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1.
Emerg Microbes Infect ; 9(1): 664-675, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32193996

RESUMEN

The H7N9 viruses have been circulating for six years. The insertion of a polybasic cleavage site in the haemagglutinin (HA) protein of H7N9 has resulted in the emergence of a highly pathogenic (HP) avian influenza virus. Currently, there are limited studies on neutralizing monoclonal antibodies(mAbs) against HP H7N9 AIVs. In this study, mice were immunized with inactivated H7N9 vaccine of A/ZJU01/PR8/2013 to produce murine mAbs. Finally, two murine mAbs against the HA of low pathogenic (LP) virus were produced and characterized. Characterization included determining mAbs binding breadth and affinity, in vitro neutralization capacity, and potential in vivo protection. Two of these mAbs, 1H10 and 2D1, have been identified to have therapeutic and prophylactic efficacy against the HP strain in mouse passive transfer-viral challenge experiments. The mAb 1H10 was most efficacious, even if the treatment-time was as late as 72 h post-infection, or the therapeutic dose was as low as 1 mg/kg; and it was confirmed to have haemagglutination inhibition and neutralizing activity on both LP-and HP-H7N9 strains. Further study indicated that the protection provided by 2D1 was mediated by antibody-dependent cellular cytotoxicity. The mAbs described here provide promising results and merit further development into potential antiviral therapeutics for H7N9 infection.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Subtipo H7N9 del Virus de la Influenza A/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/terapia , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Antivirales/administración & dosificación , Citotoxicidad Celular Dependiente de Anticuerpos , Línea Celular , Mapeo Epitopo , Femenino , Pruebas de Hemaglutinación , Glicoproteínas Hemaglutininas del Virus de la Influenza , Inmunización Pasiva , Subtipo H7N9 del Virus de la Influenza A/metabolismo , Subtipo H7N9 del Virus de la Influenza A/patogenicidad , Ratones , Ratones Endogámicos BALB C , Mutación , Pruebas de Neutralización , Filogenia
2.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(2): 219-224, 2020 Mar.
Artículo en Chino | MEDLINE | ID: mdl-32220191

RESUMEN

Objective: This study was designed to investigate the effects of low concentration hydrogen inhalation on asthma and sleep function in mice and the potential mechanism. Methods: In the asthma experiment, BALB/c mice were randomly divided into normal control group, asthma model group and hydrogen treatment group. After establishing ovalbumin (OVA)-induced asthma model, the hydrogen treatment group mice were treated by inhalation of hydrogen (24-26 mL/L per day) for 7 consecutive days, and the normal control group and asthma model group mice received similar treatment by inhalation of air. The levels of interleukin (IL)-4, IL-13, and interferon-γ (IFN-γ) in bronchoalveolar lavage fluid (BALF) were measured by commercially available ELISA kits. The levels of malondialdehyde (MDA) and glutathione (GSH), as well as the activity of superoxide dismutase (SOD) in lung tissue were detected by colorimetric assays. The pathological changes in lung tissue were assessed by HE staining. In the sleep experiment, ICR mice were randomly divided into blank control group and 1 d, 3 d, 5 d hydrogen treatment groups and diazepam group. The effects of inhalation of 24-26 mL/L per day hydrogen on the sleep duration induced by intraperitoneal injection of upper-threshold dose of sodium pentobarbital and the sleep latency in response to subthreshold dose were evaluated. Results: In the asthma experiment, the asthma model group showed higher levels of IL-4 and IL-13 ( P<0.05) and lower levels of IFN-γ ( P<0.001) in BALF, as compared to the normal control group. The content of MDA in lung tissue was also significantly increased ( P<0.01), companied by a decreased GSH concentration ( P <0.05) and a mildly reduced SOD activity ( P>0.05). Compared to the asthma model group, treatment with hydrogen significantly decreased the levels of IL-4 and IL-13 and increased the level of IFN-γ in BALF ( P<0.05). Moreover, without alteration of the MDA production ( P>0.05), hydrogen inhalation greatly increased GSH level and restored the SOD activity ( P<0.05) in lung tissue. Additionally, the HE staining data showed that the hydrogen treatment attenuated the pulmonary histopathological changes. In the sleep experiment, compared with the blank control group, the sleep latency was significantly shorter ( P<0.05) and the sleep duration was longer ( P<0.001) in all the hydrogen treatment groups after receiving an upper-threshold dose of sodium pentobarbital. Meanwhile, in all the hydrogen treatment groups, the sleep latency was significantly longer ( P<0.001) and the sleep duration was shorter ( P<0.001) when compared to the diazepam group. Compared with the blank control group, after intraperitoneal injection of a subthreshold dose of sodium pentobarbital, the sleep latency was significantly increased in both 1 d and 5 d hydrogen treatment groups, and there was no significant difference as compared to the diazepam group. In the 3 d hydrogen treatment group, the sleep latency was only slightly increased ( P>0.05), which was significantly lower than that of the diazepam group ( P<0.05). Conclusion: Low concentration hydrogen inhalation could alleviate OVA-induced asthma in mice, and the mechanism might be related to the anti-oxidative and anti-inflammatory effects of hydrogen. Also, low concentration hydrogen inhalation could improve sleep function in mice.


Asunto(s)
Asma , Hidrógeno , Sueño , Administración por Inhalación , Animales , Asma/terapia , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Hidrógeno/administración & dosificación , Hidrógeno/farmacología , Pulmón , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ovalbúmina , Sueño/efectos de los fármacos
3.
Pharm Res ; 37(4): 72, 2020 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-32215748

RESUMEN

PURPOSE: Combination of PCI and chemotherapy represents a promising strategy for combating drug resistance of cancer. However, poor solubility of photosensitizers and unselectively released drugs at unwanted sites significantly impaired the treatment efficacy. Therefore, in the present study, we aimed to develop a nano-platform which could efficiently co-entrapping photosensitizers and chemotherapeutics for active targeting therapy of drug resistant cancers. METHODS: Two pro-drugs were respectively developed by covalently linking the Ce6 with each other via the GSH-sensitive linkage and the PTX with mPEG-PLA-COOH through the ROS sensitive-linker. The dual-responsive nanoparticles (PNP-Ce6) was developed by emulsion/solvent evaporation method and further modified with tLyp-1 peptides. Physicochemical properties of nanoparticles were determined by the TEM and DLC. Cellular uptake assay was investigated with the Ce6 acting as the fluorescent probe and cell growth was studied by the MTT experiment. In vivo tumor targeting and anti-tumor assay was investigated on the colorectal cancer-bearing mice. RESULTS: The developed tPNP-Ce6 were stable enough under the normal physiological conditions. However, free Ce6 and PTX were completely released when exposed the tPNP-Ce6 to the redox environment. Excellent tumor-targeting drug delivery was achieved by the tPNP-Ce6, which in turn resulted in satisfactory anit-tumor effect. Of great importance, super inhibition effect on tumor progress was achieved by the combination therapy when compared with the group only received with chemotherapy.. CONCLUSION: The results obtained in the present study indicated that the developed tPNP-Ce6 may have great potential in enhancing the therapeutic efficacy of drug-resistant colorectal cancer. Graphical Abstract Left: Targeting delivery of drug to tumor site by the tumor recognizable and dual-responsive nanoparticles and penetrating into tumor inner via the mediation of irradiation. Right: Nanoparticle distribution within tumor tissues with green represents the blood vessels stained with CD31, blue signal represents the cell nuclei stained with DAPI and red shows fluorescence of Ce6 as the indicator of the nanoparticles.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos , Nanopartículas , Fotoquimioterapia , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Fármacos Fotosensibilizantes/administración & dosificación , Profármacos , Ensayos Antitumor por Modelo de Xenoinjerto
4.
J Cancer Res Clin Oncol ; 146(4): 861-874, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32088783

RESUMEN

PURPOSE: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and ranked top in terms of incidence and mortality in men and women. Recently, improvements in treatment approaches for NSCLC have reported, but still, there is a need to devise innovative treatment strategies, especially to manage the advanced and metastatic stage of NSCLC. Aloperine (ALO), an herbal alkaloid, has exerted anti-cancer effects in many cancers. However, the use of any chemotherapeutic agents is dose limited due to possible adverse effects and drug-resistance issues. Therefore, a combination of chemotherapy with viral-based targeted gene therapy may provide a novel treatment strategy for NSCLC. METHODS/RESULTS: In this study, the results of the MTT and flow cytometry-based assays showed that Aloperine-Adbic (adenoviral vector expressing p14ARF/p53) combined treatment on NSCLC cells synergistically produced anti-proliferative effects, induced apoptosis, and arrested cell cycle at the G1 phase. Furthermore, the expression analysis suggested that the p53/p21 pathway might contribute to achieving aforesaid cytotoxic effects. The ALO-Adbic combined treatment prolonged the percent survival of NSCLC xenograft models. CONCLUSION: In conclusion, ALO-Adbic combination can produce synergistic anti-cancer effects at low doses, and may offer a more effective and less toxic new treatment strategy for NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/terapia , Terapia Genética/métodos , Neoplasias Pulmonares/terapia , Piperidinas/farmacología , Adenoviridae/genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Terapia Combinada , Vectores Genéticos/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Distribución Aleatoria , Proteína p14ARF Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/genética , Ensayos Antitumor por Modelo de Xenoinjerto
5.
J Cancer Res Clin Oncol ; 146(4): 875-882, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32107624

RESUMEN

PURPOSE: Presently, liver cancer is still one of the malignant tumors with high mortality. As far as the treatment of liver cancer is concerned, the most effective method is still liver transplantation. But every year, many liver cancer patients die from the lack of a proper liver transplant, or from waiting for a liver transplant. Therefore, it is very important to find new and effective treatment for patients with liver cancer. METHODS: Herein, the cell model and the orthotropic liver tumor mice model have been performed to verify the results of our treatment. We found that the in situ synthesized gold nanocluster-PTEN (GNC-PTEN) complexes can effectively target and realize the fluorescence imaging of the liver tumor. RESULTS: GNC-PTEN complexes could inhibit the proliferation, invasion, and metastasis of liver cancer cells. And the results also showed that GNC-PTEN complexes could be well targeted liver tumor at 6 h and the liver tumor in mice group treated with GNC-PTEN complexes almost disappeared. CONCLUSION: This is a simply and effectively method to realize liver cancer imaging and inhibition. This may raise the possibility for the accurate image/diagnosis and simultaneously efficient treatment of liver cancer in the relevant clinic application.


Asunto(s)
Oro/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas del Metal/administración & dosificación , Fosfohidrolasa PTEN/administración & dosificación , Animales , Oro/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/genética , Nanopartículas del Metal/química , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosfohidrolasa PTEN/química , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Distribución Aleatoria , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Arch Virol ; 165(3): 593-607, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32016547

RESUMEN

The eradication of hepatitis C virus (HCV) infection is a public health priority. Despite the efficiency of treatment with direct-acting antivirals, the high cost of the therapy and the lack of accurate data about the HCV-infected population worldwide constitute important factors hampering this task. Hence, an affordable preventive vaccine is still necessary for reducing transmission and the future disease burden globally. In this work, chimeric proteins (EnvCNS3 and NS3EnvCo) encompassing conserved and immunogenic epitopes from the HCV core, E1, E2 and NS3 proteins were produced in Escherichia coli, and their immunogenicity was evaluated in BALB/c mice. The impact of recombinant HCV E2.680 protein and oligodeoxynucleotide 39M (ODN39M) on the immune response to chimeric proteins was also assessed. Immunization with chimeric proteins mixed with E2.680 enhanced the antibody and cellular response against HCV antigens and chimeric proteins. Interestingly, the combination of NS3EnvCo with E2.680 and ODN39M as adjuvant elicited a potent antibody response characterized by an increase in antibodies of the IgG2a subclass against E2.680, NS3 and chimeric proteins, suggesting the induction of a Th1-type response. Moreover, a cytotoxic T lymphocyte response and a broad response of IFN-γ-secreting cells against HCV antigens were induced with this formulation as well. This T cell response was able to protect vaccinated mice against challenge with a surrogate model based on HCV recombinant vaccinia virus. Overall, the vaccine candidate NS3EnvCo/E2.680/ODN39M might constitute an effective immunogen against HCV with potential for reducing the likelihood of viral persistence.


Asunto(s)
Hepacivirus/inmunología , Anticuerpos contra la Hepatitis C/sangre , Proteínas Recombinantes/inmunología , Secuencia de Aminoácidos , Animales , Linfocitos T CD4-Positivos , Clonación Molecular , Epítopos , Femenino , Regulación de la Expresión Génica/inmunología , Antígenos de la Hepatitis C/inmunología , Inmunidad Celular , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Ratones , Ratones Endogámicos BALB C , Plásmidos
7.
Exp Parasitol ; 210: 107847, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32004535

RESUMEN

Leishmaniasis is an infectious disease that has high endemicity and is among the six parasitic diseases of higher occurrence in the world. The current treatments are limited due to their toxicity, treatment resistance and high cost which have increased the search for new substances of natural origin for its therapy. Based on this, an in vitro biological and chemical investigation was carried out to evaluate the potential of Piper marginatum against Leishmania amazonesis. P. marginatum leaves were collected to obtain the essential oil (EO) and the ethanolic extract (CE). The chemical profile of the CE and fractions was obtained by 1H NMR. The analysis of the EO chemical composition was performed by GC-MS. EO, CE and fractions were submitted to antileishmanial and cytotoxicity assays against macrophages. The chromatographic profiles of EO, CE and fractions showed the presence of phenolic compounds and terpenoids, having 3,4-Methylenedioxypropiophenone as a major compound. All P. marginatum samples showed low toxicity to macrophages. The CE and the methanolic, hexane and ethyl acetate fractions had low cytotoxicity when compared to Pentamidine. All tested samples inhibited growth of L. amazonensis promastigotes. The antileishmanial activity of EO, CE and fractions were evaluated in macrophages infected with L. (L.) amazonensis and treated with the concentrations 1, 10 and 100 µg/mL for 48 h. All samples were active, but EO and CE showed superior activity against amastigote forms when compared to the promastigote forms of L. amazonensis. This work describes for the first time the antileishmanial activity of the species P. marginatum and its cytotoxicity against macrophages, suggesting that it can be an alternative source of natural products in the phytotherapeutic treatment of leishmaniasis.


Asunto(s)
Leishmania mexicana/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Aceites Volátiles/farmacología , Piper/química , Extractos Vegetales/farmacología , Animales , Brasil/epidemiología , Enfermedades Endémicas , Cromatografía de Gases y Espectrometría de Masas , Concentración 50 Inhibidora , Leishmaniasis Cutánea/epidemiología , Leishmaniasis Cutánea/parasitología , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Espectroscopía de Resonancia Magnética , Ratones , Ratones Endogámicos BALB C , Enfermedades Desatendidas/tratamiento farmacológico , Enfermedades Desatendidas/epidemiología , Enfermedades Desatendidas/parasitología , Aceites Volátiles/química , Aceites Volátiles/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta/química , Aceites Vegetales/química , Aceites Vegetales/aislamiento & purificación , Aceites Vegetales/farmacología
8.
Gene ; 735: 144402, 2020 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-32004669

RESUMEN

Colon cancer is one of the most common malignancies in the world; there is no effective therapeutic treatment after surgery. Our previous studies indicate that RNA helicase DHX33 plays a critical role in cell proliferation and cell growth. Here in this study, DHX33 is found to be highly expressed in colon cancer tissues and colon cancer cell lines. Knockdown of DHX33 significantly decreased cell proliferation and triggered apoptosis. Mechanistically, DHX33 was found to transcriptionally control multiple critical genes involved in cell cycle, apoptosis and migration. DHX33 deficiency caused decreased tumor growth for colon cancer cells in a xenograft model in vivo. With Wnt/ß-cateninactivator and inhibitors, we further discovered that Wnt/ß-catenin pathway regulates DHX33 transcriptionally. This study for the first time demonstratesthe important role of DHX33 in colon cancer development and reveals the underlying molecular mechanism. We also provide the initial evidence for the relationship between DHX33 and Wnt/ß-catenin signaling pathway in colon cancer development.


Asunto(s)
Carcinoma/genética , Neoplasias del Colon/genética , ARN Helicasas DEAD-box/genética , Vía de Señalización Wnt , Animales , Apoptosis , Carcinoma/metabolismo , Carcinoma/patología , Proliferación Celular , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , ARN Helicasas DEAD-box/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos
9.
J Photochem Photobiol B ; 204: 111808, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32006892

RESUMEN

Photodynamic therapy (PDT) is effective in the treatment of different types of cancer, such as basal cell carcinoma and other superficial cancers. However, improvements in photosensitizer delivery are still needed, and the use of PDT against more deeply located tumors has been the subject of many studies. Thus, the goal of this study was to evaluate the efficacy of a nanoemulsion containing aluminium-phthalocyanine (AlPc-NE) as a mediator of photodynamic therapy (PDT-AlPc-NE) against grafted 4T1 breast adenocarcinoma tumors in mice (BALB/c). Short after the appearance of the tumor, the animals were divided into groups (n = 5) as follows: untreated; only AlPc-NE and treated with PDT-AlPc-NE. The tumor volume was measured with a digital calliper at specific times. The presence of metastasis in the lungs was evaluated by microtomography and histopathological analyses. The results show that the application of PDT-AlPc-NE eradicated the transplanted tumors in all the treated animals, while the animals from control groups presented a robust increase in the tumor volume. Still more significantly, microtomography showed the animals submitted the PDT-AlPc-NE to be free of detectable metastasis in the lungs. The histological analysis of the lungs further confirmed the results verified by the microtomography. Therefore, this study suggests that PDT-AlPc-NE is effective in the elimination of experimentally grafted breast tumors in mice and also in preventing the formation of metastasis in the lungs.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Aluminio/química , Neoplasias de la Mama/tratamiento farmacológico , Indoles/química , Neoplasias Pulmonares/tratamiento farmacológico , Nanoestructuras/química , Fármacos Fotosensibilizantes/uso terapéutico , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Nanoestructuras/uso terapéutico , Nanoestructuras/toxicidad , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Trasplante Homólogo , Microtomografía por Rayos X
10.
Artículo en Chino | MEDLINE | ID: mdl-32074755

RESUMEN

Objective: To observe the effect of olfactory training on mice with olfactory dysfunction induced by 3-methylindole (3-MI). Methods: Thirty-one male BALB/c mice were randomly divided into 3 groups by random digits table: control group (group A, n=10), olfactory dysfunction group (group B, n=10) and olfactory dysfunction+olfactory training group (group C, n=11). Mice in group B and group C were intraperitoneally injected with 150 mg/kg 3-MI to induce olfactory dysfunction model, while mice in group A were intraperitoneally injected with corn oil of the same volume. From the first day after injection, mice in group C were treated with 4 kinds of odors by inhalation, while mice in group B were treated with distilled water by inhalation, with 2 times/d, 30 min/time/kind of odor, and continuous training for 28 d. Group A was not treated. Buried food pellet tests were conducted before injection and at 7, 14, 21 and 28 days after injection, respectively. The olfactory epithelium was harvested for observation of the number of olfactory marker protein (OMP) and the thickness of olfactory epithelium on the 28th day after injection. SPSS 23.0 software was used for statistical analysis. Results: Before injection, all mice in each group had no olfactory dysfunction. At the 7th, 14th, 21st and 28th days after injection, the food finding time of mice in group C was shorter than that in group B, and the difference was statistically significant ((175.88±100.50) s vs (266.73±46.83) s, (132.00±84.62) s vs (264.10±48.50) s, (103.57±77.43) s vs (197.43±69.78) s, (67.79±32.54) s vs (176.63±61.06) s, all P<0.05), but food finding time of mice in group B and C was longer than that in group A (the food finding time of group A at the 7th, 14th, 21st and 28th days after injection was (27.13±5.36) s, (25.83±7.28) s, (23.13±2.72) s, (26.63±7.60) s, respectively, all P<0.05). At the 28th day after olfactory training, the number of OMP positive cells in group B and C were fewer than that in group A, and the difference was statistically significant ((108.00±28.19)/HP vs (288.22±84.06)/HP, (199.33±58.55)/HP vs (288.22±84.06)/HP, all P<0.05). The number of OMP positive cells in group C were higher than that in group B (P<0.05). The number of OMP positive cells had negative correlation with food finding time (r=-0.886, P<0.01). As for the thickness of the olfactory epithelium, the thickness of group B was thinner than that in group A and C, and the difference was statistically significant ((59.57±31.27) µm vs (114.55±40.70)µm vs (90.54±37.72) µm, all P<0.05). Conclusion: Olfactory training can accelerate the recovery of olfactory function in 3-MI-induced olfactory impaired mice.


Asunto(s)
Trastornos del Olfato/terapia , Mucosa Olfatoria/fisiopatología , Animales , Masculino , Ratones , Ratones Endogámicos BALB C , Trastornos del Olfato/inducido químicamente , Distribución Aleatoria , Olfato
11.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(2): 171-176, 2020 Feb.
Artículo en Chino | MEDLINE | ID: mdl-32051086

RESUMEN

OBJECTIVE: To study the role and mechanism of action of Huai Qi Huang (HQH) in the rat model of asthma. METHODS: Forty Sprague-Dawley rats were randomly divided into a control group, an asthma model group, a budesonide group, and an HQH group, with 10 rats in each group. A rat model of asthma was established by ovalbumin sensitization and challenge. The budesonide group was given budesonide aerosol 2 mg before each challenge. The HQH group was given HQH 4 g/kg dissolved in water by gavage before each challenge. Hematoxylin and eosin staining was used to observe the pathological changes of lung tissues. The percentage of eosinophils in bronchoalveolar lavage fluid (BALF) was measured. Enzyme-linked immunosorbent assay was used to determine the levels of interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-10 (IL-10), interferon gamma (INF-γ), and immunoglobulin E (IgE) in BALF. Flow cytometry was used to determine T-helper type 1 (Th1)/T-helper type 2 (Th2) ratio in peripheral blood and the spleen. RT-PCR and Western blot were used to measure the mRNA and protein expression of T-bet and GATA-3 in lung tissue. RESULTS: Compared with the control group, the asthma model group showed significant increases in the degree of airway inflammation, the percentage of eosinophils in BALF, and the levels of IL-3, IL-4, IL-5 and IgE in BALF (P<0.05), however, the asthma model group showed significant reductions in the levels of IL-10 and INF-γ in BALF (P<0.05). The asthma model group had significantly lower percentage of Th1 cells but significantly higher percentage of Th2 cells in peripheral blood and the spleen compared with the control group (P<0.05). The mRNA and protein expression of T-bet in lung tissue was significantly lower, but the mRNA and protein expression of GATA-3 in lung tissue was significantly higher in the asthma group than those in the control group (P<0.05). Both HQH and budesonide significantly improved airway inflammation and the above markers in asthmatic rats (P<0.05), with comparable effects between them. However, there were still significant differences in these indices between the control group and the HQH or budesonide group (P<0.05). CONCLUSIONS: HQH can reduce the airway inflammation of asthmatic rats and alleviate the symptoms of asthma, possibly by regulating the levels of related cytokines and Th1/Th2 ratio through the T-bet/GATA-3 pathway.


Asunto(s)
Asma , Animales , Líquido del Lavado Bronquioalveolar , Medicamentos Herbarios Chinos , Pulmón , Ratones Endogámicos BALB C , Ratas , Ratas Sprague-Dawley , Células Th2
12.
Zhonghua Bing Li Xue Za Zhi ; 49(2): 162-167, 2020 Feb 08.
Artículo en Chino | MEDLINE | ID: mdl-32074730

RESUMEN

Objective: To establish patient derived xenograft (PDX) model of malignant peritoneal mesothelioma (MPM), and to identify the key characteristics of tumor biology of the model, so as to provide an experiment platform for studying the pathologic mechanisms and new therapeutic strategies for MPM. Methods: Surgically excised MPM tumor tissues were inoculated subcutaneously in BALB/c-nu/nu mice for 3 stable passages. In the 4th passage, the subcutaneous tumors were harvested under aseptic conditions, cleaned and made into MPM tumor cell homogenate. Four nude mice (two males and two females) were selected and one male and one female nude mouse were inoculated in the abdominal cavity at the dose of 100 µL, others were inoculated at a dose of 200 µL. The PDX model of MPM was established. The changes of body mass in nude mice were measured regularly, the extent of abdominal and pelvic tumors was judged by experimental peritoneal cancer index (ePCI) score, and the pathologic characteristics of tumors were analyzed. Results: The subcutaneous and abdominal animal models of MPM were successfully established. The subcutaneous tumor model grew into tumor on the 20th day, followed by a slow growth stage between the 20th and 29th day, then a rapid growth stage between the 30th and 57th day. According to the dose of tumor cells (100, 200 µL) and timing (14th and 69th days after grafting), the abdominal tumor model successfully simulated the early and late clinical stages of MPM. The HE staining results of the MPM nude mice model showed that the tumor was epithelial mesothelioma and invaded most of the organs, including liver, spleen, pancreas, mesentery. Immunohistochemical staining for calretinin, cytokeratin 5/6, WT1 and Ki-67 were positive. Whole-genome exon sequencing identified 26 and 36 high frequency gene mutations in tumors derived from the PDX model and clinical sample from patients, including 21 common gene mutations. Conclusions: The PDX model of MPM is established. The model is characterized by highly malignant tumor with rapid growth and high invasiveness.


Asunto(s)
Neoplasias Pulmonares , Mesotelioma , Neoplasias Pleurales , Animales , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos
13.
Chem Commun (Camb) ; 56(20): 3069-3072, 2020 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-32049075

RESUMEN

Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes (PtRu 1-4) have been synthesized and evaluated for their antitumor performance. Using the optimal complex, PtRu-1, we show that this water-soluble chimeric prodrug not only potently inhibits the metastasis and proliferation of tumor cells but also has an unexpectedly higher safety margin in animals compared with the traditionally-used, clinically approved drug cisplatin.


Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Niacina/farmacología , Platino (Metal)/farmacología , Rutenio/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/química , Cisplatino/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Niacina/química , Platino (Metal)/química , Rutenio/química , Relación Estructura-Actividad
14.
Life Sci ; 245: 117387, 2020 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-32007575

RESUMEN

The aim of this study was to investigate the inhibition of daidzein or/and regular exercise on breast cancer and to reveal the potential biological mechanisms. BALB/c mice pretreated with regular exercise training for 20 days (15 m/min, 60 min/d) were orthotopically transplanted with mouse breast cancer cells (4T1), and then treated with daidzein (145 mg/kg) by gavage for another 22 days. Results showed that exercise or daidzein inhibited tumor growth in mice to a different degree. Particularly, co-treatment with exercise and daidzein showed an obviously synergistic inhibition on the tumor growth (P < 0.01), compared with the tumor control. Further researches indicated that the combination of exercise and daidzein synergistically mobilized and redistributed natural killer cells through upregulating the level of epinephrine and interleukin-6. Moreover, exercise combined with daidzein induces apoptosis in cancer cells via Fas/FasL-initiated mitochondrial apoptosis signaling pathway. These results suggested that regular exercise combined with daidzein may explore a candidate way to prevent and treat the breast cancer.


Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/terapia , Terapia por Ejercicio/métodos , Isoflavonas/uso terapéutico , Células Asesinas Naturales/efectos de los fármacos , Animales , Western Blotting , Línea Celular Tumoral , Terapia Combinada , Femenino , Citometría de Flujo , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias
15.
Life Sci ; 248: 117454, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32088211

RESUMEN

AIMS: Dihydroartemisinin (DHA) is currently considered as the promising cancer therapeutic drug. In this study, we aimed to investigate the anti-proliferative and anti-metastasis effects of DHA. MAIN METHODS: Utilizing breast cancer cells MCF-7, MDA-MB-231 and BT549, cell proliferation, migration and invasion were detected. RT-qPCR was performed to detect CIZ1, TGF-ß1 and Snail expression, and the interactions of these related molecules were analyzed by GeneMANIA database. Western blot detected CIZ1, TGF-ß1/Smads signaling and Snail expression in DHA-treated cells, in TGFß1-induced cells with enhanced metastatic capacity, and in cells treated with DHA plus TGFß1/TGFß1 inhibitor SD-208. KEY FINDINGS: Results indicated DHA inhibited breast cancer cell proliferation and migration, with more potent effects compared with that of artemisinin. RT-qPCR and Western blot showed DHA inhibited CIZ1, TGF-ß1 and Snail expression, and these molecules were shown to have protein-protein interactions by bioinformatics. Furthermore, TGFß1-treatment enhanced MCF-7 migration and invasion, and CIZ1, TGF-ß1/Smads signaling and snail activities; DHA, SD-208, combination of DHA and SD-208 reversed these conditions, preliminarily proving the cascade regulation between TGF-ß1 signaling and CIZ1. MCF-7 xenografts model demonstrated the inhibition of DHA on tumor burden, and its mechanisms and well-tolerance in vivo; combination of DHA and SD-208 tried by us for the first time showed better treatment effects, but possible liver impairment made its use still keep cautious. SIGNIFICANCE: DHA treatment inhibits the proliferation and metastasis of breast cancer, through suppressing TGF-ß1/Smad signaling and CIZ1, suggesting the promising potential of DHA as a well-tolerated antitumor TGF-ß1 pathway inhibitor.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Artemisininas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Proteínas Nucleares/genética , Factor de Crecimiento Transformador beta1/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal , Femenino , Humanos , Metástasis Linfática , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Pteridinas/farmacología , Transducción de Señal , Proteínas Smad/genética , Proteínas Smad/metabolismo , Factores de Transcripción de la Familia Snail/antagonistas & inhibidores , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Emerg Microbes Infect ; 9(1): 427-438, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32079505

RESUMEN

Enterovirus 71 (EV71) is a major pathogen that causes hand, foot and mouth disease (HFMD), which is a life threatening disease in certain children. The pathogenesis of EV71-caused HFMD is poorly defined due to the lack of simple and robust animal models with severe phenotypes that recapitulate symptoms observed in humans. Here, we generated the infectious clone of a clinical isolate from a severe HFMD patient. Virus rescued from the cDNA clone was infectious in cell lines. When administrated intraperitoneally to neonatal ICR, BALB/c and C57 immune competent mice at a dosage of1.4 × 104 pfu per mouse, the virus caused weight loss, paralysis and death in the infected mice after 4-5 days of infection. In the infected mice, detectable viral replication was detected in various tissues such as heart, liver, brain, lung, kidney, small intestine, leg skeletal muscle and medulla oblongata. The histology of the infected mice included massive myolysis, glomerular atrophy, villous blunting in small intestine, widened alveolar septum, diminished alveolar spaces and lymphocytes infiltration into the lung. By using the UV-inactivated virus as a control, we elucidated that the virus first amplified in the leg skeletal muscle tissue and the muscle tissue served as a primary viral replication site. In summary, we generated a stable EV71 infectious clone that is capable of infecting neonatal immune competent mice without adaptive mutations and provide a simple, valuable animal model for the studies of EV71pathogenesis and therapy.


Asunto(s)
Enterovirus Humano A/genética , Enterovirus Humano A/patogenicidad , Enfermedad de Boca, Mano y Pie/virología , Animales , Animales Recién Nacidos , Línea Celular Tumoral , ADN Complementario , Modelos Animales de Enfermedad , Humanos , Lactante , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Mutación , ARN Viral , Organismos Libres de Patógenos Específicos , Células Vero , Virulencia , Replicación Viral
17.
J Agric Food Chem ; 68(9): 2664-2672, 2020 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-32033515

RESUMEN

The immunomodulatory activity of a few Lactobacillus exopolysaccharides (EPS) has been reported. However, whether Lactobacillus EPS can promote the differentiation of CD4 T lymphocytes (CD4+T) cells into T-helper 17 cells (Th17 cells) in the Peyer's Patches (PPs) of mice has not been addressed. In this study, we found the molecular weight (Mw) of the purified EPS from L. casei ranged from 2.7 × 106 Da to 1.7 × 107 Da, and the average Mw was approximately 8.4 × 106 Da. In healthy BALB/c mice, EPS elevated the numbers of Th17 cells and levels of Th17-related cytokines. In vitro, EPS induced BMDCs to stimulate the differentiation of CD4+T cells of PPs into Th17 cells and the related cytokine secretions. Results suggest that L. casei EPS can effectively induce and promote the differentiation of CD4+T cells of PPs into Th17 cells in healthy mice and has the potential ability to improve intestinal mucosa immunity.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Factores Inmunológicos/farmacología , Lactobacillus casei/química , Ganglios Linfáticos Agregados/efectos de los fármacos , Polisacáridos Bacterianos/farmacología , Células Th17/inmunología , Animales , Citocinas/genética , Citocinas/inmunología , Femenino , Factores Inmunológicos/química , Factores Inmunológicos/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Lactobacillus casei/metabolismo , Ratones , Ratones Endogámicos BALB C , Peso Molecular , Ganglios Linfáticos Agregados/citología , Ganglios Linfáticos Agregados/inmunología , Polisacáridos Bacterianos/química , Polisacáridos Bacterianos/metabolismo , Células Th17/citología , Células Th17/efectos de los fármacos
18.
J Agric Food Chem ; 68(9): 2648-2663, 2020 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-32064872

RESUMEN

Nutritional regulation of endogenous antimicrobial peptide (AMP) expression is considered a promising nonantibiotic approach to suppressing intestinal infection of pathogen. The current study investigated the effects of l-arginine on LPS-induced intestinal inflammation and barrier dysfunction in vivo and in vitro. The results revealed that l-arginine attenuated LPS-induced inflammatory response, inhibited the downregulation of tight junction proteins (TJP) (p < 0.05) by LPS, and maintained intestinal integrity. In porcine intestinal epithelial cells (IPEC-J2), l-arginine obviously suppressed (p < 0.05) the levels of IL-6 (220.63 ± 2.82), IL-8 (333.95 ± 3.75), IL-1ß (693.08 ± 2.38), and TNF-α (258.04 ± 4.14) induced by LPS. Furthermore, l-arginine diminished the LPS-induced expression of Toll-like receptor 4 (TLR4) and inhibited activation of TLR4-mediated nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Importantly, we proposed a new mechanism that l-arginine had the ability to stimulate the expression of porcine epithelial ß-defensins through activating the mammalian target of the rapamycin (mTOR) pathway, which exerts anti-inflammatory influence. Moreover, pBD-1 gene overexpression decreased (p < 0.05) the TNF-α level stimulated by LPS in IPEC-J2 cells (4.22 ± 1.64). The present study indicated that l-arginine enhanced disease resistance through inhibiting the TLR4/NF-κB and MAPK pathways and partially, possibly through increasing the intestinal ß-defensin expression.


Asunto(s)
Arginina/administración & dosificación , Intestinos/inmunología , Proteínas Quinasas Activadas por Mitógenos/inmunología , FN-kappa B/inmunología , Receptor Toll-Like 4/inmunología , beta-Defensinas/genética , Animales , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Intestinos/efectos de los fármacos , Lipopolisacáridos/efectos adversos , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Quinasas Activadas por Mitógenos/genética , FN-kappa B/genética , Porcinos , Receptor Toll-Like 4/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , beta-Defensinas/inmunología
19.
J Biomed Nanotechnol ; 16(1): 125-135, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31996291

RESUMEN

Theranostic nanosystems encompassing imaging reagents and therapeutic genes are promising for concurrent tumor diagnosis and gene therapy. In this work, we developed bioresponsive gadolinium (Gd)-based nanopolyplexes (denoted as Gdplexes) for in vivo tumor theranostic applications. Gdplexes were generated by a hierarchical assembly method involving the neutralization of DNA with a Gd-chelated bioreducible cationic polyurethane (termed as GdCPUA), which was followed by condensation of DNA with a cationic dextran conjugate (DP800). By adjusting GdCPUA/DP800 ratios, the resultant Gdplexes had GdCPUA/DNA complex as an inner core and a dextran outer shell; thus, Gdplexes exhibit an improved colloidal stability under physiological conditions and perform active gene release in an intracellular reductive environment. In vitro tests against cancer cells revealed that optimized Gdplexes afforded comparable transfection efficiency to that of the 25 kDa branched polyethylenimine used as a positive control. Additionally, the Gdplexes could robustly transfer small hairpin RNA plasmids to silence vascular endothelial growth factor expression in SKOV-3 cells. In vivo, the Gdplexes loaded with plasmid were practical for systemic gene delivery via intravenous administration, yielding marked growth repression of an SKOV-3 tumor xenograft in a BALB/c nude mouse model. The tumor could be visualized by T1-weighted magnetic resonance (MR) imaging. Such efficient gene therapy had no adverse effects on hepatorenal functions and weight gain in the mouse. This work highlights Gdplexes as biosafe and robust nanocarriers for tumor theranostic applications in vivo.


Asunto(s)
Nanomedicina Teranóstica , Animales , Línea Celular Tumoral , Terapia Genética , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos BALB C , Factor A de Crecimiento Endotelial Vascular
20.
Emerg Microbes Infect ; 9(1): 78-87, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31894728

RESUMEN

The H7N9 influenza virus has been circulating in China for more than six years. The neuraminidase (NA) has gained great concern for the development of antiviral drugs, therapeutic antibodies, and new vaccines. In this study, we screened seven mouse monoclonal antibodies (mAbs) and compared their protective effects against H7N9 influenza virus. The epitope mapping from escape mutants showed that all the seven mAbs could bind to the head region of the N9 NA close to the enzyme activity sites, and four key sites of N9 NA were reported for the first time. The mAbs D3 and 7H2 could simultaneously inhibit the cleavage of the sialic acid of fetuin protein with large molecular weight and NA-XTD with small molecule weight in the NA inhibition experiment, prevent the formation of virus plaque at a low concentration, and effectively protect the mice from the challenge of the lethal dose of H7N9 virus.


Asunto(s)
Anticuerpos Monoclonales/química , Subtipo H7N9 del Virus de la Influenza A/inmunología , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/química , Infecciones por Orthomyxoviridae/prevención & control , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antígenos Virales , Dominio Catalítico , Línea Celular , Perros , Mapeo Epitopo , Humanos , Gripe Humana/tratamiento farmacológico , Gripe Humana/prevención & control , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/tratamiento farmacológico
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