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1.
Anticancer Res ; 40(1): 221-227, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892570

RESUMO

BACKGROUND/AIM: Autophagy can be either tumor promotive or suppressive. We previously identified an autophagy-inducing activity in the 30-100 kDa fraction of areca-nut-extract (ANE 30-100K) and showed that several tumor cells subjected to chronic ANE 30-100K stimulation (CAS) exhibited higher resistance against stressed environments including serum-free (SF) conditions in vitro. Herein, we aimed to assess whether CAS can also provide growth advantages for tumor cells in vivo and the therapeutic effect of autophagy inhibition on CAS-treated tumors. MATERIALS AND METHODS: Esophageal CE81T/VGH cells and nude mice were used as experimental models. Autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ), as well as another anticancer drug cisplatin (DDP), were chosen to challenge CAS-treated CE81T/VGH cells in vitro and in vivo. RESULTS: CAS-treated CE81T/VGH cells expressed higher levels of microtubule-associated protein 1 light chain 3A/B-II (LC3-II) and beclin 1 proteins, and showed stronger resistance to SF and hypoxia conditions, that were mitigated by CQ or 3-MA in vitro. Furthermore, CAS-treated CE81T/VGH cells induced significantly larger tumors in mice, which were also attenuated by single 3-MA or CQ treatment. Finally, the combined treatment of 3-MA or CQ with DDP further up-regulated DDP-induced caspase-3 activity in vitro and exhibited synergistic anti-tumor effects on mice. CONCLUSION: CAS may up-regulate tumoral autophagy and provide growth advantage for tumors both in vitro and in vivo. Furthermore, autophagy inhibition alone or in combination with DDP may achieve positive therapy for tumors encountered with CAS.


Assuntos
Areca/química , Autofagia , Neoplasias/patologia , Nozes/química , Regulação para Cima , Animais , Autofagia/genética , Hipóxia Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus
2.
J Colloid Interface Sci ; 559: 51-64, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610305

RESUMO

Aiming at the inefficiency and toxicity in traditional antitumor therapy, a novel multifunctional nanoplatform was constructed based on hollow mesoporous carbon (HMC) to achieve triple stimuli response and dual model antitumor therapy via chemo-photothermal synergistic effect. HMC was used as an ideal nanovehicle with a high drug loading efficiency as well as a near-infrared (NIR) photothermal conversion agent for photothermal therapy. Acid-dissoluble, luminescent ZnO quantum dots (QDs) were used as the proper sealing agents for the mesopores of HMC, conjugated to HMC via disulfide linkage to prevent drug (doxorubicin, abbreviated as Dox) premature release from Dox/HMC-SS-ZnO. After cellular endocytosis, the Dox was released in a pH, GSH and NIR laser triple stimuli-responsive manner to realize accurate drug delivery. Moreover, the local hyperthermia effect induced by NIR irradiation could promote the drug release, enhance cell sensitivity to chemotherapeutic agents, and also directly kill cancer cells. As expected, Dox/HMC-SS-ZnO exhibited a high drug loading capacity of 43%, well response to triple stimuli and excellent photothermal conversion efficiency η of 29.7%. The therapeutic efficacy in 4T1 cells and multicellular tumor spheroids (MCTSs) demonstrated that Dox/HMC-SS-ZnO + NIR had satisfactory chemo-photothermal synergistic effect with a combination index (CI) of 0.532. The cell apoptosis rate of the combined treatment group was more than 95%. The biodistribution and pharmacodynamics studies showed its biosecurity to normal tissues and synergistic inhibition effect to tumor cells. These distinguished results indicated that the Dox/HMC-SS-ZnO nanoplatform is potential to realize efficient triple stimuli-responsive drug delivery and dual model chemo-photothermal synergistic antitumor therapy.


Assuntos
Antineoplásicos/química , Carbono/química , Terapia Combinada/métodos , Portadores de Fármacos/química , Nanopartículas/química , Pontos Quânticos/química , Óxido de Zinco/química , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Liberação Controlada de Fármacos , Corantes Fluorescentes/química , Humanos , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Fototerapia/métodos , Porosidade , Propriedades de Superfície , Distribuição Tecidual , Óxido de Zinco/farmacocinética
3.
Zhonghua Nei Ke Za Zhi ; 59(1): 47-51, 2020 Jan 01.
Artigo em Chinês | MEDLINE | ID: mdl-31887836

RESUMO

Objective: To study the influences of dihydrotestosterone (DHT) on the development of experimental autoimmune Graves disease (EAGD), and to observe the effect of DHT on cytokines in male BALB/c mice model. Methods: Male BALB/c mice aged 6-8 weeks were divided into 4 groups using random number table: (1) control group; (2) EAGD group; (3) placebo group; (4) DHT group. EAGD mice were induced with an adenovirus expressing the human thyroid stimulating hormone receptor antibody A-subunit (Ad-TSHR289). DHT (5mg) or a matching placebo were implanted one week before the first immunization. Thyroid hormones were detected with radioimmunoassay kit.. Cytokines [such as interferonγ (IFNγ), interleukin (IL)-4, IL-10, IL-9, and IL-17] producing cells from the spleen were detected using flow cytometry. Results: As expected Ad-TSHR289 treatment increased total thyroxine [EAGD group vs. control group: (117.76±32.69) nmol/L vs. (33.08±12.61) nmol/L, P<0.0001] and free thyroxine [EAGD group vs. control group: (15.01±11.55) pmol/L vs. (3.55±1.88) pmol/L, P<0.0001]. Treatment of DHT slightly lowered thyroid hormones [DHT group vs. placebo group: total thyroxine (114.80±44.27) nmol/L vs. (123.17±77.73) nmol/L; free thyroxine (13.48±6.01) pmol/L vs. (14.19±12.65) pmol/L], without significant difference (all P>0.05)]. However, the percentage of IL-10, but not IFN γ, IL-4, IL-9 and IL-17, secreted spleen cells increased in DHT group than in the placebo group [(7.11±3.29)% vs. (3.51±1.36)%, P<0.05]. Conclusion: The effects of DHT on thyroid hormone are mild. It might play an immunomodulatory role in the male mouse Graves disease model by up-regulating the cytokine IL-10.


Assuntos
Citocinas/efeitos dos fármacos , Di-Hidrotestosterona/farmacologia , Doença de Graves , Animais , Humanos , Interferon gama , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória
4.
Chemosphere ; 238: 124581, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31445333

RESUMO

Lead (Pb) pollution is one of the most serious environmental problems and has attracted worldwide attention. Pb causes hematological, central nervous system, as well as renal toxicity, and so on. Although many investigations about Pb in blood to evaluate pollution status and toxic effects have been reported, there are open question about biological behavior of Pb. In order to reveal any toxicological mechanisms or influences, we focused on the local distribution of Pb in mice organs. Lead acetate (100 mg/L and 1000 mg/L) in drinking water were given to the BALB/c mice (male, seven weeks of age, N = 24) for three weeks. Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) analysis revealed a homogenous distribution of Pb in the liver and inhomogeneous distribution in the kidney and brain. The hippocampus, thalamus, and hypothalamus had higher concentrations than other areas such as the white matter. Surprisingly, in the kidney, Pb tended to accumulate in the medulla rather than the cortex, strongly suggesting that high sensitivity areas and high accumulation areas differ. Moreover, distribution of stromal interacting protein 1 (STIM1) which is candidate gene of Pb pathway to the cells was homogenous in the liver and kidney whereas inhomogeneous in the brain. In contrast to our hypothesis, interestingly, Pb exposure under the current condition did not induce mRNA expressions for any candidate channel or transporter genes. Thus, further study should be conducted to elucidate the local distribution of Pb and other toxic metals, and pathway that Pb takes to the cells.


Assuntos
Química Encefálica/efeitos dos fármacos , Rim/química , Chumbo/análise , Fígado/química , Molécula 1 de Interação Estromal/análise , Animais , Encéfalo/metabolismo , Imuno-Histoquímica/métodos , Terapia a Laser , Masculino , Espectrometria de Massas/métodos , Camundongos , Camundongos Endogâmicos BALB C , Análise Espectral
5.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(12): 1223-1228, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31874664

RESUMO

OBJECTIVE: To establish and evaluate an ovalbumin (OVA)-induced bronchial asthma model in mice with intrauterine growth retardation (IUGR), and to explore the molecular mechanism of relationship between IUGR and asthma. METHODS: A total of 16 pregnant BALB/c female mice were divided into a low-protein diet group (n=8) and a normal-protein diet group (n=8), which were fed with low-protein (8%) diet and normal-protein (20%) diet respectively. The neonatal mice were weighed 6 hours after birth. Sixteen male neonatal mice with IUGR were randomly chosen from the low-protein diet group and enrolled in the IUGR group, and 16 male neonatal mice from the normal-protein diet group were enrolled in the control group. Blood samples were collected from the mice in both groups for testing of blood glucose. Enzyme-linked immunosorbent assay (ELISA) was used to determine serum insulin level. The mice in the control group were randomized into a control + PBS group and a control + OVA group (n=8 each). The mice in the IUGR group were randomized into an IUGR + PBS group and an IUGR + OVA group (n=8 each). Six-week-old mice in the control + OVA and IUGR + OVA groups were subjected to intraperitoneal injection of 2 mg/mL OVA for sensitization and aerosol inhalation of 1% OVA for challenge. Mice in the control + PBS group and the IUGR + PBS group were treated with an equivalent amount of PBS. ELISA was used to determine serum IgE level in the mice in each group. Bronchoalveolar lavage fluid (BLF) was collected from the mice in each group for cell counting. The lung tissue of the mice in each group was stained with hematoxylin and eosin to observe pathological changes. RESULTS: The body weight at 6 hours after birth was significantly lower for neonatal mice in the low-protein diet group compared with those in the normal-protein diet group (P<0.01). The IUGR group had a significantly lower serum insulin level than the control group (P<0.01). The IUGR + PBS group had a significantly lower IgE level than the control + PBS group (P<0.01). Compared with the control + PBS and IUGR + PBS groups, the control + OVA and IUGR + OVA groups had a significantly increased IgE level, and the IgE level was significantly higher in the IUGR + OVA group than in the control + OVA group (P<0.01). Compared with the control + PBS and IUGR + PBS groups, the control + OVA and IUGR + OVA groups had significantly increased counts of leukocytes, eosinophils, lymphocytes, and macrophages in the BLF (P<0.01). The pulmonary alveoli of OVA-induced IUGR mice showed massive inflammatory cell infiltration and damage of intercellular continuity. Meanwhile, airway epithelial cell proliferation, bronchial wall thickening, bronchial lumen narrowing, and massive inflammatory cell infiltration around the bronchi and the vascular wall were observed. CONCLUSIONS: An OVA-induced bronchial asthma model has been successfully established in the mice with IUGR induced by low-protein diet, which provides a basis for further study of the molecular mechanism of relationship between IUGR and airway inflammation.


Assuntos
Asma , Retardo do Crescimento Fetal , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Feminino , Pulmão , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina
6.
Exp Parasitol ; 207: 107789, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31669169

RESUMO

American visceral leishmaniasis is caused by the protozoan Leishmania infantum. The control of the disease depends on the magnitude of the Th1 cell response and IL-10 producing regulatory T cells. Administration of chemokine, such as CXCL10, has shown promising results in the leishmaniasis treatment. Previous studies from our group have shown that CXCL10 induces a reduction in parasite burden in the spleen and a decrease in IL-10 and TGF-ß production in L. infantum-infected BALB/c mice. This work investigated whether CXCL10-treatment reduces IL-10 + Treg cell populations (CD4+CD25+Foxp3+ and Tr1) and induces morphological changes in the spleen. BALB/c mice were infected and treated or not with CXCL10 on the 1st, 3rd and 7th days of infection. CXCL10-treatment was able to reduce the parasite load in the spleen in L. infantum-infected BALB/c mice and this decrease in the number of parasites correlated with the decrease in size of this organ in treated animals compared to untreated animals. 7, 23, and 45 days post-treatment (p.t.), the phenotype and frequency of IL-10 + Treg cells were evaluated by flow cytometry, and the morphological changes of the spleen were analyzed by optical microscopy. After 7 and 23 days p.t., CXCL10-treated animals showed a significant reduction of CD25-Foxp3-IL-10+ (Tr1) cells in the spleen when compared to untreated animals, whereas CD4+CD25+Foxp3+IL-10+ Treg cells reduced later at 23rd and 45th days p.t. Furthermore, while untreated animals showed a significant positive correlation between IL-10 production and Tr1 cells, in CXCL10-treated group this correlation was negative. Thus, these findings show that treatment with CXCL10 chemokine in L. infantum-infected BALB/c mice results in suppression of IL10+ Treg (Foxp3+ and Tr1) cells in the spleen, associated with a reduction in parasite load and splenomegaly.


Assuntos
Quimiocina CXCL10/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/imunologia , Baço/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Adjuvantes Imunológicos/uso terapêutico , Animais , Quimiocina CXCL10/administração & dosagem , Quimiocina CXCL10/farmacologia , Cricetinae , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Humanos , Injeções Intraperitoneais , Leishmania infantum/efeitos dos fármacos , Leishmania infantum/imunologia , Leishmania infantum/patogenicidade , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/imunologia , Carga Parasitária , Baço/parasitologia , Baço/patologia , Linfócitos T Reguladores/imunologia , Virulência
7.
J Photochem Photobiol B ; 200: 111654, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31671373

RESUMO

The Enterococcus faecalis is a microorganism that causes multiple forms of resistance to a wide range of drugs used clinically. aPDT is a technique in which a visible light activates photosensitizer (PS), resulting in generation of reactive oxygen species that kill bacteria unselectively via an oxidative burst. aPDT is an alternative to antibiotics with the advantage of not causing resistance. The search for an alternative treatment of infections caused by E. faecalis, without using antibiotics, is off great clinical importance. The aim of present investigation was to assess the efficacy of using 3.32 ηg/mL of 1,9-dimethylmethylene blue (DMMB) as photosensitizer associated with the use of either Laser (λ660 nm) or LED (λ632 ±â€¯2 nm) using different energy densities (6, 12 and 18 J/cm2) to kill E. faecalis in vitro. Under different experimental conditions, 14 study groups, in triplicate, were used to compare the efficacy of the aPDT carried out with either the laser or LED lights using different energy densities associated to DMMB. The most probable number method (MPN) was used for quantitative analysis. Photodynamic antimicrobial effectiveness was directly proportional to the energy density used, reaching at 18 J/cm2, 99.999998% reduction of the counts of E. faecalis using both light sources. The results of this study showed that the use of 3.32 ηg/mL of DMMB associated with the use 18 J/cm2 of LED light (λ632 ±â€¯2 nm) reduced >7-log counts of planktonic culture of E. faecalis.


Assuntos
Enterococcus faecalis/efeitos dos fármacos , Luz , Azul de Metileno/análogos & derivados , Fármacos Fotossensibilizantes/farmacologia , Animais , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/veterinária , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Azul de Metileno/química , Azul de Metileno/farmacologia , Azul de Metileno/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico
8.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(4): 312-316, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31701713

RESUMO

OBJECTIVE: To investigate the effects and molecular mechanisms of 2-12alkyl-6-methoxycyclohexa-2,5-diene-1,4-dione(DMDD) on diffuse large B lymphoma (DLBCL). METHODS: In animal experiments, 4-week-aged BALB/C mice were divided into 5 groups, 20 mice in each group. Mice were inguinal injected with DLBCL cell line OCI-LY19 cells 0.1 ml at the concention of 1 × 107 /ml. Two days later, mice were treated with DMDD at the doses of 0, 1, 5, 25 and 125 mg/kg by intragastric administration respectively, once /2 days. Ten mice of each group were killed on the 18th day of administration, and the tumor tissues were weighed. The survival time of the remaining mice were recorded. In cell experiments, OCI-LY19 cells were added to 96-well culture plates, 100 µl 1×105 cells/ml per well, then 100 µl DMDD was added to the well and the final concentrations were 0, 1, 5, 25 and 125 µmol/L respectively. The cells were treated with DMDD for 0, 24, 48 and 72 h, three wells in each group. The cell proliferation activity was detected by MTS assay. According to the results of cell proliferation experiments, OCI-LY19 cells were treated with DMDD at the concentrations of 0 µmol/L, 5 µmol/L and 25 µmol/L for 24 h. The apoptosis rate was analyzed by flow cytometry, the nuclear type was observed by hoechst staining, the mitochondrial membrane potential was observed by JC-1 staining, cytotoxicity of drugs was evaluated by LDH release experiment, gene expression and transcription were analyzed by qPCR and Western blot. RESULTS: Compared with 0 mg/kg drug group, DMDD at the dose of 1~125 mg/kg could inhibit the growth of tumor tissue in mice and prolong their survival time (P<0.01). Cell experiments showed: in DMDD group, the proliferation activity of OCI-LY19 cells was decreased significantly and the level of apoptosis was increased significantly (P<0.01), nuclear fragmentation, agglutination, apoptotic bodies occurred and mitochondrial membrane potential was decreased, the LDH release rate was increased significantly (P<0.01), the expressions of caspase-3 and bax genes and the phosphorylation level of Ikappa B alpha in cells were up-regulated significantly, the protein expression levels of bcl-2, bcl-xL, jak2 and stat3 were inhibited significantly (P<0.01). CONCLUSION: DMDD can inhibit the expressions of JAK2, STAT3 and p-Ikappa B alpha in JAK2/STAT3 and NF-kappa B signal pathways, down-regulate BCL-2/BAX and activate Caspase-3, finally, activate the endogenous pathway of mitochondrial apoptosis in OCI-LY19 cells and promote the apoptosis of DLBCL cells, inhibit proliferation of OCI-LY19 cells. It has inhibitive effects on DLBCL.


Assuntos
Apoptose , Cicloexenos/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Endogâmicos BALB C
9.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(4): 351-354, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31701721

RESUMO

OBJECTIVE: To study the preventive and therapeutic effects of safflower water extract on systemic scleroderma (SSc) in mice and its mechanism. METHODS: Sixty BALB/C mice were randomly divided into the control group, model group, prednisone group and safflower low, middle, high dose groups, 10 mice in each group.The control group was injected with normal saline, and the other five groups were subcutaneously injected with bleomycin hydrochloride with 100 µl at the concentration of 200 µg /ml on the back, once a day for 28 days to establish the SSc models.At the same time, the control group and model group were treated with normal saline (10 ml/kg), the prednisone group was treated with prednisone 4.5 mg/kg (10 ml/kg), and the low, middle, and high dose safflower groups were treated with safflower at the doses of 1.5, 3, 6 g/kg (10 ml/kg), and all groups were treated for 28 days.After 28 days, all mice were decapitated. The blood samples and back skin of the BLM injection part were collected.After that, all the tissue slices were taken to measure the dermal thickness, and the content of hydroxyproline (HYP) in the skin tissues was detected by hydrolysis method.The contents of tissue growth factor (CTGF) and transforming growth factor-ß (TGF-ß ) in the skin tissues and the levels of interleukin-6 (IL-6) and interleukin-17 (IL-17) in serum were determined by ELISA. RESULTS: Compared with the control group, the dermal thickness of the model group was increased(P<0.05), the contents of CTGF, TGF-ß and HYP in the skin tissues and the levels of IL-6 and IL-17 in the serum of the model group were increased(P<0.05); compared with the model group, the dermal thickness in the prednisone group and safflower groups was decreased (P<0.05), the levels of CTGF, TGF-ß and HYP in the skin tissues and the serum levels of IL-6 and IL-17 in the prednisone group and safflower groups were decreased (P<0.05). CONCLUSION: Safflower water extract can improve skin condition (or dermal thickness) in SSc mice, and its mechanism may be related to reducing immune inflammatory response.


Assuntos
Carthamus tinctorius/química , Extratos Vegetais/farmacologia , Escleroderma Sistêmico/tratamento farmacológico , Animais , Bleomicina , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Modelos Animais de Doenças , Hidroxiprolina/análise , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Pele/patologia , Fator de Crescimento Transformador beta1/metabolismo
11.
Cancer Immunol Immunother ; 68(12): 2081-2094, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31720815

RESUMO

Histone deacetylase (HDAC) inhibitors impair tumor cell proliferation and alter gene expression. However, the impact of these changes on anti-tumor immunity is poorly understood. Here, we showed that the class I HDAC inhibitor, entinostat (ENT), promoted the expression of immune-modulatory molecules, including MHCII, costimulatory ligands, and chemokines on murine breast tumor cells in vitro and in vivo. ENT also impaired tumor growth in vivo-an effect that was dependent on both CD8+ T cells and IFNγ. Moreover, ENT promoted intratumoral T-cell clonal expansion and enhanced their functional activity. Importantly, ENT sensitized normally unresponsive tumors to the effects of PD1 blockade, predominantly through increases in T-cell proliferation. Our findings suggest that class I HDAC inhibitors impair tumor growth by enhancing the proliferative and functional capacity of CD8+ T cells and by sensitizing tumor cells to T-cell recognition.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Benzamidas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD8-Positivos/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Piridinas/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Imunidade Celular , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo
12.
Zhonghua Gan Zang Bing Za Zhi ; 27(10): 782-787, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31734993

RESUMO

Objective: To investigate the curative effect of local application of CpG-oligodeoxynucleotide (CpG-ODN) combined with 4-1BB monoclonal antibody in hepatoma-bearing mice, and to evaluate the effect of 4-1BB monoclonal antibody on CpG-ODN immunotherapy. Methods: H22 single cell suspension was injected subcutaneously into the axilla and four limbs of the BALB/c male mice to establish a tumor-bearing mice model. After 7 days, 30 mice with corresponding tumor-bearing volume were screened and randomly divided into model control group, CpG group and CpG+4-1BB group, and the drug was injected into the tumors of left lower extremity. The same batch of normal mice was selected as normal control group. Survival of mice was recorded. Tumor-bearing volume and organ index were calculated. Serum levels of interleukin (IL) - 12 and interferon (IFN) gamma and spleen CD8(+)T lymphocyte ratio were measured. The measurement data were analyzed by analysis of variance. The survival rate of each group of mice was analyzed by log-rank test. Results: Mice in the model control group with tumor-bearing volume had a sustained growth before the execution. CpG group and the CpG+4-1BB group [(976.08 ± 29.55) mm(3), (47.25 ± 0.93) mm(3))] tumor-bearing volume was decreased than model group [(1 336.52 ± 39.40) mm3] (F = 5 329.273, P < 0.05). CpG+4-1BB group distant tumor-bearing volume [(611.83 ± 113.02) mm3] was decreased than model group and CpG group [(1 406.62 ± 51.09) mm(3), (1 380.01 ± 51.44) mm3] (F = 247.160, P < 0.05), but there was no significant difference between the CpG group and the model group (P > 0.05). Serum IL-12 concentration (23.90 ± 2.33 pg/ml), IFN-γ concentration (103.02 ± 6.10 pg/ml) and spleen CD8(+)T cell ratio (4.54 ± 0.62%) in the model group were lower than those in the normal group (P < 0.05). Serum IL-12 concentration in CpG group and CpG+4-1BB group (29.21 ± 2.23 pg/ml, 37.04 ± 1.49 pg/ml), IFN-γ concentration (116.12 ± 4.08 pg/ml, 138.65 ± 1.72 pg/ml), CD8(+)T cell ratio (6.65 ± 0.64%, 12.73 ± 0.88%) were higher than the model group, while CpG+4-1BB group was higher than the CpG group (P < 0.05). The survival rate of CpG+4-1BB group was higher than that of model group and CpG group (χ(2) = 25.544, P < 0.05), but there was no significant difference between CpG group and model group (P > 0.05). There was no significant difference in organ index between the four groups (P > 0.05). Conclusion: 4-1BB monoclonal antibody combined with CpG-ODN therapy can shrink hepatoma-bearing capacity, inhibit the growth of distant tumors and significantly prolong the survival time of mice.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma Hepatocelular/terapia , Imunoterapia , Neoplasias Hepáticas/terapia , Oligodesoxirribonucleotídeos/uso terapêutico , Animais , Interferon gama/sangue , Interleucina-12/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória
13.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 31(5): 504-509, 2019 Oct 14.
Artigo em Chinês | MEDLINE | ID: mdl-31713379

RESUMO

OBJECTIVE: To investigate the protective effect of excretory-secretory protein (AES) from adult Trichinella spiralis on ovalbumin (OVA)-induced allergic rhinitis in mice. METHODS: Eighteen female BALB/c mice were randomly divided into three groups, including the blank control group (Group A), OVA-induced rhinitis group (Group B) and AES treatment group (Group C). Mice in Group A were given PBS. Mice in Group B were intraperitoneally injected with antigen adjuvant suspension for systemic sensitization, once every other day for seven times; then, local excitation was intranasally induced with 5% OVA solution once a day for seven times to establish a mouse model of allergic rhinitis. In addition to induction of allergic rhinitis, mice in Group C were given 25 µg AES at baseline sensitization and local excitation. Following the final challenge, mice were observed for 30 min in each group, and the behavioral score was evaluated. The serum levels of IFN-γ, IL-4, IL-5, IL-10 and TGF-ß were determined using an enzyme-linked immunosorbent assay in mice, and the pathological changes of mouse nasal mucosa were observed under a microscope. RESULTS: There was a significant difference in the mouse behavioral scores among the three groups (F = 110.12, P < 0.01). The mouse behavioral score was significantly higher in Group B than in Group A (7.17 ± 0.75 vs. 1.33 ± 0.52, P < 0.01), and more remarkable pathological damages of mouse nasal mucosa were seen in Group B than in Group A, while the mouse behavioral score was significantly decreased in Group C than in Group B (P < 0.01), and the pathological damages of mouse nasal mucosa remarkably alleviated in Group C relative to Group B. There was a significant difference in serum IFN-γ level among the three groups (F = 7.50, P < 0.01) and the serum IFN-γ level in Group B was significantly lower than in group A and C (both P < 0.05). There were significant differences in serum IL-4 (F = 470.81, P < 0.01) and IL-5 levels (F =68.20, P < 0.01) among the three groups, and significantly greater serum IL-4 and IL-5 levels were detected in Group B than in Group A (P < 0.01), while significantly lower serum IL-4 and IL-5 levels were detected in Group C than in Group B (P < 0.01). There were significant differences in serum IL-10 (F = 174.91, P < 0.01) and TGF-ß levels (F = 9.39, P < 0.01) among the three groups, and significantly greater serum IL-10 and TGF-ß levels were seen in Group C than in Group B (both P < 0.05). CONCLUSIONS: T. spiralis AES has a remarkable protective activity against OVA-induced allergic rhinitis in mice.


Assuntos
Antígenos de Helmintos , Proteínas de Helminto , Rinite Alérgica , Trichinella spiralis , Animais , Antígenos de Helmintos/imunologia , Antígenos de Helmintos/farmacologia , Modelos Animais de Doenças , Feminino , Proteínas de Helminto/imunologia , Proteínas de Helminto/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/efeitos dos fármacos , Ovalbumina , Rinite Alérgica/induzido quimicamente , Rinite Alérgica/imunologia , Rinite Alérgica/prevenção & controle
14.
Anticancer Res ; 39(11): 5919-5925, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704816

RESUMO

BACKGROUND/AIM: The aim of the current study was to investigate the synergistic efficacy of Robo1 bichimeric antigen receptor-natural killer cell (BiCAR-NK) immunotherapy and 125I seed brachytherapy in an orthotopic pancreatic cancer mouse model. MATERIALS AND METHODS: The orthotopic pancreatic tumor model was established with human pancreatic cancer BxPC-3 cells expressing red fluorescent protein. The mice were treated with 125I seed implantation alone or the combination of 125I seeds with Robo1-specific CAR-NK cells. To assess tumor inhibition, in vivo fluorescence imaging was conducted. 7 Tesla magnetic resonance (7T-MR) scanning was applied to measure the changes in the metabolic profiles of tumor tissues. RESULTS: Tumor size was significantly reduced in the 125I and 125I +CAR-NK treated group compared to the untreated group (p<0.05). The 125I seed +CAR-NK treated group showed significantly higher tumor reduction than 125I seed treatment alone (p<0.05). T1 diffusion weighted imaging (T1DWI) sequence showed that the tumors of the 125I +BiCAR-NK treated group had a significantly higher grey scale value than the tumors from the untreated control and the group treated with 125I seed alone (p<0.05). CONCLUSION: Robo1 specific CAR-NK immunotherapy enhances efficacy of 125I seed brachytherapy in an orthotopic pancreatic cancer mouse model.


Assuntos
Braquiterapia/métodos , Imunoterapia , Radioisótopos do Iodo/uso terapêutico , Células Matadoras Naturais/imunologia , Proteínas do Tecido Nervoso/imunologia , Neoplasias Pancreáticas/terapia , Receptores de Antígenos/imunologia , Receptores Imunológicos/imunologia , Animais , Apoptose , Proliferação de Células , Citotoxicidade Imunológica/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Anticancer Res ; 39(11): 5933-5942, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704818

RESUMO

BACKGROUND/AIM: Perineural invasion (PNI) is a significant pathological feature in head and neck cancer. The molecular mechanisms of PNI are poorly understood. Contrary to the previous belief that cancer cells invade nerves, recent studies have shown that Schwann cells (SC) can dedifferentiate, intercalate between cancer cells, and promote cancer dispersion. Communication between cells through brain-derived neurotrophic factor (BDNF) activation of its receptor tropomyosin receptor kinase B (TRKB) may contribute to these cellular events. We aimed to determine the effect of TRKB inhibitor ANA-12 on the direction of cell migration and degree of SC-induced oral cancer cell dispersion. MATERIALS AND METHODS: Cell migration and dispersion assays were performed in vitro using murine SC and oral carcinoma cell lines. Assays were performed with and without ANA-12. RESULTS: Although SCs preferentially migrated towards cancer cells in control medium, there was minimal SC-associated cancer cell dispersion. In contrast, treatment with ANA-12 reduced migration of SCs and cancer cells towards each other and initiated more SC-associated cancer cell dispersion. CONCLUSION: This pilot study shows that BDNF-TRKB signaling may have a role in regulating interactions between SC and oral cancer cells that affect cell migration, intercalation, and cancer cell dispersion. Further research into these interactions may provide important clues about the molecular and cellular mechanisms of PNI.


Assuntos
Azepinas/farmacologia , Benzamidas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Carcinoma de Células Escamosas/patologia , Glicoproteínas de Membrana/antagonistas & inibidores , Neoplasias Bucais/patologia , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Receptor trkB/antagonistas & inibidores , Células de Schwann/patologia , Animais , Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Movimento Celular , Proliferação de Células , Técnicas de Cocultura , Humanos , Técnicas In Vitro , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Projetos Piloto , Receptor trkB/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células Tumorais Cultivadas
16.
Anticancer Res ; 39(11): 5963-5971, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704821

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate matrix metalloproteinase 11 (MMP11) as a promising biomarker in human pancreatic cancer. MATERIALS AND METHODS: A consecutive eliminating method was used to select biomarker candidates in pancreatic cancer. mRNA and protein expression levels of candidates were determined in tissues and whole blood samples of healthy donors and pancreatic cancer patients. The prognostic value of MMP11 was determined using various data-sets and Liptak's Z analysis. RESULTS: Analysis using Gene Expression Omnibus (GEO) database showed significantly higher MMP11 mRNA expression in pancreatic cancer tissues compared to that in various normal tissues. MMP11 protein was specifically expressed in pancreatic cancer tissues, but not in various normal or other cancer tissues. Secreted MMP11 levels could be measured using easily accessible techniques and whole blood samples of pancreatic cancer. In addition, high levels of MMP11 were associated with poor prognosis of pancreatic cancer patients. CONCLUSION: MMP11 may be a promising prognostic biomarker for pancreatic cancer patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Metaloproteinase 11 da Matriz/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Proliferação de Células , Seguimentos , Humanos , Metaloproteinase 11 da Matriz/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/enzimologia , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Anticancer Res ; 39(11): 5973-5982, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704822

RESUMO

BACKGROUND/AIM: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. MATERIALS AND METHODS: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 µM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. RESULTS: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. CONCLUSION: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Compostos de Fenilureia/farmacologia , Quinolinas/farmacologia , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Feminino , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Anticancer Res ; 39(11): 5983-5990, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704823

RESUMO

BACKGROUND/AIM: DJ-1, an oncogenic molecule, helps to maintain somatic stem cells by reducing the intracellular level of reactive oxygen species (ROS). This study investigated the role of DJ-1 in glioma stem cells (GSCs). MATERIALS AND METHODS: U87-MG (U87) and U251-MG (U251) glioblastoma cell lines that express wild-type and mutant p53, respectively, were used. These were cultured with DJ-1-targeting siRNA and subjected to a variety of in vitro experiments or intracranial transplantation into nude mice. RESULTS: Knockdown of DJ-1 reduced clonogenicity only in U87 cells, which was rescued by p53 depletion. ROS accumulated in DJ-1-depleted cells, although treatment with N-acetyl cysteine, which quenches ROS, did not affect exhaustion of CSCs among U87 cells by DJ-1 knockdown. In a serial transplantation study, DJ-1 knockdown prolonged the survival of mice in secondary transplantation. CONCLUSION: DJ-1 plays a pivotal role in maintenance of stem cell self-renewal in the U87 cell line.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Autorrenovação Celular , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Proteína Desglicase DJ-1/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Proteína Desglicase DJ-1/antagonistas & inibidores , Proteína Desglicase DJ-1/genética , RNA Interferente Pequeno/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Anticancer Res ; 39(11): 5991-5998, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704824

RESUMO

BACKGROUND/AIM: This study aimed to discuss the effect and possible molecular mechanisms of Aurora-A/NF-ĸB signaling on the radiotherapy resistance of human docetaxel-resistant lung adenocarcinoma cells. MATERIALS AND METHODS: The human lung adenocarcinoma SPC-A1 and SPC-A1/DTX cell lines were utilized in the present study. The MTT assay measured the sensitivity of cells to radiotherapy. The tumor-initiating ability of the cells was detected in vitro by cloning assays. Apoptosis was quantified by flow cytometry. Real-time quantitative PCR and western blotting were used to detect the mRNA and protein expression of the Aurora-A/NF-ĸB, respectively. Tumors transplanted subcutaneously into nude mice were used to test the effect of Aurora-A on the in vivo sensitivity of the tumors to radiotherapy. RESULTS: The SPC-A1/DTX docetaxel-resistant lung adenocarcinoma cells were radio-resistant compared with the parental SPC-A1 cells. Up-regulated aurora-A was responsible for the in vitro radio-resistance of docetaxel-resistant SPC-A1/DTX cells. Nuclear transcription factor NF-ĸB was identified as a downstream target gene of Aurora-A in SPC-A1/DTX cells, and NF-ĸB also participated in the radio-resistance of SPC-A1/DTX cells regulated by Aurora-A. CONCLUSION: The Aurora-A/NF-ĸB pathway is association with radio-resistance of human lung adenocarcinoma docetaxel-resistant cells.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Aurora Quinase A/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias Pulmonares/metabolismo , NF-kappa B/metabolismo , Tolerância a Radiação , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/radioterapia , Animais , Antineoplásicos/farmacologia , Apoptose , Aurora Quinase A/genética , Proliferação de Células , Docetaxel/farmacologia , Resistência a Múltiplos Medicamentos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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