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1.
J Clin Invest ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32809970

RESUMO

Interstitial cells of Cajal (ICCs) are pacemaker cells in the intestine, and their function can be compromised due to loss of C-KIT expression. Macrophage activation has been identified in intestine affected by Hirschsprung disease associated enterocolitis (HAEC). In this study, we examined proinflammatory macrophage activation and explored the mechanisms by which this down-regulates C-KIT expression in ICCs in colon affected by HAEC. We found that macrophage activation and TNF-α production were dramatically increased in the proximal dilated colon of HAEC patients and 3-week old Ednrb-/- mice. Moreover, ICCs lost their C-KIT+ phenotype in the dilated colon, resulting in damaged pacemaker function and intestinal dysmotility. However, macrophage depletion or TNF-α neutralization led to recovery of ICC phenotype and restored their pacemaker function. In isolated ICCs, TNF-α-mediated phosphorylated-P65 induced over-expression of miR221, resulting in suppression of C-KIT expression and pacemaker currents. We also identified a TNF-α-NF-κB-miR221 pathway which downregulated C-KIT expression in ICCs in the colon affected by HAEC. These findings suggest the important roles of proinflammatory macrophage activation in a phenotypic switch of ICCs, representing a promising therapeutic target for HAEC.

2.
Nat Metab ; 2(7): 635-647, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32694789

RESUMO

T cells undergo metabolic rewiring to meet their bioenergetic, biosynthetic and redox demands following antigen stimulation. To fulfil these needs, effector T cells must adapt to fluctuations in environmental nutrient levels at sites of infection and inflammation. Here, we show that effector T cells can utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose in vitro. T cells metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase. We demonstrate that the ribose subunit of inosine can enter into central metabolic pathways to provide ATP and biosynthetic precursors, and that cancer cells display diverse capacities to utilize inosine as a carbon source. Moreover, the supplementation with inosine enhances the anti-tumour efficacy of immune checkpoint blockade and adoptive T-cell transfer in solid tumours that are defective in metabolizing inosine, reflecting the capability of inosine to relieve tumour-imposed metabolic restrictions on T cells.

3.
Chem Soc Rev ; 49(13): 4203-4219, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32478772

RESUMO

Rechargeable zinc-ion batteries (ZIBs) are promising for large scale energy storage and portable electronic applications due to their low cost, material abundance, high safety, acceptable energy density and environmental friendliness. This tutorial review presents an introduction to the fundamentals, challenges, recent advances and prospects related to ZIBs. Firstly, the intrinsic chemical properties, challenges and strategies of metallic zinc anodes are underscored. Then, the multiple types of cathode materials are classified and comparatively discussed in terms of their structural and electrochemical properties, issues and remedies. Specific attention is paid to the mechanistic understanding and structural transformation of cathode materials based on Zn ion-(de)intercalation chemistry. After that, the widely investigated electrolytes are elaborated by discussing their effect on Zn plating/stripping behaviours, reaction kinetics, electrode/electrolyte interface chemistries, and cell performances. Finally, the remaining challenges and future perspectives are outlined for the development of ZIBs.

4.
Methods Mol Biol ; 2111: 257-265, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31933213

RESUMO

T lymphocytes are the major components of the adaptive immune system. It's been known that T cells are able to engage a diverse range of metabolic programs to meet the metabolic demands during their life cycle from early development, activation to functional differentiation. Central carbon metabolic pathways provide energy, reducing power, and biosynthetic precursors to support T cell homeostasis, proliferation, and immune functions. As such, quantitative or semiquantitative analysis of central carbon metabolic flux activities offers mechanistic details, as well as insights into the regulation of metabolic pathways and the impact of changing metabolic programs on T cell life cycle. Global profiling of cellular metabolites by mass spectrometry-based metabolomics and metabolic flux analysis (MFA) using radioactive and nonradioactive/stable isotope approaches are powerful tools for determination of central carbon metabolic pathway activity. Here, we describe in detail the procedure for the radioisotope-based approach of analyzing central carbon metabolic fluxes in T cells.

5.
Pediatr Surg Int ; 36(1): 81-91, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31541279

RESUMO

PURPOSE: The roles of commensal bacteria after intestinal ischemia and reperfusion (IIR) are unclear. In current study, we aim to investigate the effects and underlying mechanisms of commensal bacteria in injury and epithelial restitution after IIR. METHODS: Commensal gut bacteria were deleted by broad-spectrum antibiotics in mice. IIR was induced by clamping superior mesenteric artery. Intestinal injury, permeability, epithelial proliferation, and proinflammatory activity of mesenteric lymph were investigated. RESULTS: Commensals deletion improved mice survival in the early phase, but failed to improve the overall survival at 96 h after IIR. Commensals deletion reduced proliferation of intestinal epithelial cells (IEC) and augmented proinflammatory activity of mesenteric lymph after IIR. Lipopolysaccharides (LPS) supplement promoted IEC proliferation and improved survival in mice with commensals deletion after IIR. LPS induced production of prostaglandin E2 (PGE2) in mucosa via toll-like receptor 4-NFκB-cyclooxygenase 2 pathway. PGE2 enhanced IEC proliferation in vivo, which was preceded by activation of Akt and extracellular signal-regulated kinase (ERK) 1/2. Blocking of EGFR, PI3K/Akt activity abolished LPS-induced IEC proliferation. CONCLUSIONS: Commensal bacteria are essential for epithelial restitution after IIR, which enhance IEC proliferation via induction of PGE2.

7.
Eur J Pediatr Surg ; 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31013538

RESUMO

OBJECTIVE: Vascular endothelial growth factor (VEGF) and its receptor act as a major contributor to lymphangioma, but their role on nonrecurrent and recurrent lymphangiomas remain unclear. We aim to investigate those factors in the generation of recurrent lymphangioma. MATERIALS AND METHODS: Patients diagnosed with lymphangioma from January 2005 to December 2012 in our hospital were collected and divided into nonrecurrent and recurrent lymphangiomas. The clinical characteristics including age, sex, symptoms, location, and size of lymphangioma were collected. Surgical resection samples were collected for histology, protein and mRNA detection of VEGF-C, VEGF receptor-3 (VEGFR-3), and neuropilin 2 (Nrp2). Follow-ups including lymphangioma recurrent and the local symptoms such as ulcer were reviewed. RESULTS: A total of 80 patients aged from 5 months to 12 years were enrolled in this study, 51 patients had no recurrence and other 29 patients suffered from recurrent lymphangioma. There was no significant difference in demographic data and clinical characters between the two groups (p > 0.05). Immunohistochemistry staining showed that VEGFR-3 remained unchanged between nonrecurrent and recurrent lymphangiomas (p > 0.05), and VEGF-C and Nrp2 were significantly increased in recurrent lymphangioma compared with nonrecurrent lymphangioma (p < 0.05). The same expression trend was proved as detected by protein and mRNA levels. CONCLUSION: The VEGF-C/Nrp2 axis was significantly increased in the recurrent lymphangioma, indicating that VEGF-C/Nrp2 targeted therapy may serve as a potential therapeutic strategy for recurrent lymphangioma.

8.
Pediatr Surg Int ; 35(4): 473-477, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30448888

RESUMO

OBJECTIVE: The aim of this study was to investigate the pathogenesis, symptoms and individualized surgical management in pediatrics with gastroduodenal perforation (GDP). METHODS: Patients diagnosed with GDP from January 2013 to December 2016 in our hospital were collected and divided into gastric perforation (GP) group and duodenal perforation (DP) group. Demographics, clinical events, etiological factors, symptoms, the time from symptom onset to operation, intraoperative findings and surgical procedures were analyzed. Follow-ups including ulcer, perforations occurrence, and digestive symptoms were carried out by out-patient review or telephones. RESULTS: A total of 20 patients aged from 3 months to 14 years were enrolled in this study. The average age, main clinical presentations, size of perforations and operating time between two groups had no difference. The male to female ratio in DP group was higher than GP (P < 0.05). The high risk factor for DP was the use of dexamethasone, and for GP was HP infection. The most common site of perforation in DP group was duodenal bulb, and in GP group was pylorus area. Simple suture is the main management for both DP and GP, but distal gastrectomy combined with gastrojejunal Roux-en-Y anastomosis may be an alternative procedure for large perforation with diameter > 2 cm. The length of hospital days in GP group is shorter than DP group (P < 0.05). For follow-up, no patients had digestive symptoms. CONCLUSIONS: The general condition had no difference between GP and DP patients. But the risk factors and surgical repair differ depending on the patient's fundamental illness and the complexity of the perforation.


Assuntos
Úlcera Duodenal/epidemiologia , Úlcera Péptica Perfurada/epidemiologia , Úlcera Gástrica/epidemiologia , Adolescente , Criança , China/epidemiologia , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Úlcera Duodenal/cirurgia , Feminino , Humanos , Incidência , Lactente , Masculino , Úlcera Péptica Perfurada/cirurgia , Estudos Retrospectivos , Fatores de Risco , Úlcera Gástrica/cirurgia
9.
Elife ; 72018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30198844

RESUMO

Upon antigen stimulation, T lymphocytes undergo dramatic changes in metabolism to fulfill the bioenergetic, biosynthetic and redox demands of proliferation and differentiation. Glutathione (GSH) plays an essential role in controlling redox balance and cell fate. While GSH can be recycled from Glutathione disulfide (GSSG), the inhibition of this recycling pathway does not impact GSH content and murine T cell fate. By contrast, the inhibition of the de novo synthesis of GSH, by deleting either the catalytic (Gclc) or the modifier (Gclm) subunit of glutamate-cysteine ligase (Gcl), dampens intracellular GSH, increases ROS, and impact T cell differentiation. Moreover, the inhibition of GSH de novo synthesis dampened the pathological progression of experimental autoimmune encephalomyelitis (EAE). We further reveal that glutamine provides essential precursors for GSH biosynthesis. Our findings suggest that glutamine catabolism fuels de novo synthesis of GSH and directs the lineage choice in T cells.


Assuntos
Diferenciação Celular , Glutamina/metabolismo , Glutationa/biossíntese , Homeostase , Linfócitos T/citologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fumarato de Dimetilo/farmacologia , Glutamato-Cisteína Ligase/metabolismo , Dissulfeto de Glutationa/metabolismo , Homeostase/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
10.
World J Pediatr ; 14(4): 399-403, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29508360

RESUMO

BACKGROUND: To determine whether ex utero intrapartum treatment (EXIT) is an appropriate approach for managing fetuses antenatally diagnosed with giant congenital omphaloceles. METHODS: We retrospectively reviewed patients with omphaloceles who underwent either an EXIT procedure or a traditional repair surgery. Basic and clinical parameters including gender, gestational age, birth weight, maternal blood loss, operative times and operative complications were analyzed. During the 6-12-month follow-ups, postoperative complications including bowel obstruction, abdominal infections, postoperative abdominal distension were monitored, and survival rate was analyzed. RESULTS: A total of seven patients underwent the EXIT procedure and 11 patients underwent the traditional postnatal surgery. We found no differences in maternal age, gestational age at diagnosis, gestational age at delivery and birth weight between the two groups. In the EXIT group, the average operation time for mother was 68.3 ± 17.5 minutes and the average maternal blood loss was 233.0 ± 57.7 mL. The operation time in the EXIT group (22.0 ± 4.5 minutes) was shorter than that in the traditional group (35 ± 8.7 minutes), but the length of hospital stay in the EXIT group (20.5 ± 3.1 days) was longer than that in the traditional group (15.7 ± 2.5 days, P < 0.05). During the follow-up, one patient in the EXIT group had an intestinal obstruction, one developed abdominal compartment syndrome and one died in the traditional group. CONCLUSIONS: In our experience, EXIT is a safe and effective procedure for the treatment of giant congenital omphaloceles. However, more experience is needed before this procedure can be widely recommended.


Assuntos
Doenças Fetais/cirurgia , Hérnia Umbilical/cirurgia , Herniorrafia/métodos , Segurança do Paciente , Resultado da Gravidez , Ultrassonografia Pré-Natal/métodos , Estudos de Coortes , Feminino , Doenças Fetais/diagnóstico por imagem , Seguimentos , Hérnia Umbilical/diagnóstico por imagem , Humanos , Recém-Nascido , Masculino , Gravidez , Cuidado Pré-Natal/métodos , Estudos Retrospectivos , Medição de Risco , Resultado do Tratamento
11.
Cell Death Dis ; 9(2): 220, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29445162

RESUMO

Heightened aerobic glycolysis and glutaminolysis are characteristic metabolic phenotypes in cancer cells. Neuroblastoma (NBL), a devastating pediatric cancer, is featured by frequent genomic amplification of MYCN, a member of the Myc oncogene family that is primarily expressed in the early stage of embryonic development and required for neural crest development. Here we report that an enriched glutaminolysis gene signature is associated with MYCN amplification in children with NBL. The partial knockdown of MYCN suppresses glutaminolysis in NBL cells. Conversely, forced overexpression of MYCN in neural crest progenitor cells enhances glutaminolysis. Importantly, glutaminolysis induces oxidative stress by producing reactive oxygen species (ROS), rendering NBL cells sensitive to ROS augmentation. Through a small-scale metabolic-modulator screening, we have found that dimethyl fumarate (DMF), a Food and Drug Administration-approved drug for multiple sclerosis, suppresses NBL cell proliferation in vitro and tumor growth in vivo. DMF suppresses NBL cell proliferation through inducing ROS and subsequently suppressing MYCN expression, which is rescued by an ROS scavenger. Our findings suggest that the metabolic modulation and ROS augmentation could be used as novel strategies in treating NBL and other MYC-driven cancers.


Assuntos
Antineoplásicos/farmacologia , Fumarato de Dimetilo/farmacologia , Regulação Neoplásica da Expressão Gênica , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Aloenxertos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Criança , Fumarato de Dimetilo/antagonistas & inibidores , Ensaios de Seleção de Medicamentos Antitumorais , Depuradores de Radicais Livres/farmacologia , Glutamina/agonistas , Glutamina/antagonistas & inibidores , Glutamina/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/genética , Humanos , Camundongos , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Proteína Proto-Oncogênica N-Myc/metabolismo , Crista Neural/efeitos dos fármacos , Crista Neural/metabolismo , Crista Neural/patologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Transdução de Sinais
12.
J Biol Chem ; 293(14): 5185-5199, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29467227

RESUMO

From unicellular to multicellular organisms, cell-cycle progression is tightly coupled to biosynthetic and bioenergetic demands. Accumulating evidence has demonstrated the G1/S-phase transition as a key checkpoint where cells respond to their metabolic status and commit to replicating the genome. However, the mechanism underlying the coordination of metabolism and the G2/M-phase transition in mammalian cells remains unclear. Here, we show that the activation of AMP-activated protein kinase (AMPK), a highly conserved cellular energy sensor, significantly delays mitosis entry. The cell-cycle G2/M-phase transition is controlled by mitotic cyclin-dependent kinase complex (CDC2-cyclin B), which is inactivated by WEE1 family protein kinases and activated by the opposing phosphatase CDC25C. AMPK directly phosphorylates CDC25C on serine 216, a well-conserved inhibitory phosphorylation event, which has been shown to mediate DNA damage-induced G2-phase arrest. The acute induction of CDC25C or suppression of WEE1 partially restores mitosis entry in the context of AMPK activation. These findings suggest that AMPK-dependent phosphorylation of CDC25C orchestrates a metabolic checkpoint for the cell-cycle G2/M-phase transition.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/fisiologia , Fosfatases cdc25/metabolismo , Proteína Quinase CDC2/metabolismo , Ciclo Celular/fisiologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Ciclina B/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Fase G2/fisiologia , Células HeLa , Humanos , Mitose/fisiologia , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Fosfatases cdc25/genética
13.
Pediatr Surg Int ; 33(5): 581-586, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28154903

RESUMO

BACKGROUND AND OBJECTIVE: The cardinal diagnostic sign of congenital aganglionic megacolon, or Hirschsprung's disease (HD), is an aganglionic segment of the distal colon or rectum. To determine the surgical planning of a radiological transition zone (TZ) in HD, this study investigated the association between a radiological TZ and the bowel resection length. METHODS: A prospective observational study was conducted in children (n = 192) with suspected HD determined by radiological TZ on contrast barium enema, and who underwent pull-through operations. The bowel resection length was ≥10 cm above the proximal radiological TZ levels and confirmed by intraoperative frozen sections. In the contrast enema, the presence and level of a radiological TZ were recorded. Correlation of the TZ features with ganglion cells assessed by immunostaining of neuronal nuclei (NeuN) and the odds ratio were calculated. RESULTS: The sensitivity and specificity for diagnosing HD by the presence of a radiological TZ were 86.9 and 92.1%, respectively; Youden's index was 79.0%. The positive and negative predictive values were 91.7 and 87.6%. The kappa value indicating an association between TZ and HD was 0.776 (P < 0.05). The correlation rate between a radiological TZ and the pathological results was 88.5% in the rectosigmoid colon and 44.4% in the descending colon, and was higher in children older than 3 months (85.3%) than in infants (69.0%). CONCLUSION: A preoperatively determined radiological TZ has potential value to identify the length of resected bowel in patients with HD, and it also has a high predictive value for diagnosis of HD.


Assuntos
Enema Opaco/métodos , Doença de Hirschsprung/diagnóstico por imagem , Doença de Hirschsprung/cirurgia , Cuidados Pré-Operatórios/métodos , Adolescente , Criança , Pré-Escolar , Colo/diagnóstico por imagem , Colo/cirurgia , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Reto/diagnóstico por imagem , Sensibilidade e Especificidade
14.
Pediatr Surg Int ; 32(11): 1019-1024, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27586151

RESUMO

OBJECTIVES: This study was conducted to investigate the pathological changes which occur in interstitial cells of Cajal (ICCs) and ganglion cells found in segments of resected bowel obtained from patients with Hirschsprung's disease (HD), as well as to explore the benefits of using a contrast enema (CE) with 24-h delayed X-ray films to predict the length of resected bowel. METHODS: We performed a retrospective analysis of 58 children with HD who had undergone the pull-through procedure. After each operation, the ICCs and ganglion cells present in the proximal ends of the barium residue (Level A) and resected proximal bowel segment (Level B) were analyzed using immunohistochemical staining methods. Each patient was followed up for 1 year to record their stool frequency, defecation control ability, and post-surgical complications which may have occurred. RESULTS: Immunohistochemical staining detected fewer ICCs in Level A than in Level B (p < 0.05). However, the density of ganglion cells in the two levels was not significantly different (p > 0.05). One patient had anastomotic stricture, and five patients suffered from enterocolitis. CONCLUSIONS: The density of ICCs was significantly lower in the bowel segments that displayed barium retention. A CE may be a valuable tool for predicting the length of bowel resection in patients with HD.


Assuntos
Colo/patologia , Colo/cirurgia , Doença de Hirschsprung/patologia , Doença de Hirschsprung/cirurgia , Células Intersticiais de Cajal/patologia , Neurônios/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
15.
Chin Med J (Engl) ; 129(12): 1491-7, 2016 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-27270548

RESUMO

OBJECTIVE: To systematically summary the updated results about the pathogenesis of Hirschsprung's-associated enterocolitis (HAEC). Besides, we discussed the research key and direction based on these results. DATA SOURCES: Our data cited in this review were obtained mainly from PubMed from 1975 to 2015, with keywords "Hirschsprung enterocolitis", "Hirschsprung's enterocolitis", "Hirschsprung's-associated enterocolitis", "Hirschsprung-associated enterocolitis", "HAEC", and "EC". STUDY SELECTION: Articles regarding the pathogenesis of HAEC were selected, and the articles mainly regarding the diagnosis, surgical approach, treatment, and follow-up were excluded. RESULTS: Several factors, mainly including mucus barrier, intestinal microbiota, and immune function, as well as some other factors such as genetic variations and surgical reasons, have been found to be related to the pathogenesis of HAEC. Changed quantity and barrier property of mucus, different composition of microbiota, and an abnormal immune state work together or separately trigger HAEC. CONCLUSIONS: The maintenance of intestinal homeostasis is due to a well cooperation of microbiota, mucus barrier, and immune system. If any part presents abnormal, intestinal homeostasis will be broken. Meanwhile, for patients with Hirschsprung's disease or HAEC, dysfunction of these parts has been found. Thus, the happening of HAEC may be mainly attributed to the disorders of intestinal microbiota, mucus barrier, and immune system.


Assuntos
Enterocolite/patologia , Doença de Hirschsprung/patologia , Animais , Enterocolite/etiologia , Doença de Hirschsprung/complicações , Humanos , Intestinos/microbiologia , Intestinos/patologia
16.
J Immunol Res ; 2015: 906086, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26601115

RESUMO

To investigate whether the cyclic AMP-responsive element modulator α (CREMα) polymorphisms are novel susceptibility factors for systemic lupus erythematosus (SLE), four tag SNPs, rs1057108, rs2295415, rs11592925, and rs1148247, were genotyped in 889 SLE cases and 825 healthy controls. Association analyses were performed on whole dataset or clinical/serologic subsets. Association statistics were calculated by age and sex adjusted logistic regression. The G allele frequencies of rs2295415 and rs1057108 were increased in SLE patients, compared with healthy controls (rs2295415: 21.2% versus 17.8%, OR 1.244, P = 0.019; rs1057108: 30.8% versus 27.7%, OR 1.165, P = 0.049). The haplotype constituted by the two risk alleles "G-G" from rs1057108 and rs2295415 displayed strong association with SLE susceptibility (OR 1.454, P = 0.00056). Following stratification by clinical/serologic features, a suggestive association was observed between rs2295415 and anti-Sm antibodies-positive SLE (OR 1.382, P = 0.044). Interestingly, a potential protective effect of rs2295415 was observed for SLE patients with renal disorder (OR 0.745, P = 0.032). Our data provide first evidence that CREMα SNPs rs2295415 and rs1057108 maybe novel genetic susceptibility factors for SLE. SNP rs2295415 appears to confer higher risk to develop anti-Sm antibodies-positive SLE and may play a protective role against lupus nephritis.


Assuntos
Modulador de Elemento de Resposta do AMP Cíclico/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Autoanticorpos/imunologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco
17.
J Pediatr Surg ; 50(12): 2078-83, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26385564

RESUMO

PURPOSE: The purpose of this study was to investigate the mechanism of dibutyl phthalate (DBP) induced hypospadias and shortened anogenital distance (AGD). METHODS: AGD, hypospadias, and cryptorchidism incidence was observed in male offspring of DBP treated pregnant Wistar rats. Testicular development and testosterone levels of normal and DBP-treated rat embryos were compared. RESULTS: Male offspring of 300mg and 900mg DBP-treated pregnant Wistar rats exhibited shortened average AGD compared with the control group. A 22.7% hypospadias incidence was observed in the 300mg group, but no offspring with cryptorchidism were identified. In the 900mg group, hypospadias and cryptorchidism incidence reached 43.5% and 17.4%, respectively. Between E15.5 and E17.5, the 300mg group exhibited delayed testicular development and testosterone secretion. However, testicular development and testosterone secretion subsequently recovered. The 300mg treated and control groups had similar measures after E19.5. Contrastingly, testicular development and testosterone secretion were significantly diminished throughout development in the 900mg group. Exogenous testosterone partially counteracted DBP-induced changes in the reproductive organs of male offspring of DBP-treated rats. CONCLUSIONS: High-dose DBP exposure may induce testicular dysgenesis in rat embryos. Additionally, low-dose DBP may delay testicular development and testosterone secretion during urethral development. This disruption may result in hypospadias.


Assuntos
Criptorquidismo/induzido quimicamente , Dibutilftalato/toxicidade , Hipospadia/induzido quimicamente , Plastificantes/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Canal Anal/anormalidades , Animais , Biomarcadores/metabolismo , Criptorquidismo/metabolismo , Relação Dose-Resposta a Droga , Feminino , Doenças dos Genitais Masculinos/induzido quimicamente , Doenças dos Genitais Masculinos/metabolismo , Hipospadia/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Testosterona/metabolismo
18.
Am J Physiol Gastrointest Liver Physiol ; 307(2): G233-40, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24875101

RESUMO

Interferon (IFN)-γ-driven and CD8+ T cell-dependent inflammatory injury to extrahepatic biliary epithelium (EHBE) is likely to be involved in the development of biliary atresia (BA). We previously showed that viral protein NSP4 is the pathogenic immunogen that causes biliary injury in BA. In this study, NSP4 or four synthetic NSP4 (NSP4(157-170), NSP4(144-152), NSP4(93-110), NSP4(24-32)) identified by computer analysis as candidate CD8+ T cell epitopes were injected into neonatal mice. The pathogenic NSP4 epitopes were confirmed by studying extrahepatic bile duct injury, IFN-γ release and CD8+ T cell response against EHBE. The results revealed, at 7 days postinjection, inoculation of glutathione S-transferase (GST)-NSP4 caused EHBE injury and BA in neonatal mice. At 7 or 14 days postinject, inoculation of GST-NSP4, NSP4(144-152), or NSP4(157-170) increased IFN-γ release by CD8+ T cells, elevated the population of hepatic memory CD8+ T cells, and augmented cytotoxicity of CD8+ T cells to rhesus rotavirus (RRV)-infected or naive EHBE cells. Furthermore, depletion of CD8+ T cells in mice abrogated the elevation of GST-NSP4-induced serum IFN-γ. Lastly, parenteral immunization of mouse dams with GST-NSP4, NSP4(144-152), or NSP4(157-170) decreased the incidence of RRV-induced BA in their offspring. Overall, this study reports the CD8+ T cell response against EHBE is activated by epitopes within rotavirus NSP4 in experimental BA. Neonatal passive immunization by maternal vaccination against NSP4(144-152) or NSP4(157-170) is effective in protecting neonates from developing RRV-related BA.


Assuntos
Ductos Biliares Extra-Hepáticos/imunologia , Atresia Biliar/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T , Glicoproteínas/imunologia , Fragmentos de Peptídeos/imunologia , Infecções por Rotavirus/imunologia , Vacinas contra Rotavirus/imunologia , Toxinas Biológicas/imunologia , Proteínas não Estruturais Virais/imunologia , Animais , Ductos Biliares Extra-Hepáticos/patologia , Ductos Biliares Extra-Hepáticos/virologia , Atresia Biliar/patologia , Atresia Biliar/prevenção & controle , Atresia Biliar/virologia , Linfócitos T CD8-Positivos/virologia , Modelos Animais de Doenças , Feminino , Glicoproteínas/administração & dosagem , Imunização Passiva , Memória Imunológica , Injeções Intraperitoneais , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/administração & dosagem , Gravidez , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/imunologia , Infecções por Rotavirus/patologia , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/virologia , Vacinas contra Rotavirus/administração & dosagem , Linfócitos T Citotóxicos/imunologia , Toxinas Biológicas/administração & dosagem , Proteínas não Estruturais Virais/administração & dosagem
19.
Cell Tissue Res ; 356(1): 29-37, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24435644

RESUMO

Interstitial cells of Cajal (ICC) have recently been found to display phenotypic changes. The present study is designed to determine whether phenotypic changes occur in ICC associated with an inflammatory microenvironment and whether the ICC phenotype could be recovered after the discontinuation of inflammatory stimuli. Immunohistochemistry studies revealed that the functional ICC marker, c-kit, was markedly reduced in patients with Hirschsprung's disease (n = 34) compared with controls (n = 12), whereas another marker of ICC, CD34, was not altered significantly. Compared with the vehicle group (n = 6), intraperitoneal injection of lipopolysaccharide (LPS; 1.5 mg/kg) in mice (n = 6) significantly induced plasma tumor necrosis factor-alpha (TNF-α) levels as determined by enzyme-linked immunosorbent assay. Western blot and real-time polymerase chain reaction assessment further showed that LPS injection markedly suppressed intestinal c-kit protein and mRNA expression, which could be blocked by Toll-like receptor 4 (TLR4) deficiency (n = 6) rather than TLR2 deficiency (n = 6) and had no effects on CD34. Compared with the vehicle group (n = 6), intraperitoneal TNF-α (30 µg/kg) administration (n = 6) also significantly reduced intestinal c-kit protein and mRNA levels but not CD34 levels. However, the reduction of c-kit induced by TNF-α injection was not suppressed by TLR4 deficiency (n = 6). Intestinal c-kit protein and mRNA levels were markedly restored after the discontinuation of TNF-α administration for 7 days. Moreover, immunofluorescence analysis of primary ICC further confirmed that exposure to TNF-α for 24 h suppressed c-kit expression, which could be restored after discontinuation of TNF-α exposure. CD34 expression was not altered upon exposure to TNF-α. Thus, phenotypic changes in ICC occur in an inflammatory microenvironment in the gut and LPS, TLR4 and TNFα are crucial to this process.


Assuntos
Inflamação/patologia , Células Intersticiais de Cajal/patologia , Animais , Antígenos CD34/genética , Antígenos CD34/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Doença de Hirschsprung/genética , Doença de Hirschsprung/patologia , Humanos , Inflamação/genética , Células Intersticiais de Cajal/efeitos dos fármacos , Células Intersticiais de Cajal/metabolismo , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
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