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1.
Brain Imaging Behav ; 15(1): 147-156, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32125618

RESUMO

Executive function is a complex involving multiple advanced brain functions like planning, working memory, mental flexibility and psychomotor. Previous researches indicated that executive function may be impaired after acute or chronic high-altitude exposure, while the underlying neurobiological mechanism has not been totally clarified. In the present study, based on 69 young healthy volunteers immigrating to high-altitude, Stroop test was utilized to identify the potential impairment of executive function after two-year high-altitude exposure while resting-state functional MRI (rs-fMRI) technology was employed to observe the alteration of resting-state networks. Stroop test indicated that the subjects experienced significantly lower accuracies and prolonged responding time after two-year exposure. Resting-state network analysis displayed a significantly decreased degree of co-activation within the left/right frontoparietal network, sensorimotor network, and auditory network after exposure. In the frontoparietal network, decreased co-activation intensity was found in left angular gyrus, while in the right frontoparietal network, decreased co-activation intensity was found in left precentral gyrus and postcentral gyrus. Similarly, as for sensorimotor and auditory network, left middle frontal gyrus and left superior temporal gyrus was identified to have decreased co-activation, respectively. Moreover, the responding delays in ST (part II) were negatively correlated with the signal intensity alteration of the right frontoparietal network. All these evidences indicated that the high-altitude exposure induced alteration in above resting state networks may be the functional basis of executive control impairment.


Assuntos
Altitude , Emigrantes e Imigrantes , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Humanos , Imageamento por Ressonância Magnética , Lobo Parietal
2.
Theranostics ; 10(25): 11737-11753, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33052244

RESUMO

Fibrosis exists in almost all organs/tissues of the human body, plays an important role in the occurrence and development of diseases and is also a hallmark of the aging process. However, there is no effective prevention or therapeutic method for fibrogenesis. As a serine/threonine (Ser/Thr)-protein kinase, glycogen synthase kinase-3ß (GSK-3ß) is a vital signaling mediator that participates in a variety of biological events and can inhibit extracellular matrix (ECM) accumulation and the epithelial-mesenchymal transition (EMT) process, thereby exerting its protective role against the fibrosis of various organs/tissues, including the heart, lung, liver, and kidney. Moreover, we further present the upstream regulators and downstream effectors of the GSK-3ß pathway during fibrosis and comprehensively summarize the roles of GSK-3ß in the regulation of fibrosis and provide several potential targets for research. Collectively, the information reviewed here highlights recent advances vital for experimental research and clinical development, illuminating the possibility of GSK-3ß as a novel therapeutic target for the management of tissue fibrosis in the future.


Assuntos
Fibrose/patologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Envelhecimento/patologia , Animais , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Humanos , Rim/patologia , Fígado/patologia , Pulmão/patologia , Camundongos , Miocárdio/patologia , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos
3.
Brain Behav ; 10(10): e01656, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32909397

RESUMO

INTRODUCTION: High altitude (HA) exposure leads to cognitive impairment while the underlying mechanism is still unclear. Brain functional network is crucial for advanced functions, and its alteration is implicated in cognitive decline in multiple diseases. The aim of current study was to investigate the topological changes in HA-exposed brain functional network. METHODS: Based on Shaanxi-Tibet immigrant cohort, neuropsychological tests and resting-state functional MRI were applied to evaluate the participants' cognitive function and functional connection (FC) changes, respectively. GRETNA toolbox was used to construct the brain functional network. The gray matter was parcellated into 116 anatomically defined regions according to Automated Anatomical Labeling atlas. Subsequently, the mean time series for each of the 116 regions were extracted and computed for Pearson's correlation coefficients. The relation matrix was further processed and seen as brain functional network. Correlation between functional network changes and neuropsychological results was also examined. RESULTS: The cognitive performance was impaired by HA exposure as indicated by neuropsychological test. HA exposure led to alterations of degree centrality and nodal efficiency in multiple brain regions. Moreover, two subnetworks were extracted in which the FCs significantly decreased after exposure. In addition, the alterations in FCs within above two subnetworks were significantly correlated with changes of memory and reaction time. CONCLUSIONS: Our results suggest that HA exposure modulates the topological property of functional network and FCs of some important regions, which may impair the attention, perception, memory, motion ignition, and modulation processes, finally decreasing cognitive performance in neuropsychological tests.


Assuntos
Altitude , Encéfalo , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Cognição , Humanos , Imageamento por Ressonância Magnética
4.
Semin Cancer Biol ; 67(Pt 1): 114-121, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31199986

RESUMO

The epithelial-mesenchymal transition (EMT) is a process of cell transformation under certain physiological and pathological states in which epithelial cells are transformed into mesenchymal cells with fibroblast-like properties, which confers upon them the increased invasion and migration capabilities of cancer cells. Previous studies have demonstrated that SRY-related high-mobility-group box 4 (Sox4) protein coordinates EMT-related pathways and EMT-related transcription factors, thereby regulating the EMT process. The focus of this review is to evaluate recent advances regarding the role of Sox4 protein in the cancer EMT. First, we provide an overview of the general background of Sox4 (structure and function) and the EMT in cancer. Next, we introduce the interactions between Sox4 protein and various factors during cancer EMT. Finally, we suggest directions for future investigations. In general, the information compiled in this paper should serve as a comprehensive repository of information on the subject matter and contribute to the design of other research and future efforts to develop therapeutic strategies that target the Sox4 protein.

5.
Ageing Res Rev ; 57: 100997, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31816444

RESUMO

Mitochondria, which are cell compartments that are widely present in eukaryotic cells, have been shown to be involved in a variety of synthetic, metabolic, and signaling processes, thereby playing a vital role in cells. The mitochondrial unfolded protein response (mtUPR) is a response in which mitochondria reverse the signal to the nucleus and maintain mitochondrial protein homeostasis when unfolded and misfolded proteins continue to accumulate. Multiple neurodegeneration diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and familial amyotrophic lateral sclerosis (fALS), are public health challenges. Every year, countless efforts are expended trying to clarify the pathogenesis and treatment of neurological disorders, which are associated with mitochondrial dysfunction to some extent. Numerous studies have shown that mtUPR is involved in and plays an important role in the pathogenesis of neurological disorders, but the exact mechanism of the disorders is still unclear. Further study of the process of mtUPR in neurological disorders can help us more accurately understand their pathogenesis in order to provide new therapeutic targets. In this paper, we briefly review mtUPR signaling in Caenorhabditis elegans (C. elegans) and mammals and summarize the role of mtUPR in neurodegeneration diseases, including AD, PD and fALS.


Assuntos
Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Dobramento de Proteína , Resposta a Proteínas não Dobradas , Doença de Alzheimer/metabolismo , Esclerose Amiotrófica Lateral/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Humanos , Mamíferos/metabolismo , Doença de Parkinson/metabolismo , Transdução de Sinais
6.
Pharmacol Res ; 147: 104334, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31255708

RESUMO

Psoralidin (PSO) is a natural phenolic coumarin that is extracted from the seeds of Psoralea corylifolia L. PSO possesses a variety of pharmacological activities, including anti-oxidative, antibacterial, anti-inflammatory, anti-depressive and estrogenic-like effects. Other studies have indicated that PSO plays a beneficial role in multiple disease, especially cancer and osteoporosis. In this review, we first outline the basic background of PSO. Then we introduced the molecular mechanisms and signaling pathways of PSO in multiple cancers to elucidate its anticancer potential via inducing oxidative stress and apoptosis, inhibiting proliferation, promoting autophagy-dependent cell death, and activating the estrogen receptors (ER)-signaling pathway. Finally, we recommend the direction of future investigations. In general, the information compiled in this paper should serve as a comprehensive repository of information to help design PSO in other research and future efforts.


Assuntos
Antineoplásicos/uso terapêutico , Benzofuranos/uso terapêutico , Cumarínicos/uso terapêutico , Neoplasias/tratamento farmacológico , Osteoporose/tratamento farmacológico , Animais , Humanos
7.
Hum Brain Mapp ; 40(14): 4202-4212, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31206892

RESUMO

The study of individuals at high-altitude (HA) exposure provides an important opportunity for unraveling physiological and psychological mechanism of brain underlying hypoxia condition. However, this has rarely been assessed longitudinally. We aim to explore the cognitive and cerebral microstructural alterations after chronic HA exposure. We recruited 49 college freshmen who immigrated to Tibet and followed up for 2 years. Control group consisted of 49 gender and age-matched subjects from sea level. Neuropsychological tests were also conducted to determine whether the subjects' cognitive function had changed in response to chronic HA exposure. Surface-based cortical and subcortical volumes were calculated from structural magnetic resonance imaging data, and tract-based spatial statistics (TBSS) analysis of white matter (WM) fractional anisotropy (FA) based on diffusion weighted images were performed. Compared to healthy controls, the high-altitude exposed individuals showed significantly lower accuracy and longer reaction times in memory tests. Significantly decreased gray matter volume in the caudate region and significant FA changes in multiple WM tracts were observed for HA immigrants. Furthermore, differences in subcortical volume and WM integration were found to be significantly correlated with the cognitive changes after 2 years' HA exposure. Cognitive functions such as working memory and psychomotor function were found to be impaired during chronic HA. Differences of brain subcortical volumes and WM integration between HA and sea-level participants indicated potential impairments in the brain structural modifications and microstructural integrity of WM tracts after HA exposure.


Assuntos
Doença da Altitude/patologia , Doença da Altitude/fisiopatologia , Altitude , Encéfalo/patologia , Encéfalo/fisiopatologia , Adolescente , Anisotropia , Cognição/fisiologia , Imagem de Difusão por Ressonância Magnética , Emigrantes e Imigrantes , Feminino , Humanos , Estudos Longitudinais , Masculino , Tibet , Adulto Jovem
8.
Biosci Trends ; 13(1): 98-104, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30814403

RESUMO

Hypoxia exposure during high-altitude expedition cause psychomotor impairment. Neuroimaging studies indicated that the impairment may be significantly associated with neuron loss and decreased regional homogeneity (ReHo) in several brain regions, suggesting the neural functionality in these regions may be utilized to predict psychomotor impairment under exposure. In this study, 69 subjects come from Shaanxi-Tibet immigrant cohort. Reaction time (RT) tasks were performed to measure the subject's psychomotor function before and after 2-year high-altitude exposure. For each individual, the RT differences between pre-exposure and post-exposure were calculated, which were referred to as "targets" in model establishment. Rs-fMRI data were acquired at the same time with RT tasks. For each individual, the map of ReHo alteration was generated, from which the patterns would be recognized. A pattern recognition procedure was utilized to train and test the predictive models. Two different cross-validation strategies were utilized to evaluate the model performance: leave-one-out cross-validation and four-fold cross-validation. For the models displaying significant R2 and MSE, weight maps were built. As a result, the predictive models were able to decode the changes of simple and recognition reaction time from the alterations of brain activation under the exposure. The regions with highest contributions to the predictions were bilateral putamen and bilateral pallidum, suggesting that predictions were mainly based on the patterns concentrated in these regions. This study was a proof of concept study designed to examine whether individual-level psychomotor impairment under high-altitude exposure could be predicted by a combination of pattern recognition approach and neuroimaging data.


Assuntos
Doença da Altitude/fisiopatologia , Globo Pálido/fisiopatologia , Transtornos Psicomotores/fisiopatologia , Putamen/fisiopatologia , Adolescente , Doença da Altitude/diagnóstico por imagem , Feminino , Globo Pálido/diagnóstico por imagem , Humanos , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Masculino , Reconhecimento Automatizado de Padrão , Transtornos Psicomotores/diagnóstico por imagem , Putamen/diagnóstico por imagem , Adulto Jovem
9.
Pharmacol Res ; 141: 208-213, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30610961

RESUMO

Bakuchiol (BAK), [(1E,3S)-3-ethenyl-3,7-dimethyl-1,6-octadien-1-yl]phenol is a prenylated phenolic monoterpene extracted from the fruit of Psoralea corylifolia L., which belongs to the Leguminosae plant family. Previous research has shown that BAK exerts a variety of pharmacological effects, including antioxidant, antibacterial, anti-inflammatory, antiaging and estrogen-like effects. In addition, recent studies have indicated that BAK exerts protective effects in the heart, liver, skin and other organs. BAK treatment protects the heart against ischemia-reperfusion injury through modulating cardioprotective pathways. BAK also inhibits liver fibrosis via promoting myofibroblast apoptosis and relieves the hepatotoxicity of multiple toxicants by suppressing oxidative stress and inflammatory changes. BAK inhibits the proliferation of various cancer cells, including stomach, breast and skin cancer cells, thereby exerting anticancer effects. Further, BAK effectively slows skin aging by preserving skin collagen. BAK treatment can protect against bone loss and delay osteoporosis by exerting estrogen-like effects. In addition, BAK remarkably reduces blood glucose and triglycerides and might be a potential pharmacological agent that can be used to protect against pancreatic beta-cell damage and diabetes progression. In this review, the pharmacological mechanisms and protective effects of BAK in human diseases are discussed, with a focus on the protective effects of BAK in the heart, liver and other important organs.


Assuntos
Fenóis/farmacologia , Substâncias Protetoras/farmacologia , Animais , Diabetes Mellitus/tratamento farmacológico , Coração/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Osteoporose/tratamento farmacológico , Fenóis/uso terapêutico , Substâncias Protetoras/uso terapêutico
10.
J Pineal Res ; 66(2): e12548, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30597617

RESUMO

Melatonin is a signal molecule that modulates the biological circadian rhythms of vertebrates. Melatonin deficiency is thought to be associated with several disorders, including insomnia, cancer, and cardiovascular and neurodegenerative diseases. Accumulating evidence has also indicated that melatonin may be involved in the homeostasis of bone metabolism. Age-related reductions in melatonin are considered to be critical factors in bone loss and osteoporosis with aging. Thus, serum melatonin levels might serve as a biomarker for the early detection and prevention of osteoporosis. Compared to conventional antiosteoporosis medicines, which primarily inhibit bone loss, melatonin both suppresses bone loss and promotes new bone formation. Mechanistically, by activating melatonin receptor 2 (MT2), melatonin upregulates the gene expression of alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP2), BMP6, osteocalcin, and osteoprotegerin to promote osteogenesis while inhibiting the receptor activator of NF-kB ligand (RANKL) pathway to suppress osteolysis. In view of the distinct actions of melatonin on bone metabolism, we hypothesize that melatonin may be a novel remedy for the prevention and clinical treatment of osteoporosis.


Assuntos
Osso e Ossos/efeitos dos fármacos , Melatonina/farmacologia , Osteoporose/tratamento farmacológico , Animais , Humanos
11.
Toxicol Appl Pharmacol ; 363: 34-46, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30336174

RESUMO

Sepsis-induced brain injury is frequently encountered in critically ill patients with severe systemic infection. Butein (3,4,2',4'-tetrahydroxychalcone) has been demonstrated as the neuro-protective agent via reducing inflammation and oxidative stress on neurons. Moreover, activation of silent information regulator 1 (SIRT1) inhibits apoptosis, oxidation and inflammation thus alleviating sepsis-induced multiorgan injuries. In present study, we show that butein administrated intraperitoneally (10 mg/kg) saved mice from sepsis-induced lethality by increasing 7-day survival rate after cecal ligation and puncture (CLP) surgery. Additionally, butein treatment enhanced SIRT1 signaling thus decreasing the Ac-NF-κB, Ac-FOXO1 and Ac-p53 levels, thus attenuating the brain injury of mice after CLP surgery by decreasing cerebral edema, maintaining the blood-brain barrier integrity, inhibiting neuronal apoptosis, and decreasing pro-inflammatory cytokines production (IL-6, TNF-α and IL-1ß) and oxidative stress (downregulation of MDA, and upregulation of SOD and CAT) in both serum and cerebral cortex tissues. Moreover, butein treatment attenuated LPS induced neurological function loss. However, all above mentioned neuro-protective actions of butein were partially inhibited by EX527 co-treatment, one standard SIRT1 inhibitor. Collectively, butein attenuates sepsis-induced brain injury through alleviation of cerebral inflammation, oxidative stress and apoptosis by SIRT1 signaling activation.


Assuntos
Chalconas/farmacologia , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Encefalopatia Associada a Sepse/tratamento farmacológico , Sepse/complicações , Sirtuína 1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Carbazóis/farmacologia , Chalconas/uso terapêutico , Modelos Animais de Doenças , Humanos , Inflamação/etiologia , Inflamação/mortalidade , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Sepse/mortalidade , Encefalopatia Associada a Sepse/etiologia , Encefalopatia Associada a Sepse/mortalidade , Encefalopatia Associada a Sepse/patologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Resultado do Tratamento
12.
Cell Mol Life Sci ; 75(14): 2681, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29691591

RESUMO

In the original publication, affiliations were incorrectly published for the authors.

13.
Semin Cancer Biol ; 50: 21-31, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29427645

RESUMO

The epithelial-mesenchymal transition (EMT) is an acknowledged cellular transition process in which epithelial cells acquire mesenchymal-like properties that endow cancer cells with increased migratory and invasive behavior. Forkhead box O (FOXO) proteins have been shown to orchestrate multiple EMT-associated pathways and EMT-related transcription factors (EMT-TFs), thereby modulating the EMT process. The focus of the current review is to evaluate the latest research progress regarding the roles of FOXO proteins in cancer EMT. First, a brief overview of the EMT process in cancer and a general background on the FOXO family are provided. Next, we present the interactions between FOXO proteins and multiple EMT-associated pathways during malignancy development. Finally, we propose several novel potential directions for future research. Collectively, the information compiled herein should serve as a comprehensive repository of information on this topic and should aid in the design of additional studies and the future development of FOXO proteins as therapeutic targets.


Assuntos
Fatores de Transcrição Forkhead/genética , Família Multigênica/genética , Neoplasias/genética , Transição Epitelial-Mesenquimal/genética , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia
14.
Ageing Res Rev ; 41: 42-52, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29138094

RESUMO

Fibrosis is a universally age-related disease that involves nearly all organs. It is typically initiated by organic injury and eventually results in organ failure. There are still few effective therapeutic strategy targets for fibrogenesis. Forkhead box proteins O1 and O3 (FOXO1/3) have been shown to have favorable inhibitory effects on fibroblast activation and subsequent extracellular matrix production and can ameliorate fibrosis levels in numerous organs, including the heart, liver, lung, and kidney; they are therefore promising targets for anti-fibrosis therapy. Moreover, we can develop appropriate strategies to make the best use of FOXO1/3's anti-fibrosis properties. The information reviewed here should be significant for understanding the roles of FOXO1/3 in fibrosis and should contribute to the design of further studies related to FOXO1/3 and the fibrotic response and shed light on a potential treatment for fibrosis.


Assuntos
Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O3/metabolismo , Cirrose Hepática/metabolismo , Fibrose Pulmonar/metabolismo , Animais , Matriz Extracelular/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Fibrose/prevenção & controle , Humanos , Rim/metabolismo , Rim/patologia , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Miocárdio/metabolismo , Miocárdio/patologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle
15.
Cell Mol Life Sci ; 74(21): 3989-3998, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28795196

RESUMO

Ischemia/reperfusion (IR) injury occurs in many organs and tissues, and contributes to morbidity and mortality worldwide. Melatonin, an endogenously produced indolamine, provides a strong defense against IR injury. Mitochondrion, an organelle for ATP production and a decider for cell fate, has been validated to be a crucial target for melatonin to exert its protection against IR injury. In this review, we first clarify the mechanisms underlying mitochondrial dysfunction during IR and melatonin's protection of mitochondria under this condition. Thereafter, special focus is placed on the protective actions of melatonin against IR injury in brain, heart, liver, and others. Finally, we explore several potential future directions of research in this area. Collectively, the information compiled here will serve as a comprehensive reference for the actions of melatonin in IR injury identified to date and will hopefully aid in the design of future research and increase the potential of melatonin as a therapeutic agent.


Assuntos
Antioxidantes/farmacologia , Melatonina/farmacologia , Mitocôndrias/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Humanos , Mitocôndrias/efeitos dos fármacos , Traumatismo por Reperfusão/metabolismo
16.
Pharmacol Res ; 119: 373-383, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28274852

RESUMO

Curcumin, which was first used 3000 years ago as an anti-inflammatory agent, is a well-known bioactive compound derived from the active ingredient of turmeric (Curcuma longa). Previous research has demonstrated that curcumin has immense therapeutic potential in a variety of diseases via anti-oxidative, anti-apoptotic, and anti-inflammatory pathways. Cardiac diseases are the leading cause of mortality worldwide and cause considerable harm to human beings. Numerous studies have suggested that curcumin exerts a protective role in the human body whereas its actions in cardiac diseases remain elusive and poorly understood. On the basis of the current evidence, we first give a brief introduction of cardiac diseases and curcumin, especially regarding the effects of curcumin in embryonic heart development. Secondly, we analyze the basic roles of curcumin in pathways that are dysregulated in cardiac diseases, including oxidative stress, apoptosis, and inflammation. Thirdly, actions of curcumin in different cardiac diseases will be discussed, as will relevant clinical trials. Eventually, we would like to discuss the existing controversial opinions and provide a detailed analysis followed by the remaining obstacles, advancement, and further prospects of the clinical application of curcumin. The information compiled here may serve as a comprehensive reference of the protective effects of curcumin in the heart, which is significant to the further research and design of curcumin analogs as therapeutic options for cardiac diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Cardiotônicos/uso terapêutico , Curcumina/uso terapêutico , Cardiopatias/tratamento farmacológico , Coração/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Cardiotônicos/química , Cardiotônicos/farmacologia , Curcuma/química , Curcumina/química , Curcumina/farmacologia , Coração/embriologia , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos
17.
Biochim Biophys Acta Mol Basis Dis ; 1863(2): 486-498, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27890702

RESUMO

Cardiac diseases have a high morbidity and mortality and affect the global population. Based on recent accumulating evidence, Forkhead box O (FOXOs) play important roles in cardiac diseases. Therefore, a summary of the current literature on the molecular mechanisms and roles of FOXOs in the heart will provide valuable information. In this review, we first briefly introduce the molecular features of FOXOs. Then, we discuss the regulation and cardiac actions of the FOXO pathways. Based on this background, we expand our discussion to the roles of FOXOs in several major cardiac diseases, such as ischemic cardiac diseases, diabetic cardiomyopathy and myocardial hypertrophy. Then, we describe some methodological problems associated with the FOXO gene-modified animal models. Finally, we discuss potential future directions. The information reviewed here may be significant for the design of future studies and may increase the potential of FOXOs as therapeutic targets.


Assuntos
Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O3/metabolismo , Cardiopatias/metabolismo , Animais , Proteína Forkhead Box O1/análise , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O3/análise , Proteína Forkhead Box O3/genética , Regulação da Expressão Gênica , Cardiopatias/genética , Cardiopatias/patologia , Humanos , Miocárdio/metabolismo , Miocárdio/patologia , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Ativação Transcricional
18.
Sci Rep ; 6: 35196, 2016 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-27731378

RESUMO

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent for esophageal squamous cell carcinoma (ESCC). Forced expression of CHOP, one of the key downstream transcription factors during endoplasmic reticulum (ER) stress, upregulates the death receptor 5 (DR5) levels and promotes oxidative stress and cell death. In this study, we show that ER stress mediated by thapsigargin promoted CHOP and DR5 synthesis thus sensitizing TRAIL treatment, which induced ESCC cells apoptosis. These effects were reversed by DR5 siRNA in vitro and CHOP siRNA both in vitro and in vivo. Besides, chemically inhibition of AMPK by Compound C and AMPK siRNA weakened the anti-cancer effect of thapsigargin and TRAIL co-treatment. Therefore, our findings suggest ER stress effectively sensitizes human ESCC to TRAIL-mediated apoptosis via the TRAIL-DR5-AMPK signaling pathway, and that activation of ER stress may be beneficial for improving the efficacy of TRAIL-based anti-cancer therapy.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/administração & dosagem , Tapsigargina/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Humanos , Invasividade Neoplásica/prevenção & controle , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidores , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Fator de Transcrição CHOP/antagonistas & inibidores , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Cell Physiol Biochem ; 38(3): 1226-44, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26982591

RESUMO

BACKGROUND/AIMS: Pterostilbene (PTE), a natural dimethylated resveratrol analog from blueberries, is known to have diverse pharmacological activities, including anticancer properties. In this study, we investigated the anticancer activity of PTE against human esophageal cancer cells both in vitro and in vivo and explored the role of endoplasmic reticulum (ER) stress (ERS) signaling in this process. METHODS: Cell viability, the apoptotic index, Caspase 3 activity, adhesion, migration, reactive oxygen species (ROS) levels, and glutathione (GSH) levels were detected to explore the effect of PTE on human EC109 esophageal cancer cells. Furthermore, siRNA transfection and a chemical inhibitor were employed to confirm the role of ERS. RESULTS: PTE treatment dose- and time-dependently decreased the viability of human esophageal cancer EC109 cells. PTE also decreased tumor cell adhesion, migration and intracellular GSH levels while increasing the apoptotic index, Caspase 3 activity and ROS levels, which suggest the strong anticancer activity of PTE. Furthermore, PTE treatment increased the expression of ERS-related molecules (GRP78, ATF6, p-PERK, p-eIF2α and CHOP), upregulated the pro-apoptosis-related protein PUMA and downregulated the anti-apoptosis-related protein Bcl-2 while promoting the translocation of cytochrome c from mitochondria to cytosol and the activation of Caspase 9 and Caspase 12. The downregulation of ERS signaling by CHOP siRNA desensitized esophageal cancer cells to PTE treatment, whereas upregulation of ERS signaling by thapsigargin (THA) had the opposite effect. N-Acetylcysteine (NAC), a ROS scavenger, also desensitized esophageal cancer cells to PTE treatment. CONCLUSIONS: Overall, the results indicate that PTE is a potent anti-cancer pharmaceutical against human esophageal cancer, and the possible mechanism involves the activation of ERS signaling pathways.


Assuntos
Antineoplásicos/administração & dosagem , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Estilbenos/administração & dosagem , Animais , Antineoplásicos/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Sci Rep ; 6: 21145, 2016 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-26892033

RESUMO

In this study, we investigated the antitumor activity of icariin (ICA) in human esophageal squamous cell carcinoma (ESCC) in vitro and in vivo and explored the role of endoplasmic reticulum stress (ERS) signaling in this activity. ICA treatment resulted in a dose- and time-dependent decrease in the viability of human EC109 and TE1 ESCCs. Additionally, ICA exhibited strong antitumor activity, as evidenced by reductions in cell migration, adhesion, and intracellular glutathione (GSH) levels and by increases in the EC109 and TE1 cell apoptotic index, Caspase 9 activity, reactive oxygen species (ROS) level, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Furthermore, ICA treatments upregulated the levels of ERS-related molecules (p-PERK, GRP78, ATF4, p-eIF2α, and CHOP) and a pro-apoptotic protein (PUMA) and simultaneously downregulated an anti-apoptotic protein (Bcl2) in the two ESCC cell lines. The downregulation of ERS signaling using eIF2α siRNA desensitized EC109 and TE1 cells to ICA treatment, and the upregulation of ERS signaling using thapsigargin sensitized EC109 and TE1 cells to ICA treatment. In summary, ERS activation may represent a mechanism of action for the anticancer activity of ICA in ESCCs, and the activation of ERS signaling may represent a novel therapeutic intervention for human esophageal cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Flavonoides/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Caspase 9/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Glutationa/metabolismo , Humanos , Masculino , Camundongos , NADP/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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