RESUMO
Aberrant angiogenesis is a hallmark of cancer and is critically associated with tumor progression. Perivascular cells are essential components of blood vessels, and the role of tumor perivascular cell-derived extracellular vesicles (TPC-EVs) in angiogenesis remains elusive. In the present study, using genetic mouse models and pharmacological inhibitors, we found that ablation of perivascular cells inhibited angiogenesis in allografted colorectal cancer tumors. Further studies demonstrated that TPC-EVs promoted the proliferation, migration, invasion, viability, and tube formation of HUVECs. They also facilitated vessel spouting in rat aortic rings and induced neovascularization in chick chorioallantoic membranes (CAMs). Silencing of Gas6 or blockade of the Axl pathway suppressed TPC-EV-induced angiogenesis in vitro and ex vivo. Moreover, inhibition of the Gas6/Axl signaling pathway impaired TPC-EV-mediated angiogenesis in vivo. Our findings present a deeper insight into the biological functions of TPCs and TPC-EVs in tumor angiogenesis and demonstrate that TPC-EV-derived Gas6 could be an attractive and innovative regulator of tumor angiogenesis.
Assuntos
Neoplasias Colorretais/genética , Vesículas Extracelulares/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neovascularização Patológica/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Animais , Aorta/crescimento & desenvolvimento , Aorta/patologia , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Galinhas , Membrana Corioalantoide/enzimologia , Membrana Corioalantoide/patologia , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neovascularização Patológica/patologia , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/patologia , Ratos , Receptor Tirosina Quinase AxlRESUMO
OBJECTIVE: To examine the prevalence of the double burden of malnutrition and its associated factors among adolescents in rural China. STUDY DESIGN: A birth cohort of adolescents born to women in northwestern China who participated in a double-blind, randomized, controlled trial of micronutrient supplementation during pregnancy from August 2002 to January 2006 was enrolled. Follow-up was conducted from June to December 2016. RESULTS: A total of 2115 participants were analyzed (median age 12 years; IQR ± 1), the majority of whom were male (59.7%). The nutritional status distribution was 17.72% underweight, 8.62% overweight, 0.96% obese, and 2.58% stunted. Girls were less likely to be overweight/obese (relative risk ratio [RRR] 0.67, 95% CI 0.48-0.92) but more likely to be underweight (RRR 1.65, 95% CI 1.25-2.17) or stunted (RRR 2.26, 95% CI 1.21-4.22). Children of underweight mothers (RRR 1.63, 95% CI 1.19-2.25) with a history of small for gestational age (RRR 1.64, 95% CI 1.14-2.36) or described as being a "picky eater" (RRR 1.53, 95% CI 1.18-1.99) had a greater risk of being underweight. Children whose fathers' education was primary or below (RRR 2.25, 95% CI 1.11-4.59), with maternal height <150.1 cm (RRR 2.46, 95% CI 1.12-5.39), or who had mothers with underweight (RRR 2.80, 95% CI 1.37-5.72) had a greater likelihood of stunting. Overweight/obesity was associated with high and middle household wealth (RRR 1.62, 95% CI 1.14-2.32), mothers with overweight (RRR 1.86, 95% CI 1.25-2.78), and picky eating (RRR 0.62, 95% CI 0.46-0.84). CONCLUSIONS: Malnutrition (undernutrition and overweight/obesity) is common in rural Chinese adolescents and is associated with perinatal, genetic, and economic conditions.
Assuntos
Desnutrição , Sobrepeso , Adolescente , Coorte de Nascimento , Criança , China/epidemiologia , Feminino , Seguimentos , Transtornos do Crescimento/epidemiologia , Humanos , Masculino , Desnutrição/epidemiologia , Mães , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Gravidez , Prevalência , Fatores Socioeconômicos , Magreza/epidemiologiaRESUMO
BACKGROUND: Psoriasis is a common chronic inflammatory skin disease. Keratinocytes hyperproliferation and excessive inflammatory response contribute to psoriasis pathogenesis. The agents able to attenuate keratinocytes hyperproliferation and excessive inflammatory response are considered to be potentially useful for psoriasis treatment. Daphnetin exhibits broad bioactivities including anti-proliferation and anti-inflammatory. This study aims to evaluate the anti-psoriatic potential of daphnetin in vitro and in vivo, and explore underlying mechanisms. METHODS: HaCaT keratinocytes was stimulated with the mixture of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α (M5) to establish psoriatic keratinocyte model in vitro. Cell viability was measured using Cell Counting Kit-8 (CCK-8). Quantitative Real-Time PCR (qRT-PCR) was performed to measure the mRNA levels of hyperproliferative marker gene keratin 6 (KRT6), differentiation marker gene keratin 1 (KRT1) and inflammatory factors IL-1ß, IL-6, IL-8, TNF-α, IL-23A and MCP-1. Western blotting was used to detect the protein levels of p65 and p-p65. Indirect immunofluorescence assay (IFA) was carried out to detect p65 nuclear translocation. Imiquimod (IMQ) was used to construct psoriasis-like mouse model. Psoriasis severity (erythema, scaling) was scored based on Psoriasis Area Severity Index (PASI). Hematoxylin and eosin (H&E) staining was performed to examine histological change in skin lesion. The expression of inflammatory factors including IL-6, TNF-α, IL-23A and IL-17A in skin lesion was measured by qRT-PCR. RESULTS: Daphnetin attenuated M5-induced hyperproliferation in HaCaT keratinocytes. M5 stimulation significantly upregulated mRNA levels of IL-1ß, IL-6, IL-8, TNF-α, IL-23A and MCP-1. However, daphnetin treatment partially attenuated the upregulation of those inflammatory cytokines. Daphnetin was found to be able to inhibit p65 phosphorylation and nuclear translocation in HaCaT keratinocytes. In addition, daphnetin significantly ameliorate the severity of skin lesion (erythema, scaling and epidermal thickness, inflammatory cell infiltration) in IMQ-induced psoriasis-like mouse model. Daphnetin treatment attenuated IMQ-induced upregulation of inflammatory cytokines including IL-6, IL-23A and IL-17A in skin lesion of mice. CONCLUSIONS: Daphnetin was able to attenuate proliferation and inflammatory response induced by M5 in HaCaT keratinocytes through suppression of NF-κB signaling pathway. Daphnetin could ameliorate the severity of skin lesion and improve inflammation status in IMQ-induced psoriasis-like mouse model. Daphnetin could be an attractive candidate for future development as an anti-psoriatic agent.
Assuntos
Adjuvantes Imunológicos , Anti-Inflamatórios , Imiquimode , Inflamação , Psoríase , Umbeliferonas , Adjuvantes Imunológicos/efeitos adversos , Animais , Anti-Inflamatórios/farmacologia , Proliferação de Células , Humanos , Imiquimode/efeitos adversos , Inflamação/tratamento farmacológico , Queratinócitos , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Coelhos , Umbeliferonas/farmacologiaRESUMO
BACKGROUND: Psoriasis is a common chronic inflammatory skin disease. Keratinocytes hyperproliferation and excessive inflammatory response contribute to psoriasis pathogenesis. The agents able to attenuate keratinocytes hyper-proliferation and excessive inflammatory response are considered to be potentially useful for psoriasis treatment. Daphnetin exhibits broad bioactivities including anti-proliferation and anti-inflammatory. This study aims to evaluate the anti-psoriatic potential of daphnetin in vitro and in vivo, and explore underlying mechanisms. METHODS: HaCaT keratinocytes was stimulated with the mixture of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α (M5) to establish psoriatic keratinocyte model in vitro. Cell viability was measured using Cell Counting Kit-8 (CCK-8). Quantitative Real-Time PCR (qRT-PCR) was performed to measure the mRNA levels of hyperproliferative marker gene keratin 6 (KRT6), differentiation marker gene keratin 1 (KRT1) and inflammatory factors IL-1ß, IL-6, IL-8, TNF-α, IL-23A and MCP-1. Western blotting was used to detect the protein levels of p65 and p-p65. Indirect immunofluorescence assay (IFA) was carried out to detect p65 nuclear translocation. Imiquimod (IMQ) was used to construct psoriasis-like mouse model. Psoriasis severity (erythema, scaling) was scored based on Psoriasis Area Severity Index (PASI). Hematoxylin and eosin (H&E) staining was performed to examine histological change in skin lesion. The expression of inflammatory factors including IL-6, TNF-α, IL-23A and IL-17A in skin lesion was measured by qRT-PCR. RESULTS: Daphnetin attenuated M5-induced hyperproliferation in HaCaT keratinocytes. M5 stimulation significantly upregulated mRNA levels of IL-1ß, IL-6, IL-8, TNF-α, IL-23A and MCP-1. However, daphnetin treatment partially attenuated the upregulation of those inflammatory cytokines. Daphnetin was found to be able to inhibit p65 phosphorylation and nuclear translocation in HaCaT keratinocytes. In addition, daphnetin significantly ameliorate the severity of skin lesion (erythema, scaling and epidermal thickness, inflammatory cell infiltration) in IMQ-induced psoriasis-like mouse model. Daphnetin treatment attenuated IMQ-induced upregulation of inflammatory cytokines including IL-6, IL-23A and IL-17A in skin lesion of mice. CONCLUSIONS: Daphnetin was able to attenuate proliferation and inflammatory response induced by M5 in HaCaT keratinocytes through suppression of NF-κB signaling pathway. Daphnetin could ameliorate the severity of skin lesion and improve inflammation status in IMQ-induced psoriasis-like mouse model. Daphnetin could be an attractive candidate for future development as an anti-psoriatic agent.
Assuntos
Humanos , Animais , Camundongos , Coelhos , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Umbeliferonas/farmacologia , Adjuvantes Imunológicos/efeitos adversos , Imiquimode/efeitos adversos , Inflamação/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Queratinócitos , Proliferação de Células , Camundongos Endogâmicos BALB CRESUMO
The myodural bridge (MDB) is confirmed that connecting the most of suboccipital muscles to the cervical dura mater through the posterior intervertebral spaces and widely exists in mammals and birds. In order to reveal whether the MDB is universally existing in amniota of vertebrates, we explored the existence and the morphological features of the MDB in the Trachemys scripta elegans. Twenty fresh red-eared slider specimens were observed by the gross anatomy dissection and histological analysis. In the results, three kind of muscles in the postoccipital region of the red-eared slider were found. The rectus capitis dorsum minor muscle originated from the posterior margin of the occiput (C0) and terminated at the spinous process of the atlas (C1). The transversospinales muscle was attached to the vertebral arch and the postzygapophysis of the atlas and extended to the spinous process of the axis (C2). The C2-C3 intertransversales muscle were extended from the postzygapophysis of C2 and the one of C3. The three muscles covered the dorsal interspaces among C0-C3, and meantime they were closely connected with dense connective tissues, which filled in these interspaces. Each of these thick dense connective tissue membranes sent off several short and strong fibrous bundles ventrally to merge with the cervical spinal dura mater. Furthermore the connective tissues connecting these muscles with cervical spinal dura mater directly were revealed under the microscopy and they consisted of parallel and intensive collagen fibers with orientation from dorsal to ventral. In conclusion, this study for the first time demonstrated the existence of the MDB in the testudines, in all of the dorsal atlantooccipital, atlantoaxial and C2-C3 intervertebral spaces. Based on our results and comparative anatomical evidences in recent year, it could be inferred that the MDB might be its highly conserved structure in the evolution of amniota.
Se confirma que el puente miodural (PMD) conecta la mayoría de los músculos suboccipitales con la duramadre cervical a través de los espacios intervertebrales posteriores y existe ampliamente en mamíferos y aves. Para revelar si el MDB existe universalmente en la amniota de vertebrados, exploramos la existencia y las características morfológicas del PMD en Trachemys scripta elegans. Veinte muestras se observaron mediante disección anatómica y análisis histológico. En los resultados, se encontraron tres tipos de músculos en la región occipital. El músculo recto capitis dorsum minor se originó en el margen posterior del occipital (C0) y terminó en el proceso espinoso del atlas (C1). El músculo transverso espinal se unió al arco vertebral y el proceso del atlas y se extendió al proceso espinoso del axis (C2). El músculo intertransversario C2-C3 se extendió entre los procesos transversos de C2 y el de C3. Los tres músculos cubrían los espacios intermedios dorsales entre C0-C3 y, mientras tanto, estaban estrechamente conectados con tejidos conectivos densos, que rellenaban estos espacios. Cada una de estas membranas densas de tejido conectivo envían varios haces fibrosos cortos y fuertes ventralmente para fusionarse con la duramadre espinal cervical. Además, los tejidos conectivos que conectan estos músculos con la duramadre cervical y espinal se revelaron directamente bajo microscopía y consistían en intensas fibras de colágeno, paralelas, con orientación desde dorsal a ventral. En conclusión, este estudio demostró por primera vez la existencia del PMD en los estudios de prueba, en todos los espacios dorsales atlantooccipital, atlantoaxial e intervertebral C2-C3. Sobre la base de nuestros resultados y las evidencias anatómicas comparativas de los últimos años, se podría inferir que el PMD podría ser una estructura altamente conservada en la evolución de la amniota.