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1.
Genes (Basel) ; 13(2)2022 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-35205242

RESUMO

Oligo-fluorescence in situ hybridization (FISH) facilitates precise chromosome identification and comparative cytogenetic analysis. Detection of autosomal chromosomes of Hippophaë rhamnoides has not been achieved using oligonucleotide sequences. Here, the chromosomes of five H. rhamnoides taxa in the mitotic metaphase and mitotic metaphase to anaphase were detected using the oligo-FISH probes (AG3T3)3, 5S rDNA, and (TTG)6. In total, 24 small chromosomes were clearly observed in the mitotic metaphase (0.89-3.03 µm), whereas 24-48 small chromosomes were observed in the mitotic metaphase to anaphase (0.94-3.10 µm). The signal number and intensity of (AG3T3)3, 5S rDNA, and (TTG)6 in the mitotic metaphase to anaphase chromosomes were nearly consistent with those in the mitotic metaphase chromosomes when the two split chromosomes were integrated as one unit. Of note, 14 chromosomes (there is a high chance that sex chromosomes are included) were exclusively identified by (AG3T3)3, 5S rDNA, and (TTG)6. The other 10 also showed a terminal signal with (AG3T3)3. Moreover, these oligo-probes were able to distinguish one wild H. rhamnoides taxon from four H. rhamnoides taxa. These chromosome identification and taxa differentiation data will help in elucidating visual and elaborate physical mapping and guide breeders' utilization of wild resources of H. rhamnoides.


Assuntos
Hippophae , RNA Ribossômico 5S , Cromossomos de Plantas/genética , DNA Ribossômico/genética , Hippophae/genética , Hibridização in Situ Fluorescente , RNA Ribossômico 5S/genética
2.
Hum Mutat ; 43(5): 557-567, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35143115

RESUMO

Glycogen storage disease (GSD) Type VI is a glycogenolysis disorder caused by variants of PYGL. Knowledge about this disease is limited because only approximately 50 cases have been reported. We investigated the clinical profiles, molecular diagnosis, and treatment outcomes in patients with GSD VI from 2000 to 2021. The main initial clinical features of this cohort include hepatomegaly, short stature, elevated liver transaminases, hypertriglyceridemia, fasting hypoglycemia, and hyperuricemia. After uncooked cornstarch treatment, the stature and biochemical parameters improved significantly (p < 0.05). However, hyperuricemia recurred in most patients during adolescence. Among the 56 GSD VI patients, 54 biallelic variants and two single allelic variants of PYGL were identified, of which 43 were novel. There were two hotspot variants, c.1621-258_2178-23del and c.2467C>T p.(Gln823*), mainly in patients from Southwest and South China. c.1621-258_2178-23del is a 3.6 kb deletion that results in an out-of-frame deletion r.1621_2177del and an in-frame deletion r.1621_2265del. Our data show for the first time that long-term monitoring of uric acid is recommended for older GSD VI patients. This study also broadens the variant spectrum of PYGL and indicates that there are two hot-spot variants in China.


Assuntos
Doença de Depósito de Glicogênio Tipo VI , Doença de Depósito de Glicogênio , Hiperuricemia , Adolescente , Seguimentos , Glicogênio Fosforilase Hepática , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio Tipo VI/diagnóstico , Humanos
3.
Childs Nerv Syst ; 38(5): 947-952, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35083513

RESUMO

PURPOSE: There was no evidence whether the mammalian/mechanistic target of rapamycin pathway hyperactivation and long-term use of mTOR inhibitors have any effects on the physical development of children. The aim was to evaluate these effects by comparing the physical development of children with TSC and normal children. METHODS: A total of 120 eligible children were enrolled. They were administered sirolimus and followed for at least 12 months. Height, weight, BMI and lipid metabolism index were collected during treatment. Pearson's chi-square and Fisher's exact test were used for comparison of proportions of patients exhibiting normal and abnormal physical growth before and after 1 year of treatment. Logistic regression was used to evaluate the influence of age, sex and abnormal lipid metabolism on the increased BMIs of TSC patients after treatment. RESULTS: Most of the enrolled TSC children were in the normal height, weight and BMI ranges at baseline (91.7%, 95.8% and 78.3%, respectively). Most remained in the normal height, weight and BMI ranges after 1 year of sirolimus treatment (94.2%, 95% and 76.7%, respectively). There was no significant difference in the proportion of physical development before and after treatment (p > 0.05). Thirty-eight (38/106, 35.8%) patients had increased BMIs after 1 year of treatment, but there was no significant correlation between age, sex and lipid metabolism and increased BMI. CONCLUSIONS: Overactivation of the mTOR pathway and long-term administration of sirolimus does not affect the physical development of children with TSC.


Assuntos
Esclerose Tuberosa , Animais , Criança , Humanos , Mamíferos , Sirolimo/efeitos adversos , Esclerose Tuberosa/tratamento farmacológico
4.
Hum Cell ; 35(2): 486-497, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34978047

RESUMO

Cardiovascular disease (CVD) is a leading non-communicable disease with a high fatality rate worldwide. Hypertension, a common cardiovascular condition, is a significant risk factor for the development of heart failure because the activation of the renin-angiotensin system (RAS) is considered to be the major promoting reason behind myocardial fibrosis (MF). In this study, Angiotensin II (Ang II) stimulation-induced endothelial to mesenchymal transition (End-MT) in HCAECs, including the decrease of CD31 level, the increase of α-SMA, collagen I, slug, snail, and TGF-ß1 levels, and the promotion of Smad2/3 phosphorylation. Meanwhile, the c-Ski level was reduced in Ang II-stimulated HCAECs. In HCAECs, Ang II-induced changes could be partially attenuated by c-Ski overexpression. miR-214-3p directly targeted c-Ski and inhibited c-Ski expression. Moreover, miR-214-3p inhibition reduced Ang II-caused End-MT in HCAECs. miR-214-3p overexpression further enhanced Ang II-induced End-MT, while c-Ski overexpression could markedly reverse the effects of miR-214-3p overexpression. In the Ang II-induced mouse cardiac hypertrophic model, Ang II-caused increase of cellular cross-sectional area and cardiac fibrosis were partially ameliorated by LV-c-Ski; when mice were co-treated with LV-c-Ski and agomir-214-3p, the beneficial effects of LV-c-Ski were reversed. In conclusion, the miR-214-3p/c-Ski axis modulated Ang II-induced End-MT in HCAECs and cardiac hypertrophy and fibrosis in the mice model.


Assuntos
Proteínas de Ligação a DNA , Células Endoteliais , MicroRNAs , Proteínas Proto-Oncogênicas , Animais , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Fibrose , Humanos , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Transdução de Sinais
5.
Seizure ; 95: 64-74, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35007884

RESUMO

OBJECTIVE: Syntaxin binding protein 1 (STXBP1) plays an important role in the release of synaptic vesicles. STXBP1-related encephalopathy is a brain dysfunction caused by STXBP1 variation. Levetiracetam (LEV) exerts antiepileptic effects by binding to synaptic vesicle protein 2A (SV2A). This study aimed to analyze the prognosis of LEV treatment of STXBP1 encephalopathy (STXBP1-E) and the correlation among genotype, phenotype, and LEV efficacy. METHODS: Patients with pathogenic STXBP1 variants were collected from multiple centers, and their clinical history, video electroencephalogram (vEEG) characteristics, imaging examination data, and anti-seizure medication (ASM) history were systematically analyzed. The ASMs related to the prognosis were explored. RESULTS: Forty patients with STXBP1-E were enrolled in this study. The detailed ASM usage of 37 patients was recorded without intervening in ASM selection. At the endpoint of six months treatment, the results of Fisher's exact test showed that in all ASMs, LEV affected the prognosis of patients with STXBP1-E. LEV was effective in improving the partial remission rate but did not achieve seizure freedom. However, LEV monotherapy could achieve seizure freedom in patients with other early-onset epileptic and encephalopathy. For refractory West syndrome (WS) or Ohtahara syndrome (OS), LEV combined with other ASMs could improve the seizure remission rate. CONCLUSION: LEV increased the seizure reduction rate and improved the vEEG characteristics in patients with STXBP1-E, but not seizure freedom. LEV combined with other ASMs could increase the seizure reduction rate, especially for refractory WS or OS. Thus, LEV could be considered after identifying the pathogenicity of STXBP1 variants.


Assuntos
Encefalopatias , Piracetam , Anticonvulsivantes/uso terapêutico , Encefalopatias/tratamento farmacológico , Humanos , Levetiracetam/uso terapêutico , Proteínas Munc18/genética , Fenótipo , Piracetam/uso terapêutico
6.
Epilepsia ; 63(1): 120-129, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34786694

RESUMO

OBJECTIVE: Vigabatrin (VGB) is the first-line treatment for infantile spasms (IS). Previous studies have shown that VGB exposure may cause vigabatrin-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM). Based on previous studies, this study aimed to go further to explore the possible risk factors and the incidence of VABAM. In addition, diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI) were compared to explore whether DWI should be used as a routine examination sequence when MRI is performed in children receiving VGB. METHODS: Children with IS receiving VGB were selected as the study subjects. Whether VABAM occurred or not was categorized as the VABAM group and the non-VABAM group, respectively. Their general clinical data and medication exposure were collected. The possible risk factors of VABAM and different MRI sequences were compared and statistically analyzed. RESULTS: A total of 77 children with IS were enrolled in the study, of which 25 (32.5%) developed VABAM. Twenty-three of the 25 VABAM cases have a peak dosage of VGB between 50 and 150 mg/kg/day. The earliest observation time of VABAM was 30 days. Regression analysis of relevant risk factors showed that the peak dosage of VGB was the risk factor for VABAM. Comparison between different MRI sequences showed that DWI is more sensitive than T2WI to the evaluation of VABAM. SIGNIFICANCE: In our study, the occurrence of VABAM was 32.5%, indicating a higher incidence than in most previous reports. In addition, we once again verified that the peak dosage of VGB was the risk factor of VABAM. Caution should be exercised that our data also suggest that VABAM may occur even using the conventional dosage of VGB (ie, 50-150 mg/kg/day). Therefore, even when using the conventional dosage of VGB, regular MRI examination should be required. Furthermore, DWI sequence should be used as a routine examination sequence when MRI is performed in children with IS who are receiving VGB.


Assuntos
Espasmos Infantis , Vigabatrina , Anticonvulsivantes/efeitos adversos , Encéfalo/diagnóstico por imagem , Criança , Humanos , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Espasmos Infantis/induzido quimicamente , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/tratamento farmacológico , Vigabatrina/efeitos adversos
7.
J Clin Lipidol ; 16(1): 40-51, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34969652

RESUMO

BACKGROUND: Sitosterolemia is a rare autosomal recessive disease characterized by phytosterol accumulation in the blood and tissues. However, the detailed clinical and genetic spectra are lacking. OBJECTIVE: To describe and compare the clinical, biochemical, genetic, therapeutic, and follow-up characteristics of 55 pediatric and five adult sitosterolemia patients. METHODS: Clinical, genetic and therapeutic data from 60 patients at Xinhua Hospital from January 2016 to June 2021 were retrospectively collected. RESULTS: Pediatric patients' manifestations included xanthomas(93%), hematological disorders(30%), arthralgia(24%), splenomegaly(11%), atherosclerosis(10%). Adult patients had symptoms such as atherosclerosis(5/5), xanthomas(4/5), hematological disorders(3/5), arthralgia(3/5), splenomegaly(3/5). Elevated total cholesterol(TC) and low-density lipoprotein cholesterol(LDL-C) were observed in 96% patients (pediatric 98%, adult 3/4), and phytosterol levels in 100% patients. The age of onset was also negatively correlated with blood TC (P < 0.0001, r = -0.5548) and LDL-C (P = 0.0001, r = -0.4859) levels. Targeted treatments resulted in symptomatic remission(pediatric 96%, adult 4/5), and significantly decreased lipid and phytosterol levels(all P<0.05). In the dietary-therapy cohort(n=34), blood lipid levels decreased(all P<0.05). In the 13 pediatric patients from the dietary-therapy cohort who switched from dietary to combination therapy with ezetimibe, dietary therapy decreased TC and LDL-C levels by 54% and 52%, and ezetimibe further decreased them by 18% and 20%, respectively. Further, we identified 15 novel ABCG5/ABCG8 variants. CONCLUSIONS: This study expands the clinical and genetic spectra of sitosterolemia. The low-phytosterol diet is the cornerstone of sitosterolemia treatment. Ezetimibe can further decrease blood lipid levels and increase daily dietary phytosterol tolerance.


Assuntos
Aterosclerose , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Xantomatose , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Artralgia/induzido quimicamente , Artralgia/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Criança , LDL-Colesterol , Ezetimiba/uso terapêutico , Perfil Genético , Humanos , Hipercolesterolemia , Enteropatias/diagnóstico , Enteropatias/tratamento farmacológico , Enteropatias/genética , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/genética , Lipoproteínas/genética , Fitosteróis/efeitos adversos , Fitosteróis/genética , Estudos Retrospectivos , Esplenomegalia/induzido quimicamente , Esplenomegalia/tratamento farmacológico , Xantomatose/tratamento farmacológico
8.
Int J Mol Med ; 49(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34841436

RESUMO

Myocardial remodeling is a complex pathological process and its mechanism is unclear. The present study investigated whether epigallocatechin gallate (EGCG) prevents myocardial remodeling by regulating histone acetylation and explored the mechanisms underlying this effect in the heart of a mouse model of transverse aortic constriction (TAC). A TAC mouse model was created by partial thoracic aortic banding (TAB). Subsequently, TAC mice were injected with EGCG at a dose of 50 mg/kg/day for 12 weeks. The hearts of mice were collected for analysis 4, 8 and 12 weeks after TAC. Histopathological changes in the heart were observed by hematoxylin and eosin, Masson trichrome and wheat germ agglutinin staining. Protein expression levels were investigated using western blotting. Cardiac function of mice was detected by echocardiography. The level of histone acetylated lysine 27 on histone H3 (H3K27ac) first increased and then decreased in the hearts of mice at 4, 8 and 12 weeks after TAC. The expression levels of two genes associated with pathological myocardial remodeling, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), also increased initially but then decreased. The expression levels of histone deacetylase 5 (HDAC5) gradually increased in the hearts of mice at 4, 8 and 12 weeks after TAC. Furthermore, EGCG increased acetylation of H3K27ac by inhibiting HDAC5 in the heart of TAC mice treated with EGCG for 12 weeks. EGCG normalized the transcriptional activity of heart nuclear transcription factor myocyte enhancer factor 2A in TAC mice treated for 12 weeks. The low expression levels of myocardial remodeling­associated genes (ANP and BNP) were reversed by EGCG treatment for 12 weeks in TAC mice. In addition, EGCG reversed cardiac enlargement and improved cardiac function and survival in TAC mice when treated with EGCG for 12 weeks. Modification of the HDAC5­mediated imbalance in histone H3K27ac served a key role in pathological myocardial remodeling. The present results show that EGCG prevented and delayed myocardial remodeling in TAC mice by inhibiting HDAC5.


Assuntos
Catequina/análogos & derivados , Insuficiência Cardíaca/tratamento farmacológico , Histona Desacetilases/metabolismo , Acetilação , Animais , Fator Natriurético Atrial/metabolismo , Remodelamento Atrial/fisiologia , Catequina/farmacologia , Constrição , Modelos Animais de Doenças , Eletrocardiografia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/prevenção & controle , Histonas/metabolismo , Lisina/metabolismo , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Peptídeo Natriurético Encefálico/metabolismo , Taxa de Sobrevida , Remodelação Ventricular
9.
Int J Biol Macromol ; 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34871656

RESUMO

Previous studies showed that the water extract (PVW) from Spica of Prunella vulgaris Linn. (Labiatae) exerts anti-herpes simplex virus (HSV) activity. Evaluation the antiviral activity of the graded ethanol precipitations indicated that 30% ethanol precipitate (PVE30) was the active principle of water extract (PVW). Further activity-oriented separation of PVE30 through salting-out method revealed that the anti-HSV activity of P. vulgaris glycoconjugates (PVG) was more potent than PVE30 and PVW, 2-fold and 4-fold, respectively. UPLC-QTOF-MS/MS, FT-IR and NMR techniques identified PVG as a type of polyphenolic-protein-polysaccharides (PPPs) with an average molecular weight of 41.69 kDa. PVG was composed of dibenzylbutyrolactone lignan units, and rich in galacturonic acid, xylose, rhamnose, rhamnose, arabinose, glucose monosaccharide units, glutamic acid and aspartic acid. Further in vitro antiviral testing confirmed that PVG substantially and stably inhibited acyclovir (ACV) resistant HSV strains; its inhibitory action was even better than the positive control ACV. Overall, our findings support PVG as a potential drug resource for anti-HSV therapy.

10.
PLoS One ; 16(12): e0261388, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34914791

RESUMO

Cardiac hypertrophy is a complex process induced by the activation of multiple signaling pathways. We previously reported that anacardic acid (AA), a histone acetyltransferase (HAT) inhibitor, attenuates phenylephrine (PE)-induced cardiac hypertrophy by downregulating histone H3 acetylation at lysine 9 (H3K9ac). Unfortunately, the related upstream signaling events remained unknown. The mitogen-activated protein kinase (MAPK) pathway is an important regulator of cardiac hypertrophy. In this study, we explored the role of JNK/MAPK signaling pathway in cardiac hypertrophy induced by PE. The mice cardiomyocyte hypertrophy model was successfully established by treating cells with PE in vitro. This study showed that p-JNK directly interacts with HATs (P300 and P300/CBP-associated factor, PCAF) and alters H3K9ac. In addition, both the JNK inhibitor SP600125 and the HAT inhibitor AA attenuated p-JNK overexpression and H3K9ac hyperacetylation by inhibiting P300 and PCAF during PE-induced cardiomyocyte hypertrophy. Moreover, we demonstrated that both SP600125 and AA attenuate the overexpression of cardiac hypertrophy-related genes (MEF2A, ANP, BNP, and ß-MHC), preventing cardiomyocyte hypertrophy and dysfunction. These results revealed a novel mechanism through which AA might protect mice from PE-induced cardiomyocyte hypertrophy. In particular, AA inhibits the effects of JNK signaling on HATs-mediated histone acetylation, and could therefore be used to prevent and treat pathological cardiac hypertrophy.


Assuntos
Ácidos Anacárdicos/farmacologia , Cardiomegalia/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Acetilação , Ácidos Anacárdicos/metabolismo , Animais , Antracenos/farmacologia , Cardiomegalia/metabolismo , China , Modelos Animais de Doenças , Feminino , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenilefrina/efeitos adversos , Fenilefrina/farmacologia , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição de p300-CBP
11.
Zhongguo Zhong Yao Za Zhi ; 46(13): 3337-3348, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34396753

RESUMO

A high performance liquid chromatography( HPLC) method was established for the fast,and precise determination of ten nucleosides in Fritillariae Cirrhosae Bulbus and its counterfeits. Then multivariate statistical analyses,such as clustering analysis,principal component analysis( PCA),and Fisher' s linear discriminant analysis( LDA),were conducted to establish a discriminant function model for an integrated analysis. The results indicated that data acquisition time of a single sample was shortened within 16 min by the HPLC method. In the range of 5-1 000 mg·kg~(-1),the mass concentrations of all nucleosides exhibited good linear relationships with the corresponding peak areas( R2> 0. 999). The spiked recoveries were in the range of 93. 83%-108. 9% with RSDs of0. 12%-1. 3%( n = 5). The limit of quantitation( LOQ) was 0. 98-4. 13 mg·kg~(-1). As revealed by the clustering analysis,Fritillariae Cirrhosae Bulbus and the counterfeits could be discriminated into two clusters based on the content of nucleosides. Fisher's LDA could achieve this discrimination,while PCA dimension reduction failed. The accuracy of the discriminant function model established on the screened characteristic indicators reached 97. 5%. The present study proposed a new identification method of Fritillariae Cirrhosae Bulbus with one-dimensional indicators,which is simple,accurate,and reliable. It can provide a scientific basis for further optimizing the identification techniques for Fritillariae Cirrhosae Bulbus and inspiration for quality control strategy development of Chinese medicinal materials.


Assuntos
Medicamentos de Ervas Chinesas , Fritillaria , Cromatografia Líquida de Alta Pressão , Nucleosídeos , Raízes de Plantas
12.
Mol Med Rep ; 24(3)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34278478

RESUMO

Cardiomyocyte hypertrophy is a compensatory phase of chronic heart failure that is induced by the activation of multiple signaling pathways. The extracellular signal­regulated protein kinase (ERK) signaling pathway is an important regulator of cardiomyocyte hypertrophy. In our previous study, it was demonstrated that phenylephrine (PE)­induced cardiomyocyte hypertrophy involves the hyperacetylation of histone H3K9ac by P300/CBP­associated factor (PCAF). However, the upstream signaling pathway has yet to be fully identified. In the present study, the role of the extracellular signal­regulated protein kinase (ERK)1/2 signaling pathway in PE­induced cardiomyocyte hypertrophy was investigated. The mice cardiomyocyte hypertrophy model was successfully established by treating cells with PE in vitro. The results showed that phospho­(p­)ERK1/2 interacted with PCAF and modified the pattern of histone H3K9ac acetylation. An ERK inhibitor (U0126) and/or a histone acetylase inhibitor (anacardic acid; AA) attenuated the overexpression of phospho­ERK1/2 and H3K9ac hyperacetylation by inhibiting the expression of PCAF in PE­induced cardiomyocyte hypertrophy. Moreover, U0126 and/or AA could attenuate the overexpression of several biomarker genes related to cardiac hypertrophy (myocyte enhancer factor 2C, atrial natriuretic peptide, brain natriuretic peptide and ß­myosin heavy chain) and prevented cardiomyocyte hypertrophy. These results revealed a novel mechanism in that AA protects against PE­induced cardiomyocyte hypertrophy in mice via the ERK1/2 signaling pathway, and by modifying the acetylation of H3K9ac. These findings may assist in the development of novel methods for preventing and treating hypertrophic cardiomyopathy.


Assuntos
Sistema de Sinalização das MAP Quinases/fisiologia , Miócitos Cardíacos/metabolismo , Fenilefrina/farmacologia , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Ácidos Anacárdicos , Animais , Butadienos , Cardiomegalia/metabolismo , Sobrevivência Celular , Modelos Animais de Doenças , Feminino , Histona Acetiltransferases , Histonas/metabolismo , Fatores de Transcrição MEF2 , Masculino , Camundongos , Nitrilas , Transdução de Sinais/efeitos dos fármacos
13.
EBioMedicine ; 69: 103322, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34161886

RESUMO

BACKGROUND: Hereditary hearing loss (HHL) is the most common sensory deficit, which highly afflicts humans. With gene sequencing technology development, more variants will be identified and support genetic diagnoses, which is difficult for human experts to diagnose. This study aims to develop a machine learning-based genetic diagnosis model of HHL-related variants of GJB2, SLC26A4 and MT-RNR1. METHODS: This case-control study included 1898 subjects, among which 1354 were HHL patients and 544 were carriers. Risk assessment models were established based on variants at 144 sites in three genes related to HHL by building six machine learning (ML) models. We compared the ML models with the genetic risk score (GRS) and expert interpretation (EI) to verify the clinical performance. FINDINGS: Among the six ML models, the support vector machine (SVM) showed the best performance. For the prediction of HHL-related gene sites in subjects with variants, the area under the receiver operating characteristic (AUC) of the SVM model was 0.803 (0.680-0.814) in the 10-fold stratified cross-validation and 0.751 (0.635-0.779) in external validation. The predicted results were better than both EI and GRS. Furthermore, 11 sites were identified as the smallest feature set that can be accurately predicted. INTERPRETATION: The developed SVM model has great potential to be an efficient and effective tool for HHL prediction when high throughput sequencing data are available. FUNDING: This study was supported by the National Key Research and Development Program (2017YFC1001800).


Assuntos
Conexina 26/genética , Diagnóstico por Computador/métodos , Testes Genéticos/métodos , Perda Auditiva Neurossensorial/genética , RNA Ribossômico/genética , Transportadores de Sulfato/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Lactente , Masculino , Mutação , Máquina de Vetores de Suporte
14.
Genome ; 64(6): 655-664, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33797299

RESUMO

Hibiscus exhibits high variation in chromosome number both within and among species. The Hibiscus mutabilis L. karyotype was analyzed in detail using fluorescence in situ hybridization (FISH) with oligonucleotide probes for (AG3T3)3 and 5S rDNA, which were tested here for the first time. In total, 90 chromosomes were counted in prometaphase and metaphase, and all exhibited similarly intense (AG3T3)3 signals at both ends. (AG3T3)3 showed little variation and thus did not allow discrimination among H. mutabilis chromosomes, but its location at both ends confirmed the integrity of each chromosome, thus contributing to accurate counting of the numerous, small chromosomes. Oligo-5S rDNA marked the proximal/distal regions of six chromosomes: weak signals on chromosomes 7 and 8, slightly stronger signals on chromosomes 15 and 16, and very strong signals on chromosomes 17 and 18. Therefore, 5S rDNA could assist in chromosome identification in H. mutabilis. Metaphase chromosome lengths ranged from 3.00 to 1.18 µm, indicating small chromosomes. The ratios of longest to shortest chromosome length in prometaphase and metaphase were 2.58 and 2.54, respectively, indicating karyotype asymmetry in H. mutabilis. These results provide an exact chromosome number and a physical map, which will be useful for genome assembly and contribute to molecular cytogenetics in the genus Hibiscus.


Assuntos
DNA Ribossômico/genética , Hibiscus/genética , Hibridização in Situ Fluorescente/métodos , Sondas de Oligonucleotídeos/genética , Mapeamento Cromossômico , Cromossomos de Plantas , DNA de Plantas , Cariótipo , Cariotipagem , Meiose/genética , Metáfase , RNA Ribossômico 5S/genética
15.
Taiwan J Obstet Gynecol ; 60(2): 299-304, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33678331

RESUMO

OBJECTIVE: The present study aimed to determine the diagnostic value of prenatal chromosomal microarray analysis (CMA) for fetuses with several indications of being at high risk for various conditions. MATERIALS AND METHODS: This retrospective analysis included 1256 pregnancies that were prenatally evaluated due to high-risk indications using invasive CMA. The indications for invasive prenatal diagnosis mainly included ultrasound anomalies, high-risk for maternal serum screening (MSS), high-risk for non-invasive prenatal tests (NIPT), family history of genetic disorders or birth defects, and advanced maternal age (AMA). The rate of clinically significant genomic imbalances between the different groups was compared. RESULTS: The overall prenatal diagnostic yield was 98 (7.8%) of 1256 pregnancies. Clinically significant genomic aberrations were identified in 2 (1.5%) of 132 patients with non-structural ultrasound anomalies, 36 (12.7%) of 283 with structural ultrasound anomalies, 2 (4.5%) of 44 at high-risk for MSS, 38 (26.6%) of 143 at high-risk for NIPT, 11 (3.8%) of 288 with a family history, and 7 (2.1%) of 328 with AMA. Submicroscopic findings were identified in 29 fetuses, 19 of whom showed structural ultrasound anomalies. CONCLUSION: The diagnostic yields of CMA for pregnancies with different indications greatly varied. CMA could serve as a first-tier test for structural anomalies, especially multiple anomalies, craniofacial dysplasia, urinary defects, and cardiac dysplasia. Our results have important implications for genetic counseling.


Assuntos
Aberrações Cromossômicas/estatística & dados numéricos , Transtornos Cromossômicos/diagnóstico , Análise em Microsséries/estatística & dados numéricos , Adulto , China , Aberrações Cromossômicas/embriologia , Transtornos Cromossômicos/embriologia , Contraindicações de Procedimentos , Feminino , Desenvolvimento Fetal/genética , Humanos , Testes para Triagem do Soro Materno/efeitos adversos , Análise em Microsséries/métodos , Gravidez , Estudos Retrospectivos , Medição de Risco , Ultrassonografia Pré-Natal/estatística & dados numéricos
16.
Life Sci ; 264: 118727, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33221345

RESUMO

Hypertension is one of the most prevalent diseases worldwide. Increased synthesis of the vasoconstrictor peptide endothelin 1 (encoded by EDN1) might be responsible for high blood pressure. The present study further confirmed the abnormal EDN1 upregulation within adipose tissue-derived stromal cells (ADSCs) derived from morbidly obese subjects. The overexpression of EDN1 in ADSCs derived from non-obese subjects significantly promoted the proliferation and migration of HUVECs and tube formation by human umbilical vein endothelial cell (HUVEC). Transcription factor NR4A3 was positively correlated with EDN1, binding to EDN1 promoter region to upregulate EDN1 expression. Similarly, the overexpression of NR4A3 in ADSCs derived from non-obese subjects significantly promoted the proliferation and migration of HUVECs and tube formation by HUVECs, as well as EDN1 protein levels in ADSCs. However, the effects of NR4A3 overexpression on EDN1 protein levels in ADSCs and the proliferation and migration of HUVECs and tube formation by HUVECs were significantly reversed by EDN1 silencing in ADSCs. In conclusion, NR4A3 is abnormally upregulated in ADSCs derived from morbidly obese subjects; NR4A3 could promote HUVEC angiogenesis through binding to EDN1 promoter and upregulating EDN1 expression.


Assuntos
Tecido Adiposo/patologia , Proteínas de Ligação a DNA/metabolismo , Endotelina-1/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Regulação para Cima/genética , Sobrevivência Celular , Endotelina-1/metabolismo , Humanos , Neovascularização Fisiológica/genética , Obesidade Mórbida/genética , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Células Estromais/metabolismo
17.
Orphanet J Rare Dis ; 15(1): 335, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33256793

RESUMO

BACKGROUND: Phelan-McDermid syndrome (PMS) or 22q13 deletion syndrome is a rare developmental disorder characterized by hypotonia, developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD) and dysmorphic features. Most cases are caused by 22q13 deletions encompassing many genes including SHANK3. Phenotype comparisons between patients with SHANK3 mutations (or deletions only disrupt SHANK3) and 22q13 deletions encompassing more than SHANK3 gene are lacking. METHODS: A total of 29 Mainland China patients were clinically and genetically evaluated. Data were obtained from medical record review and a standardized medical history questionnaire, and dysmorphology evaluation was conducted via photographic evaluation. We analyzed 22q13 deletions and SHANK3 small mutations and performed genotype-phenotype analysis to determine whether neurological features and other important clinical features are responsible for haploinsufficiency of SHANK3. RESULTS: Nineteen patients with 22q13.3 deletions ranging in size from 34 kb to 8.7 Mb, one patient with terminal deletions and duplications, and nine patients with SHANK3 mutations were included. All mutations would cause loss-of function effect and six novel heterozygous variants, c.3838_3839insGG, c.3088delC, c.3526G > T, c.3372dupC, c.3120delC and c.3942delC, were firstly reported. Besides, we demonstrated speech delay (100%), DD/ID (88%), ASD (80%), hypotonia (83%) and hyperactivity (83%) were prominent clinical features. Finally, 100% of cases with monogenic SHANK3 deletion had hypotonia and there was no significant difference between loss of SHANK3 alone and deletions encompassing more than SHANK3 gene in the prevalence of hypotonia, DD/ID, ASD, increased pain tolerance, gait abnormalities, impulsiveness, repetitive behaviors, regression and nonstop crying which were high in loss of SHANK3 alone group. CONCLUSIONS: This is the first work describing a cohort of Mainland China patients broaden the clinical and molecular spectrum of PMS. Our findings support the effect of 22q13 deletions and SHANK3 point mutations on language impairment and several clinical manifestations, such as DD/ID. We also demonstrated SHANK3 haploinsufficiency was a major contributor to the neurological phenotypes of PMS and also responsible for other important phenotypes such as hypotonia, increased pain tolerance, impulsiveness, repetitive behaviors, regression and nonstop crying.


Assuntos
Transtorno do Espectro Autista , Transtornos Cromossômicos , Transtorno do Espectro Autista/genética , China , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22/genética , Estudos de Associação Genética , Haploinsuficiência/genética , Humanos , Proteínas do Tecido Nervoso/genética , Fenótipo
18.
Aging (Albany NY) ; 13(1): 894-909, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-33260155

RESUMO

Glioma is a primary, malignant, and aggressive brain tumor in adults. To develop new therapeutic strategies for glioma, we must determine its underlying mechanisms. In the present study, we aimed to investigate the potential role of miR-1272-ADAM9-CDCP1 signaling in the progression of glioma. We found that ectopic expression of miR-1272 produced significant inhibitory effects on cell proliferation and migration and was associated with cell cycle G0/G1 arrest in A172 and SHG44 glioma cells. Using the luciferase reporter assay, we identified ADAM9 as a target of miR-1272. The expression of ADAM9 was markedly decreased or increased after overexpression or inhibition, respectively, of miR-1272 in glioma cells. Moreover, overexpression of ADAM9 reversed the inhibitory effects of miR-1272 on glioma cell progression. Furthermore, CDCP1 served as a potential downstream molecule of miR-1272/ADAM9 signaling in glioma and promoted the proliferation and migration of glioma. Results derived from clinical samples and online databases confirmed correlations between the expression of ADAM9 and CDCP1 and both the severity and prognosis of glioma. In conclusion, these results suggest that miR-1272 and CDCP1 may act as novel regulators in glioma. The miR-1272/ADAM9/CDCP1 pathway may serve as a potential candidate pathway for the prevention of glioma.


Assuntos
Proteínas ADAM/genética , Antígenos de Neoplasias/genética , Neoplasias Encefálicas/genética , Moléculas de Adesão Celular/genética , Glioma/genética , Proteínas de Membrana/genética , MicroRNAs/metabolismo , Proteínas ADAM/metabolismo , Antígenos de Neoplasias/metabolismo , Astrocitoma/genética , Astrocitoma/metabolismo , Astrocitoma/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioma/metabolismo , Glioma/patologia , Humanos , Proteínas de Membrana/metabolismo , MicroRNAs/genética , Transdução de Sinais
19.
Ann Transl Med ; 8(17): 1058, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33145277

RESUMO

BACKGROUND: Newborn screening (NBS) in China is mainly aimed at detecting biochemical levels of metabolites in the blood, which may generate false-positive/negative results. Current biochemical NBS includes tandem mass spectrometry (MS/MS) screening for metabolites as well as phenylalanine (Phe), thyroid-stimulating hormone (TSH), 17-α-hydroxyprogesterone (17-OHP), and glucose-6-phosphate dehydrogenase (G6PD) test. This study intended to explore whether next-generation sequencing (NGS) for dried blood spots combining with biochemical screening could improve the current screening efficiency and to investigate the carrier frequencies of mutations in causative genes related to amino acid metabolism, organic acid metabolism, and fatty acid oxidation in this cohort. METHODS: We designed a panel of 573 genes related to severe inherited disorders and performed NGS in 1,127 individuals who had undergone biochemical NBS. The NGS screening results of neonates were used to compare with the biochemical results. RESULTS: NGS screening results revealed that all the four newborns with abnormal G6PD values carried hemizygous G6PD mutations, which were consistent with the decreased G6PD enzymatic activity. The NGS results revealed an individual with compound heterozygous mutations of SLC22A5, who was biochemically negative in 2016. The MS/MS screening results in 2019 showed free carnitine deficiency, which was consistent with the genetic findings. The top five genes with the highest carrier frequencies of mutations in these newborns were PAH (1:56, 1.79%), ETFDH (1:81, 1.23%), MMACHC (1:87, 1.15%), SLC25A13 (1:102, 0.98%), and GCDH (1:125, 0.80%). CONCLUSIONS: Our study highlighted that combining NGS screening with biochemical screening could improve the current NBS efficiency. This is the first study to investigate carrier frequencies of mutations in 77 genes causing inherited metabolic diseases (IMDs) in China.

20.
Regul Toxicol Pharmacol ; 118: 104811, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33122045

RESUMO

Eucommia ulmoides Oliver is native to China and frequently used in traditional Chinese medicine formulations. However, studies show that Eucommia ulmoides extract (EUE) are potentially genotoxic and nephrotoxic. To evaluate its safety, the Ames test, bone marrow micronucleus assay and chromosomal aberration assay, along with acute (24 h) and sub-chronic (13 weeks) toxicity were conducted. EUE was non-genotoxic within the dose ranges of 0.0352-22 mg/plate (raw plant equivalent as below), 22-88 g/kg body weight and 2-20 mg/mL. The maximum tolerated dose of EUE was not less than 168 g/kg, which is 1260 times that of clinical doses in human adults. Long-term (13 weeks) administration led to dose-dependent increase in nephrotoxicity-related indices, and pathological changes in renal tissues. These changes were alleviated 5 weeks after ceasing the low dosage of 11.2 g/kg but persisted at the high dosage of 56 g/kg. Conclusively, EUE is non-genotoxic, and do not result in acute toxicity. However, long-term and high-dose administration can lead to partly reversible nephrotoxicity.


Assuntos
Medicamentos de Ervas Chinesas/toxicidade , Eucommiaceae/toxicidade , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Extratos Vegetais/toxicidade , Testes de Toxicidade , Animais , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Eucommiaceae/química , Feminino , Rim/patologia , Nefropatias/patologia , Dose Letal Mediana , Masculino , Dose Máxima Tolerável , Camundongos , Testes para Micronúcleos , Extratos Vegetais/isolamento & purificação , Ratos Wistar , Medição de Risco , Fatores de Tempo , Testes de Toxicidade Subaguda
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