RESUMEN
BACKGROUND: Sugarcane mosaic virus (SCMV) is the prevalent virus inducing maize dwarf mosaic and sugarcane mosaic diseases in China. According to the phylogenetic results of the complete genomic and coat protein gene sequences, SCMV was divided into four or five molecular groups, respectively. Previously, we detected SCMV isolates of group SO from Canna spp. in Ji'nan, Shandong province, China. FINDINGS: In this study, we collected two SCMV isolates infecting Canna spp. in Ji'nan (Canna-Ji'nan) and Tai'an (Canna-Tai'an) of Shandong, China. Their complete genome sequences had genome of 9576 nucleotides and contained a large open reading frame encoding a polyprotein of 3063 amino acids. The phylogenetic analysis showed that the both Canna-Ji'nan and Canna-Tai'an were clustered into an independent group based on the complete genome sequence. CONCLUSION: In this study, we report the complete genome sequences of SCMV infecting Canna spp. from Ji'nan and Tai'an. This is the first report on SCMV belonging to SO group.
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Genoma Viral , Potyvirus/genética , Análisis de Secuencia de ADN , Zingiberales/virología , China , Análisis por Conglomerados , Sistemas de Lectura Abierta , Filogenia , Enfermedades de las Plantas/virología , Poliproteínas/genética , Potyvirus/clasificación , Potyvirus/aislamiento & purificación , Homología de Secuencia , Proteínas Virales/genéticaRESUMEN
Fosfomycin has become a therapeutic option in urinary tract infections. We identified 57 fosfomycin-resistant Escherichia coli from 465 urine-derived extended-spectrum ß-lactamase (ESBL)-producing isolates from a Chinese hospital during 2010-2014. Of the 57 fosfomycin-resistant isolates, 51 (89·5%) carried fosA3, and one carried fosA1. Divergent pulsed-field gel electrophoresis profiles and multi-locus sequence typing results revealed high clonal diversity in the fosA3-positive isolates. Conjugation experiments showed that the fosA3 genes from 50 isolates were transferable, with IncFII or IncI1 being the most prevalent types of plasmids. The high prevalence of fosA3 was closely associated with that of bla CTX-M. Horizontal transfer, rather than clonal expansion, might play a central role in dissemination. Such strains may constitute an important reservoir of fosA3 and bla CTX-M, which may well be readily disseminated to other potential human pathogens. Since most ESBL-producing E. coli have acquired resistance to fluoroquinolones worldwide, further spread of fosA3 in such E. coli isolates should be monitored closely.
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Farmacorresistencia Bacteriana , Infecciones por Escherichia coli/epidemiología , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Infecciones Urinarias/epidemiología , Orina/microbiología , beta-Lactamasas/genética , Antibacterianos/farmacología , China/epidemiología , Conjugación Genética , Electroforesis en Gel de Campo Pulsado , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Escherichia coli/aislamiento & purificación , Infecciones por Escherichia coli/microbiología , Fosfomicina/farmacología , Transferencia de Gen Horizontal , Variación Genética , Genotipo , Humanos , Tipificación de Secuencias Multilocus , Plásmidos/análisis , Plásmidos/clasificación , Prevalencia , Centros de Atención Terciaria , Infecciones Urinarias/microbiologíaRESUMEN
OBJECTIVE: Lung cancer (LC) is the highest contributor to cancer-associated mortality worldwide. Approximately 85% of all LC incidences involve non-small cell LC (NSCLC). Unfortunately, owing to a significant lack of sensitive and robust bioindicators, most patient diagnoses occur at advanced stages of the disease, thereby resulting in extremely poor patient outcomes. Herein, we elucidated the role of interleukin-17A (IL-17A) among NSCLC patients. MATERIALS AND METHODS: Circulating IL-17A content was measured using enzyme-linked immunosorbent assay (ELISA), and its diagnostic and prognostic abilities were assessed using the receiver operating characteristic (ROC) curve and Kaplan-Meier analysis, respectively. RESULTS: Our analysis revealed that circulating IL-17A levels were significantly augmented among NSCLC vs. control samples. Moreover, based on our area under the curve (AUC) analysis, circulating IL-17A levels fared considerably better than the standard bioindicator carcinoembryonic antigen (CEA) in both testing and validation cohorts. Notably, we also revealed that the circulating IL-17A levels were accurately and reliably predicted in early-stage NSCLC patients. Besides, we demonstrated a strong correlation between elevated circulating IL-17A expression and worse prognosis among NSCLC patients. CONCLUSIONS: Herein, we demonstrated that circulating IL-17A levels can serve as reliable and potent diagnostic and prognostic bioindicators for NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Biomarcadores Ambientales , Interleucina-17/metabolismo , Biomarcadores de Tumor , Pronóstico , Curva ROCRESUMEN
We analyzed data for 89 patients with leukemia undergoing bone marrow transplantation (BMT) (n=44) or peripheral blood stem cell transplantation (PBSCT) (n=45) from unrelated donors between May 2000 and February 2009 in our institution. PBSCT resulted in faster hematopoietic engraftment, compared with BMT (P<0.001). There was no difference between BMT and PBSCT in infectious episodes and CMV antigenemia within the first 100 days post-transplantation. The frequency of acute graft-versus-host disease (GVHD) grades II-IV was 49.7% and 47.0% (P=0.838) and of chronic GVHD 42.4% and 43.9% (P=0.827) in BMT and PBSCT. The 5-year cumulative percent of relapse was 18.5 in BMT and 48.6 in PBSCT (P=0.041), and the transplant-related mortality (TRM) was 40% and 29.5% (P=0.800), respectively. The 5-year cumulative percent of disease-free survival (DFS) was 50.8 and 38.9 (P=0.439); overall survival (OS) was 55.3% and 48.5% (P=0.447) in BMT and PBSCT, respectively. The reconstitution of T and B cells at 1, 3, 6, 9, and 12 months post-transplantation was not different between BMT and PBSCT, except that the level of regulatory T cells (T-regs) was higher after PBSCT than after BMT at 1 month (P=0.001).
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Trasplante de Médula Ósea , Leucemia/cirugía , Trasplante de Células Madre de Sangre Periférica , Donantes de Tejidos , Adolescente , Adulto , Trasplante de Médula Ósea/inmunología , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/patología , Humanos , Infecciones/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Adulto JovenRESUMEN
OBJECTIVE: To illustrate the biological function of long non-coding RNA (lncRNA) BCAR4 in triggering osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), thus mediating the progression of osteoporosis. MATERIALS AND METHODS: Relative levels of BCAR4 in BMSCs undergoing indicated time points of osteogenic differentiation were examined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). After intervening BCAR4 levels in osteogenically differentiated BMSCs, the relative levels of serum osteocalcin (OCN) and osteopontin (OPN) were detected, as well as ALP activity and mineralization capacity. Female Sprague Dawley (SD) rats were classified into sham group, BMSCs group (administration with BMSCs), RNAi group (administration with BMSCs transfected with si-BCAR4), and control group, with 10 rats per group. Osteoporosis model was generated in the latter three groups by resection of bilateral ovaries. Positive expressions of procollagen type I N propeptide (PINP) and ß-C-terminal telopeptide (ß-CTx), and ß-CTx in rats were determined by enzyme-linked immunosorbent assay (ELISA). Bone density in rat femurs and bone biomechanics were examined using the dual energy X-ray bone densitometer and the three-point bending test, respectively. RESULTS: BCAR4 was downregulated on the 3rd and 7th day of osteogenic differentiation in BMSCs. Overexpression of BCAR4 downregulated OCN and OPN. In the meantime, BCAR4 was able to weaken alkaline phosphatase (ALP) activity and mineralization capacity in BMSCs. The promotive effects of silenced BCAR4 on osteogenic potentials in BMSCs were abolished by overexpression of GLI2. In rats of RNAi group, positive expression of PINP and bone biomechanics were remarkably higher than BMSCs group, whereas they were lower than the sham group. Positive expression of ß-CTx was declined in RNAi group compared with that of BMSCs group, and it was still higher than that of sham group. CONCLUSIONS: BCAR4 is involved in the osteogenic differentiation of BMSCs. The knockdown of BCAR4 can alleviate the progression of osteoporosis.
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Osteoporosis/genética , ARN Largo no Codificante/genética , Animales , Diferenciación Celular/genética , Células Cultivadas , Regulación hacia Abajo/genética , Femenino , Silenciador del Gen , Células Madre Mesenquimatosas/metabolismo , Osteogénesis/genética , ARN Largo no Codificante/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Arterial stiffness may be an early marker for vascular changes associated with hypertension in young adults. Individuals with a family history of hypertension are at high risk of developing hypertension. We investigated whether arterial stiffness measured, such as mean arterial pressure (MAP) and brachial to ankle pulse wave velocity (baPWV), were increased in normotensive offspring with a parental history of hypertension. PATIENTS AND METHODS: We compared MAP and baPWV in a sample of 1953 non-hypertensive participants (974 men, mean age 42±3 years) recruited in the previous Hanzhong adolescent hypertension cohort study. Standardized questionnaires, physical examinations and laboratory tests were used to obtain information, with a particular focus on family hypertension history, anthropometric, hemodynamic, and biochemical factors. RESULTS: A total of 1039, 759, 155 participants had 0, 1, and 2 parents with hypertension, respectively. Parental hypertension was associated with elevated offspring MAP (in multivariable-adjusted models, B=1.5 mm Hg, 95% CI 0.8-2.2 for 1 parent with hypertension; B=3.0 mm Hg, 95% CI 1.8-4.3, for 2 parents with hypertension; p<0.001 for each). A significant positive correlation was also observed between MAP and baPWV (r=0.543, p<0.001). BaPWV displayed a similar correlation with parental hypertension in age-adjusted, sex-adjusted and body mass index (BMI)-adjusted models (B=23.1 cm/s, 95% CI 8.0-38.1, for 1 parent with hypertension, p<0.01; B=53.0 cm/s, 95% CI 25.8-80.2, p<0.001 for 2 parents with hypertension), but associations were attenuated in multicovariate models after adjustment for MAP. In multivariable-adjusted models, logistic regression analysis showed that the risk of belonging to the upper quartile of MAP was significantly increased for offspring whose parents had hypertension (OR=1.5, 95% CI 1.2-1.9, for 1 parent with hypertension; OR=2.3, 95% CI 1.6-3.4, for 2 parents with hypertension; p<0.001 for each). Similarly, the odds ratios of belonging to the upper quartile of baPWV increased (OR=1.3, 95% CI 1.1-1.6, for 1 parent with hypertension, p<0.05; OR=2.1, 95% CI 1.5-3.0, for 2 parents with hypertension, p<0.001, in age-sex-BMI-adjusted models), and were then brought down in the fully adjusted models including MAP, but the increase remained significant for 2 parents with hypertension (OR=1.6, 95% CI 1.0-2.3, p<0.05). CONCLUSIONS: These findings provide evidence that arterial stiffness is higher in young-to middle-aged normotensive subjects with a family history of hypertension, suggesting that increased arterial stiffness may occur in the early stages during the pathogenesis of hypertension.
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Hipertensión/diagnóstico , Rigidez Vascular , Adolescente , Adulto , Presión Sanguínea , Índice de Masa Corporal , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Padres , Análisis de la Onda del PulsoRESUMEN
OBJECTIVE: Researches on the potential correlation between Helicobacter pylori (Hp) infection and Crohn's disease (CD) are controversial. This study aims to clarify their correlation and provide a new theoretical basis for uncovering the pathogenesis of inflammatory bowel diseases (IBD). MATERIALS AND METHODS: Relevant literature has been searched reporting the correlation between Hp infection and susceptibility to CD in Medline, PubMed, and Cochrane Collaboration database published from 1991 to 2019. Data of the eligible literature were extracted and analyzed for the OR and the corresponding 95% CI using the Review Manager (RevMan) software. RESULTS: A total of 20 pieces of literature involving 2055 cases of CD patients and 3442 cases of controls were enrolled. Hp infection rate in CD patients and controls was 30.6% and 42.7%, respectively. There was a significant difference in Hp infection rate between CD patients and controls [OR=0.42, 95% CI (0.33-0.54), p<0.00001], showing a negative correlation. Heterogeneity existed between the included studies. CONCLUSIONS: Hp infection is a protective factor for CD. However, heterogeneity and publication bias may restrict the accuracy of the conclusions. It is necessary to further explore the potential influence of the Hp infection on CD.
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Enfermedad de Crohn/epidemiología , Infecciones por Helicobacter/epidemiología , Helicobacter pylori/inmunología , Enfermedad de Crohn/inmunología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/aislamiento & purificación , Humanos , Factores ProtectoresRESUMEN
OBJECTIVE: LncRNA MALAT1 has been proved to be involved in the development of various types of human cancers while the involvement of MALAT1 in tongue squamous cell carcinoma has not been reported. In view of this, our study aimed to investigate the functionality of MALAT1 in tongue squamous cell carcinoma. PATIENTS AND METHODS: The expression of MALAT1 in tumor tissues and adjacent healthy tissues of tongue cancer patients, and the serum from tongue cancer patients as well as healthy controls, were detected by quantitative Real Time-PCR (qRT-PCR). ROC curve analysis was performed to analyze the diagnostic value of plasma MALAT1 for tongue cancer. Survival curves were plotted using the Kaplan-Meier method to evaluate the prognostic value of plasma MALAT1 for tongue cancer. CCK-8 assay, transwell migration and invasion assay were performed to investigate the effects of MALAT1 knockdown on the proliferation, migration and invasion of tongue cancer cells, respectively. The effects of MALAT1 overexpression on the PI3K/Akt pathway and MMP-9 expression were detected by Western blot. RESULTS: The expression level of MALAT1 was remarkably higher in tumor tissues than that in adjacent healthy tissues. Serum MALAT1 was significantly higher in tongue cancer patients than in healthy controls. MALAT1 knockdown markedly inhibits the proliferation, migration and invasion of tongue cancer cells. MALAT1 knockdown also reduced the phosphorylation level of Akt as well as the expression level of MMP-9. It showed no significant effects on Akt expression, while PI3K activator treatment reduced the inhibitory effects of MALAT1 knockdown on the proliferation, migration and invasion of tongue cancer cells. CONCLUSIONS: LncRNA MALAT1 expression inhibition can inhibit the proliferation, migration and invasion of tongue cancer cells by inactivating the PI3K/Akt pathway and downregulating MMP-9. MALAT1 may serve as a target for the treatment of tongue squamous cell carcinoma.
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Regulación Neoplásica de la Expresión Génica , Metaloproteinasa 9 de la Matriz/genética , ARN Largo no Codificante/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Neoplasias de la Lengua/genética , Adulto , Anciano , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación hacia Abajo , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/sangre , ARN Largo no Codificante/genética , Transducción de Señal/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Lengua/patología , Neoplasias de la Lengua/sangre , Neoplasias de la Lengua/mortalidad , Neoplasias de la Lengua/patología , Adulto JovenRESUMEN
OBJECTIVE: Glucose transporter 1 (GLUT1) is a key player in glucose metabolism that has important roles in oral squamous cell carcinoma (OSCC), while microRNA-218 can target GLUT1 to achieve its biological roles. Therefore, we hypothesize that microRNA-218 may target GLUT1 to participate in OSCC. PATIENTS AND METHODS: Tumor tissues and adjacent healthy tissues were collected from OSCC patients, and blood samples were collected from both OSCC patients and healthy controls. Expression of microRNA-218 and GLUT1 in those tissues was detected by qRT-PCR. All patients were followed up for 5 years. Diagnostic and prognostic values of serum microRNA-218 for OSCC were investigated by ROC curve analysis and survival curve analysis, respectively. MicroRNA-218 knockdown OSCC cell lines were established. The effects on cell proliferation, glucose uptake as well as GLUT1 expression were detected by CCK-8 assay, glucose uptake assay and Western blot. RESULTS: MicroRNA-218 expression level was decreased while GLUT1 expression level was increased in tumor tissues compared with adjacent healthy tissues. Serum level of microRNA-218 was lower, while serum level of GLUT1 was higher in cancer patients than that in healthy control. Serum microRNA-218 and GLUT1 can be used to accurately predict OSCC and its prognosis. MicroRNA-218 knockdown promoted tumor cell proliferation, increased glucose uptake and promoted GLUT1 expression. CONCLUSIONS: Inhibition of microRNA-218 can promote oral cancer cell growth by targeting GLUT1 to affect glucose metabolism.
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Carcinoma de Células Escamosas/genética , Transportador de Glucosa de Tipo 1/genética , MicroARNs/genética , Neoplasias de la Boca/genética , Adulto , Anciano , Carcinoma de Células Escamosas/patología , Proliferación Celular/genética , Femenino , Glucosa/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: The changes in the gut barrier (GB) and associated mechanisms in postoperative ileus (POI) are still unclear. Toll-like receptor 4 (TLR4) is involved in inflammation, which may cause GB dysfunction and POI. Here, the roles of the GB in POI in relation to TLR4-dependent signaling pathways were explored. METHODS: POI was induced by small bowel manipulation in wild-type (WT) and TLR4-knockout (TLR4-/-) mice. Twenty-four hours after manipulation, indices of gastrointestinal (GI) transit, GB structure and function, inflammation, and related signaling pathways were analyzed. KEY RESULTS: Normal GI motility and GB function were not affected by TLR4 knockout. Compared with WT POI mice, TLR4-/-POI mice showed milder GI transit retardation, GB dysfunction, and inflammatory responses. In WT mice, GB disorder was characterized by colonic goblet cells depletion, increased gut claudin-2 expression, and decreased CD4+/CD8+ ratios in intestinal Peyer's patches. Green fluorescent protein-tagged Escherichia coli in the gut was detected in plasma and extraintestinal organs, followed with increased plasma lipopolysaccharide. These changes displayed in WT POI mice were less severe in TLR4-/-POI mice. Furthermore, the mRNA and protein expression of interleukin-6, monocyte chemotactic protein-1, pp38 and pJNK in the intestine, and TNF-α level in plasma were significantly increased in WT, but not TLR4-/-POI mice. CONCLUSIONS & INFERENCES: These results indicate that GB is impaired in the experimental POI, with inflammation being involved in this pathological process. TLR4 deficiency alleviated GB dysfunction and suppressed inflammation by disrupting the activation of mitogen-activated protein kinase signaling pathways, thereby ameliorating POI.
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Absorción Gastrointestinal/fisiología , Ileus/metabolismo , Complicaciones Posoperatorias/metabolismo , Receptor Toll-Like 4/deficiencia , Animales , Femenino , Ileus/etiología , Ileus/fisiopatología , Mediadores de Inflamación/metabolismo , Laparotomía/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/fisiopatologíaRESUMEN
The interaction of intrathecally (i.t.) applied galanin (GAL) with substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), somatostatin (SOM) and C-fibre conditioning stimulation (CS) with regard to their effects on the spinal nociceptive flexor reflex was studied in decerebrate, spinalized, unanaesthetized rats with intact or sectioned sciatic nerves. SP, CGRP, VIP and SOM applied onto the surface of lumbar spinal cord or a brief CS train (1 Hz, 20 s) to the sural nerve facilitated the flexor reflex for several minutes in animals with intact or sectioned nerves. Pretreatment with GAL, which by itself had a biphasic effect on the flexor reflex in a dose-dependent manner, antagonized the reflex facilitation induced by sural CS before and after sciatic nerve section. SP-induced facilitation of the flexor reflex was antagonized by GAL in rats with intact sciatic nerves, but not after nerve section. In contrast, VIP-induced reflex facilitation was antagonized by GAL only after sectioning of the sciatic nerve. GAL was effective in antagonizing the facilitatory effect of CGRP under both situations, but had no effect on SOM-induced facilitation. A parallel immunohistochemical study revealed that after sciatic nerve section GAL-like immunoreactivity (LI) and VIP-LI are increased in the dorsal root ganglia and that these two peptides coexist in many cells. The present results indicate that GAL antagonizes the excitatory effect of some neuropeptides which exist in the spinal cord. This antagonism could explain the inhibitory effect of GAL on C-fibre CS-induced facilitation of the flexor reflex, which is presumably due to the release of some of these neuropeptides from the terminals of primary afferents. Furthermore, the interaction between GAL and other neuropeptides is altered by sciatic nerve section, paralleling changes in the levels of these neuropeptides in primary afferents and their pattern of coexistence after nerve section. It is proposed that SP and CGRP are important mediators of the spinal flexor reflex in intact rats. However, after axotomy VIP may replace SP in this capacity, paralleling the decrease in SP and marked increase in VIP levels. In general the study provides further support for involvement of peptides in sensory function.
RESUMEN
We examined a pain-related syndrome, which includes mechanical allodynia and autotomy, in rats after ischemic spinal cord injury photochemically induced by laser irradiation for 5-20 min. This procedure results in an acute allodynia-like phenomenon which lasts for several days and is possibly related to dysfunction of the GABAB system in the spinal cord. In some animals this is followed by a chronic allodynia-like symptom with an onset varying between 1 week and 1.5 months after injury, expressed as a clearly painful reaction to light pressure applied to a skin area at or near the dermatome of the injured spinal segments. In the majority of rats the allodynia persists over several months, in some cases accompanied by autotomy of the hind paws. Pharmacological studies indicated that the allodynia in the majority of rats could be relieved by systemic tocainide (75 mg/kg). Morphine was only effective at a sedative dose (5 mg/kg). The allodynia was not relieved by baclofen, muscimol, clonidine or carbamazepine. Low-dose systemic pentobarbital (5 mg/kg) had a slight beneficial effect. Guanethidine (20 mg/kg, s.c.) did not abolish the allodynia in most of the rats. Histological examination revealed massive damage in the spinal cord. The dorsal roots of the irradiated segments were also injured. No morphological abnormalities were seen in the dorsal root ganglia. The mechanism that may account for this chronic pain-related syndrome in spinally injured rats probably involves abnormalities in the central nervous system. The allodynia seen in chronic spinally injured rats was similar to some painful symptoms in patients after spinal cord injury or stroke. It is suggested that the chronic allodynia-like phenomenon may represent an animal model for studying the mechanisms of chronic central pain.
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Isquemia/fisiopatología , Dolor/fisiopatología , Traumatismos de la Médula Espinal/fisiopatología , Médula Espinal/irrigación sanguínea , Animales , Conducta Animal/efectos de la radiación , Enfermedad Crónica , Modelos Animales de Enfermedad , Femenino , Isquemia/complicaciones , Isquemia/patología , Dolor/tratamiento farmacológico , Dolor/etiología , Ratas , Ratas Endogámicas , Automutilación , Umbral Sensorial/fisiología , Médula Espinal/patología , Médula Espinal/efectos de la radiación , Traumatismos de la Médula Espinal/patología , SíndromeRESUMEN
We report the discovery of F 13640 and evidence suggesting this agent to produce powerful, broad-spectrum analgesia by novel molecular and neuroadaptative mechanisms. F 13640 stimulates G(alphaomicron) protein coupling to 5-HT(1A) receptors to an extent unprecedented by selective, non-native 5-HT(1A) ligands. Fifteen minutes after its injection in normal rats, F 13640 (0.01-2.5 mg/kg) decreases the vocalization threshold to paw pressure; 15 min upon injection in rats that are exposed to formalin-induced tonic nociception, F 13640 inhibits pain behavior. The initial hyperalgesia induced by 0.63 mg/kg F 13640 was followed, 8 hrs later, by paradoxical hypo-algesia; 5 mg/kg of morphine produces the opposite effects (i.e., hypo-algesia followed by hyper-algesia). Repeated F 13640 injections cause an increase in the basal vocalization threshold and a reduction of F 13640-produced hyperalgesia; in these conditions, morphine causes basal hyperalgesia and antinociceptive tolerance. Continuous two-week infusion of F 13640 (0.63 mg/day) exerts little effect on the threshold in normal rats, but markedly reduces analgesic self-administration in arthritic rats. F 13640 infusion also decreases allodynic responses to tactile and thermal stimulations in rats sustaining spinal cord or sciatic nerve injury. In these models of chronic nociceptive and neuropathic pain, the analgesia afforded by F 13640 consistently surpasses that of morphine (5 mg/day), imipramine (2.5 mg/day), ketamine (20 mg/day) and gabapentin (10 mg/day). Very-high-efficacy 5-HT(1A) receptor activation constitutes a novel mechanism of central analgesia that grows rather than decays with chronicity, that is amplified by nociceptive stimulation, and that may uniquely relieve persistent nociceptive and neuropathic pains.
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Aminas , Aminopiridinas/farmacología , Analgesia , Ácidos Ciclohexanocarboxílicos , Morfina/farmacología , Piperidinas/farmacología , Piridinas/farmacología , Receptores de Serotonina/fisiología , Serotoninérgicos/farmacología , Ácido gamma-Aminobutírico , Acetatos/farmacología , Inhibidores de Captación Adrenérgica/farmacología , Aminopiridinas/agonistas , Analgésicos/farmacología , Animales , Células CHO , Células Cultivadas , Cricetinae , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos/veterinaria , Esquema de Medicación/veterinaria , Sinergismo Farmacológico , Femenino , Fentanilo/administración & dosificación , Gabapentina , Guanosina 5'-O-(3-Tiotrifosfato) , Hiperalgesia/inducido químicamente , Imipramina/farmacología , Ketamina/farmacología , Masculino , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Umbral del Dolor/fisiología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , Factores de Tiempo , TransfecciónRESUMEN
Mice with a targeted disruption of adenosine A(3) receptor (A(3)AR) gene were assessed for their nociceptive threshold and for their localized inflammatory response following carrageenan injected into the hindpaw. Under basal conditions no difference was seen between A(3)AR knock-out (A(3)AR(-/-)) and wild-type (A(3)AR(+/+)) mice in nociceptive response to mechanical or heat stimuli. The antinociceptive response to the intrathecal adenosine analogue R-phenylisopropyl adenosine (R-PIA) was also unchanged in the A(3)AR(-/-) mice. In contrast, heat hyperalgesia, plasma extravasation and edema following carrageenan-induced inflammation in the hind paw were significantly reduced in A(3)AR(-/-) mice compared to the A(3)AR(+/+) controls. Thus, mice lacking A(3)AR had deficits in generating the localized inflammatory response to carrageenan, supporting a pro-inflammatory role of A(3)AR in peripheral tissues. However, no evidence for a role of A(3)AR in nociception and the antinociceptive effect of R-PIA was found.
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Carragenina/efectos adversos , Umbral del Dolor/fisiología , Dolor/patología , Receptores Purinérgicos P1/deficiencia , Animales , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Dolor/inducido químicamente , Dolor/genética , Dolor/metabolismo , Dimensión del Dolor/métodos , Receptor de Adenosina A3 , Receptores Purinérgicos P1/genéticaRESUMEN
The neuropeptide galanin may have a role in modulation of nociception, particularly after peripheral nerve injury. The effect of galanin is mediated by at least three subtypes of receptors. In the present study, we assessed the nociceptive sensitivity in mice lacking the galanin receptor 1 gene (Galr1) and the development of neuropathic pain-like behaviours after photochemically induced partial sciatic nerve ischaemic injury. Under basal condition, Galr1 knock-out (Galr1(-/-)) mice had shortened response latency on the hot plate, but not tail flick and paw radiant heat, tests. The mechanical sensitivity was not different between Galr1(-/-) and wild type (Galr1(+/+)) mice, whereas the cold response was moderately enhanced in Galr1(-/-) mice. Both Galr1(-/-) mice and Galr1(+/+) controls developed mechanical and heat hypersensitivity after partial sciatic nerve injury. The duration of such pain-like behaviours was significantly increased in Galr1(-/-). The Galr1(-/-) mice and Galr1(+/+) mice did not differ in their recovery from deficits in toe-spread after sciatic nerve crush. The results provide some evidence for an inhibitory function for the neuropeptide galanin acting on galanin receptor 1 (GALR1) in nociception and neuropathic pain after peripheral nerve injury in mice.
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Hiperalgesia/metabolismo , Umbral del Dolor/fisiología , Receptores de Neuropéptido/biosíntesis , Receptores de Neuropéptido/deficiencia , Animales , Frío , Calor , Hiperalgesia/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Dimensión del Dolor/métodos , Receptores de Galanina , Receptores de Neuropéptido/genética , Neuropatía Ciática/metabolismoRESUMEN
A light-element radioactive ion-beam capability has been developed at the LBNL 88-Inch Cyclotron. The system is based on the coupled-cyclotrons method and utilizes short-lived species, e.g., 11C, 14O, 13N produced by (p,n) and (p,alpha) reactions at the LBNL Biomedical Isotope Facility Cyclotron. In a first experiment, 197Au(11C,xn)208-xAt excitation functions have been measured for energies ranging from the Coulomb barrier up to 110 MeV using a beam of 11C with intensities up to (1-2)x10(8) ions/sec on target. The results of this experiment are compared to measurements of 197Au(12C, xn)209-xAt excitation functions.
RESUMEN
The aim of this study was to investigate postprandial effects of two Chinese liquors on s elected cardiovascular disease risk factors in humans. Sixteen healthy men were randomized into three groups in a three-way crossover study: tea-flavor liquor (TFL), traditional Chinese liquor (TCL) and water control (WC). Every subject consumed 60 mL of either liquor (45% (v/v) ethanol) or water together with a high-fat meal, respectively. Compared with baseline, serum uric acid was significantly increased in TFL group (0.5-hour: P = 0.012; 1-hour: P = 0.001; 2-hour: P = 0.008) and it was significantly decreased in WC group (1-hour: P = 0.001; 2-hour: P = 0.001; 4-hour: P < 0.001), while uric acid was non-significantly increased in the TCL group. High-sensitive C-reactive protein (hs-CRP) was significantly increased in the TCL (P = 0.014) and WC (P = 0.008) groups at postprandial 4 hours compared with baseline. There was no significant difference between groups during the postprandial period for these two parameters or other biochemical parameters. In conclusion, both liquors increased postprandial uric acid, and no significant difference was observed for the effects of TFL and TCL on the measured biochemical parameters.
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Bebidas Alcohólicas/efectos adversos , Proteína C-Reactiva/metabolismo , Insulina/sangre , Lipoproteínas/sangre , Periodo Posprandial/efectos de los fármacos , Adulto , Enfermedades Cardiovasculares/sangre , Estudios Cruzados , Humanos , Masculino , Distribución Aleatoria , Factores de Riesgo , Ácido Úrico/sangre , Adulto JovenRESUMEN
BACKGROUND: Chronic pain of neuropathic nature after spinal cord injury (SCI) is common and its underlying mechanisms are poorly understood. Genes, as well as sex, have been implicated, but not thoroughly investigated in experimental genetic models for complex traits. We have previously found that inbred Dark-Agouti (DA) rats develop more severe SCI pain-like behaviour than a major histocompatibility complex-congenic Piebald Virol Glaxo (PVG)-RT1(av1) strain in a model of photochemically induced SCI. METHODS: In this study, a genome-wide linkage study in an F2 cross between the susceptible DA and resistant PVG-RT1(av1) strains was performed in order to explore the influence of genes and sex for SCI pain. RESULTS: A consistent finding was that female rats in parental, F1 and F2 generations displayed increased pain sensitivity at testing before injury and also developed mechanical hypersensitivity more rapidly and to a greater extent than male rats. In addition, we could identify three quantitative trait loci (QTLs) associated with pain-like behaviour: a sex-specific QTL on chromosome 2, one on chromosome 15 and on chromosome 6. Animals carrying DA alleles at each of these loci were more susceptible to development of mechanical hypersensitivity compared with rats with PVG alleles. CONCLUSION: This is the first whole genome QTL mapping of neuropathic pain-like behaviour in a model of SCI. The results provide strong support for a significant genetic and sex component in development of pain after SCI and provide the basis for further genetic dissection and positional cloning of the underlying genes.
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Conducta Animal , Neuralgia , Traumatismos de la Médula Espinal , Animales , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hiperalgesia/etiología , Hiperalgesia/genética , Hiperalgesia/fisiopatología , Masculino , Neuralgia/etiología , Neuralgia/genética , Neuralgia/fisiopatología , Umbral del Dolor , Sitios de Carácter Cuantitativo , Ratas , Ratas Endogámicas , Factores Sexuales , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
This study investigated the effect of using small interfering RNA (siRNA) to silence the wild-type FMS-like tyrosine kinase 3 (FLT3) gene in acute myeloid leukaemia (AML) cells, in vitro and in vivo. FLT3 siRNA was introduced into the human AML cell line, THP1, and into a THP1 xenograft tumour model in BALB/c nude mice. FLT3 siRNA effectively reduced both the mRNA and the protein levels of FLT3, arrested cells in G(0)/G(1) phase, inhibited THP1 cell proliferation and increased apoptosis. Intraperitoneal injection of FLT3 siRNA suppressed tumour growth in BALB/c nude mice. FLT3 siRNA treatment also reduced cyclin D1 and Bcl-2 protein levels, and increased the nuclear level of silencing mediator for retinoic acid and thyroid hormone receptors protein both in vitro and in vivo. These data suggest that FLT3 siRNA is a strong inhibitor of FLT3 expression in vitro and in vivo, and may provide a new therapeutic target for AML.