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OBJECTIVE: In this study, the antidiabetic efficacy of Protaetia brevitarsis in alloxan-treated pancreatic islets and db/db mice was investigated. P. brevitarsis was tested for alloxan-mediated cytotoxicity and nitric oxide production in mice pancreatic islets. MATERIALS AND METHODS: The anti-diabetic effect of P. brevitarsis was also evaluated in db/db mice after 4 weeks of administration. Biochemical analysis, oral glucose tolerance test (OGTT), and pancreatic histological analysis were performed. RESULTS: P. brevitarsis displayed hypoglycemic activity in alloxan-treated mice pancreatic islets. Our results showed that P. brevitarsis protects pancreatic islets from cytotoxicity. Moreover, daily oral supplementation with P. brevitarsis for 4 weeks reduced plasma glucose levels without affecting body weight and food intake, elevated glucose tolerance in OGTT, improved blood lipid parameters, inhibited fat accumulation, and restored islet structure of db/db mice. CONCLUSIONS: The present study provided evidence for the antidiabetic effect of P. brevitarsis in alloxan-treated pancreatic islets and db/db mice. These results suggest that P. brevitarsis may be used as an adjunctive anti-diabetic agent or as a functional food.
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Productos Biológicos/farmacología , Escarabajos , Diabetes Mellitus Experimental/tratamiento farmacológico , Islotes Pancreáticos/efectos de los fármacos , Aloxano , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/metabolismoRESUMEN
OBJECTIVE: Cisplatin is a widely used anticancer drug that provokes various side effects. Nephrotoxicity is one of the well-known major side effects in the chemotherapeutic use of cisplatin. Reactive oxygen species (ROS) and p53 play important roles in cisplatin-induced nephrotoxicity. AMP-activated protein kinase (AMPK) is known to be sensitively activated by ROS and can directly activate p53. The present study investigated the role of AMPK on cisplatin-induced apoptosis in rat renal epithelial NRK-52E cells. MATERIALS AND METHODS: NRK-52E cells were treated with cisplatin in the absence or presence of specific ROS scavenger and AMPK inhibitor for indicated times under the serum-free condition. The expression and phosphorylation levels of proteins were evaluated by Western blot and densitometry analysis. RESULTS: Cisplatin induced apoptotic cell death through ROS-mediated p53 activation, which is associated with AMPK activation. AMPK inhibitor suppressed cisplatin-induced p53 activation, as well as AMPK activation. Interestingly, ROS scavenger also diminished cisplatin-induced p53 activation and AMPK activation. Furthermore, cisplatin induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuated p53 activation, but did not affect the expression levels of total p53, cleaved caspase-3 and PARP. Meanwhile, inhibition of AMPK induced premature phosphorylation of eIF2α in cisplatin-treated cells. CONCLUSIONS: Taken together, these suggest that AMPK may be required for activation of p53 by oxidative stress in cisplatin-induced nephrotoxicity. Moreover, eIF2α phosphorylation may interrupt the AMPK-activated p53 in NRK-52E cells exposed to cisplatin, but does not critically affect cisplatin-induced nephrotoxicity because AMPK activation can be disrupted eIF2α phosphorylation.
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Proteínas Quinasas Activadas por AMP/metabolismo , Antineoplásicos/toxicidad , Cisplatino/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Factor 2 Eucariótico de Iniciación/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Estrés Oxidativo/efectos de los fármacos , RatasRESUMEN
CONTEXT AND OBJECTIVE: The risk of needing lifelong thyroid hormone supplementation is an important factor affecting treatment decisions for both patients and clinicians ahead thyroid lobectomy. The purposes of this study were to assess the predictive factors of levothyroxine medication after thyroid lobectomy. METHODS: We retrospectively reviewed 252 patients who had undergone lobectomy for benign thyroid nodules between April 2009 and April 2017. We conducted two independent analyses: patients who started taking levothyroxine after surgery were compared with those who did not, and patients who did not need levothyroxine at last follow-up were compared with those who required continued treatment. We investigated the correlations of patient clinicopathological characteristics and levothyroxine medication after lobectomy. RESULTS: Ninety-eight patients started levothyroxine after surgery. Of these, 34 patients successfully ceased medication and 64 patients continued treatment as of their last follow-up. In multivariate analysis, older age and preoperative TSH ≥2.0mIU/L were associated with levothyroxine initiation after surgery. In terms of continuity of levothyroxine, both older age and TSH ≥ 3.0mIU/L showed a significant correlation with continuous medication. We created a risk-scoring system to predict likelihood of starting and maintaining levothyroxine using the two significant factors in each comparison. A risk score of 3 or more indicated an increased risk of starting levothyroxine (specificity = 81.8%; sensitivity = 48.0%). A risk score of 3 or more indicated increased risk of continuous medication, (specificity = 94.2%; sensitivity = 35.9%). CONCLUSIONS: Greater age and higher preoperative TSH levels correlated with initiation and continuity of levothyroxine medication after lobectomy.
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OBJECTIVE: This study aimed to identify the effect of lateral neck dissection on voice change in thyroidectomised patients. METHODS: Medical records from 264 patients who underwent thyroidectomy with (n = 65) or without (n = 199) lateral neck dissection were reviewed. Clinical and voice evaluation data were compared between the two groups. RESULTS: Patients who underwent surgery that included lateral neck dissection had lower fundamental frequencies and speaking fundamental frequencies. They also had a higher incidence of asymmetric mucosal wave and vocal fold oedema on videostroboscopy during the first month after surgery, with the incidence of vocal fold oedema remaining significantly higher at three months. Self-assessed voice quality scores were significantly higher in lateral neck dissection patients at both one and three months after surgery. CONCLUSION: In thyroidectomised patients, lateral neck dissection lowers the vocal pitch in the initial period after surgery and induces vocal fold oedema that persists for several months. Although most objective parameters improved within a month, subjective symptoms lasted for longer.
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Disección del Cuello/efectos adversos , Neoplasias de la Tiroides/cirugía , Tiroidectomía/métodos , Trastornos de la Voz/epidemiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Trastornos de la Voz/etiología , Calidad de la VozRESUMEN
OBJECTIVE: Nephrotoxicity is one of the major side effects that limit the use of cisplatin in cancer therapy. Cisplatin-induced apoptosis in renal cells is associated with reactive oxygen species (ROS)-mediated p53 activation. Licorice (Glycyrrhiza uralensis Fischer) is one of the most widely used medicinal herbs in Korea, China and Japan. The aim of the study was to evaluate the protective effects of licorice extract (LE) and its active compound glycyrrhizic acid (GA) against cisplatin-induced nephrotoxicity in human renal proximal tubular epithelial (HK-2) cells. MATERIALS AND METHODS: HK-2 cells were pretreated with LE or GA for 1 h and then treated with 40 µM of cisplatin for indicated times under the serum-free condition. Cell viability was evaluated by MTT assay. Apoptosis was evaluated by flow cytometric analysis and caspase-3 activity. The intracellular ROS levels were determined by DCFH-DA assay. The expression and phosphorylation levels of protein were evaluated by Western blot and densitometry analysis. RESULTS: When treating HK-2 cells with LE or GA, both of them alleviated cisplatin-induced cytotoxicity and apoptosis. LE and GA inhibited caspase-3 activity and polymerase (PARP) cleavage in cisplatin-treated cells. LE and GA also inhibited p53 expression and its phosphorylation as well as ROS production in cells exposed to cisplatin. Meanwhile, LE and GA enhanced cisplatin-induced p21 expression, which then led to S-phase arrest in cell cycle and limited cell growth. Presumably, increased p21 expression may contribute to cellular prevention from cisplatin-induced apoptosis, because p21 is the key molecule to cytoprotection during cisplatin-induced nephrotoxicity. CONCLUSIONS: These results suggest that LE and GA ameliorate cisplatin-induced apoptosis through reduction of ROS-mediating p53 activation and promotion of p21 expression in HK-2 cells.
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Cisplatino/efectos adversos , Células Epiteliales/efectos de los fármacos , Ácido Glicirrínico/farmacología , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/efectos adversos , Apoptosis/efectos de los fármacos , Línea Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Células Epiteliales/metabolismo , Glycyrrhiza/química , Humanos , Túbulos Renales Proximales/citología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The toxicity of the antifouling biocides Irgarol 1051, Diuron, Chlorothalonil, Dichlofluanid, Sea-nine 211, Copper pyrithione, Zinc pyrithione, Ziram and Zineb were evaluated on Nitzschia pungens and Artemia larvae. Results showed that EC50 for Irgarol 1051 was 0.586µgl-1 was the strongest effect on N. pungens following by Copper pyrithione (4.908µgl-1), Ziram (5.421µgl-1), Zinc pyrithione (5.513µgl-1), Diuron (6.640µgl-1), Zineb (232.249µgl-1), Sea-nine 211(267.368µgl-1), Chlorothalonil (360.963µgl-1) and Dichlofluanid (377.010µgl-1) in 96h. In Artemia larvae, the biocides were evaluated the LC50 for larval survivals at 48h. Sea-nine 211 and Copper pyrithione were 0.318 and 0.319mgl-1. Chlorothalonil, Zinc pyrithione and Ziram were 2.683, 3.147 and 4.778mgl-1. Irgarol 1051, Diuron, Zineb and Dichlofluanid were 9.734, 30.573, 41.170 and 154.944mgl-1. These results provide baseline data concerning the toxicity of antifouling biocides against marine environment.
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Artemia/efectos de los fármacos , Diatomeas/efectos de los fármacos , Desinfectantes/toxicidad , Fitoplancton/efectos de los fármacos , Zooplancton/efectos de los fármacos , Compuestos de Anilina/toxicidad , Animales , Dimetilsulfóxido , Diurona/toxicidad , Larva/efectos de los fármacos , Nitrilos/toxicidad , Compuestos Organometálicos/toxicidad , Piridinas/toxicidad , Pruebas de Toxicidad Aguda , Triazinas/toxicidad , Contaminantes Químicos del Agua/toxicidadRESUMEN
While the past 2 decades have witnessed an increasing understanding of amyotrophic lateral sclerosis (ALS) arising from East Asia, particularly Japan, South Korea, Taiwan and China, knowledge of ALS throughout the whole of Asia remains limited. Asia represents >50% of the world population, making it host to the largest patient cohort of ALS. Furthermore, Asia represents a diverse population in terms of ethnic, social and cultural backgrounds. In this review, an overview is presented that covers what is currently known of ALS in Asia from basic epidemiology and genetic influences, through to disease characteristics including atypical phenotypes which manifest a predilection for Asians. With the recent establishment of the Pan-Asian Consortium for Treatment and Research in ALS to facilitate collaborations between clinicians and researchers across the region, it is anticipated that Asia and the Pacific will contribute to unravelling the uncertainties in ALS.
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Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/epidemiología , Enfermedad de la Neurona Motora/complicaciones , Enfermedad de la Neurona Motora/epidemiología , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/mortalidad , Asia/epidemiología , Progresión de la Enfermedad , Humanos , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/mortalidad , Fenotipo , SíndromeRESUMEN
BACKGROUND: Bacterial flagellin, a Toll-like receptor 5 agonist, is used as an adjuvant for immunomodulation. In this study, we aimed to evaluate the effect and its mechanism following intralymphatic administration of OVA-flagellin (FlaB) mixture in the mouse model of allergic rhinitis. MATERIALS AND METHODS: BALB/c mice were sensitized with OVA and treated with an OVA-FlaB mixture via intranasal, sublingual, and intralymphatic routes to evaluate the effect of each treatment. Several parameters for allergic inflammation and its underlying mechanisms were then evaluated. RESULTS: Intralymphatic injection of the OVA-FlaB mixture reduced symptom scores, eosinophil infiltration in the nasal mucosa, and total and OVA-specific IgE levels more significantly than intranasal and sublingual administration. Systemic cytokine (IL-4, IL-5, IL-6, IL-17, and IFN-γ) production and local cytokine (IL-4 and IL-5) production were also reduced significantly after intralymphatic injection with OVA-FlaB. Double intralymphatic injection of the mixture was more effective than single injection. Moreover, the expression of innate cytokines such as IL-25 and IL-33 in nasal epithelial cells was reduced, and the expression of chemokines such as CCL24 (eotaxin-2), CXCL1, and CXCL2 was decreased in the nasal mucosa, suggesting the underlying mechanism for intralymphatic administration of the OVA-FlaB mixture. CONCLUSION: Intralymphatic administration of an OVA-FlaB mixture was more effective in alleviating allergic inflammation than intranasal and sublingual administration in a mouse model of allergic rhinitis. This effect may be attributed to the reduced expression of innate cytokines and chemokines. This treatment modality can be considered as a new therapeutic method and agent.
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Alérgenos/inmunología , Flagelina/inmunología , Ovalbúmina/inmunología , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/inmunología , Alérgenos/administración & dosificación , Animales , Especificidad de Anticuerpos/inmunología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Eosinófilos/metabolismo , Eosinófilos/patología , Femenino , Flagelina/administración & dosificación , Inmunización/métodos , Inmunoglobulina E/inmunología , Inmunohistoquímica , Ratones , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Mucosa Nasal/patología , Infiltración Neutrófila/inmunología , Ovalbúmina/administración & dosificación , Rinitis Alérgica/metabolismo , Rinitis Alérgica/terapia , Índice de Severidad de la Enfermedad , Bazo/citología , Bazo/inmunología , Bazo/metabolismoRESUMEN
BACKGROUND AND PURPOSE: It is known that underlying diabetes mellitus (DM) can affect the clinical and electrophysiological pattern of coexisting peripheral neuropathies of other etiologies. The aim of this study was to identify the effect of underlying DM on the clinical and electrophysiological features of Guillain-Barré syndrome (GBS) and on the prognosis of GBS with regard to functional outcome. METHODS: This study prospectively included 27 GBS patients with DM (GBS-DM+) and 58 GBS patients without DM (GBS-DM-) from two university-based hospitals. The clinical and electrophysiological findings were compared between the two groups. The functional outcomes were quantified by measuring the Hughes grade, whose values were compared between the groups at 3 months after symptom onset. RESULTS: All three sudden deaths that occurred during the acute stage of GBS were GBS-DM+ patients. GBS-DM+ patients had a tendency toward more frequent sensory involvement, and specific electrophysiological patterns and calculated indices disclosed a distal accentuation of conduction abnormalities in these patients. In addition, multivariate analysis identified history of mechanical ventilation (odds ratio 10.057, 95% confidence interval 2.057-49.164, P = 0.04) and DM (odds ratio 9.049, 95% confidence interval 2.152-38.044, P = 0.003) as independent factors for poor functional outcome at 3 months. CONCLUSIONS: The findings of this study suggest that DM exacerbates the clinical and electrophysiological features of GBS and influences long-term disability. Both chronic inflammation and nerve ischaemia in DM may intervene in the disease course of GBS, which is a prototype of acute inflammatory neuropathy.
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Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus/fisiopatología , Síndrome de Guillain-Barré/fisiopatología , Conducción Nerviosa/fisiología , Adulto , Anciano , Comorbilidad , Complicaciones de la Diabetes/epidemiología , Diabetes Mellitus/epidemiología , Femenino , Síndrome de Guillain-Barré/epidemiología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A variant of Guillain-Barré syndrome (GBS) with predominant manifestation of facial diplegia (FD) has been described recently. This study aimed to characterize and determine the incidence of this FD-predominant GBS variant. The clinical and serological information of 900 consecutive patients were reviewed. In total, eight patients were identified between January 2007 and December 2010 as having FD accompanied by some features of GBS. These features were subjective sensory symptoms such as distal paresthesia (7/8, 88%), albumin-cytological (A/C) dissociation (7/8, 88%), antecedent infection (6/8, 75%), and minor nerve conduction study (NCS) abnormalities (5/7, 71%). One patient presented with the typical NCS feature of demyelinating neuropathy. Only two patients exhibited areflexia (2/8, 25%). None of the patients possessed any anti-ganglioside antibodies; however, the serum of two patients was positive for anti-mycoplasma antibody (2/6, 33%). FD variant of GBS occurred in less than 1% of our dataset. FD can be a regional variant of GBS when it is accompanied by supporting features, such as subjective tingling, A/C dissociation, and minor NCS abnormalities.
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Autoanticuerpos/sangre , Parálisis Facial/diagnóstico , Parálisis Facial/fisiopatología , Gangliósidos/inmunología , Síndrome de Guillain-Barré/fisiopatología , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa/fisiología , Estudios Retrospectivos , Adulto JovenRESUMEN
Sepsis is a life-threatening condition that arises when the body's response to infection causes systemic inflammation. High-mobility group box 1 (HMGB1), as a late mediator of sepsis, enhances hyperpermeability, and it is therefore a therapeutic target. Despite extensive research into the underlying mechanisms of sepsis, the target molecules controlling vascular leakage remain largely unknown. Moesin is a cytoskeletal protein involved in cytoskeletal changes and paracellular gap formation. The objectives of this study were to determine the roles of moesin in HMGB1-mediated vascular hyperpermeability and inflammatory responses and to investigate the mechanisms of action underlying these responses. Using siRNA knockdown of moesin expression in primary human umbilical vein endothelial cells (HUVECs), moesin was found to be required in HMGB1-induced F-actin rearrangement, hyperpermeability, and inflammatory responses. The mechanisms involved in moesin phosphorylation were analysed by blocking the binding of the HMGB1 receptor (RAGE) and inhibiting the Rho and MAPK pathways. HMGB1-treated HUVECs exhibited an increase in Thr558 phosphorylation of moesin. Circulating levels of moesin were measured in patients admitted to the intensive care unit with sepsis, severe sepsis, and septic shock; these patients showed significantly higher levels of moesin than healthy controls, which was strongly correlated with disease severity. High blood moesin levels were also observed in cecal ligation and puncture (CLP)-induced sepsis in mice. Administration of blocking moesin antibodies attenuated CLP-induced septic death. Collectively, our findings demonstrate that the HMGB1-RAGE-moesin axis can elicit severe inflammatory responses, suggesting it to be a potential target for the development of diagnostics and therapeutics for sepsis.
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Permeabilidad Capilar/fisiología , Proteína HMGB1/toxicidad , Sepsis/sangre , Actinas/análisis , Animales , Ciego/lesiones , Adhesión Celular , Moléculas de Adhesión Celular/biosíntesis , Movimiento Celular , Citoesqueleto/ultraestructura , Modelos Animales de Enfermedad , Células Endoteliales de la Vena Umbilical Humana , Humanos , Perforación Intestinal/sangre , Lipopolisacáridos/farmacología , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos , Neutrófilos/citología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional , Proteínas Tirosina Quinasas/fisiología , Interferencia de ARN , ARN Interferente Pequeño/genética , Receptor para Productos Finales de Glicación Avanzada/fisiología , Índice de Severidad de la Enfermedad , Choque Séptico/sangre , Transducción de SeñalRESUMEN
AIM: Right retroesophageal lymph nodes (RRLNs) should be involved in central lymph nodes (CLNs) dissection in patients with papillary thyroid cancer (PTC). This study assessed the incidence and factors related to RRLNs metastasis. METHODS: From January 2008 to March 2010, 129 patients who underwent total thyroidectomy with CLNs dissection including RRLNs were enrolled. The predictive value of RRLNs metastasis was assessed. RESULTS: Twenty six (20.1%) of 129 patients exhibited nodal metastasis in RRLNs. Metastasis of RRLNs was associated with large tumor size (>1 cm; P<0.01), multiplicity (P=0.03), preoperative LN enlargement (P<0.01), metastasis of non-retroesophageal lateral LN (P<0.01) and large number of CLNs metastases (P<0.01) in univariate analysis. Multivariate analysis revealed that tumor size (>1 cm) and metastasis of non-retroesophageal lateral LN were independent correlates of RRLNs metastases. CONCLUSION: RRLNs may be removed during operation for PTC, particularly in patients with tumor >1 cm and lateral LN metastases.
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Carcinoma/secundario , Carcinoma/cirugía , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/cirugía , Tiroidectomía , Adolescente , Adulto , Anciano , Carcinoma/epidemiología , Carcinoma Papilar , Niño , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Disección del Cuello , Invasividad Neoplásica , República de Corea/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/secundario , Resultado del TratamientoRESUMEN
AIM: Sepsis is a systemic inflammatory response syndrome resulting from a microbial infection. Transforming growth factor ß-induced protein (TGFBIp) is an extracellular matrix protein expressed by human endothelial cells and platelets that induces sepsis through interaction with integrin αvß5. The aim of this study was to investigate the role of TGFBIp in vascular permeability and the underlying mechanisms using TGFBIp-neutralizing antibody. METHODS: Mice were subjected to caecal ligation and puncture (CLP) with or without neutralizing anti-TGFBIp antibody (300 µg kg(-1), intravenously). Wild-type or integrin ß5-null mice received TGFBIp (0.1 mg kg(-1), intravenously) or were subjected to CLP. Human umbilical vein endothelial cells were exposed to lipopolysaccharide (100 ng mL(-1)) with or without neutralizing anti-TGFBIp antibody (50 µg mL(-1)). RESULTS: Administration of neutralizing anti-TGFBIp antibody in mice attenuated CLP-induced secretion of TGFBIp, leucocyte migration and vascular permeability and reduced septic mortality. Injected TGFBIp did not enhance vascular barrier permeability or leucocyte migration in ß5-null mice. Finally, neutralizing anti-TGFBIp antibody inhibited the specific interactions between TGFBIp and its receptor, integrin αvß5. CONCLUSION: Our findings demonstrate that treatment with a TGFBIp-neutralizing antibody can ameliorate the deleterious effects of sepsis.
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Anticuerpos Monoclonales/uso terapéutico , Permeabilidad Capilar/inmunología , Receptores de Vitronectina/inmunología , Sepsis/inmunología , Sepsis/terapia , Factor de Crecimiento Transformador beta/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Inmunoterapia/métodos , Masculino , Ratones , Ratones Noqueados , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Inflammatory demyelinating disease (IDD), which includes multiple sclerosis (MS) and neuromyelitis optica (NMO), affects the central nervous system. Chemokine ligand 2 (CCL2/MCP-1) is considered an important contributor to the development or progression of IDD. However, genetic association studies of Asian populations are lacking. In this study, we investigated a possible association between CCL2 polymorphisms (rs1024611, rs28730833, and rs2857657) and a Korean population (178 IDD patients and 237 healthy controls) using multiple logistic regression models. However, we did not find any association, which was consistent with other studies in Caucasian populations. In conclusion, our results suggest that CCL2 variants may not contribute to the pathogenesis of IDD.
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Pueblo Asiatico/genética , Quimiocina CCL2/genética , Enfermedades Desmielinizantes/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Inflamación/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Enfermedades Desmielinizantes/complicaciones , Femenino , Frecuencia de los Genes/genética , Haplotipos/genética , Humanos , Inflamación/complicaciones , Desequilibrio de Ligamiento/genética , Modelos Logísticos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Salivary gland epithelial cells (SGEC) release several cytokines that play important roles in the inflammatory process. In this study, we examined whether capsaicin can modulate cytokine release in SGEC. After cells were stimulated with polyinosinic-polycytidylic acid [poly(I:C)] or lipopolysaccharide (LPS), mRNA transcript and protein levels were detected by reverse-transcriptase-polymerase chain-reaction (RT-PCR), real-time PCR, and enzyme-linked immunosorbent assay (ELISA). These findings demonstrated that the increases in TNFα and IL-6 mRNA transcripts were highest at 3 hrs and 1 hr after incubation with poly(I:C) and LPS, respectively. Pre-treatment of the cells with 10 µµ capsaicin, however, significantly inhibited mRNA transcripts and its protein levels. The simultaneous application of 10 µµ capsazepine with capsaicin did not block the inhibitory effect of capsaicin. Furthermore, the inhibitory effect of capsaicin was also shown in primary cultured cells from TRPV1(-/-) mice. We found that both poly(I:C) and LPS induced IκB-α degradation and phosphorylation, which resulted in NF-κB activation, and capsaicin inhibited this NF-κB pathway. These results demonstrate that SGEC release pro-inflammatory cytokines mediated by TLR, and capsaicin inhibits this process through the NF-κB pathway. This study suggests that capsaicin could potentially alleviate inflammation in salivary glands.
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Antiinflamatorios/farmacología , Capsaicina/farmacología , FN-kappa B/efectos de los fármacos , Sialadenitis/inmunología , Animales , Capsaicina/análogos & derivados , Células Cultivadas , Citocinas/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Escherichia coli , Proteínas I-kappa B/efectos de los fármacos , Mediadores de Inflamación/farmacología , Interleucina-6/análisis , Lipopolisacáridos/farmacología , Ratones , Inhibidor NF-kappaB alfa , FN-kappa B/antagonistas & inhibidores , Fosforilación , Poli I-C/farmacología , Conductos Salivales/citología , Conductos Salivales/efectos de los fármacos , Glándula Submandibular/citología , Glándula Submandibular/efectos de los fármacos , Canales Catiónicos TRPV/efectos de los fármacos , Factores de Tiempo , Receptores Toll-Like/efectos de los fármacos , Factor de Necrosis Tumoral alfa/efectos de los fármacosRESUMEN
AIMS: Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory autoimmune diseases that affect the central nervous system. Several genome-wide and candidate gene studies have identified genetic polymorphisms associated with the risk of MS or NMO. In particular, two recently published studies of meta-analysis in European-origin populations have suggested associations of single-nucleotide polymorphisms (SNPs) in CD6, TNFRSF1A and IRF8 with MS. The aim of our study was to assess the associations between SNPs in these three genes and the risk of inflammatory demyelinating disease (IDD) including MS and NMO. To the best of our knowledge, this is the first time such a study has been performed in an Asian population. METHODS: A total of 21 SNPs of CD6, TNFRSF1A and IRF8 were genotyped in 178 IDD cases (79 MS and 99 NMO patients) and 237 normal controls in a Korean population. RESULTS: Logistic analyses revealed that one SNP in CD6 (rs12288280, P = 0.04) and three SNPs in TNFRSF1A (rs767455, rs4149577 and rs1800693, P = 0.01-0.03) were associated with NMO. However, there was no association of IRF8 polymorphisms with IDD, including MS and NMO. Using further information from the SNP Function Prediction website, two exonic splicing enhancers (ESEs), including the polymorphic site of rs767455, were predicted to be binding sites for splicing factors (SRp55, SF2/ASF2 and SF2/ASF1). CONCLUSION: Although additional studies are needed, our findings could provide information regarding the genetic aetiology of IDD in the Korean population.
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Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/genética , Predisposición Genética a la Enfermedad , Factores Reguladores del Interferón/genética , Esclerosis Múltiple/genética , Neuromielitis Óptica/genética , Polimorfismo de Nucleótido Simple , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Adolescente , Adulto , Anciano , Pueblo Asiatico/genética , Niño , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , República de CoreaRESUMEN
BACKGROUND: The etiology of aspirin-exacerbated respiratory disease (AERD) has been attributed to the combination of environmental and genetic risk factors. Although widely investigated in various diseases associated with immune dysfunction, the human zinc ribbon domain containing 1 (ZNRD1) gene is thought to play a role in the pathogenesis of AERD by altering the mechanisms involved in disease development. METHODS: We selected 6 single-nucleotide polymorphisms (SNPs) for genotyping from the International HapMap database in order to analyze the association between polymorphisms in ZNRD1 and AERD in a Korean asthma cohort. Genotyping was carried out using the TaqMan assay, and differences in genotype frequency distributions were analyzed using logistic regression models. RESULTS: Nominal associations were found between ZNRD1 rs1150740 and risk ofAERD via codominant and dominant genetic inheritance (P=.03; odds ratio, 1.14 [1.14-10.16]). The same polymorphism was found to be significantly associated with a decrease in forced expiratory volume in the first second of expiration, an important diagnostic marker of AERD, even after multiple testing corrections (P=.006, P(corr)=.03 in codominant and dominant models). CONCLUSIONS: These preliminary findings suggest a possible relationship between ZNRD1 and aspirin-induced respiratory dysfunctions in a Korean population and provide essential information on the etiology of AERD.
Asunto(s)
Pueblo Asiatico/genética , Aspirina/efectos adversos , Proteínas de Unión al ADN/genética , Enfermedades Respiratorias/inducido químicamente , Enfermedades Respiratorias/genética , Adolescente , Adulto , Anciano , Asma/inducido químicamente , Asma/genética , Broncoconstricción/efectos de los fármacos , Broncoconstricción/genética , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Proyecto Mapa de Haplotipos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Adulto JovenRESUMEN
Aspirin-exacerbated respiratory disease (AERD) is prevalent in about 10% of asthma patients and is characterized by a severe decline in forced expiratory volume in 1-s (FEV(1) ), an important phenotype for total lung capacity, upon ingestion of aspirin. The general transcription factor IIH subunit 4 (GTF2H4) is positioned at 6p21.33, a part of the major histocompatibility complex (MHC) class II region that contains a number of genes that play an important role in the immune system. In addition, genetic variants in another general transcription factor IIH gene have revealed significant association with lung disease. To investigate whether GTF2H4 genetic variants could be a causative factor for AERD development and FEV(1) decline by aspirin provocation, five common single-nucleotide polymorphisms (SNPs) were genotyped in 93 patients with AERD and 96 aspirin-tolerant asthma (ATA) controls. As a result, when adjusted for age, gender, smoking status and atopy as covariates, the rs1264307 variant and two haplotypes showed nominal signals in the association with AERD (P = 0.02-0.04), but the significances disappeared after corrections for multiple testing (corrected P > 0.05). In further multiple regression analysis, no genetic variants of GTF2H4 showed significant associations with FEV(1) decline by aspirin provocation in asthmatics (P > 0.05). Despite the need for replications in larger cohorts, our preliminary findings suggest that GTF2H4 variants may not be associated with susceptibility to AERD and obstructive symptoms in asthmatics.
Asunto(s)
Asma Inducida por Aspirina/genética , Asma Inducida por Aspirina/fisiopatología , Volumen Espiratorio Forzado/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Factor de Transcripción TFIIH/genética , Factores de Transcripción/genética , Adolescente , Adulto , Anciano , Femenino , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Mapeo Físico de Cromosoma , Adulto JovenRESUMEN
BACKGROUND: Recent results have indicated that polyphosphate, released by activated platelets, can function as a procoagulant to modulate the proteolytic activity of serine proteases of the blood clotting cascade. OBJECTIVE: To determine whether polyphosphate is involved in inducing signal transduction in cellular and animal models. METHODS: The effect of polyphosphate on human umbilical vein endothelial cells was examined by monitoring cell permeability, apoptosis and activation of NF-κB after treating cells with different concentrations of polyphosphate. Moreover, the expression of cell surface adhesion molecules (VCAM-1, ICAM-1 and E-selectin) and the adhesion of THP-1 cells to polyphosphate-treated cells were monitored using established methods. In the in vivo model, the pro-inflammatory effect of polyphosphate was assessed by monitoring vascular permeability and migration of leukocytes to the peritoneal cavity of mice injected with polyphosphate. RESULTS: Polyphosphate, comprised of 45, 65 and 70 phosphate units, enhanced the barrier permeability and apoptosis in cultured endothelial cells and up-regulated the expression of cell adhesion molecules, thereby mediating the adhesion of THP-1 cells to polyphosphate-treated endothelial cells. These effects of polyphosphate were mediated through the activation of NF-κB and could not be recapitulated by another anionic polymer, heparin. Polyphosphate also increased the extravasation of the bovine serum albumin (BSA)-bound Evans blue dye and the migration of leukocytes to the mouse peritoneal cavity, which was prevented when activated protein C (APC) was intravenously (i.v.) injected 2 h before the challenge. CONCLUSION: Polyphosphate, in addition to up-regulation of coagulation, can elicit potent pro-inflammatory responses through the activation of NF-κB, possibly contributing to the pro-inflammatory effect of activated platelets.
Asunto(s)
Células Endoteliales de la Vena Umbilical Humana/metabolismo , Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Polifosfatos/metabolismo , Proteína C/metabolismo , Animales , Apoptosis , Permeabilidad Capilar , Adhesión Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular , Células Cultivadas , Quimiotaxis de Leucocito , Técnicas de Cocultivo , Relación Dosis-Respuesta a Droga , Selectina E/metabolismo , Femenino , Heparina/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/inmunología , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Inflamación/prevención & control , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Molécula 1 de Adhesión Intercelular/metabolismo , Ratones , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Polifosfatos/administración & dosificación , Proteína C/administración & dosificación , Regulación hacia Arriba , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: Lymphocyte-oriented kinase deficiency encoded by the serine/threonine kinase 10 (STK10) gene correlates with the intracellular adhesion molecule 1 (ICAM-1)/lymphocyte function associated antigen 1 (LFA-1) complex in aspirin hypersensitivity. This study investigated the association between single nucleotide polymorphisms (SNPs) of STK10 and aspirin-intolerant asthma (AIA). METHODS: A total of 54 SNPs were genotyped in 163 AIA patients and 429 aspirin-tolerant asthma (ATA) controls. RESULTS: Logistic regression revealed that a synonymous variant (rs2306961G>A) had the most significant association with AIA (P = .008 under the codominant model; P = .004 under the dominant model), suggesting that tissue-specific codon usage between Lys_TTT and Lys_CTT could play a role in regulating expression of STK10 in airway epithelium. Haplotype analysis revealed that 4 haplotypes, including STK10_BL4-ht1, which is unique to rs2306961G>A, were significantly associated with aspirin hypersensitivity in asthmatics (P < .05). CONCLUSIONS: Although replications in independent cohorts and further functional evaluations are needed, our preliminary findings suggest that STK10 polymorphisms might be susceptible genetic markers of AIA and that gene expression could be mediated by tissue-specific codon usage.