RESUMEN

The rapid spread of the coronavirus disease 2019 (COVID-19) into a global pandemic caught the world unprepared. Previously effective measures for containing disease outbreaks were overwhelmed, necessitating strict controls such as lockdowns or curfews. Among the disease control interventions, community mass masking was one of the highly controversial issues with differing opinions on its indications or effectiveness from different health authorities around the world. Regions where community mass masking was timely introduced were associated with lower transmission rates, and more effective disease control. In this article, we discuss the evidence on the effectiveness, and rationale for community mass masking to prevent the COVID-19 transmission. Areas for further research to define the role of mass masking in light of the COVID-19 pandemic will be suggested. This would help policy makers in formulating mass masking policies.

Asunto(s)

COVID-19 , Pandemias , Control de Enfermedades Transmisibles , Humanos , Pandemias/prevención & control , SARS-CoV-2

RESUMEN

Photobiomodulation (PBM) using low-level laser therapy (LLLT) is a treatment that is increasingly used in oncology. Studies reported enhancement of wound healing with reduction in pain, tissue swelling and inflammatory conditions such as radiation dermatitis, oral mucositis, and lymphedema. However, factors such as wavelength, energy density and irradiation frequency influence the cellular mechanisms of LLLT. Moreover, the effects of LLLT vary according to cell types. Thus, controversy arose as a result of poor clinical response reported in some studies that may have used inadequately planned treatment protocols. Since LLLT may enhance tumor cell proliferation, these will also need to be considered before clinical use. This review aims to summarize the current knowledge of the cellular mechanisms of LLLT by considering its effects on cell proliferation, metabolism, angiogenesis, apoptosis and inflammation. With a better understanding of the cellular mechanisms, bridging findings from laboratory studies to clinical application can be improved.

RESUMEN

Metastasis is the main cause of cancer-related mortality. Although the actual process of metastasis remains largely elusive, epithelial-mesenchymal transition (EMT) has been considered as a major event in metastasis. Besides, hypoxia is common in solid cancers and has been considered as an important factor for adverse treatment outcomes including metastasis. Since EMT and hypoxia potentially share several signaling pathways, many recent studies focused on investigate the issue of hypoxia-induced EMT. Among all potential mediators of hypoxia-induced EMT, hypoxia-inducible factor-1α (HIF-1α) has been studied extensively. Moreover, there are other potential mediators that may also contribute to the process. This review aims to summarize the recent reports on hypoxia-induced EMT by HIF-1α or other potential mediators and provide insights for further investigations on this issue. Ultimately, better understanding of hypoxia-induced EMT may allow us to develop anti-metastatic strategies and improve treatment outcomes.

RESUMEN

(1) Background: Epithelial-mesenchymal transition (EMT) and cancer cell stemness maintenance (SM) are important factors for cancer metastasis. Although hypoxia has been considered as a possible factor for EMT induction and promotion of SM, studies in this area, apart from hypoxia-inducible factor (HIF) pathways and severe hypoxia, are scant. This study aimed to evaluate the effects of different oxygen levels on EMT induction and SM and elucidate the signaling pathways involved in colorectal cancer cells. (2) Methods: Cell morphological analysis, migration assay, immunofluorescence staining of cytoskeleton and Western blotting were performed on human colorectal cancer cells HT-29, DLD-1, and SW-480 cultured at 1%, 10%, and normal (21%) O2 levels. The role played by c-Jun N-terminal kinase (JNK) was evaluated through the use of the specific JNK inhibitor SP600125. (3) Results: This study evaluated 1% and 10% O2 are possible conditions for EMT induction and SM. This study also demonstrated the partial relieve of EMT induction and SM by SP600125, showing the importance of the JNK pathway in these processes. Furthermore, this study proposed a novel pathway on the regulation of Akt by JNK-c-Jun. (4) Conclusions: This study suggests 10% O2 as another possible condition for EMT induction, and SM and JNK pathways play important roles in these processes through multiple factors. Inhibition of JNK could be explored as treatment for inhibiting metastasis in colorectal cancer cells.

RESUMEN

More than 1 billion people globally are suffering from hypertension, which is a long-term incurable medical condition that can further lead to dangerous complications and death if left untreated. In earlier studies, the brain-gut peptide secretin (SCT) was found to be able to control blood pressure by its cardiovascular and pulmonary effects. For example, serum SCT in patients with congestive heart failure was one-third of the normal level. These observations strongly suggest that SCT has a causal role in blood pressure control, and in this report, we used constitutive SCT knockout (SCT-/-) mice and control C57BL/6N mice to investigate differences in the morphology, function, underlying mechanisms and response to SCT treatment. We found that SCT-/- mice suffer from systemic and pulmonary hypertension with increased fibrosis in the lungs and heart. Small airway remodelling and pulmonary inflammation were also found in SCT-/- mice. Serum NO and VEGF levels were reduced and plasma aldosterone levels were increased in SCT-/- mice. Elevated cardiac aldosterone and decreased VEGF in the lungs were observed in the SCT-/- mice. More interestingly, SCT replacement in SCT-/- mice could prevent the development of heart and lung pathologies compared to the untreated group. Taken together, we comprehensively demonstrated the critical role of SCT in the cardiovascular and pulmonary systems and provide new insight into the potential role of SCT in the pathological development of cardiopulmonary and cardiovascular diseases.

Asunto(s)

Presión Sanguínea/fisiología , Hipertensión Pulmonar/fisiopatología , Hipertensión/fisiopatología , Pulmón/patología , Miocardio/patología , Secretina/deficiencia , Remodelación de las Vías Aéreas (Respiratorias) , Aldosterona/análisis , Angiotensina II/sangre , Animales , Hemodinámica , Hipertensión/sangre , Hipertensión/genética , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/genética , Pulmón/química , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/química , Óxido Nítrico/sangre , Renina/sangre , Secretina/genética , Telemetría , Factor A de Crecimiento Endotelial Vascular/análisis , Vasopresinas/sangre

RESUMEN

Colorectal cancer is a common cancer with metachronous distant metastases still threatening overall survival. Tumor oxygen level influences tumor radiosensitivity in relation to autophagy and apoptosis. The objective of this study is to evaluate the expression and interaction between multiple key regulators in different oxygen levels. Human colorectal adenocarcinoma HT-29 cells were cultured in 1% or 10% oxygen level and irradiated by 2 Gy with different incubation time. Autophagy key regulators, AMPK, HIFs and JNK were evaluated by Western blot. Sequential autophagy key regulator activation was observed in the order of AMPK, HIF-1α, HIF-2α and JNK. 10% oxygen level could promote autophagy with similar degree of autophagy activation as 1% oxygen level in 48-h while irradiation could slightly inhibit autophagy. The results of this study supported prior evaluation of oxygen level and autophagy regulators for improving treatment efficacy and indicated the possible directions in developing individualized radiotherapy by selective targeting of hypoxic regions.

Asunto(s)

Adenocarcinoma/metabolismo , Autofagia , Neoplasias Colorrectales/metabolismo , Oxígeno/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Adenocarcinoma/patología , Neoplasias Colorrectales/patología , Células HT29 , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Hipoxia Tumoral

RESUMEN

Pressure-induced injury (PI), such as a pressure ulcer, in patients with limited mobility is a healthcare issue worldwide. PI is an injury to skin and its underlying tissue such as skeletal muscle. Muscle compression, composed of mechanical deformation of muscle and external load, leads to localized ischemia and subsequent unloading reperfusion and, hence, a pressure ulcer in bed-bound patients. Although the gross factors involved in PI have been identified, little is known about the exact disease mechanism or its links to apoptosis, autophagy and inflammation. Here, we report that PI is mediated by intrinsic apoptosis and exacerbated by autophagy. Conditional ablation of Bax and Bak activates the Akt-mTOR pathway and Bnip3-mediated mitophagy and preserves mitochondrial contents in compressed muscle. Moreover, we find that the presence/absence of Bax and Bak alters the roles and functions of autophagy in PI. Our results suggest that manipulating apoptosis and autophagy are potential therapeutic targets for treatment and prevention of PI.

Asunto(s)

Músculo Esquelético/metabolismo , Presión/efectos adversos , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Animales , Western Blotting , Muerte Celular/genética , Muerte Celular/fisiología , Inmunoprecipitación , Masculino , Ratones , Ratones Noqueados , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Proteína X Asociada a bcl-2/genética

RESUMEN

Color Doppler vascular index (VI) was assessed alone and in combination with grey-scale ultrasound (GSU) in regionally subdivided thyroid nodules in diagnosing thyroid cancer. Color Doppler sonograms of 111 thyroid nodules were evaluated by a home-developed algorithm that performed "offsetting" (algorithm for changing the area of a region of interest, ROI, without distorting the ROI's contour) and assessed peripheral, central and overall VI of thyroid nodules. Results showed that the optimum offset for dividing peripheral and central regions of nodule was 22%. At the optimum offset, the mean VI of peripheral, central, and overall regions of malignant nodules were significantly higher than those of benign nodules (26.5 ± 16.2%, 21.7 ± 19.6%, 23.8 ± 4.6% v/s 18.2 ± 16.7%, 11.9 ± 15.1% and 16.6 ± 1.8% respectively, P < 0.05). The optimum cut-off of peripheral, central, and overall VI was 19.7%, 9.1% and 20.2% respectively. When compared to GSU alone, combination of VI assessment with GSU evaluation of thyroid nodules increased the diagnostic accuracy from 58.6% to 79.3% (P < 0.05). In conclusion, a novel algorithm for regional subdivision and quantification of thyroid nodular VI in ultrasound images was established, and the optimum offset and cut-off were derived. Assessment of intranodular VI in conjunction with GSU can increase the accuracy in ultrasound diagnosis of thyroid cancer.

Asunto(s)

Nódulo Tiroideo/irrigación sanguínea , Nódulo Tiroideo/diagnóstico por imagen , Nódulo Tiroideo/patología , Adulto , Algoritmos , Toma de Decisiones Asistida por Computador , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/diagnóstico por imagen , Sensibilidad y Especificidad , Neoplasias de la Tiroides/patología , Ultrasonografía/métodos , Ultrasonografía Doppler en Color/métodos

RESUMEN

Minimally invasive transverse aortic constriction (MTAC) is a more desirable method for the constriction of the transverse aorta in mice than standard open-chest transverse aortic constriction (TAC). Although transverse aortic constriction is a highly functional method for the induction of high pressure in the left ventricle, it is a more difficult and lengthy procedure due to its use of artificial ventilation with tracheal intubation. TAC is oftentimes also less survivable, as the newer method, MTAC, neither requires the cutting of the ribs and intercostal muscles nor tracheal intubation with a ventilation setup. In MTAC, as opposed to a thoracotomy to access to the chest cavity, the aortic arch is reached through a midline incision in the anterior neck. The thyroid is pulled back to reveal the sternal notch. The sternum is subsequently cut down to the second rib level, and the aortic arch is reached simply by separating the connective tissues and thymus. From there, a suture can be wrapped around the arch and tied with a spacer, and then the sternal cut and skin can be closed. MTAC is a much faster and less invasive way to induce left ventricular hypertension and enables the possibility for high-throughput studies. The success of the constriction can be verified using high-frequency trans-thoracic echocardiography, particularly color Doppler and pulsed-wave Doppler, to determine the flow velocities of the aortic arch and left and right carotid arteries, the dimension of the blood vessels, and the left ventricular function and morphology. A successful constriction will also trigger significant histopathological changes, such as cardiac muscle cell hypertrophy with interstitial and perivascular fibrosis. Here, the procedure of MTAC is described, demonstrating how the resulting flow changes in the carotid arteries can be examined with echocardiography, gross morphology, and histopathological changes in the heart.

Asunto(s)

Aorta Torácica/cirugía , Constricción Patológica , Modelos Animales de Enfermedad , Procedimientos Quirúrgicos Vasculares , Animales , Aorta Torácica/fisiopatología , Arterias Carótidas/fisiopatología , Ecocardiografía , Ecocardiografía Doppler , Corazón/fisiopatología , Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Procedimientos Quirúrgicos Mínimamente Invasivos , Ultrasonografía Doppler en Color

RESUMEN

Mammographic breast density (MBD) is a strong risk factor for breast cancer. The spatial distribution of MBD in the breast is variable and dependent on physiological, genetic, environmental and pathological factors. This pilot study aims to define the spatial distribution and autocorrelation patterns of MBD in Chinese women aged 40-60. By analyzing their digital mammographic images using a public domain Java image processing program for segmentation and quantification of MBD, we found their left and right breasts were symmetric to each other in regard to their breast size (Total Breast Area), the amount of BMD (overall PD) and Moran's I values. Their MBD was also spatially autocorrelated together in the anterior part of the breast in those with a smaller breast size, while those with a larger breast size tend to have their MBD clustered near the posterior part of the breast. Finally, we observed that the autocorrelation pattern of MBD was dispersed after a 3-year observation period.

Asunto(s)

Neoplasias de la Mama/diagnóstico , Mama/patología , Mamografía/métodos , Adulto , Pueblo Asiatico , China/epidemiología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Persona de Mediana Edad , Proyectos Piloto , Factores de Riesgo , Programas Informáticos

RESUMEN

Intracellular pathogens are differentially sensed by the compartmentalized host immune system. Nevertheless, gene expression studies of infected cells commonly average the immune responses, neglecting the precise pathogen localization. To overcome this limitation, we dissected the transcriptional immune response to Shigella flexneri across different infection stages in bulk and single cells. This identified six distinct transcriptional profiles characterizing the dynamic, multilayered host response in both bystander and infected cells. These profiles were regulated by external and internal danger signals, as well as whether bacteria were membrane bound or cytosolic. We found that bacterial internalization triggers a complex, effector-independent response in bystander cells, possibly to compensate for the undermined host gene expression in infected cells caused by bacterial effectors, particularly OspF. Single-cell analysis revealed an important bacterial strategy to subvert host responses in infected cells, demonstrating that OspF disrupts concomitant gene expression of proinflammatory, apoptosis, and stress pathways within cells. This study points to novel mechanisms through which bacterial internalization, localization, and injected effectors orchestrate immune response transcriptional signatures.

Asunto(s)

Disentería Bacilar/inmunología , Citometría de Flujo , Transferencia Resonante de Energía de Fluorescencia , Células HeLa , Humanos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Shigella flexneri/inmunología , Transfección

RESUMEN

EGFR signaling pathway and microRNAs (miRNAs) are two important factors for development and treatment in non-small cell lung cancer (NSCLC). Microarray analysis enables the genome-wide expression profiling. However, the information from microarray data may not be fully deciphered through the existing approaches. In this study we present an mRNA:miRNA stepwise regression model supported by miRNA target prediction databases. This model is applied to explore the roles of miRNAs in the EGFR signaling pathway. The results show that miR-145 is positively associated with epidermal growth factor (EGF) in the pre-surgery NSCLC group and miR-199a-5p is positively associated with EGF in the post-surgery NSCLC group. Surprisingly, miR-495 is positively associated with protein tyrosine kinase 2 (PTK2) in both groups. The coefficient of determination (R(2)) and leave-one-out cross-validation (LOOCV) demonstrate good performance of our regression model, indicating that it can identify the miRNA roles as oncomirs and tumor suppressor mirs in NSCLC.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , MicroARNs/genética , Modelos Genéticos , ARN Mensajero/metabolismo , Transducción de Señal , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , ARN Mensajero/genética , Análisis de Regresión

RESUMEN

AIMS: To comprehensively evaluate the effect of a short-term diabetes self-management education (DSME) on metabolic markers and atherosclerotic parameters in patients with type 2 diabetes. METHODS: 76 patients with type 2 diabetes were recruited in this study. They were divided into the intervention group (n = 36) and control group (n = 40). The patients in the intervention group received a 3-month intervention, including an 8-week education on self-management of diabetes mellitus and subsequent 4 weeks of practice of the self-management guidelines. The patients in the control group received standard advice on medical nutrition therapy. Metabolic markers, carotid intima-media thickness (CIMT), and carotid arterial stiffness (CAS) of the patients in both groups were assessed before and after the 3-month intervention. RESULTS: There was a significant reduction in hemoglobin A1c (HbA1c, -0.2 ± 0.56% versus 0.08 ± 0.741%; P < 0.05) and body weight (-1.19 ± 1.39 kg versus -0.61 ± 2.04 kg; P < 0.05) in the intervention group as compared to the control group. However, no significant improvements were found in other metabolic markers, CIMT and CAS (P > 0.05). CONCLUSIONS: DSME can improve HbA1c and body weight in patients with type 2 diabetes.

Asunto(s)

Peso Corporal , Diabetes Mellitus Tipo 2/terapia , Hemoglobina Glucada/metabolismo , Conocimientos, Actitudes y Práctica en Salud , Educación del Paciente como Asunto , Autocuidado/métodos , Anciano , Biomarcadores/sangre , Glucemia/metabolismo , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/diagnóstico , Enfermedades de las Arterias Carótidas/fisiopatología , Enfermedades de las Arterias Carótidas/terapia , Grosor Intima-Media Carotídeo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/diagnóstico , Angiopatías Diabéticas/fisiopatología , Angiopatías Diabéticas/terapia , Femenino , Hong Kong , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Rigidez Vascular

RESUMEN

AIMS. The aim of this study is to determine the extent of carotid atherosclerosis in Chinese patients with type 2 diabetes in relation to the cumulative atherosclerosis risk factors using ultrasonography. METHODS. The presence of hypertension, dyslipidemia, and chronic kidney disease (CKD) was documented in 106 Chinese subjects with type 2 diabetes. Subjects with 0, 1, and ≥2 additional atherosclerosis risk factors were assigned into groups 1, 2, and 3, respectively (n = 17, 49, and 40, resp.). Using ultrasound, the carotid arteries were assessed for the presence of carotid plaque, plaque score, intima-media thickness (IMT), and carotid arterial stiffness. RESULTS. With the adjustment for age and gender, the presence of plaque and plaque score were significantly higher in groups with more atherosclerosis risk factors (P < 0.05). In addition, age > 60 years old (odds ratio = 2.75; 95% CI: 1.26-6.0) and the presence of hypertension (odds ratio = 2.48; 95% CI: 1.11-5.58), dyslipidemia (odds ratio = 2.41; 95% CI: 1.05-5.51), and CKD (odds ratio = 7.80; 95% CI: 1.46-41.72) could independently predict higher plaque score (P < 0.05). CONCLUSIONS. Hypertension, dyslipidemia, and CKD in Chinese patients with type 2 diabetes have cumulative effects on the burden of carotid plaque.

Asunto(s)

Enfermedades de las Arterias Carótidas/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/complicaciones , Nefropatías Diabéticas/complicaciones , Dislipidemias/complicaciones , Hipertensión/complicaciones , Insuficiencia Renal Crónica/complicaciones , Adulto , Factores de Edad , Anciano , Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/epidemiología , Enfermedades de las Arterias Carótidas/fisiopatología , Grosor Intima-Media Carotídeo , Estenosis Carotídea/complicaciones , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/epidemiología , Estenosis Carotídea/fisiopatología , China/epidemiología , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/diagnóstico por imagen , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/fisiopatología , Nefropatías Diabéticas/fisiopatología , Dislipidemias/fisiopatología , Femenino , Humanos , Hipertensión/fisiopatología , Incidencia , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/fisiopatología , Factores de Riesgo , Índice de Severidad de la Enfermedad , Rigidez Vascular

RESUMEN

BACKGROUND: Epstein-Barr virus (EBV) is a tumorigenic virus which has effectively infected nearly all human beings with over 95% adult being seropositive. The persistence of latent EBV infection is not fully understood. Recent studies point towards a hypothesis of immune suppression and immune evasion involving regulatory T cells (Tregs) and dendritic cells (DCs). We sought to explore the mechanism of EBV suppression and immune evasion. METHODS: We compared the effects of EBV on cord blood (CB) and adult DCs differentiation and maturation including phenotype by flow cytometry, cytokine by ELISA and RT-PCR. And we evaluated the function of DC by co-culture DC and Treg by detection the expression of Foxp3, the phenotype and the cytokine profile of Tregs by flow cytometry. RESULTS: CB DCs derived from EBV-infected CB monocytes or from EBV-infected CB immature DCs (iDCs) displayed distinct phenotypes of "semi-mature" DCs with high expression of co-stimulatory molecules, such as CD40, CD80 and CD86 but low cytokine production, related to immune tolerance and homeostasis. While the EBV-infected adult iDCs resemble that of "pathogen-driven regulatory mature DCs" with high expression of co-stimulatory molecules, down-regulation of IL-12 secretion and up-regulation of IL-10 secretion, related to protection of host and immune evasion of pathogens. EBV infected cord blood monocytes-derived DCs drived Tregs development by driving the expression of Foxp3, increasing the expression of CTLA-4, decreasing the expression of GITR and promoted the generation of intracellular IL-2 and IL-10 by Tregs. CONCLUSION: Epstein-Barr virus induces the differentiation of semi-mature dendritic cells from cord blood monocytes. The differences between CB and adult DCs suggested that the developmental maturity of the cells may affect their immune responses to EBV infection.

Asunto(s)

Diferenciación Celular , Células Dendríticas/citología , Células Dendríticas/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Monocitos/citología , Monocitos/inmunología , Adolescente , Adulto , Recuento de Células , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/virología , Infecciones por Virus de Epstein-Barr/virología , Sangre Fetal/citología , Herpesvirus Humano 4/genética , Humanos , Inmunofenotipificación , Recién Nacido , Monocitos/metabolismo , Fenotipo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Adulto Joven

RESUMEN

OBJECTIVE: Recent genome-wide association studies have revealed numerous genetic associations between specific single-nucleotide polymorphisms (SNPs) and immune-mediated inflammatory diseases. The current challenge is to identify associations of the genetic variants with effector mechanisms implicated in pathogenesis. This study was undertaken to investigate the link between genetic variation at loci associated with spondyloarthritis (SpA) and the effector function of CD4+ T lymphocyte subsets involved in chronic inflammatory disease. METHODS: Expression of Th17 and Th1 cytokines and transcription factors was measured in CD4+ T cells isolated from patients with SpA. Correlation analyses were performed to assess potential associations of these expression levels with the patient's genotype at loci genetically linked to SpA. RESULTS: The effector functions of Th17 and Th1 cells in patients with SpA were found to be under combinatorial control by multiple SNPs at genes associated with the interleukin-23 (IL-23)/Th17 pathway. Patients with SpA carrying risk-associated alleles of genes in the IL-23/Th17 pathway expressed the highest levels of genes involved in the differentiation and function of Th17 and Th1 cells, whereas the presence of protective alleles was associated with low-level expression of these genes. In contrast, variation at loci that were genetically linked to SpA, but not associated with the IL-23 pathway, did not affect the expression of Th17- and Th1-specific genes, suggesting that these SNPs may contribute to the pathogenesis of SpA through distinct cellular mechanisms. CONCLUSION: These results show that genetic variations at genes associated with the IL-23 signaling pathway may influence the effector functions of Th17 and Th1 cells in patients with SpA. These findings provide a framework to delineate the mechanisms by which genetic variants contribute to pathology.

Asunto(s)

Linfocitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , Interleucina-23/genética , Espondiloartropatías/metabolismo , Células TH1/metabolismo , Células Th17/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Variación Genética , Genotipo , Humanos , Interleucina-23/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Espondiloartropatías/genética , Adulto Joven

RESUMEN

The type I interferon (IFN) family comprises 15 cytokines (in human 13α, 1ß, 1ω), which exert several cellular functions through binding to a common receptor. Despite initial activation of the same Jak/Stat signalling pathway, the cellular response may differ depending on type I IFN subtype. We investigated the activity of six type I IFN subtypes - IFNα1, α2, α8, α21, ω and ß- to promote the differentiation of dendritic cells (DC). Transcriptome analyses identified two distinct groups, the IFNα/ω-DC and the IFNß-DC. In addition, the expression level of seven chemokines and several cell surface markers characteristic of DC distinguished IFNα-DC and IFNß-DC. These differences are unlikely to impact the efficacy of T cell functional response since IFNα2-DC and IFNß-DC were equipotent in inducing the proliferation and the polarization of allogenic naïve CD4 T cells into Th1 cells and in stimulating autologous antigen specific CD4 or CD8 T cells. Of the functional parameters analysed, the only one that showed a modest differential was the phagocytic uptake of dead cells which was higher for IFNα2-DC.

Asunto(s)

Células Dendríticas/citología , Interferón Tipo I/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Diferenciación Celular , Membrana Celular/metabolismo , Proliferación Celular , Quimiotaxis , Citocinas/metabolismo , Perfilación de la Expresión Génica , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Fagocitosis , ARN/metabolismo , Transducción de Señal , Células TH1/citología , Transcriptoma

RESUMEN

The physiologic role played by plasmacytoid dendritic cells (pDCs) in the induction of innate responses and inflammation in response to pathogen signaling is not well understood. Here, we describe a new mouse model lacking pDCs and establish that pDCs are essential for the in vivo induction of NK-cell activity in response to Toll-like receptor 9 (TLR9) triggering. Furthermore, we provide the first evidence that pDCs are critical for the systemic production of a wide variety of chemokines in response to TLR9 activation. Consequently, we observed a profound alteration in monocyte, macrophage, neutrophil, and NK-cell recruitment at the site of inflammation in the absence of pDCs in response to CpG-Dotap and stimulation by microbial pathogens, such as Leishmania major, Escherichia coli, and Mycobacterium bovis. This study, which is based on the development of a constitutively pDC-deficient mouse model, highlights the pivotal role played by pDCs in the induction of innate immune responses and inflammation after TLR9 triggering.

Asunto(s)

Células Dendríticas/inmunología , Infecciones/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/microbiología , Receptor Toll-Like 9/inmunología , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Movimiento Celular/inmunología , Quimiocinas/inmunología , Citocinas/inmunología , Proteínas de Unión al ADN/genética , Células Dendríticas/citología , Infecciones por Escherichia coli/inmunología , Inmunidad Innata/inmunología , Leishmania major/inmunología , Macrófagos/citología , Macrófagos/inmunología , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Monocitos/citología , Monocitos/inmunología , Neutrófilos/citología , Neutrófilos/inmunología , Transducción de Señal/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Receptor Toll-Like 9/metabolismo , Tuberculosis/inmunología

RESUMEN

BACKGROUND: Mannose-binding lectin (MBL) is a pattern-recognition molecule, which functions as a first line of host defense. Pandemic H1N1 (pdmH1N1) influenza A virus caused massive infection in 2009 and currently circulates worldwide. Avian influenza A H9N2 (H9N2/G1) virus has infected humans and has the potential to be the next pandemic virus. Antiviral function and immunomodulatory role of MBL in pdmH1N1 and H9N2/G1 virus infection have not been investigated. METHODS: In this study, MBL wild-type (WT) and MBL knockout (KO) murine models were used to examine the role of MBL in pdmH1N1 and H9N2/G1 virus infection. RESULTS: Our study demonstrated that in vitro, MBL binds to pdmH1N1 and H9N2/G1 viruses, likely via the carbohydrate recognition domain of MBL. Wild-type mice developed more severe disease, as evidenced by a greater weight loss than MBL KO mice during influenza virus infection. Furthermore, MBL WT mice had enhanced production of proinflammatory cytokines and chemokines compared with MBL KO mice, suggesting that MBL could upregulate inflammatory responses that may potentially worsen pdmH1N1 and H9N2/G1 virus infections. CONCLUSIONS: Our study provided the first in vivo evidence that MBL may be a risk factor during pdmH1N1 and H9N2/G1 infection by upregulating proinflammatory response.

Asunto(s)

Inflamación/metabolismo , Subtipo H1N1 del Virus de la Influenza A/metabolismo , Subtipo H9N2 del Virus de la Influenza A/metabolismo , Lectina de Unión a Manosa/metabolismo , Infecciones por Orthomyxoviridae/metabolismo , Animales , Quimiocinas/metabolismo , Citocinas/metabolismo , Inflamación/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H9N2 del Virus de la Influenza A/inmunología , Pulmón/patología , Pulmón/virología , Lectina de Unión a Manosa/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/virología , Carga Viral , Pérdida de Peso

RESUMEN

Multiple stress pathways result in the induction of autophagy and apoptosis. Current methods (e.g., protein gel blot, microscopy) do not offer quantitative single-cell resolution, thus making it difficult to discern if these pathways are mutually exclusive or, in some situations, cooperative in executing cell death. We report a novel method that enables high-throughput, high-content assessment of LC3 puncta and caspase-3 cleavage at the single cell level.

Asunto(s)

Apoptosis , Autofagia , Citometría de Imagen/métodos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Autofagia/efectos de los fármacos , Autofagia/efectos de la radiación , Cloroquina/farmacología , Embrión de Mamíferos/citología , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de la radiación , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de la radiación , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Lisosomas/efectos de la radiación , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Factores de Tiempo , Rayos Ultravioleta