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On January 10, 2018, a 35-year-old male patient with a 3 day stingray stinger injury in his left thigh was admitted to Xuzhou Central Hospital. At the time of admission, the patient's left thigh was red, swollen, and painful. On the day of admission, the patient underwent emergency operation in the outpatient operating room for local debridement to remove the infected and necrotic tissue. After the routine dressing change and the wound got better, surgical debridement and negative-pressure wound therapy were performed, and finally local flap was used to repair the wound. On the 14th day after the flap repair operation, the suture was removed and the patient was discharged. After half a year follow-up, the appearance of the operation area recovered well. This case suggests that the timely and correct pre-hospital treatment, thorough and timely debridement, and systemic antibiotic application are important means to reduce further injury of toxin. The local flap can achieve satisfactory result on wound healing after the wound bed is prepared by negative-pressure wound therapy.
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Mordeduras y Picaduras/terapia , Terapia de Presión Negativa para Heridas , Procedimientos de Cirugía Plástica , Rajidae , Traumatismos de los Tejidos Blandos , Adulto , Animales , Desbridamiento , Humanos , Masculino , Trasplante de Piel , Traumatismos de los Tejidos Blandos/cirugía , Resultado del TratamientoRESUMEN
MicroRNA (miR)-103a-3p has been shown to be involved in the development and progression of several types of cancer. However, the role of miR-103a-3p in thyroid cancer remains unclear. This study investigated the effects of miR-103a-3p on the biological characteristics of thyroid cancer cells and related mechanisms. In the present study, we found that the expression of miR-103a-3p was increased in thyroid cancer tissues compared to that in non-cancerous tissues. Additionally, the expression of miR-103a-3p in thyroid cancer cell lines (TPC-1, SW579, BHT101, K1) was markedly higher than that in the human thyroid cell line (Nthy-ori3-1). Silencing of miR-103a-3p obviously inhibited proliferation, migration, and invasion and promoted apoptosis of BHT101 cells. miR-103a-3p upregulation promoted the proliferation, migration, and invasion and inhibited apoptosis of K1 cells. Mechanistically, LATS1 was identified as a functional target of miR-103a-3p, and miR-103a-3p negatively regulated LATS1 expression. miR-103a-3p knockdown (or upregulation) partially reversed the effects of LATS1 knockdown (or overexpression) on proliferation, apoptosis, migration, and invasion of thyroid cancer cells. LATS1 knockdown inhibited the phosphorylation of YAP in BHT101 cells and promoted the nuclear translocation of YAP. Whereas, miR-103a-3p downregulation reversed the inhibitory effect of LATS1 knockdown on the Hippo signaling pathway. Moreover, overexpression of LATS1 induced YAP phosphorylation in K1 cells and inhibits nuclear translocation of YAP, and the upregulation of miR-103a-3p reversed this effect. The knockdown of miR-103a-3p inhibited tumor growth and progression in vivo. Taken together, knockdown of miR-103a-3p inhibits proliferation, migration, and invasion and promotes apoptosis of thyroid cancer cells through the Hippo signaling pathway by upregulating LATS1.
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MicroARNs/genética , Proteínas Serina-Treonina Quinasas/genética , Neoplasias de la Tiroides , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Técnicas de Silenciamiento del Gen , Vía de Señalización Hippo , Humanos , Transducción de Señal , Neoplasias de la Tiroides/genéticaRESUMEN
Natural killer (NK) cell-based immunotherapy is promising, as NK cells are in the first line of defense against cancer and capital of lysing tumor cells without pre-stimulation. However, NK cells from multiple myeloma (MM) patients are always deficient in numbers and the expression of certain activating receptors, disabling them in cytotoxicity against the cancer. Therefore, effective strategies to expand NK cells and increase NK cell-mediated cytotoxicity against MM are significant. Here, NK cells were efficiently expanded from peripheral blood mononuclear cells (PBMCs) of newly diagnosed MM patients after co-culture with irradiated K562 cells transfected with 41BBL and membrane-bound interleukin (IL)-15 (K562-mb15-41BBL) in the presence of 200 IU/ml human IL-2. The ex vivo-expanded NK cells were demonstrated to vigorously kill both MM cells and autologous primary MM cells without significant lysis of patient normal cells. Further exploration revealed a significant increase in cell surface expression of most activating receptors of NK cells and indicated that expanded NK (exp-NK) cell killing of MM cells was mediated by perforin/granzyme. NK cells are capital of lysing human leukocyte antigen (HLA) I-deficient tumor cells and carfizomib, a selective proteasome inhibitor approved for the treatment of relapsed/refractory MM patient, down-regulates the expression of HLA class I, thus enhancing NK cell-mediated lysis in MM. Here, we found for the first time that carfizomib dramatically augmented ex vivo exp-NK cell cytotoxicity against patient autologous MM cells, suggesting the use of exp-NK alone or in combination with the drug to treat MM patient.
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Inmunoterapia , Células Asesinas Naturales/citología , Mieloma Múltiple/terapia , Oligopéptidos/uso terapéutico , Células Cultivadas , Citotoxicidad Inmunológica , Humanos , Células K562 , Leucocitos Mononucleares , TransfecciónRESUMEN
The European Male Aging Study (EMAS) has recently defined strict diagnostic criteria for late-onset hypogonadism (LOH) including the levels of serum total testosterone (TT), free testosterone (FT) and three sexual symptoms. However, there is no report on risk factors for LOH using these criteria. In this study, we investigated risk factors for LOH based on these criteria. We recruited 277 men (aged 36-80 years) who completed both a health check-up and two questionnaires (a health and lifestyle questionnaire, and a sexual function questionnaire). Data on parameters, such as systolic blood pressure (SBP), glucose, triglyceride (TG) and high-density lipoprotein (HDL), were obtained from medical records of the hospital in Shantou. TT and sex hormone-binding globulin (SHBG) were measured by chemiluminescent immunoassay, and FT was calculated. TT, FT, age, waist circumference, SBP and glucose showed significant differences between LOH-positive and LOH-negative individuals. Univariate regression analyses showed that age, waist circumference, SBP, glucose and health status were risk factors for LOH. Pearson's correlation analysis revealed that TT was inversely correlated with waist circumference, glucose and SBP, and FT was inversely correlated with age, SBP and health status. In conclusion, age, waist circumference, SBP, glucose and health status were risk factors for LOH.
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Glucemia/análisis , Hipogonadismo/sangre , Hipogonadismo/epidemiología , Lipoproteínas HDL/sangre , Globulina de Unión a Hormona Sexual/metabolismo , Testosterona/sangre , Triglicéridos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Presión Sanguínea , Humanos , Enfermedades de Inicio Tardío , Masculino , Persona de Mediana Edad , Factores de Riesgo , Encuestas y Cuestionarios , Circunferencia de la CinturaRESUMEN
Objective: To investigate the clinical features of imbalance between Th1 and Th22 cells and its association with disease progression in patients with liver cirrhosis, and to explore immune therapeutic strategies for targeted therapy for liver cirrhosis. Methods: In vitro peripheral blood mononucleated cells (PBMCs) were collected by centrifugation. CD3-BV500 and CD8-PerCP-Cy5.5 staining was performed for these cells. IFNγ-PE-Cy7, IL-17a-APC, IL-22-PE, or the corresponding isotype control was added, and then PBMCs were fixed with 1% polyoxymethylene after being washed once by permeabilization-wash buffer. Flowjo software was used for the analysis of T lymphocyte subsets and cytokines. Th1 (CD4+IFNγ(+)), Th17 (CD4+IL-17a(+)), Th22 (CD4+IL-22(+)), Tc1 (CD8+IFNγ(+)), Tc17 (CD8+IL-17a(+)), and Tc22 (CD8+IL-22(+)) subsets were defined and the secretions of interferon-γ (IFN-γ), interleukin-17a (IL-17a), and interleukin-22 (IL-22) were measured for all subsets. LX-2 cells were cultured in a serum-free medium and different concentrations of recombinant human IL-22 protein (25, 50, 100 ng/ml) were added; 24 hours later, the activation marker α-smooth muscle actin (α-SMA) was used to measure LX-2 activation. Fetal bovine serum with a volume fraction of 10% was used as a positive control. Enzyme-linked immunosorbent assay (chemiluminescence) was used to measure the concentrations of hyaluronic acid, type III precollagen, and type IV collagen in supernatant. A one-way analysis of variance, the non-parametric Mann-Whitney U test, and the non-parametric Kruskal-wallis H test were used for statistical analysis based on data type. Results: Compared with the health control group, the liver cirrhosis groups with various causes had significant increases in peripheral Tc1, Th17, and Th22 cells. The percentage of Th17 cells in the liver cirrhosis group was 1.64 times that in the control group (4.25%±2.45% vs 2.59%±1.36%, P < 0.05), and the mean percentage of Th22 cells in the liver cirrhosis group was 2.18 times that in the control group (4.17%±2.55% vs 1.31%±0.64%, P < 0.05). The percentages of Th17 (5.89%±3.44%) and Th22 cells (5.32%±3.67%) in the patients with alcoholic cirrhosis were 1.27 and 3.06 times those in the control group (P < 0.05). The patients with alcoholic cirrhosis had a significant increase in Th22 cells. The patients with different types of liver cirrhosis had a significant reduction in the ratio between anti-fibrotic and pro-fibrotic factors (Th1/Th22), which was positively correlated with the severity of liver cirrhosis and was a common immunological feature of liver cirrhosis with different causes. In addition, IL-22 activated hepatic stellate cells and promoted the production of collagen. Conclusion: The imbalance between anti-fibrotic and pro-fibrotic factors (Th1/Th22) is a common feature of the progression of liver fibrosis with various causes and may contribute to the progression of liver fibrosis.
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Progresión de la Enfermedad , Inmunoterapia , Interleucina-17 , Interleucinas , Cirrosis Hepática/patología , Balance Th1 - Th2 , Humanos , Interferón gamma/metabolismo , Cirrosis Hepática/terapia , Subgrupos de Linfocitos T , Células TH1 , Células Th17 , Células Th2RESUMEN
Xanthurenic acid (XA), formed from 3-hydroxykynurenine (3-HK) in the kynurenine pathway of tryptophan degradation, may modulate glutamatergic neurotransmission by inhibiting the vesicular glutamate transporter and/or activating Group II metabotropic glutamate receptors. Here we examined the molecular and cellular mechanisms by which 3-HK controls the neosynthesis of XA in rat, mouse and human brain, and compared the physiological actions of 3-HK and XA in the rat brain. In tissue homogenates, XA formation from 3-HK was observed in all three species and traced to a major role of kynurenine aminotransferase II (KAT II). Transamination of 3-HK to XA was also demonstrated using human recombinant KAT II. Neosynthesis of XA was significantly increased in the quinolinate-lesioned rat striatum, indicating a non-neuronal localization of the process. Studies using rat cortical slices revealed that newly produced XA is rapidly released into the extracellular compartment, and that XA biosynthesis can be manipulated experimentally in the same way as the production of kynurenic acid from kynurenine (omission of Na+ or glucose, depolarizing conditions, or addition of 2-oxoacids). The synthesis of XA from 3-HK was confirmed in vivo by striatal microdialysis. In slices from the rat hippocampus, both 3-HK and XA reduced the slopes of dentate gyrus field EPSPs. The effect of 3-HK was reduced in the presence of the KAT inhibitor aminooxyacetic acid. Finally, both 3-HK and XA reduced the power of gamma-oscillatory activity recorded from the hippocampal CA3 region. Endogenous XA, newly formed from 3-HK, may therefore play a physiological role in attentional and cognitive processes.
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Encéfalo/citología , Encéfalo/metabolismo , Quinurenina/análogos & derivados , Xanturenatos/química , Xanturenatos/metabolismo , Anciano , Animales , Encéfalo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Femenino , Fluoroquinolonas/farmacología , Glucosa/metabolismo , Glutamina/farmacología , Humanos , Técnicas In Vitro , Quinurenina/metabolismo , Quinurenina/farmacología , Masculino , Ratones , Persona de Mediana Edad , Piperazinas/farmacología , Cambios Post Mortem , Ácido Pirúvico/metabolismo , Ácido Quinolínico/farmacología , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Tacrolimus/análogos & derivados , Tacrolimus/metabolismo , Temperatura , Distribución Tisular/efectos de los fármacos , Distribución Tisular/fisiología , Transaminasas/metabolismo , Veratridina/metabolismoRESUMEN
Growth traits are important economic traits in broiler chicken production. AluI and Hin1I loci are two restriction sites, which are respectively located in exons 2 and 3 of the IGF-1R gene. These two loci are significantly related to the growth traits in Jinghai Yellow chickens. In this study, a correlation analysis was performed between these two loci and the growth traits of Bian chickens. The results showed a G376A mutation at the AluI site and a C919A mutation at the Hin1I site, which respectively resulted in three genotypes AA, AB, and BB in exon 2 and three genotypes CC, CD, and DD in exon 3. Correlation analysis showed that the female Bian chickens with the AA genotype of the AluI locus had higher body weights than those with the AB genotype (P < 0.05) at 8, 14, 16, and 18 weeks; individuals with CD genotype of Hin1I locus had higher body weights at 6, 8, 10, 12, and 14 weeks compared to the CC genotype (P < 0.05 or P < 0.01). Combined genotypes analysis showed that at the age of 8, 14, 16, and 18 weeks, the body weight of AACC genotype combination was higher than that of the ABCC genotype combination (P < 0.05); at the age of 6, 8, 12, 14, 16, and 18 weeks, the AACD genotype combination had higher (P < 0.05 or P < 0.01) body weight than that of the ABCC genotype.
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Peso Corporal/genética , Pollos/genética , Polimorfismo de Longitud del Fragmento de Restricción , Carácter Cuantitativo Heredable , Receptores de Somatomedina/genética , Animales , Pollos/crecimiento & desarrollo , GenotipoRESUMEN
Cognitive deficits represent core symptoms in schizophrenia (SZ) and predict patient outcome; however, they remain poorly treated by current antipsychotic drugs. Elevated levels of the endogenous alpha7 nicotinic receptor negative allosteric modulator and NMDA receptor antagonist, kynurenic acid (KYNA), are commonly seen in post-mortem tissue and cerebrospinal fluid of patients with SZ. When acutely or chronically elevated in rodents, KYNA produces cognitive deficits similar to those seen in the disease, making down-regulation of KYNA, via inhibition of kynurenine aminotransferase II (KAT II), a potential treatment strategy. We determined, in adult Wistar rats, if the orally available KAT II inhibitor BFF816 a) prevents KYNA elevations in prefrontal cortex (PFC) after a systemic kynurenine injection and b) reverses the kynurenine-induced attenuation of evoked prefrontal glutamate release caused by stimulation of the nucleus accumbens shell (NAcSh). Systemic injection of kynurenine (25 or 100 mg/kg, i.p.) increased KYNA levels in PFC (532% and 1104% of baseline, respectively). NMDA infusions (0.15 µg/0.5 µL) into NAcSh raised prefrontal glutamate levels more than 30-fold above baseline. The two doses of kynurenine reduced evoked glutamate release in PFC (by 43% and 94%, respectively, compared to NMDA alone). Co-administration of BFF816 (30 or 100 mg/kg, p.o.) with kynurenine (25 mg/kg, i.p.) attenuated the neosynthesis of KYNA and dose-dependently restored NMDA-stimulated glutamate release in the PFC (16% and 69%, respectively). The ability to prevent KYNA neosynthesis and to normalize evoked glutamate release in PFC justifies further development of KAT II inhibitors for the treatment of cognitive deficits in SZ.
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Inhibidores Enzimáticos/administración & dosificación , Ácido Glutámico/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Transaminasas/antagonistas & inhibidores , Administración Oral , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Electrodos , Inhibidores Enzimáticos/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Ácido Quinurénico/metabolismo , Quinurenina/farmacología , Masculino , Microdiálisis , N-Metilaspartato/farmacología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Ratas , Ratas Wistar , Tiazolidinedionas/farmacología , Transaminasas/metabolismoRESUMEN
Objective: To determine the feasibility and safety of anterior cervical decompression and fusion in severe cervical kyphosis treatment. Methods: Totally 29 patients with severe cervical kyphosis(Cobb angle>50°) underwent anterior cervical decompression and fusion from June 2008 to May 2016 were studied retrospectively. There were 19 males and 10 females. The average age was 32.6 years ranging from 14 to 53 years. According to the etiology, 12 patients had iatrogenic deformity (11 had post-laminectomy cervical kyphosis, 1 had kyphosis due to anterior graft subsidence), 5 had neurofibromatosis, 4 had infective kyphosis, 8 had idiopathic cervical kyphosis. The curvature of cervical angle was measured by two-line Cobb method. The severity of cervical kyphosis was evaluated by kyphosis index (KI). Parameters including kyphosis levels, the apex of the kyphosis, C(2-7) sagittal vertical axis(SVA) and T(1) slope were also measured on lateral radiographs in the neutral position in each patient. The pre- and post-operative Japanese Orthopaedic Association(JOA) scores, visual analogue scale (VAS) of neek pain, neck disability index (NDI) and cervical alignment were compared. All patients were treated by skull traction. Motor evoked potential and somatosensory evoked potential were applied intraoperation as the spinal cord monitor. Results: Skull traction was performed for an average of 6.3 days. The mean vertebral number in kyphotic region was 4.7. The average operation time was 155 minutes and blood loss was 135 ml. The preoperative C(2-7)Cobb angle was 46.6°±18.1° in average. It was reduced to 11.4°±6.4° in average after operation. The Cobb angle of operation region was 72.9°±19.6° in average before operation. It was reduced to 11.2°±6.4° in average after operation. The kyphosis region correction rate was 84.6%. The mean preoperative C(2-7)SVA changed from (3.8±14.6) mm to (12.6±7.8) mm postoperatively. The mean preoperative T(1) slope changed from -10.6°±16.4° to 7.1°±14.9° postoperatively. The average postoperative C(2-7) Cobb angle, Cobb angle of kyphosis region, KI, C(2-7) SVA and T(1) slope changed significantly compared with preoperation (F=12.700-218.200, all P<0.01). The average postoperative JOA, VAS and NDI scores improved significantly compared with preoperation (F=225.500, 217.900, 131.200, all P<0.01). Conclusion: For severe cervical kyphosis, anterior correction is a safe and effective technique, sufficient decompression will be achieved.
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Descompresión Quirúrgica , Cifosis/cirugía , Adulto , Vértebras Cervicales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cuello , Dimensión del Dolor , Periodo Posoperatorio , Radiografía , Estudios Retrospectivos , Resultado del Tratamiento , Escala Visual AnalógicaRESUMEN
Objective: To study the effect of specific immunotherapy on the psychological health level and quality of life in patients with allergic rhinitis(AR).Method:Selected 97 cases diagnosed as moderate to severe persistent AR patients, were treated with specific immunotherapy for one year. All patients received the evaluation with symptom check list 90(SCL-90) and rhinoconjunctivitis quality of life questionnaire(RQLQ) before specific immunotherapy, six, and 12 months after specific immunotherapy.Result:The total scores, scores of somatization, obsessive, anxiety, depression and phobia in SCL-90 of AR patients after 12 months treatment were significantly lower than that before treatmentï¼P < 0.05ï¼. Total score of quality of life and subitem score in RQLQ of AR patients after 12 months treatment were obviously lower than that before treatment (P < 0.05ï¼.Conclusion:Specific immunotherapy can effectively alleviate the clinical symptoms and improve psychological health level and quality of life of AR patients.
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Desensibilización Inmunológica , Inmunoterapia/métodos , Calidad de Vida , Rinitis Alérgica/terapia , Humanos , Rinitis Alérgica/inmunología , Rinitis Alérgica/psicología , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del TratamientoRESUMEN
Objective:This project aimed to study the dynamic change of the cytokines associated with specific immunotherapy(SIT) pre- and post-SIT.Searching for immune regulatory indicators would used in SIT.Method:One hundred cases who had accepted SIT were enrolled in the project.Data of serum specific IgE and cytokines were statistically analyzed.In the three periods,pre-SIT,17 weeks post-SIT,57 weeks post-SIT,the levels of the eight kinds of cytokines(IL-4,IL-5,IL-8,IL-10,IL-13,IL-17,IFN-γ and TNF-α)were detected,and the dynamic change of the nasal symptoms score were analyzed.Result:The six kinds of cytokines(IL-5,IL-8,IL-10,IL-13,IL-17 and TNF-α)had no significant difference before and after SIT.The level of house dust mite sIgE level was positively correlated with serum IL-5 when the SIT pre-treatment and 57weeks (P<0.05).Pre-treatment and in 17 weeks after treatment,serum IL-5,IL-17 content difference and reduce the magnitude of nasal symptom scores were positively correlated (P<0.01).In 17 weeks of treatment and 57 weeks of treatment,difference of serum IL-10,IL-13,TNF-α levelsand the difference of nasal symptom scores were negatively correlated(P<0.01).Pre- treatment and 57 weeks,difference of serum IL-13,IL-17,TNF-α and the difference of nasal symptom scores were positively correlated (P<0.05),serum IL-10 levels of difference between the nose ministry of magnitude lower symptom scores were negatively correlated (P<0.01).Conclusion:The cytokines (IL-4,IL-5,IL-8,IL-10,IL-13,IL-17,IFN-γ and TNF-α) associated with the SIT play an important role in allergy and can objectively reflect the immune status during SIT.
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Citocinas/metabolismo , Desensibilización Inmunológica , Rinitis Alérgica Perenne/inmunología , Animales , Femenino , Humanos , Inmunoglobulina E/sangre , Interleucina-10 , Interleucina-17 , Masculino , Pyroglyphidae/inmunología , Rinitis Alérgica , Rinitis Alérgica Perenne/terapia , Factor de Necrosis Tumoral alfaRESUMEN
We present a novel approach to address one of the technical hurdles the current light-emitting diode (LED) lighting field faces: the packaged efficacy of warm-white LEDs is 20%-30% lower than that of cool-white LEDs depending on the color rendering index. With a differentiated luminaire design in combination with a new class of nano materials, we have greatly improved the efficacy of warm white by 15% at the luminaire system level, which translates to less energy being required to achieve the same light output, and thus offers a more energy-efficient solution. Reliability test of the luminaire shows no performance degradation within the tested period of more than 3000 h. A modeling has been developed to predict the optical performance of luminaires incorporating the nano materials, which agrees well with the experimental data and serves as a powerful tool for designing luminaires with targeted performance.
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Levels of kynurenic acid (KYNA), an endogenous α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, are elevated in the brain of patients with schizophrenia (SZ) and might contribute to the pathophysiology and cognitive deficits seen in the disorder. As developmental vulnerabilities contribute to the etiology of SZ, we determined, in rats, the effects of perinatal increases in KYNA on brain chemistry and cognitive flexibility. KYNA's bioprecursor l-kynurenine (100mg/day) was fed to dams from gestational day 15 to postnatal day 21 (PD21). Offspring were then given regular chow until adulthood. Control rats received unadulterated mash. Brain tissue levels of KYNA were measured at PD2 and PD21, and extracellular levels of KYNA and glutamate were determined by microdialysis in the prefrontal cortex in adulthood (PD56-80). In other adult rats, the effects of perinatal l-kynurenine administration on cognitive flexibility were assessed using an attentional set-shifting task. l-Kynurenine treatment raised forebrain KYNA levels â¼3-fold at PD2 and â¼2.5-fold at PD21. At PD56-80, extracellular prefrontal KYNA levels were moderately but significantly elevated (+12%), whereas extracellular glutamate levels were not different from controls. Set-shifting was selectively impaired by perinatal exposure to l-kynurenine, as treated rats acquired the discrimination and intra-dimensional shift at the same rate as controls, yet exhibited marked deficits in the initial reversal and extra-dimensional shift. Acute administration of the α7nAChR-positive modulator galantamine (3.0mg/kg, i.p.) restored performance to control levels. These results validate early developmental exposure to l-kynurenine as a novel, naturalistic animal model for studying cognitive deficits in SZ.
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Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Galantamina/farmacología , Ácido Quinurénico/metabolismo , Quinurenina/farmacología , Nootrópicos/farmacología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Atención/efectos de los fármacos , Atención/fisiología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Femenino , Ácido Glutámico/metabolismo , Masculino , Embarazo , Ratas , Ratas Wistar , Disposición en PsicologíaRESUMEN
Using two in vivo methods, microdialysis and rapid in situ electrochemistry, this study examined the modulation of extracellular glutamate levels by endogenously produced kynurenic acid (KYNA) in the prefrontal cortex (PFC) of awake rats. Measured by microdialysis, i.p. administration of KYNA's bioprecursor L-kynurenine dose-dependently elevated extracellular KYNA and reduced extracellular glutamate (nadir after 50 mg/kg kynurenine: 60% decrease from baseline values). This dose-dependent decrease in glutamate levels was also seen using a glutamate-sensitive microelectrode array (MEA) (31% decrease following 50 mg/kg kynurenine). The kynurenine-induced reduction in glutamate was blocked (microdialysis) or attenuated (MEA) by co-administration of galantamine (3 mg/kg i.p.), a drug that competes with KYNA at an allosteric potentiating site of the alpha 7 nicotinic acetylcholine receptor. In separate experiments, extracellular glutamate levels were measured by MEA following the local perfusion (45 min) of the PFC with kynurenine (2.5 microM) or the selective KYNA biosynthesis inhibitor S-ethylsulfonylbenzoylalanine (S-ESBA; 5 mM). In agreement with previous microdialysis studies, local kynurenine application produced a reversible reduction in glutamate (nadir: -29%), whereas perfusion with S-ESBA increased glutamate levels reversibly (maximum: +38%). Collectively, these results demonstrate that fluctuations in the biosynthesis of KYNA in the PFC bi-directionally modulate extracellular glutamate levels, and that qualitatively very similar data are obtained by microdialysis and MEA. Since KYNA levels are elevated in the PFC of individuals with schizophrenia, and since prefrontal glutamatergic and nicotinic transmission mediate cognitive flexibility, normalization of KYNA levels in the PFC may constitute an effective treatment strategy for alleviating cognitive deficits in schizophrenia.
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Química Encefálica/fisiología , Técnicas Electroquímicas/métodos , Ácido Glutámico/metabolismo , Ácido Quinurénico/metabolismo , Microdiálisis/métodos , Corteza Prefrontal/metabolismo , Animales , Masculino , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Clusterin (CLU) is expressed in a wide variety of human tissues and fluids. Overexpression of cytoplasmic clusterin (sCLU) has been implicated in cancer development and progression. The aim of the present study is to evaluate the association of sCLU overexpression with clinicopathological features of human gastric carcinomas (GC).We constructed a gastric cancer tissue microarray containing 173 primary gastric carcinomas and 70 paired non-neoplastic mucosa specimens. The expression of sCLU was studied by immunohistochemistry. The correlations between sCLU expression and clinicopathological features, p53 abnormality, as well as Ki67 activation were analyzed. Overexpressions of sCLU was detected in 28.5% (n=165) of primary GCs by immunohistochemical staining, but not in non-neoplastic mucosa. Clinical association study found that overexpression of sCLU was significantly correlated with lymph-node metastasis (p < 0.001), tumor invasion (p < 0.001) and TNM stage (p < 0.001). In Kaplan-Meier survival analysis, overexpression of sCLU was significantly correlated with unfavorable survival in advanced GCs (p < 0.03). Furthermore, the association of sCLU with abnormal expression of p53 was ascertained. These results suggested that overexpression of sCLU was involved in the progression of GC and it's oncogenic function might be associated with p53 abnormality. Overexpression of sCLU seems to be related with patient's shorter survival in late stage GC.
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Clusterina/fisiología , Neoplasias Gástricas/patología , Análisis de Matrices Tisulares/métodos , Adulto , Anciano , Anciano de 80 o más Años , Clusterina/análisis , Citoplasma/química , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Neoplasias Gástricas/química , Neoplasias Gástricas/mortalidad , Proteína p53 Supresora de Tumor/análisisRESUMEN
We tested the hypothesis that fluctuations in the levels of kynurenic acid (KYNA), an endogenous antagonist of the alpha7 nicotinic acetylcholine (ACh) receptor, modulate extracellular ACh levels in the medial prefrontal cortex in rats. Decreases in cortical KYNA levels were achieved by local perfusion of S-ESBA, a selective inhibitor of the astrocytic enzyme kynurenine aminotransferase II (KAT II), which catalyses the formation of KYNA from its precursor L-kynurenine. At 5 mm, S-ESBA caused a 30% reduction in extracellular KYNA levels, which was accompanied by a two-threefold increase in basal cortical ACh levels. Co-perfusion of KYNA in the endogenous range (100 nm), which by itself tended to reduce basal ACh levels, blocked the ability of S-ESBA to raise extracellular ACh levels. KYNA perfusion (100 nm) also prevented the evoked ACh release caused by d-amphetamine (2.0 mg/kg). This effect was duplicated by the systemic administration of kynurenine (50 mg/kg), which resulted in a significant increase in cortical KYNA formation. Jointly, these data indicate that astrocytes, by producing and releasing KYNA, have the ability to modulate cortical cholinergic neurotransmission under both basal and stimulated conditions. As cortical KYNA levels are elevated in individuals with schizophrenia, and in light of the established role of cortical ACh in executive functions, our findings suggest that drugs capable of attenuating the production of KYNA may be of benefit in the treatment of cognitive deficits in schizophrenia.
Asunto(s)
Acetilcolina/metabolismo , Astrocitos/metabolismo , Corteza Cerebral/metabolismo , Ácido Quinurénico/metabolismo , Terminales Presinápticos/metabolismo , Anfetamina/farmacología , Animales , Astrocitos/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Corteza Cerebral/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Ácido Quinurénico/antagonistas & inhibidores , Masculino , Antagonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Terminales Presinápticos/efectos de los fármacos , Ratas , Ratas Wistar , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Transaminasas/antagonistas & inhibidores , Transaminasas/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Fluctuations in the endogenous levels of kynurenic acid (KYNA), a potent alpha7 nicotinic and NMDA receptor antagonist, affect extracellular dopamine (DA) concentrations in the rat brain. Moreover, reductions in KYNA levels increase the vulnerability of striatal neurons to NMDA receptor-mediated excitotoxic insults. We now assessed the role of a key KYNA-synthesizing enzyme, kynurenine aminotransferase II (KAT II), in these processes in the rodent striatum, using KAT II KO mice-which have reduced KYNA levels-and the selective KAT II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (S-ESBA) as tools. S-ESBA (applied by reverse dialysis) raised extracellular DA levels in the striatum of KYNA-deficient mice threefold and caused a much larger, 15-fold increase in wild-type mice. In the rat striatum, S-ESBA produced a 35% reduction in extracellular KYNA, which was accompanied by a 270% increase in extracellular DA. The latter effect was abolished by co-infusion of 100 nM KYNA. Intrastriatal S-ESBA pre-treatment augmented the size of a striatal quinolinate lesion by 370%, and this potentiation was prevented by co-infusion of KYNA. In separate animals, acute inhibition of KAT II reduced the de novo synthesis of KYNA during an early excitotoxic insult without enhancing the formation of the related neurotoxic metabolites 3-hydroxykynurenine and quinolinate. Taken together, these results provide further support for the concept that KAT II is a critical determinant of functionally relevant KYNA fluctuations in the rodent striatum.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Líquido Extracelular/metabolismo , Ácido Quinurénico/antagonistas & inhibidores , Ácido Quinurénico/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacología , Animales , Animales Recién Nacidos , Cuerpo Estriado/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Líquido Extracelular/efectos de los fármacos , Lateralidad Funcional , Ácido Quinurénico/farmacología , Quinurenina/análogos & derivados , Quinurenina/farmacología , Ratones , Ratones Noqueados , Microdiálisis/métodos , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/patología , Degeneración Nerviosa/prevención & control , Norbornanos/farmacología , Ácido Quinolínico/toxicidad , Transaminasas/deficiencia , Tritio/metabolismoRESUMEN
Self-incompatibility (SI) has been studied extensively at the molecular level in Solanaceae, Rosaceae and Scrophulariaceae, all of which exhibit gametophytic self-incompatibility (GSI). In the present study, four PpsS-haplotypes (Prunus pseudocerasus S-haplotypes) comprising at least two genes, i.e., PpsS-RNase (P. pseudocerasus S-RNase) and PpsSFB (P. pseudocerasus S-haplotype-specific F-box) have been successfully isolated in tetraploid P. pseudocerasus Lindl. CV. Nanjing Chuisi ("NC") which exhibited self-compatibility (SC), and its S-genotype was determined as S-1/S-3'/S-5/S-7. These PpsS-RNases, which were expressed exclusively in style, shared the typical structural features with S-RNases from other Prunus species exhibiting GSI. All PpsSFBs showed similar structure characteristics of SFBs from other Prunus species, and matched with the necessary conditions for pollen S-determinant. No mutations leading to dysfunction of S-haplotype were found in their full-length c-DNA sequences, except for PpsS-3'-haplotype which was not amplified by PCR. These four S-haplotypes complied with tetrasomic inheritance. Diploid pollen grains with S-genotypes S-7/S-1, S-7/S-5 and S-1/S-5 can grow the full length of the style after self-pollination, while pollen grains with S-3'/S-7, S-3'/S-1 and S-3'/S-5 cannot. These results suggest that PpsS-haplotypes-1, -5 and -7 are functional, and that competitive interaction between two of them confer self-compatibility on cultivar "NC". Furthermore, in terms of recognition specificity, diploid pollen grains carrying PpsS-3'-haplotype are equal to monoploid pollen grains carrying the other functional S-haplotype.
Asunto(s)
Haplotipos , Polinización/genética , Prunus/crecimiento & desarrollo , Prunus/genética , Secuencia de Aminoácidos , Clonación Molecular , Proteínas F-Box/genética , Datos de Secuencia Molecular , Proteínas de Plantas/genética , Tubo Polínico/genética , Tubo Polínico/crecimiento & desarrollo , Poliploidía , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleasas/genética , Alineación de SecuenciaRESUMEN
Cockroach-derived materials are known to be a major source of potent aeroallergens, causing allergic respiratory diseases such as asthma and allergic rhinitis. The aim of this study was to determine the localization of the major allergen, Per a 3 (Cr-PI), within the American cockroach (Periplaneta americana), which might reveal the relative importance of excreted materials and nonexcreted cockroach components as allergen sources. American cockroaches (P. americana) and their faecal pellets were embedded in paraffin, and serial sections were cut and collected on glass slides. After being stained with mouse polyclonal antiserum against Per a 3, the sections were incubated sequentially with biotin-labelled sheep antimouse immunoglobulin G (IgG) and a preformed fluorescent isothiocyanate (FITC)-avidin complex. Finally, the sections were mounted and examined under a fluorescent microscope. Examination of Per a 3 immunoreactivity on the sections of the American cockroaches (P. americana) revealed that the midgut mucosa, gut contents and faecal pellets were all strongly labelled. Per a 3 immunoreactive products were not detected in any other internal organs of the American cockroaches. These results suggest that Per a 3 allergen might be synthesized in and secreted from the epithelia of the midgut mucosa and excreted from the body in the faecal pellets.
Asunto(s)
Alérgenos/análisis , Heces/química , Intestinos/inmunología , Periplaneta/inmunología , Animales , Distribución TisularRESUMEN
The N-methyl-d-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in two- to threefold increases in excitotoxic lesion size. Pre-treatment with a kynurenine 3-hydroxylase inhibitor or with dopamine receptor antagonists, i.e., two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum.