangue , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias
11.
J Nutr Biochem ; 79: 108132, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-30857673

RESUMO

Doxorubicin (DOX) is a broad spectrum antitumor agent. However, its clinical utility is limited due to the well-known cardiotoxicity. Resveratrol (RSV) has been reported to exert cardioprotective effect in some cardiovascular diseases. In this study, we aimed to determine the effect of RSV on DOX-induced cardiotoxicity, and further explore the underlying mechanism in this process.Male Sprague-Dawley (SD) rats were randomly divided into four groups: CON, DOX, RSV, or DOX+RSV group (10 rats in each group). DOX treatment significantly decreased cardiac function, and increased the release of serum lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB) in rat serum. Increased cell death and apoptosis of cardiomyocytes were also observed in DOX group in comparison with CON group. DOX treatment dramatically down-regulated expression of VEGF-B either in vivo or in vitro. In contrast, the combination of RSV and DOX markedly attenuated DOX-induced cardiotoxicity with the up-regulation of VEGF-B. Inhibition of VEGF-B by small interfering RNA (siRNA) abolished the protective effects of RSV on DOX-treated cardiomyocytes.Consequently,our findings indicated that RSV attenuates DOX-induced cardiotoxicity through up-regulation of VEGF-B.


Assuntos
Cardiotônicos/farmacologia , Doenças Cardiovasculares/metabolismo , Doxorrubicina/toxicidade , Resveratrol/farmacologia , Fator B de Crescimento do Endotélio Vascular/metabolismo , Animais , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Cardiotônicos/administração & dosagem , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Resveratrol/administração & dosagem , Regulação para Cima/efeitos dos fármacos
12.
Exp Ther Med ; 16(6): 5350-5358, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30542494

RESUMO

The immunosuppressive tumor microenvironment limits the application of adoptive immunotherapy for solid tumors. Hypoxia is closely associated with the formation of the immunosuppressive tumor microenvironment. Hypoxia-inducible factor-1 (HIF-1) is an oxygen-sensitive transcriptional activator that drives the transcription of several immunosuppressive molecules. In addition, previous studies confirmed that rhein downregulated the expression of HIF-1α, a subunit of HIF-1, in pancreatic cancer cells. The present study established correlations between mRNA expression levels of HIF-1α and six immunosuppressive molecules in colorectal cancer (CRC) tissue samples. This study examined the effect of rhein on the expression levels of HIF-1α and six immunosuppressive molecules in CRC cell lines under hypoxic conditions by western blot analysis and reverse transcription-quantitative polymerase chain reaction. This study demonstrated that rhein downregulated the expression of HIF-1α and immunosuppressive molecules in CRC cells under hypoxic conditions. In addition, the present study analyzed the cytotoxicity of peripheral blood lymphocytes in vitro using a non-toxic cytotoxicity assay. This study demonstrated that in vitro, rhein enhanced the cytotoxicity of effector lymphocytes toward tumor cells under hypoxic conditions, and therefore rhein may be used in combination with effector lymphocytes for the treatment of CRC.

13.
BMC Cancer ; 18(1): 360, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29609556

RESUMO

BACKGROUND: Cancer cachexia is a cancer-induced metabolic disorder and a major cause of cancer-induced death. The constituents of cancer cachexia include an increase in energy expenditure, hepatic gluconeogenesis, fat lipolysis, and skeletal-muscle proteolysis and a decrease in body weight. The aetiology of cancer cachexia is unclear and may involve cancer-cell metabolism and secretion. In this study, we investigated whether the high glycolysis in cancer cells (the Warburg effect) triggers cachexia in athymic mice carrying pancreatic cancer cells. METHODS: First, we examined five human pancreatic cancer cell lines for glycolysis and cachectic-cytokine secretion. Consequently, MiaPaCa2 and AsPC1 cells were selected for the present study, because the glycolysis in MiaPaCa2 cells was typically high and that in AsPC1 cells was exceptionally low. In addition, both MiaPaCa2 and AsPC1 cells were competent in the secretion of examined cytokines. Next, we transplanted MiaPaCa2 and AsPC1 cells subcutaneously in different athymic mice for 8 weeks, using intact athymic mice for control. In another experiment, we treated normal mice with the supernatants of MiaPaCa2 or AsPC1 cells for 7 days, using vehicle-treated mice for control. In both models, we measured food intake and body weight, assayed plasma glucose, triglycerides, and TNF-α and used Western blot to determine the proteins that regulated hepatic gluconeogenesis, fat lipolysis, and skeletal-muscle proteolysis in the corresponding tissues. We also studied the effect of MiaPaCa2-cell supernatants on the proteolysis of C2C12 skeletal-muscle cells in vitro. RESULTS: The athymic mice carrying high-glycolytic MiaPaCa2 cells had anorexia and also showed evidence for cachexia, including increased hepatic gluconeogenesis, fat lipolysis and skeletal-muscle proteolysis and decreased body weight. The athymic mice carrying low-glycolytic AsPC1 cells had anorexia but did not show the above-mentioned evidence for cachexia. When normal mice were treated with the supernatants of MiaPaCa2 or AsPC1 cells, their energy homeostasis was largely normal. Thus, the cachexia in the athymic mice carrying MiaPaCa2 cells may not result from humeral factors released by the cancer cells. In vitro, MiaPaCa2-cell supernatants did not induce proteolysis in C2C12 cells. CONCLUSION: The Warburg effect in pancreatic cancer cells is an independent aetiological factor for pancreatic cancer-induced cachexia.


Assuntos
Caquexia/etiologia , Caquexia/metabolismo , Metabolismo Energético , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/metabolismo , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Xenoenxertos , Homeostase , Humanos , Masculino , Camundongos , Camundongos Nus , Carga Tumoral
14.
Cardiology ; 130(3): 175-184, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25720823

RESUMO

OBJECTIVE: Exercise training (ET) provides a cardioprotective effect against pathological cardiac hypertrophy. Nitric oxide (NO) plays an important role in modulating cardiac hypertrophy. However, few studies explore the relationship between NO signaling and the inhibitory effect of ET on pathological cardiac remodeling. METHODS: In this study, we evaluated ET effects on isoproterenol (ISO)-induced cardiac hypertrophy in female mice. Moreover, L-NAME (Nω-nitro-L-arginine methyl ester), a nonselective NO synthase (NOS) inhibitor, was used to assess the involvement of NO signaling in cardiac hypertrophy. Morphological and echocardiographic variables were assessed. Cardiac hypertrophy-related gene expression was detected by real-time PCR and the protein levels of NOS signaling molecules were determined by Western blot. RESULTS: L-NAME treatment prevented the beneficial effects of ET against the increase in heart weight (HW)/body weight (BW), HW/tibia length and lung weight/BW and echocardiographic variables following ISO injection. Also, L-NAME co-administration reversed ET-induced inhibition of myocardial fibrosis and fetal gene reactivation in ISO-treated mice. Furthermore, L-NAME treatment prevented ET-mediated up-regulation of phosphorylated endothelial NOS and plasma NO in ISO-treated mice. CONCLUSIONS: Our findings demonstrate that L-NAME treatment could abolish ET-induced cardioprotection against pathological cardiac hypertrophy and that NOS modulation may be involved in the antihypertrophic effects induced by ET.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Miocárdio/patologia , NG-Nitroarginina Metil Éster/uso terapêutico , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Modelos Animais de Doenças , Ecocardiografia , Inibidores Enzimáticos/uso terapêutico , Feminino , Fibrose , Isoproterenol/efeitos adversos , Camundongos , Óxido Nítrico/sangue , Fosforilação , Condicionamento Físico Animal , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
15.
J Artif Organs ; 17(4): 337-43, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24944122

RESUMO

Islet preservation plays an important role for the success of islet transplantation. To determine the optimal method for islet preservation, we compared the outcomes of islet culture, cold preservation, and cryopreservation in this study. Isolated rat islets were divided into three groups: 37 °C group (conventional culture at 37 °C in RPMI-1640 medium), 4 °C group (cold preservation at 4 °C in University of Wisconsin (UW) solution), and -80 °C group (cryopreservation at -80 °C with dimethyl sulfoxide (DMSO)). Recovery rate, Calcein-AM/PI double staining, insulin release, mRNA level of hypoxia-inducible factor-1α (HIF-1α), and protein level of Bax in islets were examined after short-term (1 day) or long-term (7 days) preservation. After either short-term or long-term preservation, 4 °C group showed higher recovery rate of the islets number, lower percentage of PI positive area, better insulin release ability, and lower expression levels of HIF-1α and Bax in comparison to the 37 or -80 °C group. Meanwhile, islets in 37 °C group showed better function, and down-regulation of HIF-1α and Bax than those in -80 °C group on day 1; however, worse function of islets, up-regulated HIF-1α and Bax in 37 °C group were observed in comparison to -80 °C group on day 7. These results suggest that cold preservation at 4 °C in UW solution is the optimal method in comparison to the conventional culture at 37 °C or cryopreservation at -80 °C for short-term or long-term islet preservation. Furthermore, the potential mechanism may relate to, at least in part, apoptosis induced by the HIF-1α.


Assuntos
Criopreservação/métodos , Transplante das Ilhotas Pancreáticas/métodos , Ilhotas Pancreáticas/fisiologia , Técnicas de Cultura de Órgãos/métodos , Preservação de Tecido/métodos , Animais , Temperatura Baixa , Masculino , Ratos , Ratos Wistar
16.
PLoS One ; 9(5): e96892, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24809512

RESUMO

Extensive data have shown that exercise training can provide cardio-protection against pathological cardiac hypertrophy. However, how long the heart can retain cardio-protective phenotype after the cessation of exercise is currently unknown. In this study, we investigated the time course of the loss of cardio-protection after cessation of exercise and the signaling molecules that are responsible for the possible sustained protection. Mice were made to run on a treadmill six times a week for 4 weeks and then rested for a period of 0, 1, 2 and 4 weeks followed by isoproterenol injection for 8 days. Morphological, echocardiographic and hemodynamic changes were measured, gene reactivation was determined by real-time PCR, and the expression and phosphorylation status of several cardio-protective signaling molecules were analyzed by Western-blot. HW/BW, HW/TL and LW/BW decreased significantly in exercise training (ER) mice. The less necrosis and lower fetal gene reactivation induced by isoproterenol injection were also found in ER mice. The echocardiographic and hemodynamic changes induced by ß-adrenergic overload were also attenuated in ER mice. The protective effects can be sustained for at least 2 weeks after the cessation of the training. Western-blot analysis showed that the alterations in the phosphorylation status of endothelial nitric oxide synthase (eNOS) (increase in serine 1177 and decrease in threonine 495) continued for 2 weeks after the cessation of the training whereas increases of the phosphorylation of Akt and mTOR disappeared. Further study showed that L-NG-Nitroarginine methyl ester (L-NAME) treatment abolished the cardio-protective effects of ER. Our findings demonstrate that stimulation of eNOS in mice through exercise training provides acute and sustained cardioprotection against cardiac hypertrophy.


Assuntos
Coração/fisiopatologia , Miocárdio/enzimologia , Óxido Nítrico Sintase Tipo III/metabolismo , Condicionamento Físico Animal , Receptores Adrenérgicos beta/metabolismo , Animais , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Cardiomegalia/prevenção & controle , Fibrose , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Isoproterenol/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/patologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Ativação Transcricional/efeitos dos fármacos
17.
J Cancer Res Clin Oncol ; 140(5): 749-55, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24604347

RESUMO

PURPOSE: Although the potential anticancer effect of resveratrol (RSV) on pancreatic cancer has been reported, its mechanism was not fully understood. The role of vascular endothelial growth factor B (VEGF-B) in cancer remains controversial. Herein, we aimed to examine whether the anticancer effect of RSV was related to the VEGF-B. METHODS: The effect of RSV on pancreatic cancer cell line (capan-2 cells) was evaluated by CCK-8 assay, Hoechst 33342 staining, and flow cytometry. The mRNA level of VEGF-B was measured by real-time PCR. VEGF-B expression was knockdown by small interfering RNA (siRNA).The protein levels of VEGF-B, glycogen synthase kinase-3 beta (GSK-3ß), and Bax were measured by Western blot. RESULTS: Resveratrol treatment inhibited tumor growth, induced apoptosis, and up-regulated Bax expression in capan-2 cells. The mRNA and protein levels of VEGF-B were up-regulated after RSV treatment. However, VEGF-B siRNA treatment increased the apoptotic rate, and inhibited tumor activator GSK-3ß, while Bax expression was not affected. The combination of RSV and VEGF-B siRNA showed significantly higher apoptotic rate in comparison with RSV or VEGF-B siRNA mono-treatment group. CONCLUSIONS: Resveratrol plays dual roles in pancreatic cancer: as a tumor suppressor via the up-regulation of Bax; as a tumor activator via the up-regulation of VEGF-B; and the anticancer effect of RSV is much stronger than the cancer promotion effect. The combination of RSV with pharmacological inhibitor of VEGF-B might, therefore, be a promising modality for clinical pancreatic cancer therapy.


Assuntos
Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Estilbenos/administração & dosagem , Fator B de Crescimento do Endotélio Vascular/biossíntese , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/biossíntese , Glicogênio Sintase Quinase 3 beta , Humanos , Neoplasias Pancreáticas/patologia , RNA Interferente Pequeno , Resveratrol , Fator B de Crescimento do Endotélio Vascular/genética , Proteína X Associada a bcl-2/biossíntese
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