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Signal Transduct Target Ther ; 6(1): 414, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34873151


Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 µM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.

Antivirais/administração & dosagem , Azidas/administração & dosagem , COVID-19/tratamento farmacológico , Desoxicitidina/análogos & derivados , SARS-CoV-2/metabolismo , Timo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Coronavirus Humano OC43/metabolismo , Desoxicitidina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Timo/metabolismo , Timo/virologia
Animal Model Exp Med ; 1(3): 203-211, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30891566


Background: There are few reports on the comparative medical characteristics of type 2 diabetes models in late stage. An analysis of comparative medical characteristics of Zucker diabetic fatty type 2 diabetes mellitus (ZDF-T2DM) rats during the course of development to late stage disease was performed. Methods: In this study, ZDF rats were fed with high-sugar and high-fat diets to raise the fasting blood glucose, and develop of type 2 diabetes. At the late stage of T2DM, the preliminary comparative medical characteristics of the T2DM model were analyzed through the detection of clinical indicators, histopathology, related cytokine levels, and insulin-related signaling molecule expression levels. Results: In the T2DM group, the fasting blood glucose was higher than 6.8 mmol/L, the serum insulin, leptin, and adiponectin levels were significantly decreased, and glucose intolerance and insulin resistance were measured as clinical indicators. Regarding pathological indicators, a large number of pancreatic islet cells showed the reduction of insulin secretion, resulting in damaged glycogen synthesis and liver steatosis. At the molecular level, the insulin signal transduction pathway was inhibited by decreasing the insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), phosphatidylinositol 3 kinase (PI3K), and glycogen synthesis kinase 3ß (GSK-3ß) expression levels. Conclusion: The results show that the ZDF/T2DM rats have typical clinical, histopathological, and molecular characteristics of human T2DM and thus can be used as an effective model for T2DM drug development and treatment of advanced T2DM.

Exp Clin Endocrinol Diabetes ; 123(1): 19-26, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25314651


To build an ideal animal model for studying the mechanism of occurrence, developing and treating of diabetes become a more important issue, facing with the fact that the big threat of diabetes to human health has been worsen. First, we used the normal control diets or the high-fat/high-sucrose diets to feed the adult rhesus monkeys and the macaques induced by the high-fat/high-sucrose diets in the high-fat/high-sucrose group and the type 2 diabetes mellitus (T2DM) group developed the hyperglycemia, hyperinsulinemia at 6 months in accordance with the precious researches that reported that minipigs, rats and mice could develop hyperglycemia, hyperinsulinemia, hyperlipidemia and obesity after being induced with high-fat/high-carbohydrate diets. Second, the rhesus monkeys in T2DM group were injected STZ at a low dosage of 35 mg/kg BW to induce glucose persistent elevation which maintained pretty well after 12 months. Third, we took the assay of glucose tolerance test and insulin resistance index, assessed the changing tendency of serum resistin and analysed the pathological characteristics of the tissues like pancreas and liver by staining in different ways. The results indicate the rhesus monkeys in T2DM group have lots of clinical features of T2DM. The experimental non-genetic T2DM rhesus monkeys model not only contribute to simulating of clinical manifestations and pathological features of human T2DM, but also may be a good kind of model for research on the treatment of T2DM and for new drugs evaluation.

Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Sacarose/efeitos adversos , Edulcorantes/efeitos adversos , Animais , Glicemia/metabolismo , Carboidratos da Dieta/farmacologia , Gorduras na Dieta/farmacologia , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Ratos , Sacarose/farmacologia , Edulcorantes/farmacologia
Curr Stem Cell Res Ther ; 10(2): 109-20, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25300822


Bone marrow-derived mesenchymal stem cells hold great potential for cytotherapeutics of neurodegenerative disorders, including Parkinson's disease. The neurotrophic factor neurturin can rescue dopaminergic neurons damaged during the disease process. Lmx1α can promote mesencephalic dopaminergic differentiation during embryogenesis. In this study, we tested a cytotherapeutic strategy combining NTN/Lmx1α gene therapy and cell transplantation to ameliorate disease progression in hemiparkinsonian rhesus. Rhesus BMSCs were prepared for autologous grafting by transfection with recombinant adenoviral vectors expressing secreted NTN and Lmx1α,and cultured in the presence of induce factors, particularly the Lmx1α regulatory factor sonic hedgehog, to guide dopaminergic differentiation. These induced rh-BMSCs exhibited gene/protein expression phenotypes resembling nigral dopaminergic neurons. They survived and retained dopaminergic function following stereotaxic injection into the MPTP-lesioned right-side substantia nigra as indicated by SPECT measurement of DAT activity. Injected cells preserved and supplemented the remaining endogenous population of dopamine neurons (TH-positive cell ipsilateral/contralateral ratio was 56.81% ± 7.28% vs. 3.86%±1.22% in vehicle-injected controls; p<0.05). Cell injection also partially restored motor function and reduce apomorphine-evoked rotation (p<0.05). Moreover, function recovery occurred earlier than in previous studies on injected BMSCs. Our findings demonstrate a promising strategy for restoration of PD-associated motor dysfunction by transplantation of autologous BMSCs overexpressing NTN/Lmx1α.

Neurônios Dopaminérgicos/fisiologia , Proteínas com Homeodomínio LIM/biossíntese , Células-Tronco Mesenquimais/fisiologia , Neurogênese , Neurturina/biossíntese , Doença de Parkinson Secundária/terapia , Fatores de Transcrição/biossíntese , Animais , Embrião de Galinha , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Expressão Gênica , Humanos , Proteínas com Homeodomínio LIM/genética , Macaca mulatta , Masculino , Transplante de Células-Tronco Mesenquimais , Neurturina/genética , Doença de Parkinson Secundária/fisiopatologia , Fatores de Transcrição/genética , Transplante Autólogo
Am J Primatol ; 76(1): 65-71, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24038190


Resistin protein is thought to link insulin resistance in murine models of obesity and type-2 diabetes, but the role of resistin in human studies of inflammatory metabolic disorders have generated conflicting data. Here, we describe the structure of the resistin gene using adipose tissue from non-human primates (NHPs), which have been used extensively to model a host of human diseases. Full-length cDNA from rhesus macaque resistin obtained by rapid amplification of cDNA ends (RACE) is comprised of 526 nucleotides covering an open-reading frame (ORF) that encodes a 108-amino-acid protein that is 92% homologous with the human counterpart but only 60% homologous with the murine counterpart. Using a modified polymerase chain reaction technique, we identified single nucleotide polymorphisms and a 78-bp deletion within resistin cDNA of nine rhesus macaques. Comparisons of the full-length cDNA sequence and an amplified 569-bp genomic DNA sequence revealed an error in published predictions arising from genomic studies about the gene's exon 3 region. Our data show, for the first time, the full-length macaque resistin cDNA sequence (GenBank: JF740676.1). These findings will illuminate future studies into the role of resistin in NHP models of inflammatory metabolic diseases.

Macaca mulatta/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , Animais , Sequência de Bases , Clonagem Molecular , DNA Complementar/genética , DNA Complementar/metabolismo , Macaca mulatta/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Dados de Sequência Molecular , Proteínas de Neoplasias/metabolismo , Filogenia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência