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1.
Orphanet J Rare Dis ; 18(1): 152, 2023 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-37331934

RESUMO

BACKGROUND: Allgrove disease is a rare genetic syndrome characterized by adrenal insufficiency, alacrimia, achalasia and complex neurological involvement. Allgrove disease is due to recessive mutations in the AAAS gene, which encodes for the nucleoporin Aladin, implicated in the nucleocytoplasmic transport. The adrenal insufficiency has been suggested to rely on adrenal gland-ACTH resistance. However, the link between the molecular pathology affecting the nucleoporin Aladin and the glucocorticoid deficiency is still unknown. RESULTS: By analyzing postmortem patient's adrenal gland, we identified a downregulation of Aladin transcript and protein. We found a downregulation of Scavenger receptor class B-1 (SCARB1), a key component of the steroidogenic pathway, and SCARB1 regulatory miRNAs (mir125a, mir455) in patient's tissues. With the hypothesis of an impairment in the nucleocytoplasmic transport of the SCARB1 transcription enhancer cyclic AMP-dependent protein kinase (PKA), we detected a reduction of nuclear Phospho-PKA and a cytoplasmic mislocalization in patient's samples. CONCLUSIONS: These results shed a light on the possible mechanisms linking ACTH resistance, SCARB1 impairment, and defective nucleocytoplasmic transport.


Assuntos
Insuficiência Adrenal , Acalasia Esofágica , MicroRNAs , Humanos , Acalasia Esofágica/genética , Acalasia Esofágica/metabolismo , Acalasia Esofágica/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Regulação para Baixo/genética , Proteínas do Tecido Nervoso/genética , Insuficiência Adrenal/genética , Insuficiência Adrenal/metabolismo , Insuficiência Adrenal/patologia , Proteínas Nucleares/genética , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo
2.
Biomed Res Int ; 2021: 8836395, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33628819

RESUMO

OBJECTIVE: To identify and evaluate characteristics of the most influential articles in achalasia research during the period 1995-2020. METHODS: Articles in Scopus, Web of Science Core Collection (WoSCC), and PubMed were scanned from 1995 to 2020 with achalasia as the keyword. We retrieved the articles that met all criteria by descending order after using EndNote to remove the duplicated references. Our bibliometric analysis highlighted publication year, country, journals, and networks of keywords. RESULTS: Fifteen percent of the top 100 most-cited articles were published in Annals of Surgery. They were performed in 15 countries, and most (n = 55) were from the USA. The number of citations of the 482 articles ranged from 30 to 953, 38 of which had been published in American Journal of Gastroenterology. Those articles were from 31 countries, and most of the studies (n = 217) had been performed in the USA. Most of articles (n = 335) were clinical research. Treatments were hotspots in the field of achalasia in the past years. The most influential title words were "achalasia," "esophagomyotomy," "pneumatic dilation," and "lower esophageal sphincter." CONCLUSION: Our study offers a historical perspective on the progress of achalasia research and identified the most significant evolution in this field. Results showed treatment was the most influence aspect in achalasia.


Assuntos
Bibliometria , Pesquisa Biomédica , Acalasia Esofágica , Acalasia Esofágica/genética , Acalasia Esofágica/metabolismo , Acalasia Esofágica/patologia , Acalasia Esofágica/terapia , Humanos , Fator de Impacto de Revistas
3.
Protein Pept Lett ; 27(12): 1192-1203, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32533814

RESUMO

Triple-A Syndrome (TAS) is a rare autosomal recessive disorder characterized by three cardinal symptoms: alacrimia, achalasia and adrenal insufficiency due to ACTH insensitivity. Various progressive neurological abnormalities and skin changes have been described in association with the syndrome. The disease is caused by mutation in the AAAS gene on chromosome 12q13. Mutations in AAAS were identified in more than 90% of individuals and families with TAS. The protein encoded by AAAS was termed ALADIN and is part of the WD repeat family of proteins, that have been found to be involved in many different functions such as protein-protein interaction, RNA processing, cytoskeleton assembly, control of cell division, signal transduction and apoptosis. Immunohistochemical analysis showed that mutated or truncated ALADIN localizes to the cytoplasm rather than to the nuclear pore complex. The exact function of ALADIN and the mechanisms that lead to the ACTH-resistant adrenal phenotype remains largely unknown. Nonetheless, recent studies provided some insights on the role of ALADIN as a member of the Nuclear Pore Complex not only implicated in the import of proteins involved in DNA repair and oxidative stress homeostasis but also in the strengthening of the mitotic spindle assembly. Early identification of the syndrome is challenging, given the rarity of the condition and high phenotypic heterogeneity even among members of the same family. In this review, we aim to summarize the current knowledge of clinical and molecular profile of patients with TAS and recommendations for the diagnosis, management, and follow-up of patients.


Assuntos
Insuficiência Adrenal , Cromossomos Humanos Par 12 , Acalasia Esofágica , Estudos de Associação Genética , Mutação , Proteínas do Tecido Nervoso , Complexo de Proteínas Formadoras de Poros Nucleares , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/genética , Insuficiência Adrenal/metabolismo , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 12/metabolismo , Reparo do DNA/genética , Acalasia Esofágica/diagnóstico , Acalasia Esofágica/genética , Acalasia Esofágica/metabolismo , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Estresse Oxidativo/genética
4.
Neurogastroenterol Motil ; 32(8): e13867, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32368845

RESUMO

OBJECTIVE: To determine the differences between clinical, manometric, and neuroimmunological profile of esophagogastric junction outflow obstruction (EGJOO) and achalasia patients. METHODS: Seven EGJOO and 27 achalasia patients were enrolled in a blind cross-sectional study. Peripheral blood (PB) of 10 healthy donors and 10 lower esophageal sphincter (LES) muscle biopsies from organ transplant donors were included as controls. The presence of ganglion cells, cells of Cajal, Th22/Th7/Th2/Th1/Tregs/Bregs/pDCregs in tissue, and PB was assessed by immunohistochemistry and flow cytometry. Serum concentration of IL-22/IL-17A/IL-17F/IL-4/IFN-γ/IL-1ß/IL-6/IL-23/IL-33/TNF-α/IL-10 was determined using bioplex plates. ANAs and antineuronal antibodies were evaluated by immunofluorescence and Western blot. KEY RESULTS: EGJOO and achalasia patients had lower ganglion cells and cells of Cajal percentage vs. controls, while fibrosis was present only in achalasia patients. EGJOO and controls had lower cell percentage of Th22/Th17/Th2 vs. achalasia. EGJOO tissue had lower Th1/Treg cell number vs. achalasia, but higher levels vs. control group. Bregs and pDCregs percentage was higher in EGJOO vs. control group. Percentage of PB subpopulations in EGJOO was not significantly different from control group. Serum cytokine levels were higher for IL-1ß/IL-6/TNF-α, while IL-17A levels were lower in EGJOO vs. achalasia and control group. EGJOO group was negative for ANAs, while in achalasia group, 54% were positive. GAD65 and PNMa/Ta2 antibodies were present in achalasia, whereas Yo and recoverin were positive in EGJOO group. CONCLUSIONS AND INFERENCES: Although EGJOO shares some clinical characteristics with achalasia, the neuroimmunological profile is completely different, suggesting that EGJOO might be a different entity.


Assuntos
Acalasia Esofágica/diagnóstico , Transtornos da Motilidade Esofágica/diagnóstico , Junção Esofagogástrica/metabolismo , Esôfago/metabolismo , Adulto , Idoso , Estudos Transversais , Citocinas/sangue , Acalasia Esofágica/metabolismo , Transtornos da Motilidade Esofágica/metabolismo , Feminino , Humanos , Masculino , Manometria , Pessoa de Meia-Idade
5.
Cornea ; 39(6): 782-783, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32073457

RESUMO

PURPOSE: To report 2 novel variants in the AAAS gene consistent with the diagnosis of Allgrove syndrome. METHODS: A 12-year-old girl was referred to our clinic for progressive bilateral decrease in visual acuity. She was known for achalasia that had been surgically treated at a very early age. On examination, she was found to have dry eye disease secondary to lacrimal insufficiency. She also had anisocoria, light-near dissociation, and bilateral optic nerve atrophy. RESULTS: Neurological examination and brain magnetic resonance imaging were within normal limits. Genetic workup revealed compound heterozygosity for 2 novel variants in the AAAS gene, confirming the diagnosis of Allgrove syndrome. The patient was referred to endocrinology to screen for adrenocorticotropic hormone insufficiency. She was started on topical lubricating therapy that improved her symptoms. CONCLUSIONS: Allgrove syndrome is a rare genetic disease that is characterized by the triad of achalasia, alacrima, and adrenal insufficiency. Early diagnosis, confirmed with genetic testing, is essential to initiate an appropriate follow-up and prevent a life-threatening addisonian crisis. Report of novel mutations is important to further characterize this disease.


Assuntos
Insuficiência Adrenal/genética , DNA/genética , Acalasia Esofágica/genética , Mutação , Proteínas do Tecido Nervoso/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/metabolismo , Criança , Análise Mutacional de DNA , Diagnóstico Diferencial , Acalasia Esofágica/diagnóstico , Acalasia Esofágica/metabolismo , Feminino , Humanos , Proteínas do Tecido Nervoso/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
6.
Mol Med Rep ; 21(3): 1276-1284, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31922241

RESUMO

Achalasia is characterized by impaired swallowing due to lower esophageal sphincter (LES) dysfunction and an increased risk of esophageal carcinoma. Aflatoxin is a known carcinogen. Esophageal retention is relieved by per oral endoscopic myotomy (POEM), which lowers the esophageal cancer risk. The present study determined whether aflatoxin is involved in the pathogenesis of achalasia or esophageal cancer. A total of 75 patients with achalasia were prospectively enrolled from a tertiary center. Aflatoxin levels in their esophageal contents were measured using ELISA, and esophageal mucosal specimens were immunohistochemically evaluated for Ki67 and p53 expression prior to and 3 months after POEM. The effect of aflatoxin on esophageal contractility was assessed using murine specimens. Aflatoxin was detected in 67 patients before POEM and only 2 patients after POEM. The number of Ki67­ and p53­immunopositive cells in the esophageal mucosa significantly decreased after POEM: [Ki67: 27.8% (95% confidence interval (CI), 25.98­29.70) vs. 20.7% (95% CI, 19.78­24.03), P=0.04 and p53: 2.14% (95% CI, 1.85­2.41) vs. 1.45% (95% CI, 1.22­1.68), P=0.03]. In vitro experiments revealed that 500 ng/ml aflatoxin significantly increased the amplitude (P<0.05) and frequency (P<0.05) of spontaneous LES contractions compared with the control group. These increases were blocked by co­treatment with atropine sulfate (P<0.05), but not with a nitric oxide synthase inhibitor (P>0.05). Aflatoxin was found in most patients with achalasia and was eliminated following POEM. Reduced Ki67 and p53 expression after POEM indicated a decreased risk of carcinogenesis. Aflatoxin accumulation increased LES contractility via cholinergic signaling. Therefore, aflatoxin may maintain achalasia symptoms and increase esophageal cancer risk.


Assuntos
Aflatoxinas/toxicidade , Acalasia Esofágica , Mucosa Esofágica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Acalasia Esofágica/induzido quimicamente , Acalasia Esofágica/metabolismo , Acalasia Esofágica/patologia , Acalasia Esofágica/cirurgia , Mucosa Esofágica/metabolismo , Mucosa Esofágica/patologia , Mucosa Esofágica/cirurgia , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Estudos Prospectivos , Piloromiotomia , Fatores de Risco
7.
Hum Mol Genet ; 28(23): 3921-3927, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600784

RESUMO

Allgrove syndrome (AS) is a rare disease with broad neurological involvement. Neurodegeneration can affect spinal motor neurons, Purkinje cells, striatal neurons and the autonomic system. The mechanisms that lead to neuronal loss are still unclear. Recessive mutations in the AAAS gene affect the encoded protein Aladin, which would normally localize to the cytoplasmic face of the nuclear membrane as part of the nuclear pore complex (NPC). While the NPC is known to be a key factor for nucleocytoplasmic transport, the precise role of Aladin has not been elucidated yet. Here, we explored the consequences of the homozygous AAAS mutation c.464G>A (p.R155H) in central nervous system tissues and fibroblasts of a novel AS patient presenting motor neuron disease, cerebellar ataxia and autonomic dysfunction. Neuropathological analyses showed severe loss of motor neurons and Purkinje cells, with significant reduction in the perinuclear expression of Aladin. A reduced amount of protein was detected in the nuclear membrane fraction of the patient's brain. RNA analysis revealed a significant reduction of the transcript AAAS-1, while the AAAS-2 transcript was upregulated in fibroblasts. To our knowledge, this is the first study to demonstrate the effects of AAAS mutations in the human central nervous system.


Assuntos
Insuficiência Adrenal/genética , Acalasia Esofágica/genética , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Complexo de Proteínas Formadoras de Poros Nucleares/deficiência , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Insuficiência Adrenal/metabolismo , Idade de Início , Idoso , Substituição de Aminoácidos , Sistema Nervoso Central/metabolismo , Regulação para Baixo , Acalasia Esofágica/metabolismo , Fibroblastos/metabolismo , Humanos , Masculino , Mutação Puntual , Análise de Sequência de DNA
8.
J Steroid Biochem Mol Biol ; 189: 73-80, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30817990

RESUMO

Hereditary adrenocorticotropin (ACTH) resistance syndromes encompass the genetically heterogeneous isolated or Familial Glucocorticoid Deficiency (FGD) and the distinct clinical entity known as Triple A syndrome. The molecular basis of adrenal resistance to ACTH includes defects in ligand binding, MC2R/MRAP receptor trafficking, cellular redox balance, cholesterol synthesis and sphingolipid metabolism. Biochemically, this manifests as ACTH excess in the setting of hypocortisolaemia. Triple A syndrome is an inherited condition involving a tetrad of adrenal insufficiency, achalasia, alacrima and neuropathy. FGD is an autosomal recessive condition characterized by the presence of isolated glucocorticoid deficiency, classically in the setting of preserved mineralocorticoid secretion. Primarily there are three established subtypes of the disease: FGD 1, FGD2 and FGD3 corresponding to mutations in the Melanocortin 2 receptor MC2R (25%), Melanocortin 2 receptor accessory protein MRAP (20%), and Steroidogenic acute regulatory protein STAR (5-10%) respectively. Together, mutations in these 3 genes account for approximately half of cases. Whole exome sequencing in patients negative for MC2R, MRAP and STAR mutations, identified mutations in minichromosome maintenance 4 MCM4, nicotinamide nucleotide transhydrogenase NNT, thioredoxin reductase 2 TXNRD2, cytochrome p450scc CYP11A1, and sphingosine 1-phosphate lyase SGPL1 accounting for a further 10% of FGD. These novel genes have linked replicative and oxidative stress and altered redox potential as a mechanism of adrenocortical damage. However, a genetic diagnosis is still unclear in about 40% of cases. We describe here an updated list of FGD genes and provide a description of relevant mouse models that, despite some being flawed, have been precious allies in the understanding of FGD pathobiology.


Assuntos
Insuficiência Adrenal/genética , Acalasia Esofágica/genética , Glucocorticoides/genética , Erros Inatos do Metabolismo de Esteroides/genética , Insuficiência Adrenal/metabolismo , Insuficiência Adrenal/patologia , Hormônio Adrenocorticotrópico/genética , Hormônio Adrenocorticotrópico/metabolismo , Animais , Modelos Animais de Doenças , Acalasia Esofágica/metabolismo , Acalasia Esofágica/patologia , Predisposição Genética para Doença , Glucocorticoides/metabolismo , Humanos , Mutação , Erros Inatos do Metabolismo de Esteroides/metabolismo , Erros Inatos do Metabolismo de Esteroides/patologia
11.
FASEB J ; 32(10): 5703-5715, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29768039

RESUMO

Sonic hedgehog ( Shh) is crucial for organogenesis in the foregut. This study investigated the function of Shh at the late-gestational stage; during which, the esophagus continues to differentiate. We established cytokeratin 14 ( CK14)-Cre;Shhfl/fl mice in which the down-regulation of Shh in the epithelium occurred at approximately the same time as esophageal muscle conversion. Hematoxylin and eosin and immunohistochemical staining, with antibodies against keratin 14, Shh, patched 1 (Ptch1), Gli1, proliferating cell nuclear antigen (PCNA), α-smooth muscle actin (αSMA), high-molecular-weight caldesmon (hCD), myogenin, paired box 7 (Pax7), ß3-tubulin, and protein gene product 9.5 (PGP9.5), was performed to detect specific tissue dysplasia. Organ culture was conducted in vitro, and total mRNA was extracted to determine the transcriptional dysregulation. The esophagus of CK14-Cre;Shhfl/fl mice developed into an independent tube with an obvious dilatation at postnatal d 0.5. The number of cell layers and the expression of PCNA were decreased in mutant mice, compared with those in wild-type mice. The expression of hCD declined progressively in the middle, distal, and lower esophageal sphincter levels of the mutant esophagus from embryonic d 17.5, compared with the expression in wild-type littermates. Pax7 accumulation and myogenin reduction in mutant mice indicated that esophageal skeletal-myoblast progression was blocked. RNA sequencing analysis revealed a significant down-regulation of genes involved in proliferation and muscular motivation in CK14-Cre;Shhfl/fl mice. Thus, loss of Shh at the late-gestational stage leads to megaesophagus with reduced proliferation and a muscle development disorder in mice.-Jia, X., Min, L., Zhu, S., Zhang, S., Huang, X. Loss of sonic hedgehog gene leads to muscle development disorder and megaesophagus in mice.


Assuntos
Acalasia Esofágica , Proteínas Hedgehog/deficiência , Proteínas Musculares , Músculo Esquelético , Doenças Musculares , Mutação , Animais , Animais Geneticamente Modificados , Acalasia Esofágica/embriologia , Acalasia Esofágica/genética , Acalasia Esofágica/metabolismo , Acalasia Esofágica/patologia , Camundongos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/embriologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/epidemiologia , Doenças Musculares/genética , Doenças Musculares/metabolismo , Doenças Musculares/patologia
12.
Neurogastroenterol Motil ; 30(9): e13346, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29644781

RESUMO

BACKGROUND: Achalasia is a rare motility disorder characterized by myenteric neuron and interstitial cells of Cajal (ICC) abnormalities leading to deranged/absent peristalsis and lack of relaxation of the lower esophageal sphincter. The mechanisms contributing to neuronal and ICC changes in achalasia are only partially understood. Our goal was to identify novel molecular features occurring in patients with primary achalasia. METHODS: Esophageal full-thickness biopsies from 42 (22 females; age range: 16-82 years) clinically, radiologically, and manometrically characterized patients with primary achalasia were examined and compared to those obtained from 10 subjects (controls) undergoing surgery for uncomplicated esophageal cancer (or upper stomach disorders). Tissue RNA extracted from biopsies of cases and controls was used for library preparation and sequencing. Data analysis was performed with the "edgeR" option of R-Bioconductor. Data were validated by real-time RT-PCR, western blotting and immunohistochemistry. KEY RESULTS: Quantitative transcriptome evaluation and cluster analysis revealed 111 differentially expressed genes, with a P ≤ 10-3 . Nine genes with a P ≤ 10-4 were further validated. CYR61, CTGF, c-KIT, DUSP5, EGR1 were downregulated, whereas AKAP6 and INPP4B were upregulated in patients vs controls. Compared to controls, immunohistochemical analysis revealed a clear increase in INPP4B, whereas c-KIT immunolabeling resulted downregulated. As INPP4B regulates Akt pathway, we used western blot to show that phospho-Akt was significantly reduced in achalasia patients vs controls. CONCLUSIONS & INFERENCES: The identification of altered gene expression, including INPP4B, a regulator of the Akt pathway, highlights novel signaling pathways involved in the neuronal and ICC changes underlying primary achalasia.


Assuntos
Acalasia Esofágica/metabolismo , Monoéster Fosfórico Hidrolases/biossíntese , Proteínas Proto-Oncogênicas c-kit/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Regulação para Baixo , Feminino , Humanos , Células Intersticiais de Cajal/metabolismo , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Transcriptoma , Adulto Jovem
13.
Eur J Endocrinol ; 178(3): 199-207, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29237697

RESUMO

OBJECTIVE: Triple-A or Allgrove syndrome is an autosomal recessive disorder due to mutations in the AAAS gene, which encodes a nucleoporin named ALADIN. It is characterized by a classical clinical triad: alacrima, achalasia and adrenal insufficiency, the canonic symptoms that are associated with progressive peripheral neuropathy. Only a few cohorts have been reported. The objective of the present study was to characterize the various spectra of adrenal function in Triple-A patients. METHODS: A retrospective clinical and biological monitoring of 14 patients (10 families) was done in a single multidisciplinary French center. All had AAAS gene sequenced and adrenal function evaluation. RESULTS: Nine different AAAS mutations were found, including one new mutation: c.755G>C, p.(Trp252Ser). Regarding adrenal function, defects of the zona fasciculata and reticularis were demonstrated by increased basal ACTH levels and low DHEAS levels in all cases regardless of the degree of glucocorticoid deficiency. In contrast, mineralocorticoid function was always conserved: i.e., normal plasma renin level associated with normal aldosterone level. The main prognostic feature was exacerbation of neuropathy and cognitive disorders. CONCLUSIONS: These data suggest that, in Triple-A patients, adrenal function can be deficient, insufficient or compensated. In our cohort after the first decade of life, there does not appear to be any degradation of adrenal function over time. However, patients with compensated adrenal function should be informed and educated to manage a glucocorticoid replacement therapy in case of stressful conditions, with no need for systematic long-term treatment.


Assuntos
Insuficiência Adrenal/genética , Acalasia Esofágica/genética , Proteínas do Tecido Nervoso/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Adolescente , Insuficiência Adrenal/complicações , Insuficiência Adrenal/metabolismo , Insuficiência Adrenal/fisiopatologia , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Idoso , Aldosterona/metabolismo , Criança , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Estudos de Coortes , Sulfato de Desidroepiandrosterona/metabolismo , Progressão da Doença , Acalasia Esofágica/complicações , Acalasia Esofágica/metabolismo , Acalasia Esofágica/fisiopatologia , Feminino , França , Glucocorticoides/deficiência , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Fenótipo , Prognóstico , Renina/metabolismo , Estudos Retrospectivos , Adulto Jovem , Zona Fasciculada/metabolismo , Zona Reticular/metabolismo
14.
Sci Rep ; 7(1): 3563, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28620185

RESUMO

The gastrointestinal tract is responsible for food digestion and absorption. The muscularis propria propels the foodstuff through the GI tract and defects in intestine motility may cause obstruction disorders. Our present genetic studies identified non-receptor tyrosine kinase c-Abl as an important regulator of the muscularis propria homeostasis and a risk factor for rectal prolapse. Mouse deficient for c-Abl showed defects in the muscularis propria of gastrointestinal tract and older c-Abl -/- mice developed megaesophagus and rectal prolapse. Inhibition of c-Abl with imatinib mesylate, an anti-CML drug, or ablation of c-Abl using Prx1-Cre, which marks smooth muscle cells, recapitulated most of the muscularis propria phenotypes. The pathogenesis of rectal prolapse was attributable to overproliferation of smooth muscle cells, which was caused by enhanced ERK1/2 activation. Administration of ERK inhibitor U0126 impeded the development of rectal prolapse in c-Abl deficient mice. These results reveal a role for c-Abl-regulated smooth muscle proliferation in the pathogenesis of rectal prolapse, and imply that long-term use of imatinib mesylate may cause gastrointestinal problems in patients while ERK inhibitor may be effective in treating rectal prolapse.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Genes abl , Homeostase , Mucosa Intestinal/metabolismo , Animais , Proliferação de Células , Acalasia Esofágica/tratamento farmacológico , Acalasia Esofágica/etiologia , Acalasia Esofágica/metabolismo , Acalasia Esofágica/patologia , Esôfago/efeitos dos fármacos , Esôfago/metabolismo , Genes p16 , Predisposição Genética para Doença , Homeostase/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Fenótipo , Prolapso Retal/etiologia , Prolapso Retal/metabolismo , Prolapso Retal/patologia
15.
Sci Rep ; 6: 31549, 2016 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-27511445

RESUMO

Idiopathic achalasia is characterized by the absence of peristalsis secondary to loss of neurons in the myenteric plexus that hampers proper relaxation of the lower esophageal sphincter. Achalasia can be considered a multifactorial disorder as it occurs in related individuals and is associated with HLA class II genes, thereby suggesting genetic influence. We used microarray technology and advanced in-silico functional analyses to perform the first genome-wide expression profiling of mRNA in tissue samples from 12 achalasia and 5 control patients. It revealed 1,728 differentially expressed genes, of these, 837 (48.4%) were up-regulated in cases. In particular, genes participating to the smooth muscle contraction biological function were mostly up-regulated. Functional analysis revealed a significant enrichment of neuronal/muscular and neuronal/immunity processes. Upstream regulatory analysis of 180 genes involved in these processes suggested TLR4 and IL18 as critical key-players. Two functional gene networks were significantly over-represented: one involved in organ morphology, skeletal muscle system development and function, and neurological diseases, and the other participating in cell morphology, humoral immune response and cellular movement. These results highlight on pivotal genes that may play critical roles in neuronal/muscular and neuronal/immunity processes, and that may contribute to the onset and development of achalasia.


Assuntos
Acalasia Esofágica/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Contração Muscular , Músculo Liso/metabolismo , Plexo Mientérico/metabolismo , Adulto , Idoso , Acalasia Esofágica/genética , Acalasia Esofágica/patologia , Feminino , Estudo de Associação Genômica Ampla , Antígenos HLA/biossíntese , Antígenos HLA/genética , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso/patologia , Plexo Mientérico/patologia
16.
Mol Biol Cell ; 26(19): 3424-38, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26246606

RESUMO

The formation of the mitotic spindle is a complex process that requires massive cellular reorganization. Regulation by mitotic kinases controls this entire process. One of these mitotic controllers is Aurora A kinase, which is itself highly regulated. In this study, we show that the nuclear pore protein ALADIN is a novel spatial regulator of Aurora A. Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment. ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition. Of interest, mutations in ALADIN cause triple A syndrome. We find that some of the mitotic phenotypes that we observe after ALADIN depletion also occur in cells from triple A syndrome patients, which raises the possibility that mitotic errors may underlie part of the etiology of this syndrome.


Assuntos
Aurora Quinase A/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Fuso Acromático/metabolismo , Insuficiência Adrenal/enzimologia , Insuficiência Adrenal/metabolismo , Animais , Ciclo Celular/fisiologia , Células Cultivadas , Drosophila melanogaster , Acalasia Esofágica/enzimologia , Acalasia Esofágica/metabolismo , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Mitose/fisiologia , Ligação Proteica
17.
Neurogastroenterol Motil ; 27(9): 1274-81, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26087745

RESUMO

BACKGROUND: The aim of the present study was to investigate whether the synthesis of endogenous hydrogen sulfide (H2 S) was altered in achalasia patients and to determine the effects of H2 S on esophageal motility. METHODS: (1) Tissue samples in lower esophageal sphincter (LES) were obtained from 22 achalasia patients during peroral endoscopic myotomy. LES muscle from eight esophageal carcinoma patients was obtained as control. The expression of cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) was detected by immunohistochemical staining. (2) Rabbit esophageal smooth muscle strips were used to measure isometric contractions. The effects of sodium hydrosulfide (NaHS) and L-cysteine on contractile activity and bethanechol-stimulated contractile activity were evaluated. The contraction of esophageal muscle strips was also measured after the inhibition of CBS and CSE by aminooxyacetic acid (AOA) and propargylglycine (PAG). KEY RESULTS: Both CBS and CSE could be detected in biopsies from achalasia patients and controls. Compared with controls, the expression of CBS and CSE in the LES of achalasia patients was significantly reduced (p < 0.001). Both NaHS and L-cysteine concentration-dependently inhibited esophageal contractile activity (both p < 0.05). After inhibition of CBS and CSE by PAG and AOA, esophageal contractile activity increased significantly, and this effect could be restored by NaHS but not L-cysteine (p < 0.05). CONCLUSIONS & INFERENCES: H2 S synthesis enzymes are significantly reduced in patients with achalasia compared with the controls. H2 S inhibits esophageal contractile activity concentration-dependently, and the inhibition of H2 S synthesis enzymes increases esophageal contractile activity. H2 S might be involved in the development of achalasia.


Assuntos
Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Acalasia Esofágica/enzimologia , Esfíncter Esofágico Inferior/enzimologia , Motilidade Gastrointestinal , Sulfeto de Hidrogênio/metabolismo , Adulto , Alcinos/farmacologia , Ácido Amino-Oxiacético/farmacologia , Animais , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina gama-Liase/antagonistas & inibidores , Acalasia Esofágica/metabolismo , Feminino , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Contração Muscular/efeitos dos fármacos , Coelhos , Adulto Jovem
18.
J Renin Angiotensin Aldosterone Syst ; 16(3): 578-86, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24468662

RESUMO

INTRODUCTION: Angiotensin II (AngII) elicits smooth muscle contractions via activation of AngII type 1 receptor (AT1R) in the intestinal wall and in sphincter regions in several species. Achalasia is a rare swallowing disorder and is characterized by a loss of the wave-like contraction that forces food through the oesophagus and a failure of the lower oesophageal sphincter to relax during swallowing. AIMS AND METHODS: The present study was undertaken to elucidate expression and distribution of a local renin-angiotensin system (RAS) in the muscular layer of distal normal human oesophagus as well as in patients with achalasia using western blot analysis, immunohistochemistry and polymerase chain reaction (PCR). RESULTS: AT1R, together with enzyme renin and cathepsin D expression were decreased in patients with achalasia. In contrast, the mast cells chymase, cathepsin G, neprilysin and the receptor for angiotensin 1-7 peptides, the MAS receptor, were increased in patients with achalasia. CONCLUSION: The results showed the existence of a local RAS in human oesophageal muscular layer. The enzymes responsible for AngII production are different and there has been a shift in receptor physiology from AT1R to MAS receptor in patients with achalasia. These changes in the RAS might play a significant role in the physiological motor control for patients with achalasia.


Assuntos
Acalasia Esofágica/metabolismo , Músculos/metabolismo , Sistema Renina-Angiotensina , Idoso , Angiotensina I/metabolismo , Estudos de Casos e Controles , Catepsina G/metabolismo , Quimases/metabolismo , Esôfago/metabolismo , Esôfago/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Mastócitos/enzimologia , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores de Angiotensina/metabolismo , Coloração pela Prata
19.
Am J Hum Genet ; 94(3): 385-94, 2014 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-24581742

RESUMO

Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the α1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble α1ß1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and nonsyndromic moyamoya.


Assuntos
Acalasia Esofágica/metabolismo , Guanilato Ciclase/genética , Guanilato Ciclase/fisiologia , Doença de Moyamoya/metabolismo , Óxido Nítrico/química , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/fisiologia , Adolescente , Adulto , Plaquetas/metabolismo , Criança , Pré-Escolar , GMP Cíclico/metabolismo , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Músculo Liso Vascular/metabolismo , Mutação , Óxido Nítrico/metabolismo , Linhagem , Adesividade Plaquetária , Agregação Plaquetária , Guanilil Ciclase Solúvel , Adulto Jovem
20.
Endocrinology ; 154(9): 3209-18, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23825130

RESUMO

UNLABELLED: Triple A syndrome is a rare, autosomal recessive cause of adrenal failure. Additional features include alacrima, achalasia of the esophageal cardia, and progressive neurodegenerative disease. The AAAS gene product is the nuclear pore complex protein alacrima-achalasia-adrenal insufficiency neurological disorder (ALADIN), of unknown function. Triple A syndrome patient dermal fibroblasts appear to be more sensitive to oxidative stress than wild-type fibroblasts. To provide an adrenal and neuronal-specific disease model, we established AAAS-gene knockdown in H295R human adrenocortical tumor cells and SH-SY5Y human neuroblastoma cells by lentiviral short hairpin RNA transduction. AAAS-knockdown significantly reduced cell viability in H295R cells. This effect was exacerbated by hydrogen peroxide treatment and improved by application of the antioxidant N-acetylcysteine. An imbalance in redox homeostasis after AAAS knockdown was further suggested in the H295R cells by a decrease in the ratio of reduced to oxidized glutathione. AAAS-knockdown SH-SY5Y cells were also hypersensitive to oxidative stress and responded to antioxidant treatment. A further impact on function was observed in the AAAS-knockdown H295R cells with reduced expression of key components of the steroidogenic pathway, including steroidogenic acute regulatory and P450c11ß protein expression. Importantly a significant reduction in cortisol production was demonstrated with AAAS knockdown, which was partially reversed with N-acetylcysteine treatment. CONCLUSION: Our in vitro data in AAAS-knockdown adrenal and neuronal cells not only corroborates previous studies implicating oxidative stress in this disorder but also provides further insights into the pathogenic mechanisms in triple A syndrome.


Assuntos
Corticosteroides/metabolismo , Córtex Suprarrenal/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Estresse Oxidativo , Fosfoproteínas/metabolismo , Esteroide 11-beta-Hidroxilase/metabolismo , Córtex Suprarrenal/efeitos dos fármacos , Insuficiência Adrenal/tratamento farmacológico , Insuficiência Adrenal/etiologia , Insuficiência Adrenal/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Acalasia Esofágica/tratamento farmacológico , Acalasia Esofágica/etiologia , Acalasia Esofágica/metabolismo , Técnicas de Silenciamento de Genes , Glutationa/metabolismo , Humanos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Complexo de Proteínas Formadoras de Poros Nucleares/antagonistas & inibidores , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Oxidantes/farmacologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Inibidores da Síntese de Proteínas/farmacologia , Puromicina/farmacologia , RNA Interferente Pequeno , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Esteroide 11-beta-Hidroxilase/genética
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