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1.
Int J Oral Sci ; 12(1): 5, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32024813

RESUMEN

Rheumatoid arthritis (RA) is an autoimmune disease affecting 1% of the world population and is characterized by chronic inflammation of the joints sometimes accompanied by extra-articular manifestations. K/BxN mice, originally described in 1996 as a model of polyarthritis, exhibit knee joint alterations. The aim of this study was to describe temporomandibular joint (TMJ) inflammation and damage in these mice. We used relevant imaging modalities, such as micro-magnetic resonance imaging (µMRI) and micro-computed tomography (µCT), as well as histology and immunofluorescence techniques to detect TMJ alterations in this mouse model. Histology and immunofluorescence for Col-I, Col-II, and aggrecan showed cartilage damage in the TMJ of K/BxN animals, which was also evidenced by µCT but was less pronounced than that seen in the knee joints. µMRI observations suggested an increased volume of the upper articular cavity, an indicator of an inflammatory process. Fibroblast-like synoviocytes (FLSs) isolated from the TMJ of K/BxN mice secreted inflammatory cytokines (IL-6 and IL-1ß) and expressed degradative mediators such as matrix metalloproteinases (MMPs). K/BxN mice represent an attractive model for describing and investigating spontaneous damage to the TMJ, a painful disorder in humans with an etiology that is still poorly understood.


Asunto(s)
Artritis Experimental/patología , Artritis Reumatoide/patología , Huesos/diagnóstico por imagen , Articulación Temporomandibular/diagnóstico por imagen , Articulación Temporomandibular/lesiones , Microtomografía por Rayos X/métodos , Animales , Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Huesos/metabolismo , Huesos/patología , Modelos Animales de Enfermedad , Humanos , Imagen por Resonancia Magnética , Metaloproteinasa 8 de la Matriz/inmunología , Ratones , Ratones Transgénicos , Articulación Temporomandibular/metabolismo , Tomografía Computarizada por Rayos X
2.
Cell Physiol Biochem ; 54(1): 142-159, 2020 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-32028545

RESUMEN

BACKGROUND/AIMS: It is well established that oxidative stress and inflammation are common pathogenic features of retinal degenerative diseases. ITH12674 is a novel compound that induces the transcription factor Nrf2; in so doing, the molecule exhibits anti-inflammatory, and antioxidant properties, and affords neuroprotection in rat cortical neurons subjected to oxidative stress. We here tested the hypothesis that ITH12674 could slow the retinal degeneration that causes blindness in rd10 mice, a model of retinitis pigmentosa. METHODS: Animals were intraperitoneally treated with 1 or 10 mg/Kg ITH12674 or placebo from P16 to P30. At P30, retinal functionality and visual acuity were analyzed by electroretinography and optomotor test. By immunohistochemistry we quantified the photoreceptor rows and analyzed their morphology and connectivity. Oxidative stress and inflammatory state was studied by Western blot, and microglia reactivity was monitored by flow cytometry. The blood-brain barrier permeation of ITH12674 was evaluated using a PAMPA-BBB assay. RESULTS: In rd10 mice treated with 10 mg/Kg of the compound, the following changes were observed (with respect to placebo): (i) a decrease of vision loss with higher scotopic a- and b-waves; (ii) increased visual acuity; (iii) preservation of cone photoreceptors morphology, as well as their synaptic connectivity; (iv) reduced expression of TNF-α and NF-κB; (v) increased expression of p38 MAPK and Atg12-Atg5 complex; and (vi) decreased CD11c, MHC class II and CD169 positive cell populations. CONCLUSION: These data support the view that a Nrf2 inducer compound may arise as a new therapeutic strategy to combat retinal neurodegeneration. At present, we are chemically optimising compound ITH12674 with the focus on improving its neuroprotective potential in retinal neurodegenerative diseases.


Asunto(s)
Isotiocianatos/uso terapéutico , Melatonina/análogos & derivados , Factor 2 Relacionado con NF-E2/agonistas , Retinitis Pigmentosa/tratamiento farmacológico , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Electrorretinografía , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Isotiocianatos/química , Isotiocianatos/farmacología , Masculino , Melatonina/química , Melatonina/farmacología , Melatonina/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Células Fotorreceptoras/efectos de los fármacos , Células Fotorreceptoras/patología , Retina/efectos de los fármacos , Retina/metabolismo , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/patología , Factor de Necrosis Tumoral alfa/metabolismo , Agudeza Visual/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
3.
Adv Exp Med Biol ; 1191: 169-184, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32002929

RESUMEN

This chapter describes the various animal models that seem relevant to the development of anxiolytic drugs, as well as the human models of induced anxiety, or more precisely the panic inducers including cholecystokinin. It is also mentioned the theoretical model of Deakin and Graeff which seems to keep all its relevance. The knock animals are evoked as relevant tools as well as a new optogenetic technique that needs to be used in this field.


Asunto(s)
Ansiolíticos , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/psicología , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Animales , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Colecistoquinina/efectos adversos , Humanos , Optogenética
4.
Anticancer Res ; 40(1): 527-534, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892608

RESUMEN

Simple steatosis in non-alcoholic fatty liver disease (NAFLD) progresses to non-alcoholic steatohepatitis (NASH) when excessive fat accumulation is accompanied by ballooning, inflammation, and progressive hepatocellular injury. Due to the increasing global incidence of NAFLD/NASH and the lack of effective drugs, current treatment options are currently dominated by lifestyle interventions, including dietary and physical activity modifications. In this regard, vitamin D has received widespread attention in recent years. In line with its pleiotropic physiological effects, preclinical animal models and patient cohorts have demonstrated anti-inflammatory, anti-fibrotic and anti-proliferative effects of vitamin D on NAFLD and NASH. Several animal models have confirmed the association of vitamin D deficiency and NALFD/NASH severity in humans and revealed potential benefits of dietary vitamin D supplementation. These preclinical models also provide critical guidance to define the roles and therapeutic potential of vitamin D as well as its downstream functional mechanisms in the pathogenesis of fatty liver disease. This review summarizes vitamin D research in currently available animal models of fatty liver disease.


Asunto(s)
Hígado Graso/metabolismo , Vitamina D/metabolismo , Animales , Investigación Biomédica , Modelos Animales de Enfermedad , Humanos
5.
Plast Reconstr Surg ; 145(2): 337e-347e, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31985634

RESUMEN

BACKGROUND: Three-dimensionally-printed bioceramic scaffolds composed of ß-tricalcium phosphate delivering the osteogenic agent dipyridamole can heal critically sized calvarial defects in skeletally mature translational models. However, this construct has yet to be applied to growing craniofacial models. In this study, the authors implanted three-dimensionally-printed bioceramic/dipyridamole scaffolds in a growing calvaria animal model and evaluated bone growth as a function of geometric scaffold design and dipyridamole concentration. Potential adverse effects on the growing suture were also evaluated. METHODS: Bilateral calvarial defects (10 mm) were created in 5-week-old (approximately 1.1 kg) New Zealand White rabbits (n = 16 analyzed). Three-dimensionally-printed bioceramic scaffolds were constructed in quadrant form composed of varying pore dimensions (220, 330, and 500 µm). Each scaffold was coated with collagen and soaked in varying concentrations of dipyridamole (100, 1000, and 10,000 µM). Controls consisted of empty defects. Animals were killed 8 weeks postoperatively. Calvariae were analyzed using micro-computed tomography, three-dimensional reconstruction, and nondecalcified histologic sectioning. RESULTS: Scaffold-induced bone growth was statistically greater than bone growth in empty defects (p = 0.02). Large scaffold pores, 500 µm, coated in 1000 µM dipyridamole yielded the most bone growth and lowest degree of scaffold presence within the defect. Histology showed vascularized woven and lamellar bone along with initial formation of vascular canals within the scaffold lattice. Micro-computed tomographic and histologic analysis revealed patent calvarial sutures without evidence of ectopic bone formation across all dipyridamole concentrations. CONCLUSION: The authors present an effective pediatric bone tissue-engineering scaffold design and dipyridamole concentration that is effective in augmentation of calvarial bone generation while preserving cranial suture patency.


Asunto(s)
Regeneración Ósea/efectos de los fármacos , Fosfatos de Calcio/uso terapéutico , Dipiridamol/uso terapéutico , Fracturas Craneales/cirugía , Ingeniería de Tejidos/métodos , Andamios del Tejido , Animales , Dipiridamol/administración & dosificación , Modelos Animales de Enfermedad , Conejos , Cráneo/efectos de los fármacos , Cráneo/lesiones , Fracturas Craneales/tratamiento farmacológico
6.
Ther Adv Cardiovasc Dis ; 14: 1753944719895902, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31918629

RESUMEN

Acute right heart failure is associated with impaired prognosis in cardiogenic shock. Since most pharmacological therapies are not evaluated for the failing right ventricle, or even contraindicated, there is a need for rapid minimal invasive circulatory right heart support. The PERKAT RV is such a device for acute therapy in congestive heart failure. It reduces the central venous pooling by pumping blood from the inferior vena cava into the pulmonary artery with flow rates of up to 4 litres/min. The device was evaluated in an animal model of acute pulmonary embolism after careful in vitro tests. PERKAT RV increased cardiac output by 59% in sheep suffering from acute right heart failure. We await the first human implantation in the near future. Based on the PERKAT concept, future devolvement will also focus on left heart support.


Asunto(s)
Insuficiencia Cardíaca/terapia , Corazón Auxiliar , Flujo Pulsátil , Disfunción Ventricular Derecha/terapia , Función Ventricular Derecha , Animales , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/fisiopatología , Humanos , Diseño de Prótesis , Oveja Doméstica , Disfunción Ventricular Derecha/fisiopatología
7.
Cancer Immunol Immunother ; 69(2): 307-314, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31912230

RESUMEN

Sensory nerves sensitive to capsaicin are afferent nerve fibers which contain TRPV1 channels. Activation of these channels induces release of neuropeptides which regulate local blood flow and immune response. Inactivation of sensory neurons either with high-dose capsaicin treatment or local ablation of vagal sensory nerve activity markedly increases metastasis of breast carcinoma formed by 4T1 derivative cells. These cancer cells also induce an extensive systemic inflammatory response. Further findings have documented that lack of local sensory neuromediators alters phenotype of cancer cells within primary tumor leading to overgrowth of metastatic subsets. This might be due to decreases in local and systemic immune response to growing tumor. Specifically, Substance P, one of the most abundant sensory neuropeptides, enhances anti-tumoral immune response evoked by radiotherapy under in vivo conditions. These findings further suggest that activation of TRPV1 channels on sensory neurons may induce an anti-tumoral immune response. We are testing this hypothesis. Our initial results as reported here demonstrate anti-inflammatory consequences of low-dose systemic capsaicin treatment. In conclusion, sensory nerve fibers sensitive to capsaicin have important roles in defense against metastatic breast carcinoma; hence, controlled activation of these neural pathways might be effective in cancer therapy. Specifically, activation of sensory fibers of left vagus nerve using a perineuronal stimulation may inhibit metastasis of breast carcinoma. Likewise, pharmacological modulators of TRPV1 channels may induce anti-tumoral immune response. Exact players of this newly explored defense system are, however, only partly validated, and further studies are required.


Asunto(s)
Neoplasias de la Mama/etiología , Neoplasias de la Mama/metabolismo , Neuroinmunomodulación , Células Receptoras Sensoriales/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Desnervación , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Metástasis de la Neoplasia , Fenotipo , Radioterapia
8.
Cancer Immunol Immunother ; 69(2): 315-324, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31915854

RESUMEN

There is mounting evidence that the immune system can spontaneously clear malignant lesions before they manifest as overt cancer, albeit this activity has been difficult to demonstrate in humans. The calreticulin (CALR) exon 9 mutations are driver mutations in patients with chronic myeloproliferative neoplasms (MPN), which are chronic blood cancers. The CALR mutations generate a neo-antigen that is recognized by patient T cells, and T cells isolated from a patient with a CALR-mutation can recognize and kill autologous CALR-mutant cells. Surprisingly, healthy individuals display frequent and strong T cell responses to the CALR neo-antigens too. Furthermore, healthy individuals display immune responses to all parts of the mutant CALR epitope, and the CALR neo-epitope specific responses are memory T cell responses. These data suggest that although healthy individuals might acquire a CALR mutation, the mutant cells can be eliminated by the immune system. Additionally, a small fraction of healthy individuals harbor a CALR exon 9 mutation. Four healthy individuals carrying CALR mutations underwent a full medical examination including a bone marrow biopsy after a median follow up of 6.2 years. None of these patients displayed any signs of CALR-mutant MPN. Additionally, all healthy individuals displayed strong CALR neo-epitope specific T cell responses suggesting that these healthy individuals retained their CALR-mutant cells in the editing stage for several years. Thus, we suggest that CALR-mutant MPN could be a disease model of cancer immuno-editing, as we have demonstrated that CALR-mutant MPN displays all three stages described in the theory of cancer immuno-editing.


Asunto(s)
Susceptibilidad a Enfermedades , Neoplasias Hematológicas/etiología , Inmunomodulación , Escape del Tumor , Animales , Antígenos de Neoplasias/inmunología , Biomarcadores de Tumor , Calreticulina/genética , Calreticulina/metabolismo , Transformación Celular Neoplásica , Modelos Animales de Enfermedad , Epítopos/inmunología , Neoplasias Hematológicas/metabolismo , Humanos , Inmunomodulación/genética , Mutación , Escape del Tumor/genética
9.
Expert Opin Investig Drugs ; 29(2): 209-219, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31937152

RESUMEN

Background: Oxidative stress has been implicated in metabolic syndrome (MetS); however, antioxidants such as vitamin E have had limited success in the clinic. This prompts the question of what effects amore potent antioxidant might produce. A prime candidate is the recently developed bioengineered antioxidant, poly(ethylene glycol)-functionalizedhydrophilic carbon clusters (PEG-HCCs), which are capable of neutralizing the reactive oxygen species (ROS) superoxide anion and hydroxyl radical at106/molecule of PEG-HCC. In this project, we tested the potential of PEG-HCCs as a possible therapeutic for MetS.Results: PEG-HCC treatment lessened lipid peroxidation, aspartate aminotransferase levels, non-fastingblood glucose levels, and JNK phosphorylation inob/ob mice. PEG-HCC-treated WT mice had an increased response to insulin by insulin tolerance tests and adecrease in blood glucose by glucose tolerance tests. These effects were not observed in HFD-fed mice, regardless of treatment. PEG-HCCs were observed in the interstitial space of liver, spleen, skeletal muscle, and adipose tissue. No significant difference was shown in gluconeogenesis or inflammatory gene expression between treatment and dietary groups.Expert Opinion: PEG-HCCs improved some parameters of disease possibly due to a resulting increase in peripheral insulin sensitivity. However, additional studies are needed to elucidate how PEG-HCCsare producing these effects.


Asunto(s)
Antioxidantes/farmacología , Síndrome Metabólico/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/química , Bioingeniería , Glucemia/efectos de los fármacos , Carbono/química , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Interacciones Hidrofóbicas e Hidrofílicas , Insulina/metabolismo , Resistencia a la Insulina , Masculino , Síndrome Metabólico/fisiopatología , Ratones , Ratones Endogámicos C57BL , Polietilenglicoles/química , Especies Reactivas de Oxígeno/metabolismo
10.
J Trauma Acute Care Surg ; 88(2): 298-304, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31996655

RESUMEN

BACKGROUND: Partial resuscitative endovascular balloon occlusion of the aorta (pREBOA) and intermittent REBOA (iREBOA) are techniques to extend the therapeutic duration of REBOA by balloon titration for distal flow or cyclical balloon inflation/deflation to allow transient distal flow, respectively. We hypothesized that manually titrated pREBOA would reduce blood losses and ischemic burden when compared with iREBOA. METHODS: Following 20% blood volume controlled hemorrhage, 10 anesthetized pigs underwent uncontrolled hemorrhage from the right iliac artery and vein. Once in hemorrhagic shock, animals underwent 15 minutes of complete zone 1 REBOA followed by 75 minutes of either pREBOA or iREBOA (n = 5/group). After 90 minutes, definitive hemorrhage control was obtained, animals were resuscitated with the remaining collected blood, and then received 2 hours of critical care. RESULTS: There were no differences in mortality. Animals randomized to iREBOA spent a larger portion of the time at full occlusion when compared with pREBOA (median, 70 minutes; interquartile range [IQR], 70-80 vs. median, 20 minutes; IQR, 20-40, respectively; p = 0.008). While the average blood pressure during the intervention period was equivalent between groups, this was offset by large fluctuations in blood pressure and significantly more rescue occlusions for hypotension with iREBOA. Despite lower maximum aortic flow rates, the pREBOA group tolerated a greater total amount of distal aortic flow during the intervention period (median, 20.9 L; IQR, 20.1-23.0 vs. median, 9.8 L; IQR, 6.8-10.3; p = 0.03) with equivalent abdominal blood losses. Final plasma lactate and creatinine concentrations were equivalent, although iREBOA animals had increased duodenal edema on histology. CONCLUSION: Compared with iREBOA, pREBOA reduced the time spent at full occlusion and the number of precipitous drops in proximal mean arterial pressure while delivering more distal aortic flow but not increasing total blood loss in this highly lethal injury model. Neither technique demonstrated a survival benefit. Further refinement of these techniques is necessary before clinical guidelines are issued.


Asunto(s)
Oclusión con Balón/métodos , Procedimientos Endovasculares/métodos , Resucitación/métodos , Choque Hemorrágico/terapia , Heridas y Traumatismos/terapia , Animales , Aorta/cirugía , Oclusión con Balón/efectos adversos , Oclusión con Balón/instrumentación , Modelos Animales de Enfermedad , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/instrumentación , Humanos , Masculino , Resucitación/efectos adversos , Resucitación/instrumentación , Choque Hemorrágico/etiología , Choque Hemorrágico/mortalidad , Análisis de Supervivencia , Sus scrofa , Factores de Tiempo , Índices de Gravedad del Trauma , Resultado del Tratamiento , Heridas y Traumatismos/complicaciones , Heridas y Traumatismos/diagnóstico
11.
Anticancer Res ; 40(1): 53-66, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892552

RESUMEN

BACKGROUND/AIM: Medulloblastoma (MB) accounts for ~20% of pediatric malignant central nervous system tumors. Treatment strategies, including surgery, radiation therapy and/or chemotherapy, are effective, but recurrence and metastasis frequently occur. Therefore, novel therapies are required. Herein, the effects of fibroblast growth factor receptor (FGFR) and phosphoinositide 3-kinase (PI3K) inhibitors on MB cells lines were evaluated. MATERIALS AND METHODS: MB cell lines (UW228-3, DAOY, Med8a, D425, D283) were tested for sensitivity to FGFR (AZD4547) and PI3K (BEZ235 and BYL719) inhibitors by viability, cytotoxicity, apoptosis, and proliferation assays. RESULTS: Single treatments with FGFR and PI3K inhibitors decreased viability and proliferation in a dose-dependent pattern in most cell lines. Combinination of the two type of drugs, increased sensitivity, especially of the most resistant cell line UW228-3. CONCLUSION: Combination treatments with FGFR and PI3K inhibitors were superior to single treatments with FGFR and PI3K inhibitors, especially with BEZ235, for MB cell lines.


Asunto(s)
Meduloblastoma/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Meduloblastoma/patología , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Anticancer Res ; 40(1): 109-119, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892559

RESUMEN

BACKGROUND/AIM: Although molecular targeting therapy is an attractive treatment for cancer, resistance eventually develops in most cases. Here, we evaluated chemotherapeutic efficacy on non-small cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor inhibitors mechanistically. MATERIALS AND METHODS: Antitumor effects of taxotere were evaluated using multiple models, including xenograft, and patient-derived models developed from adenocarcinoma cancer patients. Protein expressions were analyzed after drug treatment. RESULTS: Taxotere inhibited tumor growth of NSCLC cells harboring drug resistance, and reduced the expression of phosphorylated MET proto-oncogene, receptor tyrosine kinase (MET). A tumor-inhibitory effect of taxotere was also demonstrated in vivo in xenografts in mice, patient-derived primary lung tumor cells and patient-derived xenograft with concomitant repression of phosphorylated MET expression. Chemotherapeutic and MET-targeting drug exhibited a synergistic cell growth-inhibitory effect. CONCLUSION: These results suggest that the anticancer drug taxane may be an adjuvant for lung tumors exhibiting enhanced signaling of MET networks.


Asunto(s)
Antineoplásicos/farmacología , Docetaxel/farmacología , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Animales , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Anticancer Res ; 40(1): 169-176, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892565

RESUMEN

BACKGROUND/AIM: Cancer stem cells (CSCs) are considered to be one of the causes of tumor recurrence after chemotherapy. The purpose of our study was to isolate CSCs from human colorectal cancer cell (CRC) lines. MATERIALS AND METHODS: Nine CRC lines were screened based on the expression level of potential CSC markers to identify putative CSCs. Tumor formation capacity in immunodeficient mice was compared with that of their counterparts. Stemness, differentiation potency and sensitivity to 5-fluorouracil (5-FU), in vitro, were also assessed. Microarray analysis was used to characterize the features of the putative CSCs. RESULTS: COLO 201 cells were separated into two populations based on CD44 expression. CD44 positive (CD44+) cells showed significantly higher tumor formation capacity than CD44- cells in immunodeficient mice. CD44+ cells also possessed stemness properties and lower sensitivity to 5-FU in vitro. Moreover, cancer stemness and chemoresistance-related genes were highly up-regulated in CD44+ cells. CONCLUSION: CD44+ COLO 201 cells possessed the features of CSCs; therefore, the present CSC model could serve as a valuable tool to accelerate CSC research.


Asunto(s)
Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Biomarcadores , Biomarcadores de Tumor , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Fluorouracilo/farmacología , Xenoinjertos , Humanos , Receptores de Hialuranos/genética , Ratones
14.
Anticancer Res ; 40(1): 191-199, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892567

RESUMEN

AIM: To evaluate the feasibility of conducting studies of saliva circulating tumor DNA (ctDNA) as a biomarker of metastasis or recurrence in our orthotopic head and neck cancer (HNC) mouse model. MATERIALS AND METHODS: A mouse model of recurrence or metastasis after tongue cancer resection was developed. Blood and saliva were collected at baseline and at the establishment of recurrence or metastasis. Real-time polymerase chain reaction was performed to quantify human long interspersed element (hLINE) in samples to assess the amount of ctDNA. RESULTS: In our model, salivary hLINE increased as the cancer developed and decreased after surgery. Plasma hLINE was significantly elevated in mice with metastasis. The presence of tongue cancer recurrence in mice was more correlated with hLINE concentration in saliva than in plasma. CONCLUSION: In our orthotopic model, salivary ctDNA better reflected tumor development and recurrence than did plasma ctDNA.


Asunto(s)
Biomarcadores de Tumor , ADN Tumoral Circulante , Neoplasias de Cabeza y Cuello/metabolismo , Saliva/metabolismo , Animales , Apoptosis/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/patología , Xenoinjertos , Humanos , Elementos de Nucleótido Esparcido Largo , Ratones , Recurrencia
15.
Zhonghua Er Ke Za Zhi ; 58(1): 30-34, 2020 Jan 02.
Artículo en Chino | MEDLINE | ID: mdl-31905473

RESUMEN

Objective: To investigate the impact of hypoxic-ischemic brain injury (HIBI) on brain development in neonatal rats of different sexes. Methods: From January 1 to December 31, 2018, 60 7-day-old SD rats were randomly divided into HIBI-F group (20 rats), HIBI-M group (20 rats), and control group (20 rats, 10 females and 10 males). The animal model of HIBI was established with Rice-Vannucci method, with the rats' left common carotid artery double-ligated and severed. The rats were then placed in an incubator and exposed to a hypoxic gas mixture (8% O(2), 92% N(2)) for 90 minutes. No intervention was given to the control group. Two weeks after HIBI, the motor development was evaluated by footprint analysis, the residual brain volume was measured by brain magnetic resonance imaging (MRI), and the damage of synaptic ultra structure was analyzed by transmission electron microscope. One-way ANOVA or χ(2) test was used for inter-group statistical analysis, and paired sample t test was used to compare the bilateral step length and toe distance of rats in the same group. Results: The mortality rate of HIBI-F was significantly higher than that of HIBI-M (20%(4/20) vs. 10%(2/20), χ(2)=40.000, P=0.001). The right step length and toe distance in HIBI-M group and HIBI-F group were significantly shorter than those in control group ((7.5±0.3) cm and (7.9±0.5) cm vs. (8.2±0.5) cm, F=9.605, P<0.01, (0.9±0.1) cm and (1.0±0.0) cm vs. (1.1±0.1) cm, F=71.437, P<0.01). Besides, according to above data, the right step length and toe distance in HIBI-M group were significantly shorter than those in the HIBI-F group (both P<0.01). Furthermore, the right step length was significantly shorter than the left step length ((8.3±0.4) and (8.3±0.5) cm, t=5.289 and 10.580, P=0.001 and 0.010, respectively) and toe distance ((1.1±0.1) and (1.1±0.1) cm, t=7.953 and 6.435, respectively, both P<0.01) in both HIBI-M group and HIBI-F group. Similarly, the synaptic gap of the left precentral gyrus neurons was longer in HIBI-M group and HIBI-F group than that in control group ((23.4±1.3) and (19.7±1.6) nm vs. (18.9±0.6) nm, F=71.719, P<0.01), and also longer in HIBI-M group than that in HIBI-F group (t=7.645, P<0.01). Likewise, the residual brain volume in HIBI-M group and HIBI-F group was significantly less than that in control group ((67±4)% and (75±5)% vs. 100%, F=406.122, P<0.01), and the residual brain volume in HIBI-M group was significantly less than that in HIBI-F group (t=-5.281, P<0.01). Conclusions: Male neonatal rats are more vulnerable to HIBI and have severer subsequent brain injury and hemiplegia. Different treatment strategies for HIBI patients of different sexes should be developed.


Asunto(s)
Hipoxia-Isquemia Encefálica , Animales , Animales Recién Nacidos , Encéfalo , Modelos Animales de Enfermedad , Femenino , Humanos , Hipoxia-Isquemia Encefálica/mortalidad , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley
16.
Cell Physiol Biochem ; 54(1): 1-14, 2020 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-31916733

RESUMEN

BACKGROUND/AIMS: Deubiquitinating enzymes (DUBs) are crucially involved in controlling signal transductions, and reverse ubiquitination by removing the ubiquitin from protein substrates. The Hippo signaling has an important role in tissue growth, cell proliferation, differentiation, and apoptosis. Since disruption of the Hippo signaling is associated with a number of diseases, it is imperative to investigate the molecular mechanism of the Hippo signaling. METHODS: DUB screening was performed using the kidney of the mouse unilateral ureteric obstruction (UUO) model to identify the cellular mechanism of the DUB-regulated Hippo signaling. In addition, kidney cells were used to confirm cell proliferation and protein levels in the Hippo signaling pathway. Densitometric analysis was conducted to compare the expression level of proteins using Image J. RESULTS: We found that YOD1, also known as OTU1, is downregulated in the mouse UUO model. We also demonstrated that YOD1 binds to and deubiquitinates neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4). Furthermore, we observed that YOD1 suppresses NEDD4-induced cell proliferation. CONCLUSION: YOD1 regulates the Hippo signaling pathway through NEDD4, and the K63-linked polyubiquitin chain of NEDD4 plays an important role. Also, our results indicate that YOD1 plays an important role in kidney diseases.


Asunto(s)
Ubiquitina-Proteína Ligasas Nedd4/metabolismo , Transducción de Señal , Tioléster Hidrolasas/metabolismo , Animales , Línea Celular , Proliferación Celular , Modelos Animales de Enfermedad , Humanos , Ratones , Mutagénesis , Ubiquitina-Proteína Ligasas Nedd4/química , Ubiquitina-Proteína Ligasas Nedd4/genética , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Tioléster Hidrolasas/química , Ubiquitina/genética , Ubiquitina/metabolismo , Ubiquitinación
17.
Nihon Yakurigaku Zasshi ; 155(1): 16-19, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-31902839

RESUMEN

Stress urinary incontinence (SUI) is a common and bothersome problem among middle-aged women. However, there are few useful drugs for SUI. Urethral hypermobility and intrinsic sphincter deficiency are two main causes of SUI. Various animal models of SUI, such as vaginal distention, pudendal nerve injury, or ovariectomy, have been developed to study the pathophysiology of SUI. In addition, we have previously reported that cerebral infarction rats also induce SUI. Leak point pressure measurements are the most commonly used methods to evaluate the urethral dysfunction in SUI animal models. Originally, we have developed microtransducer-tipped catheter measurements of urethral activity during sneezing. Previous or our basic research has clarified potential strategies for pharmacotherapy of SUI in the central nervous system. Therapeutic targets include adrenergic and serotonergic (5-HT) receptors in the spinal cord, which stimulate pudendal nerve innervating the external urethral sphincter and/or sympathetic nerve innervating urethral smooth muscle. Activation of α1-adrenoceptors, 5-HT2C, or 5-HT7 receptors enhances the reflex at the spinal cord level whereas pre- or postsynaptic α2-adrenoceptors and/or 5-HT1A receptors inhibit the reflex. We have recently reported that stimulation of the spinal µ-opioid receptors by tramadol also enhances the reflex. Thus, we review the recent advances in basic SUI research and potential targets for pharmacotherapy of SUI in the central nervous system.


Asunto(s)
Incontinencia Urinaria de Esfuerzo , Animales , Sistema Nervioso Central , Modelos Animales de Enfermedad , Músculo Liso , Uretra
18.
Tumour Biol ; 42(1): 1010428319901052, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31959092

RESUMEN

Feline invasive mammary carcinomas are characterized by their high clinical aggressiveness, rare expression of hormone receptors, and pathological resemblance to human breast cancer, especially triple-negative breast cancer (negative to estrogen receptor, progesterone receptor, and epidermal growth factor receptor type 2). Recent gene expression studies of triple-negative breast cancers have highlighted their heterogeneity and the importance of immune responses in their biology and prognostic assessment. Indeed, regulatory T cells may play a crucial role in producing an immune-suppressed microenvironment, notably in triple-negative breast cancers. Feline invasive mammary carcinomas arise spontaneously in immune-competent animals, in which we hypothesized that the immune tumor microenvironment also plays a role. The aims of this study were to determine the quantity and prognostic value of forkhead box protein P3-positive peritumoral and intratumoral regulatory T cells in feline invasive mammary carcinomas, and to identify an immune-suppressed subgroup of triple-negative basal-like feline invasive mammary carcinomas. One hundred and eighty female cats with feline invasive mammary carcinomas, treated by surgery only, with 2-year follow-up post-mastectomy, were included in this study. Forkhead box protein P3, estrogen receptor, progesterone receptor, Ki-67, epidermal growth factor receptor type 2, and cytokeratin 14 expression were assessed by automated immunohistochemistry. Peritumoral regulatory T cells were over 300 times more abundant than intratumoral regulatory T cells in feline invasive mammary carcinomas. Peritumoral and intratumoral regulatory T cells were associated with shorter disease-free interval and overall survival in both triple-negative (ER-, PR-, HER2-, N = 123 out of 180) and luminal (ER+ and/or PR+, N = 57) feline invasive mammary carcinomas. In feline triple-negative basal-like (CK14+) mammary carcinomas, a regulatory T-cell-enriched subgroup was associated with significantly poorer disease-free interval, overall survival, and cancer-specific survival than regulatory T-cell-poor triple-negative basal-like feline invasive mammary carcinomas. High regulatory T-cell numbers had strong and negative prognostic value in feline invasive mammary carcinomas, especially in the triple-negative basal-like subgroup, which might contain a "basal-like immune-suppressed" subtype, as described in triple-negative breast cancer. Cats with feline invasive mammary carcinomas may thus be interesting spontaneous animal models to investigate new strategies of cancer immunotherapy in an immune-suppressed tumor microenvironment.


Asunto(s)
Neoplasias Mamarias Animales/patología , Neoplasias de la Mama Triple Negativas/patología , Animales , Gatos , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunohistoquímica/métodos , Inmunosupresión/métodos , Neoplasias Mamarias Animales/metabolismo , Pronóstico , Receptores Estrogénicos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Microambiente Tumoral/fisiología
19.
Adv Exp Med Biol ; 1232: 401-408, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31893437

RESUMEN

Parkinson's disease, a progressive neurodegenerative disease, is caused by the loss of dopaminergic neurons in the substantia nigra (SN). It is characterized by the formation of intracytoplasmic Lewy bodies that are primarily composed of the protein alpha-synuclein (α-syn), along with dystrophic neurites. Acupuncture stimulation results in an enhanced survival of dopaminergic neurons in the SN in Parkinsonism animal models. We investigated the role of acupuncture in inhibiting the increase in α-syn expression that is related to dopaminergic cell loss in the SN in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinsonism mouse model. In this model, acupuncture stimulation at GB34 and LR3 attenuated the decrease in tyrosine hydroxylase in the SN. Moreover, acupuncture stimulation attenuated the increase in α-syn in SN. Acupuncture stimulation also maintained the phosphorylated α-syn on serine 129 at levels similar to the control group. Our findings indicate that the MPTP-mediated increase in α-syn, and the acupuncture-mediated inhibition of the increase in α-syn, may be responsible for the neuroprotective effects of acupuncture in the SN following damage induced by MPTP.


Asunto(s)
Terapia por Acupuntura , Trastornos Parkinsonianos , Sustancia Negra , alfa-Sinucleína , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/patología , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores , Trastornos Parkinsonianos/inducido químicamente , Sustancia Negra/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , alfa-Sinucleína/metabolismo
20.
Adv Exp Med Biol ; 1232: 415-420, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31893439

RESUMEN

Murine models have become powerful tools in leukemia research for investigating interactions between blast cells niche factors. In the tumor microenvironment, immune cells are one of the most important niche factors, capable of mounting dynamic innate or adoptive responses against leukemic cells. Acute myeloid leukemia (AML) is a systemic cancer accompanied by immune disruption. In order to exploit the enhanced activity of immune cells in AML treatment, the use of syngeneic mouse models is necessary. Studies of crosstalk between cancer blast cells and immune cells in syngeneic mouse models are beneficial, as the absence of immune functions in syngeneic models enables focus on cancer-associated immune reactions. Once AML is induced, innate and adoptive immune cells respond differently, ultimately resulting in suppression of the immune cells. Murine AML models are commonly induced by intravenous or subcutaneous injection of C1498 cells. Despite the popularity of murine models, they have not yet resulted in the elucidation of distinct differences in immune cells by the injection method. Here, we investigated the frequency of immune cells and survival rate of mice with AML induced using both injection methods.


Asunto(s)
Leucemia Mieloide Aguda , Animales , Modelos Animales de Enfermedad , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Ratones , Microambiente Tumoral/inmunología
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