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1.
Int J Mol Sci ; 21(7)2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32252330

RESUMO

Vascular calcification, which involves the deposition of calcifying particles within the arterial wall, is mediated by atherosclerosis, vascular smooth muscle cell osteoblastic changes, adventitial mesenchymal stem cell osteoblastic differentiation, and insufficiency of the calcification inhibitors. Recent observations implied a role for mesenchymal stem cells and endothelial progenitor cells in vascular calcification. Mesenchymal stem cells reside in the bone marrow and the adventitial layer of arteries. Endothelial progenitor cells that originate from the bone marrow are an important mechanism for repairing injured endothelial cells. Mesenchymal stem cells may differentiate osteogenically by inflammation or by specific stimuli, which can activate calcification. However, the bioactive substances secreted from mesenchymal stem cells have been shown to mitigate vascular calcification by suppressing inflammation, bone morphogenetic protein 2, and the Wingless-INT signal. Vitamin D deficiency may contribute to vascular calcification. Vitamin D supplement has been used to modulate the osteoblastic differentiation of mesenchymal stem cells and to lessen vascular injury by stimulating adhesion and migration of endothelial progenitor cells. This narrative review clarifies the role of mesenchymal stem cells and the possible role of vitamin D in the mechanisms of vascular calcification.

2.
Neuro Oncol ; 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32328646

RESUMO

BACKGROUND: Glioblastoma is associated with poor prognosis and high mortality. Although the use of first-line temozolomide can reduce tumor growth, therapy-induced stress drives stem cells out of quiescence, leading to chemo-resistance and glioblastoma recurrence. The Sp1 transcription factor is known to protect glioblastoma cells against temozolomide; however, how tumor cells hijack this factor to gain resistance to therapy is not known. METHODS: Sp1 acetylation in temozolomide-resistant cells and stem-like tumorspheres was analyzed by immunoprecipitation and immunoblotting experiments. Effects of the HDAC/Sp1 axis on malignant growth were examined using cell proliferation-related assays and in vivo experiments. Furthermore, integrative analysis of gene expression with ChIP-seq and the recurrent glioblastoma omics data were also used to further determine the target genes of the HDAC/Sp1 axis. RESULTS: We identified Sp1 as a novel substrate of HDAC6, and observed that the HDAC1/2/6/Sp1 pathway promotes self-renewal of malignancy by upregulating BMI1 and hTERT, as well as by regulating G2/M progression and DNA repair via alteration of the transcription of various genes. Importantly, HDAC1/2/6/Sp1 activation is associated with poor clinical outcome in both glioblastoma and low-grade gliomas. However, treatment with azaindolylsulfonamide, a potent HDAC6 inhibitor with partial efficacy against HDAC1/2, induced G2/M arrest and senescence in both temozolomide-resistant cells and stem-like tumorspheres. CONCLUSIONS: Our study uncovers a previously unknown regulatory mechanism in which the HDAC6-Sp1 axis induces cell division and maintains the stem cell population to fuel tumor growth and therapeutic resistance.

3.
Molecules ; 25(6)2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32210117

RESUMO

Temozolomide (TMZ)-induced chemoresistance to human glioblastomas is a critical challenge now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), can kill human glioblastoma cells and suppresses glioblastoma growth. This study was further aimed to evaluate the effects of honokiol on human drug-resistant glioblastoma cells and the possible mechanisms. The results by data mining in the cancer genome atlas (TCGA) database and immunohistochemistry displayed that expression of caspase-9 mRNA and protein in human glioblastomas was induced. Human TMZ-resistant U87-MG-R9 glioblastoma cells were selected and prepared from human drug-sensitive U87-MG cells. Compared to human drug-sensitive U87-MG cells, TMZ did not affect viability of U87-MG-R9 glioblastoma cells. Interestingly, treatment with honokiol suppressed proliferation and survival of human drug-resistant glioblastoma cells in concentration- and time-dependent manners. Compared to caspase-8 activation, honokiol chiefly increased activity of caspase-9 in U87-MG-R9 cells. Successively, levels of cleaved caspase-3 and activities of caspase-3 and caspase-6 in human TMZ-tolerant glioblastoma cells were augmented following honokiol administration. In parallel, honokiol triggered DNA fragmentation of U87-MG-R9 cells. Accordingly, treatment of human TMZ-resistant glioblastoma cells with honokiol induced cell apoptosis but did not affect cell necrosis. Fascinatingly, suppressing caspase-9 activity using its specific inhibitors repressed honokiol-induced caspase-6 activation, DNA fragmentation, and cell apoptosis. Taken together, this study has shown the major roles of caspase-9 in transducing honokiol-induced mitochondria-dependent apoptosis in human drug-resistant glioblastoma cells. Thus, honokiol may be clinically applied as a drug candidate for treatment of glioblastoma patients with chemoresistance.

4.
Neuromodulation ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32166843

RESUMO

BACKGROUND: Noninvasive vagus nerve stimulation (nVNS) has been proposed as a new neuromodulation therapy to treat primary headache disorders. The purpose of this study was to analyze the effectiveness and safety of peripheral nerve stimulation of the cervical branch of the vagal nerve for primary headache disorders. METHODS: A systematic review and meta-analysis of the literature was carried out on randomized controlled trials of nVNS for treating headaches. We searched the Medline, Embase, and CENTRAL databases until January 29, 2019. A random-effects model was used to report all outcomes. The primary outcomes were a reduction in headache days or attacks and pain-free status within 30 min. Secondary outcomes were: the pain-relief status within 30 min, the pain-relief status at 60 min, abortive medication use, ≥50% responder rate, pain-free status in ≥50% of treated attacks, adverse events, and satisfaction. RESULTS: In total, 983 patients were included from six trials. We found that nVNS was effective in achieving a pain-free status within 30 min (odds ratio [OR], 2.27; 95% confidence interval [CI], 1.16~4.44; p = 0.02), pain-relief status within 30 min (OR, 1.8; 95% CI, 1.17~2.78; p = 0.007), pain-relief status at 60 min (OR, 1.93; 95% CI, 1.2~3.1; p = 0.006), a reduction in abortive medication use (OR, 0.61; 95% CI, 0.41~0.92; p = 0.02), and pain-free status in ≥50% of treated attacks (OR, 2.15; 95% CI, 1.27~3.66; p = 0.005) compared to sham-device treatment. There were no significant differences in decreased headache days (standardized mean difference (SMD), -0.159; 95% CI, -0.357~0.04; p = 0.117), adverse events (OR, 1.084; 95% CI, 0.559~2.104; p = 0.811), or satisfaction (OR, 1.45; 95% CI, 0.97~2.17; p = 0.07) between nVNS and sham-device treatment. The ≥50% responder rate could not be determined (OR, 3.34; 95% CI, 0.83~13.33; p = 0.09; I 2 = 73%). CONCLUSIONS: Cervical nVNS is effective for acute pain relief for migraine and cluster headache. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42019126009.

5.
Medicine (Baltimore) ; 99(6): e19125, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32028438

RESUMO

Pain, the main symptom of osteoarthritis (OA), can lead to functional disability in patients with knee OA. Understanding the association factors related to knee pain is important since preventing OA-induced disabilities can be achieved by modifying these pain-associated issues. Therefore, this study was aimed to investigate the association factors for OA-induced knee pain in Taiwanese patients who received total knee replacements (TKR).In this retrospective study, 357 subjects who had undergone TKR at the Taipei Municipal Wan-Fang Hospital were recruited. The distribution of pain severity among patients with knee OA was evaluated. Demographic data and clinical parameters were analyzed to determine relationships between these variables and the severity of knee OA pain.Of the 357 patients studied, 54% and 33% had moderate and severe knee pain, respectively. Furthermore, a multivariate logistic regression analysis revealed that serum creatinine (>1.5 mg/dL) and an estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73 m) were significantly associated with severe knee pain in OA patients. A significant correlation between severe knee pain and serum creatinine or eGFR was demonstrated by Pearson correlations.Taken together, the renal insufficiency defined by an elevated serum creatinine or a low eGFR in OA patients who required TKR was associated with severe knee pain. These variables must be considered while treating knee OA pain, especially in those patients with severe pain.


Assuntos
Artralgia/etiologia , Artroplastia do Joelho/efeitos adversos , Osteoartrite do Joelho/complicações , Insuficiência Renal/complicações , Idoso , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Medição da Dor , Estudos Retrospectivos
6.
PLoS One ; 14(8): e0219718, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31393911

RESUMO

Osteoporosis is a continuous process of loss of bone tissue. Compared to women, osteoporosis in men is associated with greater morbidity and mortality. In this study, we conducted tomographic and biomechanical evaluations of trabecular and cortical bone in the early stage of male osteoporosis. Male Wistar rats were subjected to orchiectomy and sham operation. Four weeks after being castrated, decreased levels of testosterone in plasma were found and resulted in concurrent bone loss. Separately, the orchiectomy led to significant tomographic alterations in the trabecular bone number, trabecular separation, and trabecular pattern factor. Data of a mechanistic compression test further showed that the orchiectomy diminished the maximum loading force, displacement at maximum load, energy at maximum load, and ultimate stress. Interestingly, orchiectomy-triggered changes in the maximum loading force and tomographic parameters were highly correlated. In contrast, tomographic and biomechanical analyses showed that 4 weeks after rats were orchiectomized, the thickness, area, maximum loading force, bone stiffness, energy at maximum load, and ultimate stress of the cortical bone were not changed. Taken together, this study showed specific differences in the microarchitecture and strength of trabecular bone in the early stage of male osteoporosis.


Assuntos
Osso Esponjoso/fisiologia , Osso Cortical/fisiologia , Osteoporose/fisiopatologia , Animais , Fenômenos Biomecânicos , Densidade Óssea/fisiologia , Osso e Ossos/fisiologia , Fêmur/fisiologia , Masculino , Orquiectomia/métodos , Osteoporose/metabolismo , Ratos , Ratos Wistar , Testosterona/metabolismo , Tomografia Computadorizada por Raios X/métodos
7.
Am J Chin Med ; 47(4): 895-912, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091975

RESUMO

In children, neuroblastomas are the most common and deadly solid tumor. Our previous studies showed that honokiol can cross the blood-brain barrier and kill neuroblastoma cells. In this study, we further evaluated if exposure to honokiol for short periods could induce autophagy and subsequent apoptosis of neuroblastoma cells and possible mechanisms. Exposure of neuroblastoma neuro-2a cells to honokiol for 24 h induced morphological shrinkage and cell death. As to the mechanisms, honokiol consecutively induced cytochrome c release from mitochondria, caspase-3 activation, DNA fragmentation and cell apoptosis. Separately, honokiol time-dependently augmented the proportion of autophagic cells and the ratio of light chain 3 (LC3)-II/LC3-I. Pretreatment of neuro-2a cells with 3-methyladenine, an inhibitor of autophagy, attenuated honokiol-induced cell autophagy, caspase-3 activation, DNA damage and cell apoptosis. In contrast, stimulation of autophagy by rapamycin, an inducer of autophagy, significantly enhanced honokiol-induced cell apoptosis. Furthermore, honokiol-induced autophagic apoptosis was confirmed in neuroblastoma NB41A3 cells. Knocking down translation of p53 using RNA interference attenuated honokiol-induced autophagy and apoptosis in neuro-2a and NB41A3 cells. Taken together, this study showed that at early periods, honokiol can induce autophagic apoptosis of neuroblastoma cells through activating a p53-dependent mechanism. Consequently, honokiol has the potential to be a therapeutic option for neuroblastomas.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Neuroblastoma/genética , Neuroblastoma/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Humanos , Fatores de Tempo , Células Tumorais Cultivadas
9.
Nutrients ; 11(1)2019 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-30642029

RESUMO

Vascular calcification is a critical complication in patients with chronic kidney disease (CKD) because it is predictive of cardiovascular events and mortality. In addition to the traditional mechanisms associated with endothelial dysfunction and the osteoblastic transformation of vascular smooth muscle cells (VSMCs), the regulation of calcification inhibitors, such as calciprotein particles (CPPs) and matrix vesicles plays a vital role in uremic vascular calcification in CKD patients because of the high prevalence of vitamin K deficiency. Vitamin K governs the gamma-carboxylation of matrix Gla protein (MGP) for inhibiting vascular calcification, and the vitamin D binding protein receptor is related to vitamin K gene expression. For patients with chronic kidney disease, adequate use of vitamin D supplements may play a role in vascular calcification through modulation of the calciprotein particles and matrix vesicles (MVs).


Assuntos
Insuficiência Renal Crônica/tratamento farmacológico , Calcificação Vascular/tratamento farmacológico , Vitamina D/farmacologia , Vitamina K/farmacologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Suplementos Nutricionais , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/tratamento farmacológico , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Calcificação Vascular/sangue , Calcificação Vascular/etiologia , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina K/sangue , Deficiência de Vitamina K/tratamento farmacológico
10.
Life Sci ; 213: 279-286, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30352244

RESUMO

AIMS: Our previous study showed that propofol can protect against sepsis-induced insults through suppressing liver nitrosation and inflammation. This study further evaluated the mechanisms of propofol-caused protection from sepsis-induced liver dysfunction. MAIN METHODS: Male Wistar rats were subjected to cecal ligation and puncture (CLP) and then exposed to propofol. Levels of hepatic oxidative stress and lipid peroxidation were consecutively measured. Expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-4 messenger (m)RNA or proteins were quantified. Effects of propofol on microsomal pentoxyresorufin O-dealkelase (PROD) and ethoxycoumarin O-deethylase (ECOD) activities were determined. KEY FINDINGS: Administration of propofol to CLP-treated rats significantly attenuated sepsis-induced insults. CLP caused augmented serum aspartate aminotransferase and alanine aminotransferase activities and concurrently triggered liver damage. In contrast, treatment with propofol protected against CLP-induced liver dysfunction. As to the mechanisms, the CLP-induced increases in oxidative stress and lipid peroxidation levels and TNF-α and IL-1ß mRNA and protein expressions were subsequently attenuated by propofol. Furthermore, administration of CLP-treated rats with propofol augmented levels of IL-4 in the liver. Phenobarbital treatment of liver microsomes in CLP-treated rats produced less amplification of PROD and ECOD activities, and a smaller amount of 4-hydroxypropofol was metabolized from propofol by liver microsomes. In contrast, more drug interactions occurred with propofol, which decreased PROD and ECOD activities in liver microsomes of CLP-treated rats. SIGNIFICANCE: Taken together, the present study showed that propofol can protect against sepsis-induced liver dysfunction through suppressing hepatic oxidative stress, lipid peroxidation, inflammation, and drug biotransformation and interactions in the liver.


Assuntos
Peroxidação de Lipídeos/efeitos dos fármacos , Hepatopatias/terapia , Propofol/farmacologia , Animais , Interações Medicamentosas , Inflamação/tratamento farmacológico , Interleucina-1beta , Interleucina-4 , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Propofol/uso terapêutico , Ratos , Ratos Wistar , Sepse/complicações , Fator de Necrose Tumoral alfa
11.
Phytomedicine ; 49: 41-51, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30217261

RESUMO

BACKGROUND: Temozolomide (TMZ) is a first-line chemotherapeutic drug for malignant gliomas. Nonetheless, TMZ-induced side effects and drug resistance remain challenges. Our previous study showed the suppressive effects of honokiol on growth of gliomas. PURPOSE: This study was further aimed to evaluate if honokiol could enhance TMZ-induced insults toward malignant glioma cells and its possible mechanisms. METHODS: Human U87 MG glioma cells were exposed to TMZ, honokiol, and a combination of TMZ and honokiol. Cell survival, apoptosis, necrosis, and proliferation were successively assayed. Fluorometric substrate assays were conducted to determine activities of caspase-3, -6, -8, and -9. Levels of Fas ligand, Bax, and cytochrome c were immunodetected. Translocation of Bax to mitochondria were examined using confocal microscopy. Mitochondrial function was evaluated by assaying the mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and complex I enzyme activity. Caspase-6 activity was suppressed using specific peptide inhibitors. The honokiol-induced effects were further confirmed using human U373 MG and murine GL261 cells. RESULTS: Exposure of human U87 MG glioma cells to honokiol significantly increased TMZ-induced DNA fragmentation and cell apoptosis. Interestingly, honokiol enhanced intrinsic caspase-9 activity without affecting extrinsic Fas ligand levels and caspase-8 activity. Sequentially, TMZ-induced changes in Bax translocation, the MMP, mitochondrial complex I enzyme activity, intracellular ROS levels, and cytochrome c release were enhanced by honokiol. Consequently, honokiol amplified TMZ-induced activation of caspases-3 and -6 in human U87 MG cells. Fascinatingly, suppressing caspase-6 activity concurrently decreased honokiol-induced DNA fragmentation and cell apoptosis. The honokiol-involved improvement in TMZ-induced intrinsic apoptosis was also confirmed in human U373 MG and murine GL261 glioma cells. CONCLUSIONS: This study showed that honokiol can enhance TMZ-induced apoptotic insults to glioma cells via an intrinsic mitochondrion-dependent mechanism. Our results suggest the therapeutic potential of honokiol to attenuate TMZ-induced side effects.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Dacarbazina/análogos & derivados , Medicamentos de Ervas Chinesas/farmacologia , Glioma/patologia , Lignanas/farmacologia , Mitocôndrias/fisiologia , Animais , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Fragmentação do DNA , Dacarbazina/farmacologia , Proteína Ligante Fas/metabolismo , Glioma/tratamento farmacológico , Humanos , Potencial da Membrana Mitocondrial , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Temozolomida
12.
Environ Toxicol ; 2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-29923317

RESUMO

The major objective of the present study was to determine the ability of a triazole fungicide tebuconazole to induce cytochrome P450-dependent monooxygenases, oxidative stress, and endocrine-disrupting activity using male rats treated with tebuconazole at 10, 25, and 50 mg/kg p.o. once daily for 28 days. In liver, tebuconazole dose-dependently increased microsomal contents of cytochrome P450 and cytochrome b5 and the activities of NADPH-cytochrome P450 reductase, 7-ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, pentoxyresorufin O-dealkylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase. In kidney, tebuconazole increased 7-ethoxycoumarin O-deethylase activity without affecting other monooxygenase activities. In marked contrast to liver and kidney, tebuconazole decreased testicular 7-ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase activities. The results of immunoblot analysis of liver microsomes of controls and tebuconazole-treated rats revealed that tebuconazole induced CYP1A1/2, CYP2B1/2, CYP2E1, and CYP3A proteins in liver. Additions of tebuconazole to liver microsomes inhibited microsomal 7-ethoxycoumarin O-deethylase activity in vitro (IC50 = 1.50-1.69 µM). Treatment of rats with tebuconazole decreased glutathione content and increased glutathione S-transferase, superoxide dismutase, catalase, and glutathione peroxidase activities in liver; increased superoxide dismutase activities in kidney and testis; but decreased glutathione S-transferase activity in testis. Treatments with tebuconazole decreased serum testosterone concentration and cauda epididymal sperm count. The present study demonstrates that tebuconazole induces a multiplicity of CYPs and oxidative stress in liver; inhibits testicular P450 and glutathione S-transferase activities; and produces anti-androgenic effects in male rats.

13.
Expert Opin Drug Metab Toxicol ; 14(7): 709-720, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29888644

RESUMO

INTRODUCTION: Although used as an anesthetic drug for decades, ketamine appears to have garnered renewed interest due to its potential therapeutic uses in pain therapy, neurology, and psychiatry. Ketamine undergoes extensive oxidative metabolism by cytochrome P450 (CYP) enzymes. Considerable efforts have been expended to elucidate the ketamine-induced regulation of CYP gene expression. The safety profile of chronic ketamine administration is still unclear. Understanding how ketamine regulates CYP gene expression is clinically meaningful. Areas covered: In this article, the authors provide a brief review of clinical applications of ketamine and its metabolism by CYP enzymes. We discuss the effects of ketamine on the regulation of CYP gene expression, exploring aspects of cytoskeletal remodeling, mitochondrial functions, and calcium homeostasis. Expert opinion: Ketamine may inhibit CYP gene expression through inhibiting calcium signaling, decreasing ATP levels, producing excessive reactive oxygen species, and subsequently perturbing cytoskeletal dynamics. Further research is still needed to avoid possible ketamine-drug interactions during long-term use in the clinic.


Assuntos
Anestésicos Dissociativos/administração & dosagem , Sistema Enzimático do Citocromo P-450/genética , Ketamina/administração & dosagem , Trifosfato de Adenosina/metabolismo , Anestésicos Dissociativos/efeitos adversos , Anestésicos Dissociativos/farmacocinética , Animais , Sinalização do Cálcio/efeitos dos fármacos , Citoesqueleto/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Ketamina/efeitos adversos , Ketamina/farmacocinética , Espécies Reativas de Oxigênio/metabolismo
14.
BMC Cancer ; 18(1): 379, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29614990

RESUMO

BACKGROUND: Temozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), is safe for normal brain cells and can kill human glioma cells. This study was further aimed to evaluate the improved effects of honokiol and TMZ on drug-sensitive and -resistant glioma cells and the possible mechanisms. METHODS: TMZ-sensitive human U87-MG and murine GL261 glioma cells and TMZ-resistant human U87-MR-R9 glioma cells were exposed to honokiol and TMZ, and cell viability and LC50 of honokiol were assayed. To determine the death mechanisms, caspase-3 activity, DNA fragmentation, apoptotic cells, necrotic cells, cell cycle, and autophagic cells. The glioma cells were pretreated with 3-methyladenine (3-MA) and chloroquine (CLQ), two inhibitors of autophagy, and then exposed to honokiol or TMZ. RESULTS: Exposure of human U87-MG glioma cells to honokiol caused cell death and significantly enhanced TMZ-induced insults. As to the mechanism, combined treatment of human U87-MG cells with honokiol and TMZ induced greater caspase-3 activation, DNA fragmentation, cell apoptosis, and cell-cycle arrest at the G1 phase but did not affect cell necrosis. The improved effects of honokiol on TMZ-induced cell insults were further verified in mouse GL261 glioma cells. Moreover, exposure of drug-tolerant human U87-MG-R9 cells to honokiol induced autophagy and consequent apoptosis. Pretreatments with 3-MA and CLQ caused significant attenuations in honokiol- and TMZ-induced cell autophagy and apoptosis in human TMZ-sensitive and -tolerant glioma cells. CONCLUSIONS: Taken together, this study demonstrated the improved effects of honokiol with TMZ on autophagy and subsequent apoptosis of drug-sensitive and -tolerant glioma cells. Thus, honokiol has the potential to be a drug candidate for treating human gliomas.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lignanas/farmacologia , Temozolomida/farmacologia , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Glioma , Humanos
15.
Oncotarget ; 9(1): 1169-1186, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29416685

RESUMO

Estrogen deficiency usually leads to bone loss and osteoporosis in postmenopausal women. Osteoblasts play crucial roles in bone formation. However, osteoblast functions are influenced by mitochondrial bioenergetic conditions. In this study, we investigated the roles of the estrogen and estrogen receptor alpha (ERα) axis in mitochondrial energy metabolism and subsequent osteoblast mineralization. Exposure of rat calvarial osteoblasts to estradiol caused substantial improvements in alkaline phosphatase activities and cell calcification. In parallel, treatment of human osteoblast-like U2OS cells, derived from a female osteosarcoma patient, with estradiol specifically augmented ERα levels. Sequentially, estradiol stimulated translocation of ERα to nuclei in human osteoblasts and induced expressions of genomic respiratory chain complex NDUFA10, UQCRC1, cytochrome c oxidase (COX)8A, COX6A2, COX8C, COX6C, COX6B2, COX412, and ATP12A genes. Concurrently, estradiol stimulated translocation of ERα to mitochondria from the cytoplasm. A bioinformatic search found the existence of four estrogen response elements in the 5'-promoter region of the mitochondrial cox i gene. Interestingly, estradiol induced COX I mRNA and protein expressions in human osteoblasts or rat calvarial osteoblasts. Knocking-down ERα translation concurrently downregulated estradiol-induced COX I mRNA expression. Consequently, exposure to estradiol led to successive increases in the mitochondrial membrane potential, the mitochondrial enzyme activity, and cellular adenosine triphosphate levels. Taken together, this study showed the roles of the estradiol/ERα signaling axis in improving osteoblast maturation through upregulating the mitochondrial bioenergetic system due to induction of definite chromosomal and mitochondrial complex gene expressions. Our results provide novel insights elucidating the roles of the estrogen/ERα alliance in regulating bone formation.

16.
Life Sci ; 195: 25-32, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29307523

RESUMO

AIMS: Propofol can be applied as an anesthetic or sedative agent for septic patients. Our previous studies showed that propofol ameliorated inflammation- and nitrosative stress-induced cellular insults. This study further evaluated effects of propofol on cecal ligation and puncture (CLP)-induced septic insults to rats and its possible mechanisms. MAIN METHODS: Wistar rats were administered with CLP and effects of propofol on CLP-induced liver dysfunction and rat death were evaluated. Levels of hepatic or systemic nitrogen oxides (NOx) and interleukin (IL)-6 were quantified. Sequentially, inducible nitric oxide synthase (iNOS) and IL-6 gene expressions, toll-like receptor 4 (TLR4) protein levels, and nuclear factor (NF)-κB translocation were determined. KEY FINDINGS: Subjecting rats to CLP led to body weight loss, liver weight gain, and death. Administration of propofol lessened CLP-induced augmentations of serum and hepatic nitrosative stress and IL-6 levels. Additionally, propofol suppressed CLP-induced enhancements in levels of hepatic iNOS protein. Furthermore, the CLP-induced iNOS and IL-6 mRNA expressions in the liver were inhibited following propofol administration. Sequentially, subjecting rats to CLP enhanced hepatic TLR4 protein levels and NF-κB translocation to nuclei, but propofol inhibited these augmentations. SIGNIFICANCE: Consequently, exposure to propofol protected against CLP-induced liver dysfunction and increased the survival rates of the animals. This study shows that propofol can protect rats against septic insults through suppression of systemic and hepatic nitrosative and inflammatory stress due to inhibition of TLR4/NF-κB-mediated iNOS and IL-6 mRNA and protein expressions.


Assuntos
Hepatite/tratamento farmacológico , Hipnóticos e Sedativos/uso terapêutico , Interleucina-6/biossíntese , Fígado/metabolismo , Fígado/patologia , NF-kappa B/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/biossíntese , Nitrosação/efeitos dos fármacos , Propofol/uso terapêutico , Sepse/tratamento farmacológico , Receptor 4 Toll-Like/efeitos dos fármacos , Actinas/metabolismo , Animais , Doenças do Ceco/metabolismo , Doenças do Ceco/patologia , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatite/metabolismo , Hepatite/patologia , Interleucina-6/genética , Masculino , Óxido Nítrico Sintase Tipo II/genética , Ratos , Ratos Wistar , Sepse/metabolismo , Sepse/patologia , Translocação Genética/efeitos dos fármacos
17.
J Pain Res ; 11: 41-50, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29317848

RESUMO

Background: Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage degeneration, subchondral bone changes, osteophyte formation, and synovitis. A major symptom is pain that is triggered by peripheral and central changes within the pain pathways. Some surgery-induced joint instability rat models of OA were described to mimic traumatic OA. Several behavioral tests were developed to access OA-induced pain. However, follow-up in most studies usually only occurred for about 4 weeks. Since traumatic OA is a chronic disease which gradually develops after trauma, the pattern of pain might differ between early and late stages after the trauma. Purpose: To observe the time-dependent development of hypersensitivity after traumatic OA and to determine the best timing and methods to investigate traumatic OA-induced pain. Methods: Anterior cruciate ligament transection plus medial meniscectomy was used to induce traumatic OA in Sprague-Dawley rats. Traumatic OA-induced pain was evaluated using four different behavioral tests for 15 weeks. Results: A significant difference in mechanical hypersensitivity developed throughout the observational period. It was worst in the first 3 weeks after the operation, then became less significant after 5 weeks but persisted. There were no differences in thermal hyperalgesia or motor coordination. Conclusion: Traumatic OA induced mechanical hyperalgesia but did not cause thermal hyperalgesia or influence motor coordination. Furthermore, to investigate chronic pain induced by OA, the observational period should be at least 5 weeks after the intervention. These findings may help in further research and improve our understanding of traumatic OA-induced pain mechanisms.

18.
Exp Mol Med ; 49(11): e398, 2017 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-29170477

RESUMO

We have previously demonstrated the expression of GATA-DNA-binding protein (GATA)-3, a transcription factor, in osteoblasts and have verified its function in transducing cell survival signaling. This translational study was further designed to evaluate the roles of GATA-3 in regulating bone healing and to explore its possible mechanisms. A metaphyseal bone defect was created in the left femurs of male ICR mice. Analysis by micro-computed topography showed that the bone volume, trabecular bone number and trabecular thickness were augmented and that the trabecular pattern factor decreased. Interestingly, immunohistological analyses showed specific expression of GATA-3 in the defect area. In addition, colocalized expression of GATA-3 and alkaline phosphatase was observed at the wound site. As the fracture healed, the amounts of phosphorylated and non-phosphorylated GATA-3 concurrently increased. Separately, GATA-3 mRNA was induced during bone healing, and, levels of Runx2 mRNA and protein were also increased. The results of confocal microscopy and co-immunoprecipitation showed an association between nuclear GATA-3 and Runx2 in the area of insult. In parallel with fracture healing, Bcl-XL mRNA was significantly triggered. A bioinformatic search revealed the existence of a GATA-3-specific DNA-binding element in the promoter region of the bcl-xL gene. Analysis by chromatin immunoprecipitation assays further demonstrated transactivation activity by which GATA-3 regulated bcl-xL gene expression. Therefore, this study shows that GATA-3 participates in the healing of bone fractures via regulating bcl-xL gene expression, owing to its association with Runx2. In the clinic, GATA-3 may be used as a biomarker for diagnoses/prognoses or as a therapeutic target for bone diseases, such as bone fractures.


Assuntos
Fator de Transcrição GATA3/metabolismo , Regulação da Expressão Gênica , Cicatrização , Proteína bcl-X/genética , Fosfatase Alcalina/metabolismo , Animais , Biomarcadores , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/genética , Fraturas Ósseas/metabolismo , Fraturas Ósseas/patologia , Fator de Transcrição GATA3/genética , Camundongos , Ligação Proteica , Transporte Proteico
19.
Int J Oncol ; 50(3): 964-974, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28197638

RESUMO

Malignant glioma is the most aggressive brain tumor. Hypoxic condition has been explored for killing cancer stem cells or drug-resistant tumor cells. This study investigated the effects of hypoxia on autophagic death and the possible mechanisms. Exposure of human malignant glioma U87-MG cells to cobalt chloride (CoCl2) increased cellular hypoxia-inducible factor-1α levels and concurrently decreased cell viability concentration- and time-dependently. In parallel, treatment with CoCl2 suppressed proliferation of human U87-MG cells. Autophagic cells and levels of LC3-II were concentration- and time-dependently induced in human U87-MG cells after exposure to CoCl2. However, pretreatment with 3-mehyladenine (3-MA) and chloroquine, inhibitors of cell autophagy, caused significant alleviations in CoCl2-induced cell autophagy. In contrast, exposure to rapamycin, an inducer of cell autophagy, synergistically induced hypoxia-induced autophagy of U87-MG cells. Administration of human U87-MG cells with CoCl2 triggered caspase-3 activation and cell apoptosis. Interestingly, pretreatment with 3-MA and chloroquine remarkably suppressed CoCl2-induced caspase-3 activation and cell apoptosis. Application of p53 small interference (si)RNA into human U87-MG cells downregulated levels of this protein and simultaneously lowered hypoxia- and 3-MA-induced alterations in cell autophagy, apoptosis, and death. The hypoxia-induced autophagy and apoptosis of DBTRG-05MG cells were significantly lowered by 3-MA pretreatment and p53 knockdown. Therefore, the present study shows that CoCl2 treatment can induce autophagy of human glioma cells and subsequent autophagic apoptosis via a p53-dependent pathway. Hypoxia-induced autophagic apoptosis may be applied as a therapeutic strategy for treatment of glioma patients.


Assuntos
Antimutagênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Cobalto/uso terapêutico , Glioma/tratamento farmacológico , Adenina/análogos & derivados , Adenina/farmacologia , Neoplasias Encefálicas/patologia , Caspase 3/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Glioma/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
20.
J Cell Biochem ; 118(9): 2635-2644, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-27987330

RESUMO

Dexmedetomidine, an agonist of alpha2-adrenergic receptors, is used for critically ill patients to induce and maintain sedation and analgesia. Brain ischemia/reperfusion (I/R) usually causes severe neuronal injuries to intensive care unit patients. This study was aimed to evaluate the effects of dexmedetomidine on I/R-induced insults to neuronal cells and the possible mechanisms. Treatment of neuro-2a cells with dexmedetomidine did not affect cell viability but could protect against I/R-induced cell death. Separately, the I/R-triggered cell shrinkage, DNA fragmentation, and apoptosis in neuro-2a cells were alleviated by dexmedetomidine. As to the mechanisms, exposure of neuro-2a cells to dexmedetomidine substantially attenuated I/R-induced translocation of Bax protein from the cytosol to mitochondria and reduction in the mitochondrial membrane potential (MMP). Successively, dexmedetomidine decreased cytochrome c release from mitochondria to the cytoplasm and consequent cascade activations of caspases-9, -3, and -6 in I/R-treated neuro-2a cells. Interestingly, downregulating caspase-6 activity synergistically improved dexmedetomidine-induced defense against I/R-induced apoptosis of neuro-2a cells. The dexmedetomidine-involved neuroprotection was further confirmed in the other NB41A3 neuronal cells by significantly attenuating I/R-induced changes in the MMP, caspase-3 activation, DNA fragmentation, and cell apoptosis. Taken together, this study has shown the neuroprotective effects of dexmedetomidine against I/R-induced apoptotic insults via an intrinsic Bax-mitochondria-cytochrome c-caspase protease pathway. J. Cell. Biochem. 118: 2635-2644, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Apoptose/efeitos dos fármacos , Dexmedetomidina/farmacologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Neurônios/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Caspases/metabolismo , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Humanos , Mitocôndrias/patologia , Neurônios/patologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
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