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1.
Int. j. morphol ; 40(3): 735-741, jun. 2022. ilus, tab
Article in English | LILACS-Express | LILACS | ID: biblio-1385656

ABSTRACT

SUMMARY: This study is to investigate the regulation of Notch1 and Foxp1 by miR-34a in the development of psoriasis vulgaris. RT-PCR was used to compare the levels of miR-34a in the skin lesions of 20 patients with psoriasis vulgaris and 20 normal skin tissues. Immunohistochemistry was used to detect the expression of Notch1 and Foxp1 in 51 patients with psoriasis vulgaris, which were further compared with that in 29 normal control tissues. In addition, in HaCaT cells, we used miR-34a mimics and inhibitors to overexpress and inhibit miR-34a, respectively, and detected the mRNA and protein levels of miR-34a, Notch1, and Foxp1. The level of miR-34a in the skin lesions of patients with psoriasis vulgaris was significantly higher than that in normal skin tissues (t=2.192, P<0.05). The positive rate of Notch1 in the skin lesions of patients with psoriasis vulgaris was 76.47 %, which was significantly higher than that in normal skin tissues (13.79 %) (t=29.215, P<0.01). The positive rate of FOXP1 in the psoriasis vulgaris group was 92.16 %, which was also significantly higher than that in the normal skin group (65.52 %) (t=9.087, P<0.01). In addition, overexpression of miR-34a significantly promoted the expression of Notch1 and Foxp1. However, inhibition of miR-34a significantly reduced Notch1 and Foxp1 levels. miR- 34a is highly expressed in the skin tissues of patients with psoriasis vulgaris, and may participate in the development of psoriasis vulgaris by regulating Notch1 and Foxp1.


RESUMEN: El objetivo de este estudio fue investigar la regulación de Notch1 y Foxp1 por miR-34a en el desarrollo de la psoriasis vulgar. Se utilizó RT-PCR con el fin de comparar los niveles de miR-34a en las lesiones cutáneas de 20 pacientes con psoriasis vulgar y 20 tejidos de piel normales. Se utilizó inmunohistoquímica para detectar la expresión de Notch1 y Foxp1 en 51 pacientes con psoriasis vulgar, que se compararon además con la de 29 tejidos normales control. Además, en las células HaCaT, usamos miméticos e inhibidores de miR-34a para sobreexpresar e inhibir miR-34a, respectivamente, y detectamos los niveles de ARNm y proteína de miR-34a, Notch1 y Foxp1. El nivel de miR- 34a en las lesiones cutáneas de pacientes con psoriasis vulgar fue significativamente mayor que en los tejidos normales de la piel (t=2,192, P<0,05). La tasa de positividad de Notch1 en las lesiones cutáneas de pacientes con psoriasis vulgar fue del 76,47 %, que fue significativamente mayor que la de los tejidos normales de la piel (13,79 %) (t=29,215, P<0,01). La tasa positiva de FOXP1 en el grupo de psoriasis vulgar fue del 92,16 %, que también fue significativamente mayor que la del grupo de piel normal (65,52 %) (t=9,087, P<0,01). Además, la sobreexpresión de miR-34a promovió significativamente la expresión de Notch1 y Foxp1. Sin embargo, la inhibición de miR-34a redujo de manera importante los niveles de Notch1 y Foxp1. miR-34a se expresa en gran medida en los tejidos de la piel en pacientes con psoriasis vulgar y puede participar en el desarrollo de la psoriasis vulgar mediante la regulación de Notch1 y Foxp1.


Subject(s)
Humans , Psoriasis/genetics , MicroRNAs/genetics , Forkhead Transcription Factors/genetics , Receptor, Notch1/genetics , Psoriasis/metabolism , Immunohistochemistry , Transfection , Blotting, Western , Reverse Transcriptase Polymerase Chain Reaction , MicroRNAs/metabolism , Forkhead Transcription Factors/metabolism , Receptor, Notch1/metabolism
2.
Article in English | WPRIM | ID: wpr-929250

ABSTRACT

To explore the effectiveness and safety of a Chinese medicinal decoction Wuwei Xiaodu Drink (WWXDD) in inhibiting chronic osteomyelitis via regulatory T cells signaling. The effective constitutes of WWXDD and osteomyelitis related genes were screened. Target proteins were cross-validated using the Venny database. GO function and KEGG pathway analysis were performed for target proteins, while pharmacological network was constructed. The bone properties were analyzed by HE staining and the concentrations of immune factors were measured by ELISA. The expression of CTLA-4 and Foxp3 mRNA and STAT5, p-STAT5, CTLA-4 and Foxp3 protein were detected using Real-time PCR and Western blot, respectively. FACS was used to analyze the percentages of cells. A total of 117 genes overlapped between 785 target genes of the active compounds of WWXDD and 912 osteomyelitis related genes. Inflammation-related genes, including IL-6, TNFα, IL-1β and IL-2 showed high connection degree in the drug-compound-disease-target network. GO function and KEGG pathway analysis revealed that 117 intersection genes mainly enriched in virus infection related pathways, immune related pathways and chemokine signaling pathway. Furthermore, the development of chronic osteomyelitis was suppressed in model rats after treatment with WWXDD. Meanwhile, the concentrations of IL-2 and CD4+CD25+Foxp3 Treg percentages together with the levels of p-STAT5, CTLA-4 and Foxp3 were also down-regulated. Furthermore, IL-2 and WWXDD drug-containing serum exhibited opposite effects on regulating IL-2, IL-10, TGF-β1, Foxp3, CTLA4 and STAT5. In addition, a STAT5 phosphorylation inhibitor suppressed the expression of Foxp3 and CTLA-4. WWXDD can treat chronic osteomyelitis through suppressing the main regulating factors of Tregs and interfere its immunodepression. Our results bring a new solution for chronic osteomyelitis.


Subject(s)
Animals , Forkhead Transcription Factors/metabolism , Interleukin-2/metabolism , Osteomyelitis/metabolism , Rats , STAT5 Transcription Factor/metabolism , Signal Transduction , T-Lymphocytes, Regulatory
3.
J. pediatr. (Rio J.) ; 97(5): 546-551, Sept.-Oct. 2021. tab, graf
Article in English | LILACS | ID: biblio-1340156

ABSTRACT

Abstract Objective: The aim of this study was to evaluate the association between possible functional interleukin-10 (IL-10) polymorphisms, IL-10 expression and regulatory T cells (Tregs) frequency, and/or asthma severity in a sample of children and adolescents. Methods: This is a nested case-control genetic association study. The study sample consisted of children and adolescents aged 8-14 from public schools. Four polymorphisms of the IL-10 gene (rs1518111, rs3024490, rs3024496, rs3024491) were genotyped in asthmatic subjects and controls using real-time PCR. Tregs cells and IL-10 were analyzed in peripheral blood mononuclear cells by flow cytometry. The severity of asthma was defined according to the Global Initiative for Asthma (GINA) guideline. Results: One hundred twenty-three asthmatic subjects and fifty-eight controls participated in the study. The single nucleotide polymorphism (SNP) rs3024491 (T allele) showed association with asthma severity, presenting a higher frequency in patients in the moderate asthma group. The T allele of variant rs3024491 also showed an association with reduced IL-10 levels (p = 0.01) and with increased Tregs frequency (p = 0.01). The other variants did not present consistent associations. Conclusions: Our results suggest that moderate asthma is associated with a higher frequency of the T allele in the SNP rs3024491. In addition, the variant rs3024491 (TT) was associated with a reduction in IL-10 production and an increased percentage of Tregs cells, suggesting possible mechanisms that influence asthma severity.


Subject(s)
Humans , Child , Adolescent , Asthma/genetics , Interleukin-10/genetics , Leukocytes, Mononuclear , Polymorphism, Single Nucleotide/genetics , Forkhead Transcription Factors , Interleukin-2 Receptor alpha Subunit
4.
Article in Chinese | WPRIM | ID: wpr-922022

ABSTRACT

OBJECTIVE@#To analyze the clinical features and genetic basis of three children with mental retardation, language impairment and autistic features due to de novo variants of FOXP1 gene.@*METHODS@#Clinical data of the children were collected.Trio-whole exome sequencing was carried out for the children and their parents. Pathogenicity of the variants was analyzed through bioinformatics prediction.@*RESULTS@#All of the children had various degrees of mental retardation in conjunct with language deficit, global developmental delay, abnormal behavior and peculiar facial features, among whom two also developed autism spectrum disorders. The results of genetic testing showed that all three children harbored de novo variants of the FOXP1 gene, namely c.613_c.614delCTinsTA, c.1248delC and c.1393A>G. Two of these were frameshift variants and one was missense variant, which were all rated as pathogenic based on the guidelines of the American College of Medical Genetics (ACMG). Database search suggested that c.613_c.614delCTinsTA and c.1248delC were unreported previously.@*CONCLUSION@#For the three children from unrelated families with mental retardation in conjunct with language deficit, global growth delay, abnormal behavior and peculiar facial features, the c.613_ c. 614delCTinsTA, c.1248delC and c.1393A>G variants of the FOXP1 gene may be the pathogenic factors. Above cases have further expanded the genotype-phenotype profile of FOXP1 deficiency syndrome.


Subject(s)
Autistic Disorder/genetics , Child , Forkhead Transcription Factors/genetics , Genetic Testing , Humans , Intellectual Disability/genetics , Language Development Disorders/genetics , Repressor Proteins/genetics , Whole Exome Sequencing
5.
Article in Chinese | WPRIM | ID: wpr-921997

ABSTRACT

OBJECTIVE@#To analyze the clinical manifestations and gene variants of patients with blepharophimosis, ptosis and epicanthus inversus syndrome (BPES).@*METHODS@#Clinical data of 7 pedigrees affected with BPES were collected, and genomic DNA was extracted from peripheral blood samples of the probands and their relatives. All exons of the FOXL2 gene were subjected to Sanger sequencing. Those with negative findings were further screened by targeted capture and next generation sequencing (NGS) and microarray analysis. Pathogenicity of candidate variants were predicted by search of PubMed and related databases, and the impact of the variants was interpreted by protein prediction software. Diagnosis was confirmed by clinical phenotype, medical history and mutation analysis.@*RESULTS@#A pathogenic variant was identified in six of the 7 pedigrees, which included four known pathogenic variants and one novel FOXL2 c.299dupA variant. A heterozygous 3q22.3q23 deletion, which encompassed the FOXL2 gene, was identified in another pedigree.As predicted, the c.299dupA frameshift mutation of FOXL2 gene can lead to the premature termination of protein translation, which is pathogenic.@*CONCLUSION@#A novel and 5 known pathogenic variants have been identified in six pedigrees affected with BPES by the combined Sanger sequencing, target capture NGS and microarray analysis. Above findings have enabled genetic counseling and prenatal diagnosis for these pedigrees.


Subject(s)
Blepharophimosis/genetics , Forkhead Box Protein L2/genetics , Forkhead Transcription Factors/genetics , Humans , Mutation , Pedigree , Phenotype , Skin Abnormalities , Urogenital Abnormalities
6.
Article in English | WPRIM | ID: wpr-921386

ABSTRACT

OBJECTIVES@#To observe the effect of type 2 diabetes mellitus (T2DM) on mandibular bone regeneration and the expression of factors related to T helper cell 17 (Th17 cell) and regulatory T cell (Treg cell) in mice.@*METHODS@#Thirty-six 6-week-old C57BL/6J male mice were randomly divided into normal control (NC) and T2DM groups. Fasting blood glucose levels were detected 0 d, 7 d, 14 d, and 28 d after surgery for mandibular defects. Hematoxylin-eosin (HE) staining was used in observing the bone after 7 d, 14 d, and 28 d of the healing process. Immunohistochemical staining was used in observing the expression of alkaline phosphatase (ALP), Runt-related transcription factor 2 (RUNX2), forkhead box protein P3 (Foxp3), retinoic acid related orphan receptor gamma T (RORγt), and protein tyrosine phosphatase non-receptor type 2 (PTPN2) after 7 d, 14 d, and 28 d of healing.@*RESULTS@#HE staining showed that the area with new bones in the T2DM group was significantly smaller than that in the NC group. Immunohistochemical staining showed that the expression of osteogenesis related proteins ALP and RUNX2 were significantly reduced in the T2DM group. In addition, the number of RORγt positive cells increased, whereas the number of Foxp3 positive cells and the expression PTPN2 decreased significantly in the mandibular bone defect in mice with T2DM.@*CONCLUSIONS@#T2DM significantly inhibit mandibular bone regeneration in mice. Decline in PTPN2 expression and the transition of Treg and Th17 may be the underlying molecular mechanisms.


Subject(s)
Animals , Bone Regeneration , Diabetes Mellitus, Type 2 , Forkhead Transcription Factors , Male , Mice , Mice, Inbred C57BL , TCF Transcription Factors , Th17 Cells
7.
Journal of Experimental Hematology ; (6): 1251-1256, 2021.
Article in Chinese | WPRIM | ID: wpr-888547

ABSTRACT

OBJECTIVE@#To study the expression of B lymphocyte-induced mature protein-1 (BLIMP-1) in regulatory T cells (Tregs) of children with aplastic anemia (AA), and analyze its correlation with the number of Tregs and the levels of inhibitory cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β in plasma.@*METHODS@#The peripheral blood samples of 10 newly diagnosed AA children and 10 healthy children were collected for experiment. qPCR was used to detect FOXP3 and PRDM1 mRNA expression levels. Flow cytometry was used to detect the proportion of Tregs, the expression of BLIMP-1 in Tregs, and the levels of cytokines such as IL-2, IL-17A, IL-6, interferon (IFN)-γ, IL-10 and TGF-β in plasma. Pearson correlation model was used to evaluate the relationship between the expression of BLIMP-1 in Treg and the number of Tregs, as well as the levels of IL-10 and TGF-β in plasma.@*RESULTS@#Compared with control group, the proportion of Tregs in peripheral blood of AA children was decreased significantly (P<0.001); The plasma levels of proinflammatory cytokines IL-2, IL-6 and IFN-γ in AA children were increased significantly (P=0.033, P=0.031, P=0.006), and IL-17A also was increased but the difference was not statistically significant (P=0.052), while anti-inflammatory cytokines IL-10 and TGF-β were significantly reduced (P=0.048, P=0.002). The relative expressions level of FOXP3 and PRDM1 mRNA in AA children were significantly lower than those in control group (P=0.037, P=0.016). The expression of BLIMP-1 protein in Tregs of AA children was significantly lower than that in control group (P<0.001). The expression level of BLIMP-1 protein in Tregs was positively correlated with the percentage of Tregs in lymphocytes (r=0.671, P=0.001), and was also positively correlated with the levels of IL-10 and TGF-β in plasma (r=0.500, P=0.029; r=0.486, P=0.030).@*CONCLUSION@#The expression of BLIMP-1 in Tregs of AA children is impaired, and the low expression of BLIMP-1 is related to the decrease of the number in Tregs and IL-10 and TGF-β expressions.


Subject(s)
Anemia, Aplastic , Child , Cytokines , Flow Cytometry , Forkhead Transcription Factors , Humans , Positive Regulatory Domain I-Binding Factor 1 , T-Lymphocytes, Regulatory , Transforming Growth Factor beta
8.
Article in Chinese | WPRIM | ID: wpr-880039

ABSTRACT

OBJECTIVE@#To investigate the correlation between FOXP3, CD11c protein expression and the prognosis of patients with diffuse large B-cell lymphoma (DLBCL).@*METHODS@#This study included 48 patients with DLBCL who were admitted to Jiujiang No.1 People's Hospital and TCM-Integrated Hospital of Southern Medical University from January 2015 to January 2019. The DLBCL tissues removed during the operation were collected as test specimens. The expression of FOXP3 and CD11c protein were detected by immunohistochemistry. The deadline for postoperative follow-up was December 31, 2019, and the patient's short-term efficacy (complete remission, partial remission) and progression-free survival were recorded.@*RESULTS@#FOXP3 protein was positively expressed in the nucleus, mostly focally or diffusely distributed, the FOXP3@*CONCLUSION@#In some patients with DLBCL, FOXP3 and CD11c expresse positively, and the positive expression rate is related to the clinical stage and international prognostic index score. The positive expression of FOXP3 and CD11c indicate a good prognosis.


Subject(s)
Forkhead Transcription Factors , Humans , Immunohistochemistry , Lymphoma, Large B-Cell, Diffuse , Prognosis , Proteomics
9.
Article in Chinese | WPRIM | ID: wpr-879588

ABSTRACT

OBJECTIVE@#To describe the clinical and genetic characteristics of a child with 14q12q13.1 deletion involving the FOXG1 gene.@*METHODS@#Clinical manifestation of the child was analyzed. Peripheral blood sample of the patient was subjected to chromosomal karyotyping and single nucleotide polymorphism array (SNP-array) analysis.@*RESULTS@#The male infant has developed feeding difficulty, poor sucking, lower limb tremor, and frontal bruising 8 days after birth. Magnetic resonance imaging revealed significant enlargement of bilateral ventricles and corpus callosum dysplasia. Chromosomal analysis revealed a karyotype of 46,XY,del(14)(q12q13.1), and SNP-array confirmed that there was a 9.6 Mb deletion in 14q11.2q13.1, which encompassed the FOXG1 gene.@*CONCLUSION@#For patients with brain development abnormalities, dyskinesia, cognitive impairment, speech disorder and other manifestations, copy number variation of the FOXG1 gene should be excluded. SNP-array should be carried out as early as possible to attain the diagnosis.


Subject(s)
Child , Chromosome Deletion , DNA Copy Number Variations , Forkhead Transcription Factors/genetics , Heterozygote , Humans , Infant , Karyotyping , Male , Nerve Tissue Proteins/genetics , Polymorphism, Single Nucleotide
10.
Article in Chinese | WPRIM | ID: wpr-879565

ABSTRACT

OBJECTIVE@#To report on the clinical features and result of genetic testing for a child featuring immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.@*METHODS@#Clinical records, genetic testing, laboratory investigation and treatment of the child were summarized in addition with a comprehensive review of the literature.@*RESULTS@#The 3-year-old boy was administered due to intractable diarrhea, recurrent infections, liver dysfunction and failure to thrive, though no diabetes or skin disorder was observed. Laboratory testing showed elevated liver enzymes and total IgE, decreased albumin and electrolyte imbalance. Gastrointestinal endoscopy revealed erosion and granules in the duodenum, and edema in the terminal ileum and colon. Biopsies showed villous atrophy in the duodenum and terminal ileum. Genetic testing revealed that the patient has carried a missense c.1087A>G (p.I363V) variant in the exon 10 of the FOXP3 gene. He was treated with enteral and parenteral nutrition, anti infection and Sirolimus, and was waiting for hemopoietic stem cell transplantation.@*CONCLUSION@#Although IPEX syndrome usually occur during infancy, it should not be ruled out solely based on the age, and its presentation can be variable. For male children with refractory diarrhea, autoimmune disorder and growth retardation, the diagnosis should be suspected and confirmed by genetic testing.


Subject(s)
Child, Preschool , Diabetes Mellitus, Type 1/genetics , Diarrhea/genetics , Forkhead Transcription Factors/genetics , Genetic Diseases, X-Linked/genetics , Genetic Testing , Humans , Immune System Diseases/genetics , Male , Mutation , Polyendocrinopathies, Autoimmune/genetics
11.
Mem. Inst. Oswaldo Cruz ; 116: e200560, 2021. graf
Article in English | LILACS | ID: biblio-1154882

ABSTRACT

BACKGROUND Anisakis simplex antigens present immunomodulatory properties by the induction of tolerogenic dendritic cells (DCs) in mice. OBJECTIVES To study the capacity of DCs stimulated with A. simplex excretory-secretory (ES) or crude extract (CE) to generate Tregs. To investigate in vitro effects of antigens on the metabolic activity of splenocytes induced by LPS or CpG. METHODS Phenotypic and functional characterization of T cells co-cultured with A. simplex-pulsed DCs was performed by flow cytometry. Lymphocyte mitochondrial respiratory activity was estimated by the Alamar Blue® Assay. FINDINGS In C57BL/6J, CD4+CD25-Foxp3+ and CD8+CD25-Foxp3+ populations increased by CE-stimulated-DCs. In BALB/c, CE-stimulated-DCs caused the expansion of CD4+CD25+Foxp3+IL-10+ and CD8+CD25+Foxp3+IL-10+. IFN-γ expression raised in BALB/c CD4+CD25+ and CD4+CD25- for CE and ES, respectively. ES-stimulated-DCs increased CD4+CD25+ Foxp3+ and CD8+CD25- Foxp3+ expression in T cells. The association of ES or CE with LPS produced the increase in splenocyte activity in C57BL/6J. The association of CE with CpG decreased the proliferation caused by CpG in C57BL/6J. MAIN CONCLUSIONS A. simplex increase the frequency of Tregs, which in turn produce IL-10 and IFN-γ. The host genetic base is essential in the development of anti-Anisakis immune responses (Th2, Th1, Treg).


Subject(s)
Animals , Mice , Anisakis , T-Lymphocytes, Regulatory , Antigens/metabolism , Bone Marrow , Dendritic Cells , Forkhead Transcription Factors , Interleukin-2 Receptor alpha Subunit , Larva , Mice, Inbred BALB C , Mice, Inbred C57BL
12.
Rev. bras. cir. cardiovasc ; 35(5): 697-705, Sept.-Oct. 2020. tab, graf
Article in English | LILACS, SES-SP | ID: biblio-1137330

ABSTRACT

Abstract Objective: To investigate the association between interleukin-35 (IL-35) levels and single nucleotide polymorphisms (rs3761548, rs3761547) of the FoxP3 gene in coronary artery bypass grafting (CABG) patients. Methods: We conducted a prospective study including 140 patients, who were scheduled for elective isolated on-pump CABG with cardiopulmonary bypass (CPB) from January 2017 to September 2018 in the Jorjani heart center. Blood samples were collected before and 12 hours after the operation. Serum levels of IL-35 were measured by enzyme-linked immunosorbent assay and the pattern of genetic variations was assessed using single specific primer-polymerase chain reaction. Results: The serum concentrations of IL-35 after surgery were significantly higher than pre-surgery levels (18.4±8.3 vs. 9.89±3.2, respectively, P=0.002). There was no significant association between genotype frequencies of rs3761548 and rs3761547 and elevated IL-35 levels (P>0.05). There were significant associations between IL-35 levels and preoperative variables, including age (r=-0.34, P=0.047) and body mass index (r=-0.41, P=0.045), and intraoperative variables, including CPB time (r=0.4, P=0.02) and mean arterial pressure (r=-0.38, P=0.046), in carriers of the rs3761548 AA genotype. Conclusion: Serum IL-35 concentrations were significantly increased in CPB patients, which may contribute to the post-CPB compensatory anti-inflammatory response syndrome. IL-35 increased levels were not influenced by FoxP3 promoter polymorphisms (rs3761548, rs3761547).


Subject(s)
Humans , Male , Female , Cardiopulmonary Bypass , Coronary Artery Bypass , Interleukins/blood , Forkhead Transcription Factors/blood , Prospective Studies , Interleukins/genetics , Polymorphism, Single Nucleotide , Forkhead Transcription Factors/genetics
13.
Rev. chil. pediatr ; 91(4): 584-590, ago. 2020. tab, graf
Article in Spanish | LILACS | ID: biblio-1138675

ABSTRACT

INTRODUCCIÓN: El síndrome IPEX (inmunodesregulación, poliendocrinopatía y enteropatía autoinmune ligada a X) causado por mutaciones en el gen FOXP3, se caracteriza por diarrea prolongada, alteraciones endocrinológicas y dermatitis. El tratamiento consiste en la administración de medicamentos inmunosupresores, siendo el trasplante de médula ósea la única cura potencial. OBJETIVO: Describir una nueva mutación del gen FOXP3, así como los hallazgos y evolución de un paciente con síndrome IPEX. CASO CLÍNICO: Lactante menor masculino que debutó al mes de vida con diarrea cró nica, falla intestinal e infecciones recurrentes. Exámenes de laboratorio y biopsia intestinal sugerentes de enteropatía autoinmune. Durante el seguimiento, el paciente presentó refractariedad al manejo inmunosupresor con esteroides, ciclosporina y tacrolimus, falleciendo a los 7 meses de edad por complicaciones vasculares. Antecedente familiar por línea materna de múltiples muertes en hombres menores de 1 año. Ante la sospecha de síndrome IPEX se realizó exoma en trío que reportó una mutación probablemente patogénica en el gen FOXP3. CONCLUSIÓN: Se documentó una nueva mutación del gen FOXP3 en paciente con síndrome IPEX. A pesar de la baja prevalencia de esta enfermedad, es importante el reconocimiento de síntomas no específicos pero sugerentes del diagnóstico.


INTRODUCTION: The IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syn drome is caused by the mutations of the FOXP3 gene, characterized by persistent diarrhea, endo crine disorders, and dermatitis. The treatment is the administration of immunosuppressive drugs, where hematopoietic stem cell transplantation is the only potential cure. OBJECTIVE: To describe a new FOXP3 gene mutation, as well as the findings and evolution of a patient with IPEX syndrome. CLINICAL CASE: Male infant presenting at one month of age with chronic diarrhea, intestinal failure, and recurrent infections. Lab tests and intestinal biopsy suggested autoimmune enteropathy. During follow-up, the patient presented resistance to immunosuppressive treatment with corticosteroids, cyclosporine, and tacrolimus, dying at 7 months of age due to vascular complications. He had a ma ternal family history of multiple deaths of men under 1 year of age. IPEX syndrome was suspected therefore a trio whole-exome sequencing was performed that showed a probably pathogenic FOXP3 gene mutation. CONCLUSION: A new FOXP3 gene mutation is reported in a patient with IPEX syndro me. Despite the low prevalence of this disease, it is important to recognize non-specific but suggestive symptoms for its diagnosis.


Subject(s)
Humans , Male , Infant , Genetic Diseases, X-Linked/diagnosis , Diabetes Mellitus, Type 1/congenital , Diarrhea/diagnosis , Forkhead Transcription Factors/genetics , Immune System Diseases/congenital , Pedigree , Genetic Markers , Chronic Disease , Fatal Outcome , Genetic Diseases, X-Linked/genetics , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/genetics , Diarrhea/genetics , Immune System Diseases/diagnosis , Immune System Diseases/genetics , Mutation
14.
Biol. Res ; 53: 44, 2020. graf
Article in English | LILACS | ID: biblio-1131888

ABSTRACT

BACKGROUND: Atherosclerosis (AS) is the main pathological basis of coronary heart disease, cerebral infarction and peripheral vascular disease, which seriously endanger people's life and health. In recent years, long non-coding RNA (lncRNA) has been found to be involved in gene expression regulation, but the research on AS is still in the initial stage. In this study, we mainly studied the role of HCG11 in patients with AS. Quantitative Real-time Polymerase Chain Reaction (QRT-PCR) was used to detect the expression of HCG11 and miR-144 in the serum of AS patients and healthy volunteers. Oxidation Low Lipoprotein (Ox-LDL), interleukin-6 (IL-6) and tumor necrosis factor α (TNF α) radiation were used to establish human vascular smooth muscle cells (VSMCs) in vitro model. Cell proliferation was determined by Cell Counting Kit-8 (CCK-8) assay. The apoptosis rate was determined by flow cytometry (FACS) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining. The expression levels of Forkhead box protein F1 (FOXF1), B cell lymphoma-2 (Bcl-2) and BCL2-Associated X (Bax) were detected by qRT-PCR. Luciferase gene reporter and RNA pull down experiments confirmed the relationship between HCG11 and miR-144, miR-144 and FOXF1. RESULTS: This study showed that HCG11 was significantly upregulated in patients with AS, while miR-144 was down-regulated in patients with AS. Ox-LDL and IL-6 in VSMCs induced up-regulation of HCG11 and down-regulation of miR-144. Overexpression of HCG11 promoted the proliferation and inhibited apoptosis of VSMCs. Luciferase gene reporter gene assay showed that HCG11 could bind to miR-144, and miR-144 could bind to FOXF1. Overexpression of miR-144 reversed the effect of HCG11 on VSMCs. CONCLUSIONS: LncRNA HCG11 regulates proliferation and apoptosis of vascular smooth muscle cell through targeting miR-144-3p/FOXF1 axis.


Subject(s)
Humans , Myocytes, Smooth Muscle/cytology , MicroRNAs/genetics , Atherosclerosis/genetics , Forkhead Transcription Factors/genetics , RNA, Long Noncoding/genetics , Apoptosis/genetics , Cell Proliferation/genetics , Muscle, Smooth, Vascular/cytology
15.
Article in Chinese | WPRIM | ID: wpr-828307

ABSTRACT

OBJECTIVE@#To analyze FOXC2 gene variant in a family affected with lymphodema-distichiasis syndrome (LDS).@*METHODS@#Peripheral blood samples were collected for the extraction of DNA and protein. Whole-exome sequencing was carried out to detect variants in the proband. Suspected variant was validated by Sanger sequencing. Western blotting was used to detect changes in protein expression.@*RESULTS@#The proband and his mother were both found to carry a heterozygous nonsense variant c.177C>G (p.Tyr59X) of the FOXC2 gene, which was previously unreported. Down-regulated expression of FOXC2 was detected by Western blotting. Prenatal ultrasonography of the fetus indicated increased nuchal thickness. Amniocentesis was performed at 21+1 weeks of pregnancy, genetic testing suggested that the fetus also carried the c.177C>G variant.@*CONCLUSION@#The patients' condition may be attributed to the heterozygous nonsense variant c.177C>G of the FOXC2 gene, which resulted in a significant decrease in FOXC2 expression. Increased nuchal thickness may also be related with decreased FOXC2 expression. Above finding has expanded the variant spectrum of the FOXC2 gene.


Subject(s)
Codon, Nonsense , Eyelashes , Congenital Abnormalities , Female , Forkhead Transcription Factors , Genetics , Metabolism , Gene Expression , Genetic Testing , Genetic Variation , Humans , Lymphedema , Genetics , Pedigree , Pregnancy , Prenatal Diagnosis
16.
Acta Physiologica Sinica ; (6): 426-432, 2020.
Article in Chinese | WPRIM | ID: wpr-827045

ABSTRACT

The purpose of the present study was to investigate the effects of forkhead box O4 (FOXO4) on the senescence of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). The hUC-MSCs were induced to senescence by natural passage, and FOXO4 expression was inhibited by lentiviral shRNA transfection. The hallmark of cell senescence was analyzed by β-galactosidase staining, and the cell viability was assayed by CCK-8 method. Flow cytometry was used to investigate the apoptosis of hUC-MSCs. The expression levels of Bcl-2, Bax, FOXO4, interleukin 6 (IL-6) and cleaved Caspase-3 were detected by qPCR and Western blot. Immunofluorescence staining was used to detect FOXO4 expression. The amount of IL-6 secreted by hUC-MSCs was detected by ELISA. The results showed that, compared with the passage 1, senescent hUC-MSCs showed up-regulated expression levels of Bax and FOXO4, down-regulated expression levels of Bcl-2 and cleaved Caspase-3, and increased IL-6 mRNA expression and secretion. FOXO4 inhibition in senescent hUC-MSCs promoted cell apoptosis, reduced cell viability, and inhibited the mRNA expression and secretion of IL-6. These results suggest that FOXO4 maintains viability and function of senescent hUC-MSCs by repressing their apoptosis response, thus accelerating senescence of the whole cell colony.


Subject(s)
Apoptosis , Cell Cycle Proteins , Cell Survival , Cellular Senescence , Forkhead Transcription Factors , Humans , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Transcription Factors , Umbilical Cord
17.
Article in Chinese | WPRIM | ID: wpr-879915

ABSTRACT

OBJECTIVE@#To identify the genetic causes of a family with lymphedema-distichiasis syndrome (LDS).@*METHODS@#The whole exome sequencing was performed in a aborted fetus as the proband, and a candidate gene was identified. Peripheral blood of 8 family members were collected. Genotypic-phenotypic analysis were carried out through PCR amplification and Sanger sequencing.@*RESULTS@#The proband, and the mother, grandmother, uncle, granduncle of the proband all had distichiasis or varix of lower limb carried a @*CONCLUSIONS@#The


Subject(s)
Aborted Fetus/physiopathology , Adult , Eyelashes/pathology , Female , Forkhead Transcription Factors/genetics , Frameshift Mutation , Humans , Lymphedema/pathology , Male , Phenotype , Pregnancy , Whole Exome Sequencing
18.
Rev. chil. endocrinol. diabetes ; 13(1): 6-10, 2020. ilus, tab
Article in Spanish | LILACS | ID: biblio-1048791

ABSTRACT

Introducción: El gen FOXE1 (Forkhead box E1) codifica para un factor de transcripción involucrado en la morfogénesis tiroidea. El cáncer papilar de tiroides (CPT) se ha asociado con polimorfismos (SNP) de FOXE1 rs1867277 y rs965513 en población asiática y europea. Nuestro objetivo fue investigar la frecuencia y asociación de SNP rs1867277 y rs965513 con CPT y el riesgo de recurrencia de CPT en sujetos chilenos. Métodos: Se reclutaron sujetos con y sin CPT, se describieron sus características epidemiológicas y la forma de presentación clínica (AJCC VIII y MINSAL 2013). Se aisló ADN de leucocitos periféricos y evaluó ambos SNP mediante PCR-HRM y secuencia. Se compararon las frecuencias alélicas y genotípicas entre casos CPT y controles, y entre pacientes CPT de distintos riesgos de recurrencia. Se compararon frecuencia y se estimó el riesgo con test de Fisher y cálculo de odds-ratio (OR). Resultados: De los 184 sujetos, 156 (85%) eran mujeres, edad 39,3±12,3 años; 90 con CPT y 94 sin CPT 26 (28,9%) pacientes eran de riesgo muy bajo, 45 (50%) bajo, 16 (17,8%) intermedio y 3 (3,3%) alto según MINSAL 2013. En relación a la frecuencia de alelo menor (MAF) calculada en sujetos control y CPT, fue 31,7% y 24,5% (SNP rs965513), y 36,7% y 30,1% 8 (rs1867277), respectivamente (p NS). Tampoco fueron diferentes las MAF calculados y comparados entre pacientes con CPT de riesgo bajo e intermedio/alto. Sin embargo, la combinación de los genotipos rs1867277GG y rs965513AA se asoció a mayor riesgo de CPT. Conclusiones: En pacientes chilenos, se describe una frecuencia MAF de los SNP rs1867277 y rs965513 cercana a un 30%, las cuales no se asocian a CPT ni riesgo de recurrencia, sin embargo, sujetos con una combinación genotípica particular podrían tener mayor riesgo de CPT.


FOXE1 gene (Forkhead E1 box) codes for a transcription factor involved in thyroid morphogenesis. Papillary thyroid cancer (PTC) has been associated with FOXE1 polymorphisms (SNPs) rs1867277 and rs965513 in Asian and European population. Our aim was to investigate the frequency and the association of SNPs rs1867277 and rs965513 with PTC and the risk of recurrence of PTC in Chilean subjects. Methods: We recruited subjects with and without PTC. In those with PTC, their epidemiological characteristics and clinical features presentation are described according to AJCC VIII and MINSAL 2013 scales. Peripheral leukocyte DNA was isolated and both SNPs were evaluated using PCR-HRM and sequencing. Allelic and genotypic frequencies were compared between PTC cases and controls, and between PTC patients with different recurrence risks. Results: Of the 184 subjects, 156 (85%) were women, age 39.3 ± 12.3 years; 94 (51%) without PTC and 90 with PTC (49%): 26 (28.9%) patients had very low, 45 (50%) low, 16 (17.8%) intermediate and 3 (3.3%) high risk of recurence according to MINSAL 2013. Regarding the minor allele frequency (MAF) calculated on control and PTC subjects, was 31.7% and 24.5% (SNP rs965513), and 36.7% and 30.1% (rs1867277), respectively (p NS). In patients with PTC, MAFs were not different between patients with low and intermediate/high risk PTC. However, the combination of rs1867277GG and rs965513AA genotypes were associated with an increased risk of PTC. Conclusions: In Chilean patients, the MAF frequency of SNPs rs1867277 and rs965513 is near 30%, and they are are not associated with PTC or its risk of recurrence. However, subjects with a particular genotypic combination may have an increased risk of PTC.


Subject(s)
Humans , Male , Female , Adult , Thyroid Neoplasms/epidemiology , Polymorphism, Single Nucleotide , Thyroid Cancer, Papillary/epidemiology , Polymorphism, Genetic , Thyroid Neoplasms/genetics , Biomarkers, Tumor/genetics , Chile/epidemiology , Polymerase Chain Reaction , Risk Assessment , Genetic Predisposition to Disease , Forkhead Transcription Factors/genetics , Thyroid Cancer, Papillary/genetics , Gene Frequency , Genotype , Neoplasm Recurrence, Local/epidemiology
19.
Braz. oral res. (Online) ; 34: e096, 2020. tab, graf
Article in English | LILACS, BBO | ID: biblio-1132722

ABSTRACT

Abstract Regulatory T (Treg) cells can suppress antitumor immune response, but little is known about possible age-related differences in the number of these cells in the microenvironment of oral tongue squamous cell carcinoma (OTSCC). The aim of this study was to determine the number of FoxP3+ Treg cells in the microenvironment of OTSCC in young (≤ 45 years) and older (≥ 60 years) patients, and to correlate the findings with clinicopathological parameters (sex, tumor size/extent, regional lymph node metastasis, clinical staging, and histopathological grade of malignancy). Forty-eight OTSCCs (24 diagnosed in young patients and 24 diagnosed in older patients) were selected. Lymphocytes exhibiting nuclear immunopositivity for FoxP3 were quantified at the tumor invasive front and the results were analyzed statistically using the non-parametric Mann-Whitney test. FoxP3+ lymphocytes were observed in all cases assessed. The number of FoxP3+ lymphocytes in OTSCC tended to be higher in older patients (p = 0.055). Analysis of OTSCC in males and in early clinical stages revealed a higher number of Treg cells in older patients than in young ones (p < 0.05). In older patients, the number of Treg cells tended to be higher in smaller tumors (p = 0.079). Tumors with intense inflammatory infiltrate exhibited a larger number of Treg cells, both in young (p = 0.099) and older patients (p = 0.005). The results suggest a greater participation of Treg cells in immunoinflammatory responses in the microenvironment of OTSCC in older patients, particularly in males and in early stages.


Subject(s)
Humans , Male , Tongue Neoplasms , Carcinoma, Squamous Cell , T-Lymphocytes, Regulatory , Forkhead Transcription Factors , Tumor Microenvironment , Neoplasm Staging
20.
Clinics ; 75: e1665, 2020. tab, graf
Article in English | LILACS | ID: biblio-1133413

ABSTRACT

OBJECTIVES: This study intended to explore the effect of T regulatory cells (Tregs) in the perinatal liver against LPS-induced inflammation in a preterm birth mouse model. Moreover, the role of adoptive Tregs on the inflammatory response induced by LPS was also studied. METHODS: Female BALB/C mice were injected intraperitoneally (IP) with LPS dissolved in normal saline solution at a dose of 50 µg/kg. Spleens from pregnant mice were used to obtain Tregs. The expression of Forkhead family transcription factor-3 (Foxp3), Interleukin-6 (IL-6), Toll-like receptor-4 (TLR-4), and Heme oxygenase-1 (HO-1) were assessed from fetal liver tissues by polymerase chain reaction and western blotting. RESULTS: LPS administered to mice induced an inflammatory response in the perinatal liver, and this inflammatory response was negatively regulated by Tregs in the experimental group. Maternal-fetal tolerance was maintained by Tregs. Transmission of Tregs was estimated in different experimental groups based on the mRNA expression of TLR-4, IL-6, HO-1, and Foxp3. CONCLUSIONS: After analysis of the experimental data, it was determined that Tregs exhibited regulatory potential against LPS-induced inflammatory response. Further, it was concluded that the transmission of Tregs improved the mother's immune tolerance against LPS-induced inflammation in the fetal liver.


Subject(s)
Animals , Female , Pregnancy , Mice , Lipopolysaccharides/toxicity , Premature Birth , T-Lymphocytes, Regulatory , Forkhead Transcription Factors , Inflammation/chemically induced , Liver , Mice, Inbred BALB C
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