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1.
Mil Med Res ; 8(1): 57, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34724985

RESUMO

BACKGROUND: Mitochondria have been shown to play vital roles during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) development. Currently, it is unclear whether mitochondrial DNA (mtDNA) variants, which define mtDNA haplogroups and determine oxidative phosphorylation performance and reactive oxygen species production, are associated with COVID-19 risk. METHODS: A population-based case-control study was conducted to compare the distribution of mtDNA variations defining mtDNA haplogroups between healthy controls (n = 615) and COVID-19 patients (n = 536). COVID-19 patients were diagnosed based on molecular diagnostics of the viral genome by qPCR and chest X-ray or computed tomography scanning. The exclusion criteria for the healthy controls were any history of disease in the month preceding the study assessment. MtDNA variants defining mtDNA haplogroups were identified by PCR-RFLPs and HVS-I sequencing and determined based on mtDNA phylogenetic analysis using Mitomap Phylogeny. Student's t-test was used for continuous variables, and Pearson's chi-squared test or Fisher's exact test was used for categorical variables. To assess the independent effect of each mtDNA variant defining mtDNA haplogroups, multivariate logistic regression analyses were performed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) with adjustments for possible confounding factors of age, sex, smoking and diseases (including cardiopulmonary diseases, diabetes, obesity and hypertension) as determined through clinical and radiographic examinations. RESULTS: Multivariate logistic regression analyses revealed that the most common investigated mtDNA variations (> 10% in the control population) at C5178a (in NADH dehydrogenase subunit 2 gene, ND2) and A249d (in the displacement loop region, D-loop)/T6392C (in cytochrome c oxidase I gene, CO1)/G10310A (in ND3) were associated with a reduced risk of severe COVID-19 (OR = 0.590, 95% CI 0.428-0.814, P = 0.001; and OR = 0.654, 95% CI 0.457-0.936, P = 0.020, respectively), while A4833G (ND2), A4715G (ND2), T3394C (ND1) and G5417A (ND2)/C16257a (D-loop)/C16261T (D-loop) were related to an increased risk of severe COVID-19 (OR = 2.336, 95% CI 1.179-4.608, P = 0.015; OR = 2.033, 95% CI 1.242-3.322, P = 0.005; OR = 3.040, 95% CI 1.522-6.061, P = 0.002; and OR = 2.890, 95% CI 1.199-6.993, P = 0.018, respectively). CONCLUSIONS: This is the first study to explore the association of mtDNA variants with individual's risk of developing severe COVID-19. Based on the case-control study, we concluded that the common mtDNA variants at C5178a and A249d/T6392C/G10310A might contribute to an individual's resistance to developing severe COVID-19, whereas A4833G, A4715G, T3394C and G5417A/C16257a/C16261T might increase an individual's risk of developing severe COVID-19.

2.
Acta Pharmacol Sin ; 42(7): 1080-1089, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32939036

RESUMO

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by a mutation in the gene encoding the dystrophin protein. Catalpol is an iridoid glycoside found in Chinese herbs with anti-inflammatory, anti-oxidant, anti-apoptotic, and hypoglycemic activities that can protect against muscle wasting. In the present study we investigated the effects of catalpol on DMD. Aged Dystrophin-deficient (mdx) mice (12 months old) were treated with catalpol (100, 200 mg·kg-1·d-1, ig) for 6 weeks. At the end of the experiment, the mice were sacrificed, and gastrocnemius (GAS), tibialis anterior (TA), extensor digitorum longus (EDL), soleus (SOL) muscles were collected. We found that catalpol administration dose-dependently increased stride length and decreased stride width in Gait test. Wire grip test showed that the time of wire grip and grip strength were increased. We found that catalpol administration dose-dependently alleviated skeletal muscle damage, evidenced by reduced plasma CK and LDH activity as well as increased the weight of skeletal muscles. Catalpol administration had no effect on dystrophin expression, but exerted anti-inflammatory effects. Furthermore, catalpol administration dose-dependently decreased tibialis anterior (TA) muscle fibrosis, and inhibited the expression of TGF-ß1, TAK1 and α-SMA. In primary myoblasts from mdx mice, knockdown of TAK1 abolished the inhibitory effects of catalpol on the expression levels of TGF-ß1 and α-SMA. In conclusion, catalpol can restore skeletal muscle strength and alleviate skeletal muscle damage in aged mdx mice, thus may provide a novel therapy for DMD. Catalpol attenuates muscle fibrosis by inhibiting the TGF-ß1/TAK1 signaling pathway.


Assuntos
Glucosídeos Iridoides/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/patologia , Força da Mão/fisiologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/patologia , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia , Fator de Crescimento Transformador beta1/metabolismo
3.
Zhongguo Dang Dai Er Ke Za Zhi ; 14(7): 533-5, 2012 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-22809609

RESUMO

OBJECTIVE: To study the value of high-frequency ultrasound in the diagnosis of duchenne muscular dystrophy diseases (DMD) in children. METHODS: Eight children with DMD were enrolled as DMD group and 10 healthy children as the control group. The echogenicity of the rectus femoris muscle and the gap between the gastrocnemius and soleus muscles in the two groups were detected by high-frequency ultrasound. RESULTS: Compared with the control group, rectus femoris and gastrocnemius muscles in the DMD group showed increased echogenicity and their muscle fibers were arranged irregularly, and the gap between the gastrocnemius and soleus muscles became wilder (P<0.01). CONCLUSIONS: High-frequency ultrasound is valuable in the diagnosis of DMD.


Assuntos
Distrofia Muscular de Duchenne/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Ultrassonografia
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 28(6): 699-704, 2011 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-22161109

RESUMO

OBJECTIVE: To clarify advantages and disadvantages of using multiplex ligation-dependent probe amplification (MLPA) for detecting exonic deletions and duplications of the Dystrophin gene, and to explore the appropriate management for single-exon abnormality detected by MLPA. METHODS: MLPA were performed to detect exonic copy number changes in 70 Duchenne/Becker muscular dystrophy (DMD/BMD) patients diagnosed by clinical and histological findings. PCR, DNA sequencing and real-time PCR were applied to the samples in which MLPA indicated single-exon deletion or duplication. RESULTS: Of all 70 patients, MLPA detected exonic deletions in 42 (60%), including 12 with single-exon deletion and one with ambiguous single-exon deletion. Exon duplications were found in 7 patients (10%), among which two were single-exon duplication. 21 patients showed normal results (30%). For the 12 patients with single-exon deletion, MLPA results were confirmed by PCR in 11. In one patient, a deletion of two nucleotides (c.4470-4471delAA) was found by sequencing. A novel two-nucleotide deletion (c.4746-4747delCT) was identified in the patient with the ambiguous single-exon deletion. For the two patients showed single-exon duplication, MLPA results were confirmed by real-time PCR. CONCLUSION: MLPA should be the first choice in detecting Dystrophin gene exon deletions and duplications. Single-exon deletion/duplication resulted from MLPA should be further evaluated by other methods.


Assuntos
Variações do Número de Cópias de DNA , Distrofina/genética , Éxons , Técnicas de Amplificação de Ácido Nucleico/métodos , Sequência de Bases , Análise Mutacional de DNA , Deleção de Genes , Duplicação Gênica , Humanos
5.
Zhongguo Dang Dai Er Ke Za Zhi ; 13(4): 288-91, 2011 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-21507296

RESUMO

OBJECTIVE: Immunohistochemistry using antibodies to dystrophin is the pathological basis for the differential diagnosis of Duchenne and Becker muscular dystrophy (DMD and BMD). In rare cases, however, labelling dystrophin on sarcolemma is equivocal and similar to that observed in controls. This makes the diagnosis of BMD difficult. This study aimed to explore the diagnostic value of neuronal nitric oxide synthase (nNOS) antibody for clinically suspected BMD. METHODS: Immunohistochemical staining was performed on muscle specimens of 5 cases of BMD with positive expression of Dys-C (3 cases had a confirmed diagnosis of BMD, 2 cases were clinically suspected as BMD) by using dystrophin and nNOS antibodies. Normal muscle specimens from the children with fracture were used as controls. RESULTS: Compared with the controls, the expression of Dys-R, Dys-C and Dys-N was markedly reduced and nNOS was not expressed on sarcolemma in the three cases of definitely diagnosed BMD. The two cases of clinically suspected as BMD had a complete absence of sarcolemmal nNOS, even if had a similar expression of dystrophin on sarcolemma to the controls. CONCLUSIONS: nNOS antibody staining can be used for a definite diagnosis in children with clinically suspected BMD who have the almost normal expression of dystrophin.


Assuntos
Óxido Nítrico Sintase Tipo I/análise , Criança , Pré-Escolar , Distrofina/análise , Distrofina/química , Humanos , Imuno-Histoquímica , Lactente , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/metabolismo
6.
Zhonghua Er Ke Za Zhi ; 48(6): 425-30, 2010 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-21055263

RESUMO

OBJECTIVE: Spinal muscular atrophy (SMA), characterized by degeneration of the anterior horn cells in the spinal cord and symmetric proximal muscle weakness, is the most common autosomal recessive neuromuscular disease in infants and children. In Caucasian population, about 95% of clinically typical patients lack both copies of the telomeric survival motor neuron gene (SMN 1). However, the detection rate of the homozygous absence in Chinese patients is still controversial, which may lead to reduced confidence in the SMA genetic testing in clinical practice. The purpose of the current study was to determine the frequency of homozygous deletions of SMN 1 in Chinese patients, to evaluate the significance of the SMN 1 homozygous deletion assay in clinical applications, and the impact of the clinical re-visit followed by the genetic testing. METHODS: Totally 85 patients initially suspected of SMA were referred for SMA genetic testing. A polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) assay was used to detect the homozygous absence of SMN 1. Clinical re-visit was performed by the pediatric neurology specialists according to the international SMA diagnostic criteria, and histological examinations were carried out when they were necessary. RESULTS: Absence of both copies of SMN 1 exon 7 were found in 57 (67%) of the 85 patients, and 28 patients (33%) had at least one copy. For the 28 patients with negative results, 19 were followed up by the pediatric neurologists. The clinical diagnosis of SMA could be excluded in 15 patients, but retained in the other 4 patients after the clinical re-evaluation and histological examinations. Thus, approximately 95% of the patients with clinically typical SMA in our cohort lacked both copies of SMN 1. Homozygous deletions of SMN 1 were detected in 96% (22/23), 93% (28/30) and 100% (7/7) of the patients with SMA type I, type II and type III, respectively. There was no significant difference in the deletion frequency among the subtypes. CONCLUSIONS: The frequency of homozygous deletions of SMN 1 in this series of Chinese SMA patients was about 95%, which is similar to that reported in Caucasian population. The genetic test of homozygous deletions of SMN 1 should be considered as the first line test for the Chinese patients suspected of SMA. The clinical re-visit and re-evaluation which is essential in clinical diagnosis, genetic counseling and medical management, should be routinely performed after the genetic testing.


Assuntos
Deleção de Genes , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , /genética , Criança , Pré-Escolar , Éxons , Feminino , Testes Genéticos , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino
8.
Lab Invest ; 89(9): 1043-52, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19564844

RESUMO

Liver regeneration is a very complex and well-orchestrated process associated with signaling cascades involving cytokines, growth factors, and metabolic pathways. Adiponectin is an adipocytokine secreted by mature adipocytes, and its receptors are widely distributed in many tissues, including the liver. Adiponectin has direct actions in the liver with prominent roles to improve hepatic insulin sensitivity, increase fatty acid oxidation, and decrease inflammation. To test the hypothesis that adiponectin is required for normal progress of liver regeneration, 2/3 partial hepatectomy (PH) was performed on wild-type and adiponectin-null mice. Compared to wild-type mice, adiponectin-null mice displayed decreased liver mass regrowth, impeded hepatocyte proliferation, and increased hepatic lipid accumulation. Gene expression analysis revealed that adiponectin regulated the gene transcription related to lipid metabolism. Furthermore, the suppressed hepatocyte proliferation was accompanied with reduced signal transducer and activator of transcription protein 3 (STAT3) activity and enhanced suppressor of cytokine signaling 3 (Socs3) transcription. In conclusion, adiponectin-null mice exhibit impaired liver regeneration and increased hepatic steatosis. Increased expression of Socs3 and subsequently reduced activation of STAT3 in adiponectin-null mice may contribute to the alteration of the liver regeneration capability and hepatic lipid metabolism after PH.


Assuntos
Adiponectina/deficiência , Regeneração Hepática/fisiologia , Fator de Transcrição STAT3/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Animais , Proliferação de Células , Modelos Animais de Doenças , Hepatectomia , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fígado/patologia , Fígado/cirurgia , Masculino , Camundongos , Camundongos Knockout , Fosforilação , Fator de Transcrição STAT3/genética , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Transcrição Genética , Ativação Transcricional
9.
Cell Res ; 17(10): 858-68, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17893708

RESUMO

RIG-I (retinoid acid-inducible gene-I), a putative RNA helicase with a cytoplasmic caspase-recruitment domain (CARD), was identified as a pattern-recognition receptor (PRR) that mediates antiviral immunity by inducing type I interferon production. To further study the biological function of RIG-I, we generated Rig-I(-/-) mice through homologous recombination, taking a different strategy to the previously reported strategy. Our Rig-I(-/-) mice are viable and fertile. Histological analysis shows that Rig-I(-/-) mice develop a colitis-like phenotype and increased susceptibility to dextran sulfate sodium-induced colitis. Accordingly, the size and number of Peyer's patches dramatically decreased in mutant mice. The peripheral T-cell subsets in mutant mice are characterized by an increase in effector T cells and a decrease in naive T cells, indicating an important role for Rig-I in the regulation of T-cell activation. It was further found that Rig-I deficiency leads to the downregulation of G protein alpha i2 subunit (G alpha i2) in various tissues, including T and B lymphocytes. By contrast, upregulation of Rig-I in NB4 cells that are treated with ATRA is accompanied by elevated G alpha i2 expression. Moreover, G alpha i2 promoter activity is increased in co-transfected NIH3T3 cells in a Rig-I dose-dependent manner. All these findings suggest that Rig-I has crucial roles in the regulation of G alpha i2 expression and T-cell activation. The development of colitis may be, at least in part, associated with downregulation of G alpha i2 and disturbed T-cell homeostasis.


Assuntos
Colite/genética , RNA Helicases DEAD-box/genética , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/genética , Animais , Apoptose/genética , Apoptose/fisiologia , Northern Blotting , Western Blotting , Células Cultivadas , Colite/induzido quimicamente , Colite/patologia , Proteína DEAD-box 58 , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/fisiologia , Sulfato de Dextrana/toxicidade , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/metabolismo , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/fisiologia , Camundongos , Camundongos Knockout , Células NIH 3T3 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/citologia , Linfócitos T/metabolismo
10.
Blood ; 110(3): 870-6, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17431131

RESUMO

Palladin was originally found up-regulated with NB4 cell differentiation induced by all-trans retinoic acid. Disruption of palladin results in neural tube closure defects, liver herniation, and embryonic lethality. Here we further report that Palld(-/-) embryos exhibit a significant defect in erythropoiesis characterized by a dramatic reduction in definitive erythrocytes derived from fetal liver but not primitive erythrocytes from yolk sac. The reduction of erythrocytes is accompanied by increased apoptosis of erythroblasts and partial blockage of erythroid differentiation. However, colony-forming assay shows no differences between wild-type (wt) and mutant fetal liver or yolk sac in the number and size of colonies tested. In addition, Palld(-/-) fetal liver cells can reconstitute hematopoiesis in lethally irradiated mice. These data strongly suggest that deficient erythropoiesis in Palld(-/-) fetal liver is mainly due to a compromised erythropoietic microenvironment. As expected, erythroblastic island in Palld(-/-) fetal liver was found disorganized. Palld(-/-) fetal liver cells fail to form erythroblastic island in vitro. Interestingly, wt macrophages can form such units with either wt or mutant erythroblasts, while mutant macrophages lose their ability to bind wt or mutant erythroblasts. These data demonstrate that palladin is crucial for definitive erythropoiesis and erythroblastic island formation and, especially, required for normal function of macrophages in fetal liver.


Assuntos
Proteínas do Citoesqueleto/deficiência , Eritroblastos/metabolismo , Eritropoese/genética , Fígado/embriologia , Fosfoproteínas/deficiência , Animais , Apoptose/genética , Diferenciação Celular/genética , Ensaio de Unidades Formadoras de Colônias , Perda do Embrião/genética , Perda do Embrião/metabolismo , Perda do Embrião/patologia , Eritroblastos/patologia , Feto/metabolismo , Feto/patologia , Hematopoese Extramedular/genética , Fígado/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Defeitos do Tubo Neural/patologia , Saco Vitelino/embriologia , Saco Vitelino/metabolismo
11.
Zhongguo Zhong Yao Za Zhi ; 31(23): 1971-5, 2006 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-17348193

RESUMO

OBJECTIVE: The metabolic character of tetramethylpyrazine (TMPz) in rat liver microsomes was studied in vitro and in vivo to identify which isoforms of cytochrome P450 were responsible for TMPz metabolism in rats, offer the theoretical foundation for the fact that it is rational to use medicine in clinic. METHOD: Set up UV- HPLC method of TMPz, determine concentration of TMPz and its formation in rat plasma and liver microsomes incubation solution, analyze the correlation between TMPz's metabolic eliminate rate and each inducer. Erythromycin( ERY) N-demethylase activity of each sample in rat liver microsomes was measured using N-demethylation reaction of ERY as probe. The correlation between the rate of TMPz metabolite formation and the demethylase activity was analysed. After the SD rats who had been treated with inducer, inhibitor, or untreated, received administration of TMPz in vein, the plasma concentration of TMPz were determined by HPLC. Pharmacokinetic parameters of TMPz were computed and compared. RESULT: The disppearing rate of TMPz in the incubation solutions of the rats liver microsomes, which treated with DEX, were markedly quicker than that of control group (P < 0. 01) , while no obvious difference between P-NF group or PB and control group was observed (P > 0. 05). The activity of ERY-N-demethylase in DEX-induced group was corespondingly enhanced, was much higer than that in control group. The correlation between the rate of TMPz metabolic product formation and the activity of N-demethylase was significant. After using Ket, the CYP3A inhibitor, the metabolism of TMPz could be significantly inhibited the metabolism of TMPz in rat liver microsomes. In vivo, CL( s) were larger than that of the control group,t,/2 were smaller than the control group in DEX group; By contrary, CL(s) was smaller than the control group,t1/2 was larger than the control group in Ket group. CONCLUSION: Results suggest that CYP3A plays a major role in TMPz metabolism in rats, TMPz lie in the possibility of Interaction among the medicines between TMPz and CYP3A inducers or inhibitors when they are used in clinic.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Microssomos Hepáticos/metabolismo , Pirazinas/farmacocinética , Animais , Inibidores do Citocromo P-450 CYP3A , Dexametasona/farmacologia , Cetoconazol/farmacologia , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Pirazinas/sangue , Pirazinas/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Vasodilatadores/sangue , Vasodilatadores/metabolismo , Vasodilatadores/farmacocinética
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