ABSTRACT
BACKGROUND: Germline heterozygous gain-of-function (GOF) mutations in the PIK3CD gene lead to a rare primary immunodeficiency disease known as activated phosphoinositide 3-kinase (PI3K) δ syndrome type 1(APDS1). Affected patients present a spectrum of clinical manifestations, particularly recurrent respiratory infections and lymphoproliferation, increased levels of serum immunoglobulin (Ig) M, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) viremia. Due to highly heterogeneous phenotypes of APDS1, it is very likely that suspected cases may be misdiagnosed. METHODS: Herein we reported three patients with different clinical presentations but harboring pathogenic variants in PIK3CD gene detected by trio whole-exome sequencing (trio-WES) and confirmed by subsequent Sanger sequencing. RESULTS: Two heterozygous mutations (c.3061G > A, p.E1021K and c.1574 A > G, p.E525G) in PIK3CD (NM_005026.3) were identified by whole exome sequencing (WES) in the three patients. One of two patients with the mutation (c.3061G > A) presented with abdominal pain and diarrhea as the first symptoms, which was due to intussusception caused by multiple polyps of colon. The patient with mutation (c.1574 A > G) had an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-like clinical manifestations, including multisystemic inflammation, acute nephritic syndrome, and positive perinuclear ANCA (p-ANCA), thus the diagnosis of ANCA-AAV was considered. CONCLUSIONS: Our study expands the spectrums of clinical phenotype and genotype of APDS, and demonstrates that WES has a high molecular diagnostic yield for patients with immunodeficiency related symptoms, such as respiratory infections, multiple ecchymosis, ANCA-associated vasculitis, multiple ileocecal polyps, hepatosplenomegaly, and lymphoid hyperplasia. TRIAL REGISTRATION: Retrospectively registered.
Subject(s)
Epstein-Barr Virus Infections , Respiratory Tract Infections , Humans , Phosphatidylinositol 3-Kinase/genetics , Phosphatidylinositol 3-Kinases/genetics , Antibodies, Antineutrophil Cytoplasmic , Herpesvirus 4, Human , Class I Phosphatidylinositol 3-Kinases/genetics , Phenotype , Mutation , Respiratory Tract Infections/diagnosis , Respiratory Tract Infections/geneticsABSTRACT
BACKGROUND: Urban particulate matter (PM) contributes to the increasing number of people with asthma, which is closely related to the development of industrialization. Especially, PM with an aerodynamic diameter of <2.5 µm (PM2.5) enhances the risk of damaging respiratory organs. It has reported that PM2.5-induced pathological changes could be considered as a remarkable molecular mechanism of PM2.5-mediated cytotoxicity in respiratory disease and even lung cancer. METHODS: In this study, we have investigated the effects of PM2.5 on ovalbumin (OVA)-induced asthma mice and the therapeutic effect of Lipoxin A4 (LXA4) on improving the poor pathology. RESULTS: The exposure of PM2.5 showed that both cytokines of T helper-2 (Th2) cells and transcription factors of group 2 innate lymphoid cells (ILC2s) were significantly increased, and inflammatory cell infiltration occurred in lung tissue. The LXA4 was used to treat asthma, which was an effective option in reducing inflammatory cytokines and relieving pathological symptoms, probably by regulating the Th1/Th2 balance. CONCLUSIONS: These results suggest that PM2.5-induced inflammation plays a key role in the progression of asthma mice. In addition, LXA4 has a significant therapeutic effect on asthma, which indicates the direction for the treatment of asthma related inflammatory diseases.
ABSTRACT
In this study, we hypothesized that n-3 polyunsaturated fatty acid (PUFA) deficiency during pregnancy and lactation will make a lasting impact on brain neurogenesis and apoptosis of the adult offspring and that these harmful effects cannot be reversed by n-3 PUFA supplementation after weaning. Moreover, the underlying mechanisms may be attributable to the epigenetic changes of brain-derived neurotrophic factor (BDNF). C57BL/6J female mice were fed with n-3 PUFA-deficient diet (n-3 def) or n-3 PUFA-adequate diet (n-3 adq) throughout pregnancy and lactation. At postnatal 21 days, equal numbers of male pups from both groups were fed the opposite diet, and the remaining male pups were fed with the same diets as their mothers until 3 months of age. Feeding the n-3 adq diet to pups from the maternal n-3 def group significantly increased the n-3 PUFA concentration but did not change expressions of calretinin, Bcl2, and Bax in the hippocampus. Feeding the n-3 def diet to pups from the maternal n-3 adq group significantly reduced the n-3 PUFA concentration but did not reduce expressions of calretinin and Bcl2. Similarly, BDNF levels, especially mRNA expressions of BDNF transcripts IV and IX, were also reduced by maternal n-3 def and not reversed by n-3 PUFA supplementation after weaning. The decrease in BDNF expression by maternal n-3 def diet was associated with greater DNA methylation at special CpG sites. These results suggested that the maternal n-3 PUFA deficiency during pregnancy and lactation imprints long-term changes of brain development in adult offspring.
Subject(s)
Apoptosis , Brain-Derived Neurotrophic Factor/metabolism , DNA Methylation , Fatty Acids, Omega-3/deficiency , Lactation , Maternal Nutritional Physiological Phenomena , Neurogenesis , Animals , Brain-Derived Neurotrophic Factor/genetics , Calbindin 2/metabolism , Diet , Dietary Fats/administration & dosage , Epigenesis, Genetic , Feeding Behavior , Female , Fetal Development , Male , Mice, Inbred C57BL , Neurogenesis/genetics , Pregnancy , Prenatal Exposure Delayed Effects , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Messenger/metabolism , bcl-2-Associated X Protein/metabolismABSTRACT
Objective: although n-3 polyunsaturated fatty acids (PUFAs) play crucial roles in brain development and function, neither the optimal level of n-3 PUFAs nor the optimal ratio of n-6/n-3 PUFAs in the maternal diet are well defined. In this study, we investigated the effects of dietary n-6/n-3 PUFA ratios during pregnancy on neurogenesis and apoptosis in the brains of mouse offspring. Metods: female C57BL/6J mice were fed one of three diets with high, medium and low ratios of n-6/n-3 PUFAs (15.7:1, 6.3:1, 1.6:1), as well as a high fish oil diet with a n-6/n-3 ratio of 1:5.7; an n-3 PUFA-deficient diet served as control. The feeding regimens began two months before mouse conception and continued for the duration of the pregnancy. The neurogenesis and apoptosis of hippocampal CA3 area in the offspring were detected. Results: compared to the n-3 PUFA-deficient diet, n-3 PUFA-containing diets, particularly those with n-6/n-3 PUFA ratios of 6.3:1 and 1.6:1, significantly increased both phosphorylation of histone H3 at ser 10 (p-H3ser10) and calretinin-positive cells in hippocampus CA3 of the offspring. Furthermore, increased expression of Bcl2 protein, decreased expression of Bax protein, and reduced caspase 3 activity and numbers of TUNEL apoptotic cells were found in the three diets with high, medium and low n-6/n-3 PUFA ratios. However, there were no differences in any of these parameters between the high fish oil diet group and the n-3 PUFA-deficient diet group. Conclusions: these data suggest that a higher intake of n-3 PUFAs with a lower ratio of n-6/n-3 PUFAs of between about 6:1 to 1:1, supplied to mothers during pregnancy, may benefit brain neurogenesis and apoptosis in offspring. However, excessive maternal intake of n-3 PUFAs may exert a negative influence on brain development in the offspring (AU)
Objetivo: a pesar de que los ácidos grasos poliinsaturados n-3 (PUFAs por sus siglas en inglés) desempeñan un papel fundamental en el desarrollo y en las funciones cerebrales, aún no está bien definido el nivel óptimo de PUFAs n-3 ni la ratio óptima de PUFA n-6/n-3 en la dieta materna. En este estudio hemos investigado los efectos de las ratios nutricionales de PUFA n-6/n-3 durante la gestación sobre la neurogénesis y la apoptosis en el cerebro de crías de ratón. Métodos: se alimentó a hembras de ratón C57BL/6J con una de las tres dietas de estudio: ratio alta, media y baja de PUFA n-6/n-3 (15,7:1, 6,3:1, 1,6:1). También se añadió una dieta rica en aceite de pescado con una ratio n-6/n-3 de 1:5,7; como control se empleó una dieta deficitaria en PUFA n-3. Los regímenes alimenticios se iniciaron dos meses antes de la concepción de los ratones y continuó durante todo el embarazo. Se detectó la neurogénesis y apoptosis del área hipocampal CA3 en las crías. Resultados: en comparación con la dieta deficitaria en PUFA n-3, las dietas con PUFA que contienen n-3, particularmente aquellas con ratios PUFA n-6/n-3 de 6,3:1 y 1,6:1, aumentaron significativamente la fosforilación de histona H3 en la Ser10 (p-H3ser10) y las células calretinina positivas en el área hipocampal CA3 de las crías. Además, se detectó un aumento de la expresión de proteí- na Bcl2, una reducción de la expresión de proteína Bax, y una reducción de la actividad de caspasa 3, así como de las cifras de células apoptósicas TUNEL en las tres dietas, con ratios altas, medias y bajas de PUFA n-6/n-3. Sin embargo, no se observó diferencias en ninguno de estos parámetros entre el grupo de dieta rica en aceite de pescado y el grupo de dieta deficitaria en PUFA n-3. Conclusiones: estos datos sugieren que una ingesta más elevada de PUFA n-3 con una ratio más baja de PUFAs n-6/n-3 entre 6:1 y 1:1 aproximadamente, administrada a las madres durante la gestación, podría ser beneficiosa para la neurogénesis cerebral y la apoptosis de las crías. Sin embargo, una ingesta excesiva de PUFA n-3 puede ejercer una influencia negativa sobre el desarrollo de las crías (AU)
Subject(s)
Animals , Rats , Fatty Acids, Unsaturated/pharmacokinetics , Neurogenesis , Apoptosis , Prenatal Nutrition , Disease Models, Animal , Hippocampus/embryologyABSTRACT
OBJECTIVE: although n-3 polyunsaturated fatty acids (PUFAs) play crucial roles in brain development and function, neither the optimal level of n-3 PUFAs nor the optimal ratio of n-6/n-3 PUFAs in the maternal diet are well defined. In this study, we investigated the effects of dietary n-6/n-3 PUFA ratios during pregnancy on neurogenesis and apoptosis in the brains of mouse offspring. Metods: female C57BL/6J mice were fed one of three diets with high, medium and low ratios of n-6/n-3 PUFAs (15.7:1, 6.3:1, 1.6:1), as well as a high fish oil diet with a n-6/n-3 ratio of 1:5.7; an n-3 PUFA-deficient diet served as control. The feeding regimens began two months before mouse conception and continued for the duration of the pregnancy. The neurogenesis and apoptosis of hippocampal CA3 area in the offspring were detected. RESULTS: compared to the n-3 PUFA-deficient diet, n-3 PUFA-containing diets, particularly those with n-6/n-3 PUFA ratios of 6.3:1 and 1.6:1, significantly increased both phosphorylation of histone H3 at ser 10 (p-H3ser10) and calretinin-positive cells in hippocampus CA3 of the offspring. Furthermore, increased expression of Bcl2 protein, decreased expression of Bax protein, and reduced caspase 3 activity and numbers of TUNEL apoptotic cells were found in the three diets with high, medium and low n-6/n-3 PUFA ratios. However, there were no differences in any of these parameters between the high fish oil diet group and the n-3 PUFA-deficient diet group. CONCLUSIONS: these data suggest that a higher intake of n-3 PUFAs with a lower ratio of n-6/n-3 PUFAs of between about 6:1 to 1:1, supplied to mothers during pregnancy, may benefit brain neurogenesis and apoptosis in offspring. However, excessive maternal intake of n-3 PUFAs may exert a negative influence on brain development in the offspring.
Objetivo: a pesar de que los ácidos grasos poliinsaturados n-3 (PUFAs por sus siglas en inglés) desempeñan un papel fundamental en el desarrollo y en las funciones cerebrales, aún no está bien definido el nivel óptimo de PUFAs n-3 ni la ratio óptima de PUFA n-6/n-3 en la dieta materna. En este estudio hemos investigado los efectos de las ratios nutricionales de PUFA n-6/n-3 durante la gestación sobre la neurogénesis y la apoptosis en el cerebro de crías de ratón. Métodos: se alimentó a hembras de ratón C57BL/6J con una de las tres dietas de estudio: ratio alta, media y baja de PUFA n-6/n-3 (15,7:1, 6,3:1, 1,6:1). También se añadió una dieta rica en aceite de pescado con una ratio n-6/n-3 de 1:5,7; como control se empleó una dieta deficitaria en PUFA n-3. Los regímenes alimenticios se iniciaron dos meses antes de la concepción de los ratones y continuó durante todo el embarazo. Se detectó la neurogénesis y apoptosis del área hipocampal CA3 en las crías. Resultados: en comparación con la dieta deficitaria en PUFA n-3, las dietas con PUFA que contienen n-3, particularmente aquellas con ratios PUFA n-6/n-3 de 6,3:1 y 1,6:1, aumentaron significativamente la fosforilación de histona H3 en la Ser10 (p-H3ser10) y las células calretinina positivas en el área hipocampal CA3 de las crías. Además, se detectó un aumento de la expresión de proteína Bcl2, una reducción de la expresión de proteína Bax, y una reducción de la actividad de caspasa 3, así como de las cifras de células apoptósicas TUNEL en las tres dietas, con ratios altas, medias y bajas de PUFA n-6/n-3. Sin embargo, no se observó diferencias en ninguno de estos parámetros entre el grupo de dieta rica en aceite de pescado y el grupo de dieta deficitaria en PUFA n-3. Conclusiones: estos datos sugieren que una ingesta más elevada de PUFA n-3 con una ratio más baja de PUFAs n-6/n-3 entre 6:1 y 1:1 aproximadamente, administrada a las madres durante la gestación, podría ser beneficiosa para la neurogénesis cerebral y la apoptosis de las crías. Sin embargo, una ingesta excesiva de PUFA n-3 puede ejercer una influencia negativa sobre el desarrollo de las crías.
Subject(s)
Apoptosis , Dietary Supplements , Fatty Acids, Omega-3 , Fatty Acids, Omega-6 , Hippocampus/metabolism , Maternal Exposure , Neurogenesis , Prenatal Exposure Delayed Effects , Animal Feed , Animals , Biomarkers , Caspase 3/metabolism , Diet , Fatty Acids, Omega-3/administration & dosage , Fatty Acids, Omega-6/administration & dosage , Female , Hippocampus/cytology , Hippocampus/pathology , Mice , Models, Animal , Nutrition Assessment , PregnancyABSTRACT
Objective: The role of epigenetic modifications on leptin expression during the development of obesity has not been clearly determined. This study aimed to investigatechanges in the expression of DNA methyltransferases (DNMTs) at the leptin promoter and their effect on genetranscription during the development of obesity. Methods: Using a high-fat diet (HFD)-induced obese (DIO) mouse model, we examined adipose expression of leptin, its promoter associated DNMTs and the methyl CpG-binding domain protein 2 (MBD2) at different time points after HFD feeding. Results: The leptin expression levels in epididymal fat were significantly increased after feeding the mice aHFD for 4, 8, 12 and 18 weeks (w), as opposed to feeding them a standard diet (SD). However, the CpG promoter methylation fractions were significantly reduced at 8 w with a decreased association of MBD2 and DNMT1, and increased at 12 w and 18 w with an increased association of MBD2, DNMT3A and DNMT3B, after HFD feeding. Additionally, the binding of RNA polymerase II was increased at 8 w and decreased at 18 w after HFD feeding compared with SD feeding. Conclusions: These data indicate that time-specific changes in promoter associated DNMTs may be associated with the regulation of leptin expression, indicating that a complex and dynamic epigenetic mechanism underlies aberrant leptin expression during the development of obesity (AU)
Objetivo: El objetivo de las modificaciones epigenéticas sobre la expresión de la leptina durante el desarrollo de obesidad no ha podido ser claramente establecido. Este estudio tiene por objetivo investigar los cambios en la expresión de ADN-metiltransferasas (ADNMTs) en el promotor de leptina y su efecto sobre la trascripción génica durante el desarrollo de obesidad. Métodos: Empleando un modelo de ratones con obesidad inducida por dieta rica en grasa (DRG), examinamos la expresión adiposa de leptina, su promotor asociado ADNMTs y la proteína 2 con dominio de unión a metil-CpG (MBD2) en diferentes momentos tras la alimentación DRG. Resultados: Los niveles de expresión de leptina en grasa epididimal aumentaron significativamente tras la alimentación de los ratones con una dieta DRG durante 4, 8, 12 y 18 semanas (s), contrariamente a la alimentación con dieta estándar (DE). Sin embargo, las fracciones de metilación del promotor CpG se redujeron significativamente en la s8 con una menor asociación de MBD2 y DNMT1, y aumentaron en la s12 y s18 con una mayor asociación de MBD2, DNMT3A y DNMT3B, tras la DRG. Además, la unión de ARN polimerasa II aumentó en la s8 y disminuyó en la s18 tras la DRG en comparación con la alimentación de DE. Conclusiones: Estos datos indican que los cambios en puntos temporales específicos en ADNMTs en relación con un promotor podrían estar relacionados con la regulación de la expresión de leptina, indicando que existe un mecanismo epigenético dinámico y complejo subyacente en la expresión de leptina aberrante durante el desarrollo de obesidad (AU)
Subject(s)
Animals , Mice , /administration & dosage , /pharmacology , Epididymal Secretory Proteins/administration & dosage , Leptin/administration & dosage , /chemical synthesis , Epididymal Secretory Proteins , LeptinABSTRACT
OBJECTIVE: The role of epigenetic modifications on leptin expression during the development of obesity has not been clearly determined. This study aimed to investigate changes in the expression of DNA methyltransferases (DNMTs) at the leptin promoter and their effect on gene transcription during the development of obesity. METHODS: Using a high-fat diet (HFD)-induced obese (DIO) mouse model, we examined adipose expression of leptin, its promoter associated DNMTs and the methyl CpG-binding domain protein 2 (MBD2) at different time points after HFD feeding. RESULTS: The leptin expression levels in epididymal fat were significantly increased after feeding the mice a HFD for 4, 8, 12 and 18 weeks (w), as opposed to feeding them a standard diet (SD). However, the CpG promoter methylation fractions were significantly reduced at 8 w with a decreased association of MBD2 and DNMT1, and increased at 12 w and 18 w with an increased association of MBD2, DNMT3A and DNMT3B, after HFD feeding. Additionally, the binding of RNA polymerase II was increased at 8 w and decreased at 18 w after HFD feeding compared with SD feeding. CONCLUSIONS: These data indicate that time-specific changes in promoter associated DNMTs may be associated with the regulation of leptin expression, indicating that a complex and dynamic epigenetic mechanism underlies aberrant leptin expression during the development of obesity.
Objetivo: El objetivo de las modificaciones epigenéticas sobre la expresión de la leptina durante el desarrollo de obesidad no ha podido ser claramente establecido. Este estudio tiene por objetivo investigar los cambios en la expresión de ADN-metiltransferasas (ADNMTs) en el promotor de leptina y su efecto sobre la trascripción génica durante el desarrollo de obesidad. Métodos: Empleando un modelo de ratones con obesidad inducida por dieta rica en grasa (DRG), examinamos la expresión adiposa de leptina, su promotor asociado ADNMTs y la proteína 2 con dominio de unión a metil- CpG (MBD2) en diferentes momentos tras la alimentación DRG. Resultados: Los niveles de expresión de leptina en grasa epididimal aumentaron significativamente tras la alimentación de los ratones con una dieta DRG durante 4, 8, 12 y 18 semanas (s), contrariamente a la alimentación con dieta estándar (DE). Sin embargo, las fracciones de metilación del promotor CpG se redujeron significativamente en la s8 con una menor asociación de MBD2 y DNMT1, y aumentaron en la s12 y s18 con una mayor asociación de MBD2, DNMT3A y DNMT3B, tras la DRG. Además, la unión de ARN polimerasa II aumentó en la s8 y disminuyó en la s18 tras la DRG en comparación con la alimentación de DE. Conclusiones: Estos datos indican que los cambios en puntos temporales específicos en ADNMTs en relación con un promotor podrían estar relacionados con la regulación de la expresión de leptina, indicando que existe un mecanismo epigenético dinámico y complejo subyacente en la expresión de leptina aberrante durante el desarrollo de obesidad.
