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

RESUMO

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.


Assuntos
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
2.
Cell Res ; 31(1): 17-24, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262453

RESUMO

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8-10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Teicoplanina/análogos & derivados , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Células CACO-2 , Chlorocebus aethiops , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Ligação Proteica/efeitos dos fármacos , Teicoplanina/farmacocinética , Teicoplanina/farmacologia , Células Vero
3.
CNS Neurosci Ther ; 24(9): 828-836, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29962085

RESUMO

AIMS: It is unclear whether the impaired BRS plays a key role in the incidence of cardiovascular diseases. The molecular mechanism of impaired BRS remains to be fully elucidated. We hypothesized that selection of rats based on deficient and normal intrinsic BRS would yield models that reflect cardiovascular diseases risk. METHODS AND RESULTS: Twenty generations of selection produced arterial baroreflex low rats and normal rats that differed in BRS by about 2.5-fold change. Metabolic syndrome (including hypertension, overweight, hyperlipemia, and hyperglycemia) emerged in ABR-DRs. Although ABR-DRs consumed less food, they gained significantly more body weight. CONCLUSION: Our study demonstrated that intrinsic low BRS induced hypertension and metabolic disorder. Restoration of impaired BRS might be a potent target of therapeutic intervention in metabolic syndrome.


Assuntos
Animais Geneticamente Modificados/genética , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Síndrome Metabólica/genética , Seleção Artificial/genética , Animais , Feminino , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Síndrome Metabólica/fisiopatologia , Ratos , Ratos Sprague-Dawley
4.
CNS Neurosci Ther ; 22(8): 715-22, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27160425

RESUMO

BACKGROUND AND AIMS: Severe motion sickness is a huge obstacle for people conducting precise aviation, marine or emergency service tasks. The combination of scopolamine and d-amphetamine is most effective in preventing severe motion sickness. However, this combination is not included in any present pharmacopoeia due to the abuse liability of d-amphetamine. We wanted to find a combination to replace it for the treatment of severe motion sickness. METHODS AND RESULTS: We compared the efficacy of scopolamine, diphenhydramine, and granisetron (representing three classes of drugs) with different doses, and found that scopolamine was the most effective one. We also found scopolamine inhibited central nervous system at therapeutic doses and caused anxiety. Then, we combined it with different doses of psychostimulants (d-amphetamine, modafinil, caffeine) to find the best combination for motion sickness. The efficacy of scopolamine with modafinil (1 + 10 mg/kg) was equivalent to that of scopolamine with d-amphetamine (1 + 1 mg/kg); This combination also excited central nervous system and abolished the anxiety caused by scopolamine. CONCLUSIONS: The optimal dose ratio of scopolamine and modafinil is 1:10. This combination is beneficial for motion sickness and can abolish the side effects of scopolamine. So, it might be a good replacement of scopolamine and d-amphetamine for severe motion sickness.


Assuntos
Estimulantes do Sistema Nervoso Central/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Enjoo devido ao Movimento/prevenção & controle , Escopolamina/uso terapêutico , Análise de Variância , Animais , Compostos Benzidrílicos/farmacologia , Cafeína/uso terapêutico , Dextroanfetamina/farmacologia , Difenidramina/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Granisetron/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modafinila , Enjoo devido ao Movimento/etiologia , Rotação/efeitos adversos
5.
Mol Med Rep ; 7(1): 183-6, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23135204

RESUMO

The aims of this study were to observe the effect of exercise therapy on the function of the knee joint and the levels of cytokines and cytokine-related genes, specifically tumor necrosis factor-α (TNF-α), high sensitivity C-reactive protein (hs-CRP) and matrix metalloproteinase-3 (MMP-3), in the synovial joints of patients with knee osteoarthritis (KOA) and to explore its mechanism of action. A total of 100 KOA patients were divided into a treatment group (n=50) and a control group (n=50) according to the order of admission. The patients in the treatment group were treated with diclofenac sodium combined with exercise therapy and the patients in the control group were treated with diclofenac sodium only. The function of the knee joint and the therapeutic efficacy was evaluated and the TNF-α, hs-CRP and MMP-3 levels in the synovial fluid were measured following 4 weeks of treatment. The results revealed that the knee joint index score and the TNF-α, hs-CRP and MMP-3 levels in the synovial fluid decreased significantly in the KOA patients of the two groups following treatment (P<0.05). Compared with the control group, the knee joint index score and the TNF-α, hs-CRP and MMP-3 levels in the synovial joints were lower and the therapeutic efficacy was increased in the patients of the treatment group (P<0.05). In brief, exercise therapy may decrease cytokine and cytokine-related gene levels in the synovial fluid and inhibit inflammatory factor-mediated cartilage degradation in KOA patients, thus, effectively improving the clinical symptoms of KOA.


Assuntos
Citocinas/metabolismo , Terapia por Exercício , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/fisiopatologia , Líquido Sinovial/metabolismo , Adulto , Proteína C-Reativa/metabolismo , Feminino , Humanos , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Pessoa de Meia-Idade , Osteoartrite do Joelho/terapia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
6.
Hum Gene Ther ; 23(7): 700-10, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22372930

RESUMO

Newcastle disease virus (NDV) is a naturally oncolytic virus that has been shown to be safe and effective for cancer therapy. Tumor virotherapy using NDV emerged in the 1950s and has advanced more recently by the increased availability of reverse genetics technology. In this study, we constructed a reverse genetics system based on the virulent and oncolytic NDV Italien strain, and generated two recombinant NDVs carrying a gene encoding either enhanced green fluorescent protein or firefly luciferase. We evaluated the replication and antitumor characteristics of these viruses in vitro and in vivo. Our data showed that the insertion of exogenous reporter genes did not affect NDV replication and sensitivity to type I interferon. The recombinant NDVs kept the property of tumor-selective replication both in vitro and in vivo and strongly induced syncytium formation leading to cell death. Moreover, the recombinant NDVs significantly prolonged the survival of tumor-bearing athymic mice (p=0.017) and suppressed the loss of body weight after intratumoral injection. Taken together, our study provides a novel platform to develop recombinant oncolytic viruses based on the NDV Italien strain and shows the efficiency of recombinant NDV Italien for oncolytic virotherapy of tumors.


Assuntos
Neoplasias/terapia , Vírus da Doença de Newcastle/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Animais , Sobrevivência Celular , Clonagem Molecular , Feminino , Genes Reporter , Células Gigantes/virologia , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Células HeLa , Humanos , Interferons/farmacologia , Interferons/fisiologia , Luciferases de Vaga-Lume/biossíntese , Luciferases de Vaga-Lume/genética , Camundongos , Camundongos Nus , Neoplasias/patologia , Vírus da Doença de Newcastle/fisiologia , Vírus Oncolíticos/fisiologia , Genética Reversa , Carga Tumoral , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Hepatogastroenterology ; 59(116): 1290-3, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22281973

RESUMO

BACKGROUND/AIMS: Gastric cancer is associated with high morbidity and mortality, but reliable diagnostic and prognostic markers have not been established. Here we explored the clinical significance of two proteins, HER-2/neu and TOPIIa-associated with development and progression of various tumor types-in gastric cancer. We also analyzed the correlation between expression of these proteins and clinicopathological parameters of gastric tumors. METHODOLOGY: Tumor and adjacent normal tissue samples were collected from 62 patients with gastric cancer and subjected to immunohistochemistry with anti-HER-2/neu and -TOPIIa antibodies. RESULTS: HER-2/neu (21.0%) and TOPIIa (80.6%) were expressed more commonly in gastric cancer than in normal gastric tissue (9.7% and 60.3%, respectively; p<0.05). However, there was no correlation between HER-2/neu and TOPIIa expression in gastric tumors. Further analysis showed a correlation between HER-2/neu expression and lymph node metastasis, distant metastases and tumor stage (p<0.05); TOPIIa was correlated with infiltration depth, distant metastases and tumor stage (p<0.05). CONCLUSIONS: HER-2/neu and TOPIIa are over expressed in gastric tumors and may promote disease progression. These proteins may therefore be useful as prognostic markers in evaluation of patients with gastric cancer.


Assuntos
Antígenos de Neoplasias/análise , DNA Topoisomerases Tipo II/análise , Proteínas de Ligação a DNA/análise , Receptor ErbB-2/análise , Neoplasias Gástricas/química , Adulto , Idoso , Antígenos de Neoplasias/fisiologia , DNA Topoisomerases Tipo II/fisiologia , Proteínas de Ligação a DNA/fisiologia , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2/fisiologia , Índice de Gravidade de Doença , Estômago/química , Neoplasias Gástricas/patologia
8.
Oncol Lett ; 2(6): 1319-1322, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22848309

RESUMO

The present study aimed to investigate the expression of matrix metalloproteinase-3 (MMP-3) and the tissue inhibitor of metalloproteinase-3 (TIMP-3) in gastric cancer tissue, as well as to analyze the correlation between their expression and the occurrence of gastric cancer. Immunohistochemistry was used to determine the expression of MMP-3 and TIMP-3 in the gastric cancer tissue from 18 patients with early-stage gastric cancer (early-stage group) and 26 patients with advanced-stage gastric cancer (advanced-stage group). Transmission electron microscopy (TEM) was used to observe the lymphocytes and tumor cells in gastric cancer tissue. The results showed that the expression of TIMP-3 was significantly higher, whereas that of MMP-3 and MMP-3/TIMP-3 was lower in gastric cancer tissue of the early-stage group than in that of the advanced-stage group (P<0.05). The TEM images revealed increased lymphocytes and inconspicuous tumor cells penetrating the basement membrane in gastric cancer tissue of the early-stage group, and decreased lymphocytes and obvious tumor cells penetrating the basement membrane in the advanced-stage group. In conclusion, MMP-3 and TIMP-3 may be used as indices for the invasion and metastasis of gastric cancer and possess marked clinical significance in the prognostic judgment of gastric cancer.

9.
Zhong Xi Yi Jie He Xue Bao ; 7(6): 522-6, 2009 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-19583933

RESUMO

OBJECTIVE: To compare the distribution characteristics of common syndrome types and syndrome elements of menopause syndrome in perimenopausal and postmenopausal women on the basis of standardized syndrome differentiation extracted by experts' experiences. METHODS: A total of 1 582 outpatients with menopause syndrome who met with the diagnosis and inclusion criteria in seven grade 3 hospitals from October 2006 to June 2007 were included. A clinical epidemiological survey in the patients was carried out. The syndrome elements of disease location and characteristics were extracted and analyzed statistically by standardizing the syndrome differentiation of experts' experience in traditional Chinese medicine. RESULTS: There were 105 syndrome types after initial standardization, and the common syndrome types were kidney yin deficiency, deficiency of liver and kidney yin, stagnation of liver qi, and deficiency of both kidney yin and yang. Six syndrome elements of the disease location were extracted, among which the common elements were kidney, liver, spleen and heart. Seventeen syndrome elements of the disease characteristics were extracted, among which the common elements were yin deficiency, qi stagnation, qi deficiency, yang deficiency and deficiency. Syndrome types of stagnation of liver qi, deficiency of spleen and kidney, and qi stagnation were more frequently diagnosed during perimenopausal period, while the syndrome type of kidney yin deficiency was more frequently diagnosed during postmenopausal period, and the kidney was the main disease location. The distribution characteristics of the other syndrome types and elements were similar during the two periods. CONCLUSION: The syndrome type distribution in women with menopause syndrome is complex, while the syndrome element distribution is simple. Generally, the syndrome type and syndrome element distributions during perimenopausal and postmenopausal periods are similar, but there are significant differences in some syndrome types and syndrome elements between the two periods. All of these can give support for revealing the distribution rule of the common syndrome types and syndrome elements and give a theoretical basis for clinical treatment of menopause syndrome.


Assuntos
Diagnóstico Diferencial , Prova Pericial/métodos , Medicina Tradicional Chinesa/normas , Perimenopausa/fisiologia , Pós-Menopausa/fisiologia , Climatério/fisiologia , Feminino , Humanos , Pessoa de Meia-Idade , Perimenopausa/efeitos dos fármacos , Pós-Menopausa/efeitos dos fármacos , Deficiência da Energia Yin/diagnóstico
10.
J Asian Nat Prod Res ; 11(7): 663-9, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20183304

RESUMO

Osthole, 7-methoxy-8-[3-methylpent-2-enyl]coumarin (1), was extracted from a Chinese herb Cnidium monnieri (L.) Cuss. It showed immunity strengthening, anti-tumor, anti-hepatitis, and anti-osteoporosis activities in previous studies. Our goals are to study the effects of 1 on cell proliferation and TGF-beta of hypertrophic scar fibroblasts. Our results showed that 1 induced apoptosis and inhibited cell proliferation in hypertrophic scar fibroblasts. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that its IC(50) value toward hypertrophic scar fibroblasts was 15.5 +/- 2.2 micromol/l. Furthermore, the results of cell growth curve matched with the above results. Inducing apoptosis by 1 in hypertrophic scar fibroblasts was assessed by various morphological and biochemical characteristics, including cell shrinkage, chromatin condensation, membrane blebbing, formation of apoptotic bodies, and DNA ladder formation. A typical 'Sub-G(1) peak' was also checked through flow cytometry. We used immunohistochemistry to observe the expression of TGF-beta(1). Also, we found that 1 could obviously inhibit the expression of TGF-beta(1) of fibroblasts derived from hypertrophic scar compared with the control group (P < 0.05). These results suggest that 1 inhibits the growth of hypertrophic scar fibroblasts through apoptosis and decreases the expression of TGF-beta(1).


Assuntos
Cumarínicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Apoptose/efeitos dos fármacos , Cicatriz Hipertrófica/patologia , Cumarínicos/química , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Fibroblastos/efeitos dos fármacos , Humanos , Estrutura Molecular
11.
Virus Genes ; 31(2): 163-9, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16025241

RESUMO

H9N2 subtype influenza virus has become worldwide and prevalent in China. Previous studies illustrated that at least three sublineages had been established in terrestrial poultry of Eurasian avian. In this presentation, eight full-length genes of an H9N2 strain, A/Chicken/Shanghai/F/98 (Ck/SH/F/98) were obtained. Sequence analysis and phylogenetic studies were conducted by comparing eight genes with those of all the available H9N2 strains from the GenBank. The results showed that four genes (HA, NA, M and NS genes) of Ck/SH/F/98 were incorporated into the sublineage represented by the early mainland China strain, Ck/BJ/1/94. However, the other four of RNP genes of Ck/SH/F/98 did not show close relationship with those of the three known sublineages' viruses. Therefore, Ck/SH/F/98 was a natural reassortant between different sublineages. In addition, comparison showed that Ck/SH/F/98 could be a putative precursor of a later isolate from southern China, Dk/ST/1605/01, with at least six genes of both closely related, indicating genes of Ck/SH/F/98 and early isolates had ever been circulating. Further comparison in terms of molecular markers of species specificity of HA1 revealed that DK/ST/1605/01 also resembled Ck/SH/F/98 more than a common earlier duck strain. The results supported the idea of two-way transmission between terrestrial and aquatic birds that emphasized the importance to raise concerns on the natural evolution of all the eight genes of H9N2 avian influenza viruses.


Assuntos
Galinhas/virologia , Genes Virais , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H9N2/genética , Influenza Aviária/virologia , Vírus Reordenados/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , China , Vírus da Influenza A Subtipo H9N2/classificação , Vírus da Influenza A Subtipo H9N2/isolamento & purificação , Dados de Sequência Molecular , Filogenia , Vírus Reordenados/isolamento & purificação
12.
Artigo em Chinês | MEDLINE | ID: mdl-12916307

RESUMO

OBJECTIVE: To evaluate the clinical efficacy of fasciocutaneous flap in the repair of the III degree burn wound in the facio-cervical region. METHODS: From January 1997 to October 2001, 11 cases of III degree burn wounds in the facio-cervical region were repaired with the cervical-thoracic fasciocutaneous flap ranging from 18 cm x 8 cm to 13 cm x 5 cm. Donor sites were covered with "Z" plasty or skin grafting. RESULTS: Except for partial necrosis of distal end of the flap in 1 case, the flaps in the other 10 cases all survived and presented satisfactory appearance and function during the following up. CONCLUSION: The fasciocutaneous flap in the cervical-thoracic region may provide a large area of flap, and can be easily transferred. It's an ideal flap for the repair of skin defect in the facio-cervical region, especially for the repair of the wounds with infection or exposure of vessel, nerve and tendon.


Assuntos
Queimaduras/cirurgia , Traumatismos Faciais/cirurgia , Lesões do Pescoço/cirurgia , Retalhos Cirúrgicos , Adolescente , Adulto , Fáscia/irrigação sanguínea , Fáscia/transplante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Reconstrutivos , Técnicas de Sutura
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