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1.
J Cancer ; 12(22): 6629-6639, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659553

RESUMO

Cancer stem cells (CSCs) are characterized by self-renewal and unlimited proliferation, providing a basis for tumor occurrence, metastasis, and recurrence. Because CSCs are highly resistant to conventional chemotherapy and radiotherapy, various immunotherapies, particularly chimeric antigen receptor T cell (CAR-T) therapy and dendritic cell (DC)-based vaccine therapy, are currently being developed. Accordingly, in this study, we evaluated programmed cell death ligand-1 (PD-L1) expression in colorectal CSCs (CCSCs) and non-CCSCs and designed a combination immunotherapy synchronously utilizing PD-L1-CAR-T cells together with CCSC-DC vaccine-sensitized T cells for the treatment of colorectal cancer. PD-L1-CAR-T cells specifically recognized the PD-L1 molecule on CCSCs by binding to the extracellular domain of programmed cell death-1. The CCSC-DC vaccine was prepared using CCSC lysates. We found that aldehyde dehydrogenase 1 (ALDH1)-positive CCSCs were abundant in samples from patient tumor tissues and cancer cell lines. Moreover, PD-L1 was highly expressed in ALDH1-positive CCSCs compared with that in non-CCSCs. Monotherapy with PD-L1-CAR-T cells or CCSC-DC vaccine only elicited moderate tumor remission both in vitro and in vivo. However, combination therapy markedly killed cancer cells and relieved the tumor burden in mice. Our findings may provide a novel strategy for the clinical treatment of colorectal malignancy.

2.
J Food Biochem ; 44(9): e13405, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32710574

RESUMO

Isobavachalcone (ISO) exhibits good anti-inflammatory activity. We evaluated the renoprotective effects of ISO against diabetic nephropathy (DN). Diabetic rats established by the single injection of streptozotocin (STZ) were orally treated with ISO. The levels of serum creatinine (Scr), blood urea nitrogen (BUN), and 24 hr urinary protein were measured. In this study, ISO effectively ameliorated renal damage by reducing BUN, Scr, and 24 hr urinary protein and also improved kidney pathological appearances. ISO prevented STZ-caused apoptosis in the glomerular tissue in vivo and blocked the high glucose (HG)-induced growth inhibitory effect in human renal glomerular endothelial cells in vitro. Moreover, ISO reduced pro-inflammatory mediator production and blocked the NF-κB pathway in the damaged renal tissues and HG-treated HRGEC cells. Taken together, the results of this study indicate that ISO consumption might have significant beneficial effects on the DN and this action might be correlated with the modulation of the NF-κB pathway. PRACTICAL APPLICATIONS: ISO is an active compound from the dried ripe fruit of Psoralea corylifolia L. seed, which is traditionally served as a food ingredient in Asia. In this investigation, we observed the beneficial effects of ISO on a murine model with DN. Further research revealed that the protective action of ISO might be connected with its weak hypoglycaemic and notable anti-inflammatory effects. Our research data suggest that ISO-enriched food might be a good choice for people suffering from DN.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Chalconas , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Células Endoteliais/metabolismo , Camundongos , NF-kappa B/metabolismo , Ratos , Transdução de Sinais
3.
Cell Biol Int ; 44(9): 1911-1918, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32441799

RESUMO

The application of tyrosine kinase inhibitors (TKIs) to the epidermal growth factor receptor (EGFR) has been proven to be highly effective for non-small-cell lung cancer (NSCLC). However, patients often evolve into acquired resistance. The secondary mutations in EGFR account for nearly half of the acquired resistance. While the remaining 50% of patients exhibit tolerance to EGFR-TKIs with unclear mechanism(s). Cylindromatosis (CYLD), a deubiquitinase, functions as a tumor suppressor to regulate cell apoptosis, proliferation, and immune response, and so on. The role of CYLD in NSCLC EGFR-TKI resistance remains elusive. Here, we found CYLD was upregulated in PC-9 cells, whereas downregulated in PC-9 acquired gefitinib-resistant (PC-9/GR) cells in response to the treatment of gefitinib, which is consistent with the results in the Gene Expression Omnibus database. Overexpression of CYLD promoted a more apoptotic death ratio in PC-9/GR cells than that in PC-9 cells. In addition, silencing the expression of CYLD resulted in an increase of the expression level of interleukin-6, transforming growth factor-ß and tumor necrosis factor-α, which may contribute to acquired resistance of PC-9 cells to gefitinib. Taken together, our data in vitro demonstrate that PC-9/GR cells downregulated CYLD expression, enhanced subsequent CYLD-dependent antiapoptotic capacity and inflammatory response, which may provide a possible target for acquired gefitinib-resistant treatment in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Enzima Desubiquitinante CYLD/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Enzima Desubiquitinante CYLD/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/metabolismo , Gefitinibe/metabolismo , Gefitinibe/farmacologia , Genes Supressores de Tumor/efeitos dos fármacos , Humanos , Inflamação , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia
4.
Zhonghua Er Ke Za Zhi ; 51(6): 460-6, 2013 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-24120065

RESUMO

OBJECTIVE: To explore the effect of human umbilical cord blood mononuclear cells (UCBMC) promoting nerve behavior function and brain tissue recovery of neonatal SD rat with hypoxic ischemic brain injury (HIBI). METHOD: A modified newborn rat model that had a combined hypoxic and ischemic brain injury as described by Rice-Vannucci was used, early nervous reflex, the Morris water maze and walking track analysis were used to evaluate nervous behavioral function, and brain MRI, HE staining to evaluate brain damage recovery. RESULT: Newborn rat Rice-Vannucci model showed significant brain atrophy, obvious hemiplegia of contralateral limbs,e.g right step length [(7.67 ± 0.46) cm vs. (8.22 ± 0.50) cm, F = 1.494] and toe distance [(0.93 ± 0.06) cm vs. (1.12 ± 0.55) cm, F = 0.186] were significantly reduced compared with left side, learning and memory ability was significantly impaired compared with normal control group (P < 0.01); Cliff aversion [(8.44 ± 2.38) s vs.(14.22 ± 5.07) s, t = 4.618] and negative geotaxis reflex time [(7.26 ± 2.00) s vs. (11.76 ± 3.73) s, t = 4.755] on postnatal 14 days of HIBI+ transplantation group were significantly reduced compared with HIBI+NaCl group (P < 0.01) ; the Morris water maze experiment showed escape latency [ (23.11 ± 6.64) s vs. (34.04 ± 12.95) s, t = 3.356] and swimming distance [ (9.12 ± 1.21) cm vs.(12.70 ± 1.53) cm, t = 17.095] of HIBI+transplantation group were significantly reduced compared with those of HIBI+NaCl group (P < 0.01) ; the residual brain volume on postnatal 10 d [ (75.37 ± 4.53)% vs. (67.17 ± 4.08)%, t = -6.017] and 67 d [ (69.05 ± 3.58)% vs.(60.83 ± 3.69)%, t = -7.148]of HIBI+ transplantation group were significantly larger than those of HIBI+NaCl group (P < 0.01); After human UCBMC transplantation, left cortical edema significantly reduced and nerve cell necrosis of HIBI+ transplantation group is not obvious compared with HIBI+NaCl group. CONCLUSION: Human UCBMC intraperitoneal transplantation significantly promoted recovery of injured brain cells and neurobehavioral function development.


Assuntos
Encéfalo/patologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Hipóxia-Isquemia Encefálica/terapia , Deficiências da Aprendizagem/prevenção & controle , Animais , Animais Recém-Nascidos , Atrofia/etiologia , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Córtex Cerebral/patologia , Modelos Animais de Doenças , Feminino , Sangue Fetal/citologia , Humanos , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/patologia , Deficiências da Aprendizagem/etiologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/transplante , Imageamento por Ressonância Magnética , Masculino , Aprendizagem em Labirinto , Neurônios/patologia , Desempenho Psicomotor , Radiografia , Ratos , Ratos Sprague-Dawley , Transplante Heterólogo
5.
Fitoterapia ; 81(5): 437-42, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20026390

RESUMO

It has been reported that icariin and icariside II, two flavonoid glycosides coming from herba epimedii, which have a closely structural relationship, show some pharmacological effects such as preventing osteoporosis, cancer and depression. The content of natural icariside II is very low in herba epimedii, but it is the main component in vivo after the administration of herba epimedii. More icariside II can be obtained from icariin by enzymatic hydrolysis method than by traditional isolation method. This study focuses on finding a simple and feasible method to prepare icariside II from icariin by enzymatic hydrolysis, so as to meet the request for further pharmacologic actions study. Icariin was obtained successively with 90% ethanol extraction, isolation on macroporous resin and purification on silica gel chromatography. Enzymatic hydrolysis conditions were tested for the bioconversion of icariin into icariside II by orthogonal array design. The structures of isolated icariin and produced icariside II were identified by UV, IR, ESIMS, (1)H NMR, (13)C NMR, and DEPT spectroscope. Enzymatic hydrolysis experiment showed that icariin could be transformed into icariside II with the action of beta-glucosidase and the optimum reaction conditions were determined as follows: 50 degrees C, 0.2 M disodium hydrogen phosphate and citric acid buffer system (pH6.0), the ratio of icariin/enzyme is 1:1 and reaction time 5 h. By using this enzymatic condition, 95.5 mg icariside II (with the purity of 99.1%) was obtained eventually by transforming 200 mg icariin.


Assuntos
Berberidaceae/química , Flavonoides/biossíntese , Flavonoides/metabolismo , beta-Glucosidase/metabolismo , Composição de Medicamentos/métodos , Flavonoides/isolamento & purificação , Hidrólise , Estrutura Molecular
6.
Metabolism ; 56(3): 405-12, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17292731

RESUMO

Berberine exerts a hypoglycemic effect, but the mechanism remains unknown. In the present study, the effect of berberine on glucose uptake was characterized in 3T3-L1 adipocytes. It was revealed that berberine stimulated glucose uptake in 3T3-L1 adipocytes in a dose- and time-dependent manner with the maximal effect at 12 hours. Glucose uptake was increased by berberine in 3T3-L1 preadipocytes as well. Berberine-stimulated glucose uptake was additive to that of insulin in 3T3-L1 adipocytes, even at the maximal effective concentrations of both components. Unlike insulin, the effect of berberine on glucose uptake was insensitive to wortmannin, an inhibitor of phosphatidylinositol 3-kinase, and SB203580, an inhibitor of p38 mitogen-activated protein kinase. Berberine activated extracellular signal-regulated kinase (ERK) 1/2, but PD98059, an ERK kinase inhibitor, only decreased berberine-stimulated glucose uptake by 32%. Berberine did not induce Ser473 phosphorylation of Akt nor enhance insulin-induced phosphorylation of Akt. Meanwhile, the expression and cellular localization of glucose transporter 4 (GLUT4) were not altered by berberine. Berberine did not increase GLUT1 gene expression. However, genistein, a tyrosine kinase inhibitor, completely blocked berberine-stimulated glucose uptake in 3T3-L1 adipocytes and preadipocytes, suggesting that berberine may induce glucose transport via increasing GLUT1 activity. In addition, berberine increased adenosine monophosphate-activated protein kinase and acetyl-coenzyme A carboxylase phosphorylation. These findings suggest that berberine increases glucose uptake through a mechanism distinct from insulin, and activated adenosine monophosphate-activated protein kinase seems to be involved in the metabolic effect of berberine.


Assuntos
Berberina/farmacologia , Glucose/metabolismo , Insulina/fisiologia , Células 3T3-L1 , Adenilato Quinase/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavonoides/farmacologia , Transportador de Glucose Tipo 1/análise , Transportador de Glucose Tipo 4/análise , Camundongos , Fosfatidilinositol 3-Quinases/fisiologia , Fosforilação , Transdução de Sinais
7.
Life Sci ; 80(7): 618-25, 2007 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-17129589

RESUMO

Evidence has accumulated that ginseng and its main active constituents, ginsenosides, possess anti-diabetic and insulin-sensitizing properties which may be partly realized by regulating adipocyte development and functions. In the present study, we explored the effect of ginsenoside Rb(1), the most abundant ginsenoside in ginseng root, on adipogenesis of 3T3-L1 cells. We found that with standard differentiation inducers, ginsenoside Rb(1) facilitated adipogenesis of 3T3-L1 preadipocytes in a dose-dependent manner; 10 microM Rb(1) increased lipid accumulation by about 56%. Treatment of differentiating adipocytes with 10 microM Rb(1) increased the expression of mRNA and protein of PPARgamma(2) and C/EBPalpha, as well as mRNA of ap2, one of their target genes. After the treatment of differentiating adipocytes with Rb(1), basal and insulin-mediated glucose uptake was significantly augmented, accompanied by the up-regulation of mRNA and protein level of GLUT4, but not of GLUT1. In addition, ginsenoside Rb(1) also inhibited the proliferation of preconfluent 3T3-L1 preadipocytes. Our data indicate that anti-diabetic and insulin-sensitizing activities of ginsenosides, at least in part, are involved in the enhancing effect on PPARgamma2 and C/EBPalpha expression, hence promoting adipogenesis.


Assuntos
Adipogenia/efeitos dos fármacos , Proteína beta Intensificadora de Ligação a CCAAT/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Ginsenosídeos/farmacologia , PPAR gama/genética , Panax/química , Células 3T3 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Compostos Azo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Glucose/metabolismo , Insulina/farmacologia , Camundongos , PPAR gama/metabolismo , Extratos Vegetais/farmacologia , RNA Mensageiro/metabolismo , Triglicerídeos/análise , Triglicerídeos/metabolismo
8.
Acta Pharmacol Sin ; 26(8): 976-81, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16038631

RESUMO

AIM: To investigate the expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in the control of GnRH secretion. METHODS: Receptors of bombesin3, cholecystokinin (CCK)-A, CCK-B, glucagon-like peptide (GLP)1, melanin-concentrating hormone (MCH)1, orexin1, orexin2, neuromedin-B, neuropeptide Y (NPY)1 and NPY5, neurotensin (NT)1, NT2, NT3, and leptin receptor long form mRNA in GT1-7 cells were detected by reversed transcriptase-polymerase chain reaction. GT1-7 cells were treated with leptin, orexin A and orexin B at a cohort of concentrations for different lengths of time, and GnRH in medium was determined by radioimmunoassay (RIA). RESULTS: Receptors of bombesin 3, CCK-B, GLP1, MCH1, orexin1, neuromedin-B, NPY1, NPY5, NT1, NT3, and leptin receptor long form mRNA were expressed in GT1-7 cells, of which, receptors of GLP1, neuromedin-B, NPY1, and NT3 were highly expressed. No amplified fragments of orexin2, NT2, and CCK-A receptor cDNA were generated with GT1-7 RNA, indicating that the GT1-7 cells did not express mRNA of them. Leptin induced a significant stimulation of GnRH release, the results being most significant at 0.1 nmol/L for 15 min. In contrast to other studies in hypothalamic explants, neither orexin A nor orexin B affected basal GnRH secretion over a wide range of concentrations ranging from 1 nmol/L to 500 nmol/Lat 15, 30, and 60 min. CONCLUSION: Feeding and reproductive function are closely linked. Many orexigenic and anorexigenic signals may control feeding behavior as well as alter GnRH secretion through their receptors on GnRH neurons.


Assuntos
Hormônio Liberador de Gonadotropina/metabolismo , Leptina/farmacologia , Neuropeptídeos/farmacologia , RNA Mensageiro/metabolismo , Receptores de Peptídeos/genética , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Ingestão de Alimentos/genética , Expressão Gênica , Receptor do Peptídeo Semelhante ao Glucagon 1 , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Receptores de Orexina , Orexinas , RNA Mensageiro/genética , Radioimunoensaio , Receptor de Colecistocinina B/genética , Receptores da Bombesina/genética , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas G , Receptores de Glucagon/genética , Receptores para Leptina , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeo Y/genética , Receptores de Neurotensina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
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