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1.
Redox Biol ; 56: 102420, 2022 10.
Article in English | MEDLINE | ID: mdl-35969998

ABSTRACT

Vitamin C (VC, l-ascorbic acid) is an essential nutrient that plays a key role in metabolism and functions as a potent antioxidant in regulating the S-nitrosylation and denitrosylation of target proteins. The precise function of VC deprivation in glucose homeostasis is still unknown. In the absence of L-gulono-1,4-lactone oxidoreductase, an essential enzyme for the last step of VC synthesis, VC deprivation resulted in persistent hypoglycemia and subsequent impairment of cognitive functions in female but not male mouse pups. The cognitive disorders caused by VC deprivation were largely reversed when these female pups were given glucose. VC deprivation-induced S-nitrosylation of glycogen synthase kinase 3ß (GSK3ß) at Cys14, which activated GSK3ß and inactivated glycogen synthase to decrease glycogen synthesis and storage under the feeding condition, while VC deprivation inactivated glycogen phosphorylase to decrease glycogenolysis under the fasting condition, ultimately leading to hypoglycemia and cognitive disorders. Treatment with Nω-Nitro-l-arginine methyl ester (l-NAME), a specific inhibitor of nitric oxide synthase, on the other hand, effectively prevented S-nitrosylation and activation of GSK3ß in female pups in response to the VC deprivation and reversed hypoglycemia and cognitive disorders. Overall, this research identifies S-nitrosylation of GSK3ß and subsequent GSK3ß activation as a previously unknown mechanism controlling glucose homeostasis in female pups in response to VC deprivation, implying that VC supplementation in the prevention of hypoglycemia and cognitive disorders should be considered in the certain groups of people, particularly young females.


Subject(s)
Ascorbic Acid Deficiency , Cognition , Hypoglycemia , Neurocognitive Disorders , Animals , Antioxidants , Ascorbic Acid/pharmacology , Ascorbic Acid Deficiency/complications , Ascorbic Acid Deficiency/metabolism , Female , Glucose/metabolism , Glycogen/metabolism , Glycogen Phosphorylase , Glycogen Synthase/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Hypoglycemia/etiology , Hypoglycemia/metabolism , Lactones , Mice , NG-Nitroarginine Methyl Ester/pharmacology , Neurocognitive Disorders/etiology , Neurocognitive Disorders/metabolism , Nitric Oxide Synthase
2.
Metabolism ; 136: 155295, 2022 11.
Article in English | MEDLINE | ID: mdl-36007622

ABSTRACT

OBJECTIVE: Prader-Willi syndrome (PWS) is a rare genetic imprinting disorder resulting from the expression loss of genes on the paternally inherited chromosome 15q11-13. Early-onset life-thriving obesity and hyperphagia represent the clinical hallmarks of PWS. The noncoding RNA gene SNORD116 within the minimal PWS genetic lesion plays a critical role in the pathogenesis of the syndrome. Despite advancements in understanding the genetic basis for PWS, the pathophysiology of obesity development in PWS remains largely uncharacterized. Here, we aimed to investigate the signatures of adipose tissue development and expansion pathways and associated adipose biology in PWS children without obesity-onset at an early stage, mainly from the perspective of the adipogenesis process, and further elucidate the underlying molecular mechanisms. METHODS: We collected inguinal (subcutaneous) white adipose tissues (ingWATs) from phase 1 PWS and healthy children with normal weight aged from 6 M to 2 Y. Adipose morphology and histological characteristics were assessed. Primary adipose stromal vascular fractions (SVFs) were isolated, cultured in vitro, and used to determine the capacity and function of white and beige adipogenic differentiation. High-throughput RNA-sequencing (RNA-seq) was performed in adipose-derived mesenchymal stem cells (AdMSCs) to analyze transcriptome signatures in PWS subjects. Transient repression of SNORD116 was conducted to evaluate its functional relevance in adipogenesis. The changes in alternative pre-mRNA splicing were investigated in PWS and SNORD116 deficient cells. RESULTS: In phase 1 PWS children, impaired white adipose tissue (WAT) development and unusual fat expansion occurred long before obesity onset, which was characterized by the massive enlargement of adipocytes accompanied by increased apoptosis. White and beige adipogenesis programs were impaired and differentiated adipocyte functions were disturbed in PWS-derived SVFs, despite increased proliferation capacity, which were consistent with the results of RNA-seq analysis of PWS AdMSCs. We also experimentally validated disrupted beige adipogenesis in adipocytes with transient SNORD116 downregulation. The transcript and protein levels of PPARγ, the adipogenesis master regulator, were significantly lower in PWS than in control AdMSCs as well as in SNORD116 deficient AdMSCs/adipocytes than in scramble (Scr) cells, resulting in the inhibited adipogenic program. Additionally, through RNA-seq, we observed aberrant transcriptome-wide alterations in alternative RNA splicing patterns in PWS cells mediated by SNORD116 loss and specifically identified a changed PRDM16 gene splicing profile in vitro. CONCLUSIONS: Imbalance in the WAT expansion pathway and developmental disruption are primary defects in PWS displaying aberrant adipocyte hypertrophy and impaired adipogenesis process, in which SNORD116 deficiency plays a part. Our findings suggest that dysregulated adiposity specificity existing at an early phase is a potential pathological mechanism exacerbating hyperphagic obesity onset in PWS. This mechanistic evidence on adipose biology in young PWS patients expands knowledge regarding the pathogenesis of PWS obesity and may aid in developing a new therapeutic strategy targeting disturbed adipogenesis and driving AT plasticity to combat abnormal adiposity and associated metabolic disorders for PWS patients.


Subject(s)
Prader-Willi Syndrome , Adipogenesis/genetics , Adipose Tissue, White/metabolism , Child , Humans , Hyperphagia/metabolism , Obesity/metabolism , PPAR gamma , Prader-Willi Syndrome/genetics , Prader-Willi Syndrome/metabolism , RNA Precursors , RNA, Small Nucleolar/genetics , RNA, Small Nucleolar/metabolism , Tissue Expansion
3.
Open Forum Infect Dis ; 7(8): ofaa314, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32875002

ABSTRACT

Major histocompatibility complex (MHC) II deficiency is a rare primary immunodeficiency disorder that is characterized by the deficiency of MHC class II molecules. The disease is caused by transcription factor mutations including class II transactivator (CIITA), regulatory factor X-5 (RFX5), RFX-associated protein (RFXAP), and RFXAP-containing ankyrin repeat (RFXANK), respectively. Mutations in the RFXANK gene account for >70% of all known patients worldwide. Herein, we reported a 10-month-old boy with MHC II deficiency caused by a novel mutation in the RFXANK gene (c.337 + 1G>C). The boy was admitted to the hospital due to pneumonia and diarrhea at 4 months of age. Genetic analysis revealed a novel homozygous mutation in the RFXANK gene, which derived from the c.337 + 1G>C heterozygous mutations in the RFXANK gene of his parents. The boy died 3 months after diagnosis. More than 200 cases have been reported, and a review of the literature revealed different mutation rates of 4 transcription factors in different countries or regions. This is the first case report of MHC II deficiency from East Asia. We also describe all gene mutations that cause MHC II deficiency and the epidemiology of MHC II deficiency with gene mutations in this paper.

4.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L888-L899, 2020 05 01.
Article in English | MEDLINE | ID: mdl-32130032

ABSTRACT

We have previously demonstrated that upregulation of Sonic hedgehog (SHH) expression in allergic airway epithelia essentially contributes to the goblet cell metaplasia and mucous hypersecretion. However, the mechanism underlying the upregulation of SHH expression remains completely unknown. In cultured human airway epithelial cells, IL-4/IL-13 but not IL-5 robustly induces the mRNA and protein expression of SHH and in turn activates SHH signaling by promoting the JAK/STAT6-controlling transcription of SHH gene. Moreover, intratracheal instillation of IL-4 and/or IL-13 robustly activates STAT6 and concomitantly upregulates SHH expression in mouse airway epithelia, whereas, in Club cell 10-kDa protein (CC10)-positive airway epithelial cells of children with asthma, activated STAT6 closely correlates with the increased expression of SHH and high activity of SHH signaling. Finally, intratracheal inhibition of STAT6 by AS-1517499 significantly diminished the allergen-induced upregulation of SHH expression, goblet cell phenotypes, and airway hyperresponsiveness, in an ovalbumin- or house dust mite-induced mouse model with allergic airway inflammation,. Together, upregulation of SHH expression by IL-4/IL-13-induced JAK/STAT6 signaling contributes to allergic airway epithelial remodeling, and this study thus provides insight into how morphogen signaling is coordinated with Th2 cytokine pathways to regulate tissue remodeling in chronic airway diseases.


Subject(s)
Asthma/genetics , Hedgehog Proteins/genetics , Interleukin-13/genetics , Interleukin-4/genetics , Respiratory Mucosa/immunology , Animals , Anti-Asthmatic Agents/pharmacology , Asthma/chemically induced , Asthma/drug therapy , Asthma/pathology , Cell Line , Child , Female , Gene Expression Regulation , Goblet Cells/drug effects , Goblet Cells/immunology , Goblet Cells/pathology , Hedgehog Proteins/immunology , Humans , Interleukin-13/immunology , Interleukin-13/pharmacology , Interleukin-4/immunology , Interleukin-4/pharmacology , Interleukin-5/genetics , Interleukin-5/immunology , Janus Kinases/genetics , Janus Kinases/immunology , Mice , Mice, Inbred BALB C , Ovalbumin/administration & dosage , Primary Cell Culture , Pyrimidines/pharmacology , Pyroglyphidae/chemistry , Pyroglyphidae/immunology , Respiratory Mucosa/drug effects , Respiratory Mucosa/pathology , STAT6 Transcription Factor/antagonists & inhibitors , STAT6 Transcription Factor/genetics , STAT6 Transcription Factor/immunology , Signal Transduction , Transcription, Genetic , Uteroglobin/genetics , Uteroglobin/immunology
5.
Org Lett ; 11(6): 1201-4, 2009 Mar 19.
Article in English | MEDLINE | ID: mdl-19222182

ABSTRACT

Introduction of a continuous internal hydrogen-bonding network suppressed the conformational flexibility of a series of oligoaromatic foldamers with a lengthened backbone. The helical ordering over up to six aromatic repeating units was established in solution by a 2D NOESY study and in the solid state by an X-ray diffraction method. Computational molecular modeling further corroborates the experimentally observed helical propagation in this class of foldable molecular strands.


Subject(s)
Models, Molecular , Polymers/chemistry , Amides/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Structure
6.
Org Lett ; 10(22): 5127-30, 2008 Nov 20.
Article in English | MEDLINE | ID: mdl-18928289

ABSTRACT

Introduction of a continuous hydrogen-bonding network suppressed the conformational flexibility of an oligomeric backbone. Cyclization of a rigidified, suitably sized oligomer led to a circular aromatic pentamer. Its crystal structure determined by X-ray crystallography reveals a pseudo five-fold symmetric planarity in the solid state, which is quite unusual among all the previously described shape-persistent macrocycles and synthetic foldamers with biased conformations enforced by noncovalent forces.


Subject(s)
Organic Chemicals/chemistry , Crystallography, X-Ray , Cyclization , Magnetic Resonance Spectroscopy , Molecular Conformation
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