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1.
Medicine (Baltimore) ; 100(20): e25749, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011034

RESUMO

ABSTRACT: Thymosin alpha-1 (Tα1) is an immunomodulatory and antiviral agent with potential effects on chronic hepatitis B and liver cancer. Its impact on solitary hepatocellular carcinoma (HCC) remains controversial, so we aimed to investigate the efficacy of Tα1 in solitary HBV-related HCC patients after curative resection.Between May 2010 and April 2016, 468 patients with solitary HBV-related HCC after curative resection were analyzed. Propensity score matching (PSM) was used to minimize confounding variables. Risk factors were identified by the Cox proportional hazards model. Recurrence-free survival (RFS) rates, overall survival (OS) rates, immunological, and virologic response were compared.The median follow up was 60.0 months. Immunological response improved in the Tα1 group compared with the control group (P < .001) but the virologic response was similar between 2 groups after 24 months. Patients with Tα1 therapy had better RFS and OS before (P = .018 and P < .001) and after (P = .006 and P < .001) propensity matching. Multivariate analysis revealed that Tα1 therapy was an independent prognostic factor for both OS (P < .001, HR = 0.308, 95% CI: 0.175-0.541) and RFS (P < .001, HR = 0.381, 95% CI: 0.229-0.633).Tα1 as an adjuvant therapy improves the prognosis of solitary HBV-related HCC patients after curative liver resection.


Assuntos
Carcinoma Hepatocelular/terapia , Hepatite B Crônica/terapia , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia/epidemiologia , Timalfasina/uso terapêutico , Adulto , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Seguimentos , Hepatectomia , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/mortalidade , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Fígado/patologia , Fígado/cirurgia , Fígado/virologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
2.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669352

RESUMO

Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fibrose Cística/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Inflamatórios/farmacologia , Azitromicina/farmacologia , Azitromicina/uso terapêutico , /tratamento farmacológico , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Eicosanoides/metabolismo , Humanos , Inflamação/complicações , Inflamação/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Roscovitina/farmacologia , Roscovitina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Timalfasina/farmacologia , Timalfasina/uso terapêutico
3.
Future Oncol ; 17(9): 1097-1104, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33538178

RESUMO

We presented the rationale for the use of thymosin α1 as prophylaxis of severe COVID-19 in cancer patients undergoing active treatment, constituting the background for the PROTHYMOS study, a prospective, multicenter, open-label, Phase II randomized study, currently in its start-up phase (Eudract no. 2020-006020-13). We aim to offer new hope for this incurable disease, especially to frail patient population, such as patients with cancer. The hypothesis of an effective prophylactic approach to COVID-19 would have immediate clinical relevance, especially given the lack of curative approaches. Moreover, in the 'COVID-19 vaccine race era' both clinical and biological results coming from the PROTHYMOS trials could even support the rationale for future combinatorial approaches, trying to rise vaccine efficacy in frail individuals.


Assuntos
/complicações , Neoplasias/complicações , Timalfasina/uso terapêutico , Adjuvantes Imunológicos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
4.
Clin Lab ; 66(12)2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337843

RESUMO

BACKGROUND: Coronavirus disease (COVID-19) has affected more than 100 countries worldwide and the discharge criteria of patients with COVID-19 vary across different countries. In China, patients with two negative respiratory viral RNA tests taken at least one day apart can be discharged with no further quarantine required. Currently, PCR testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in fecal sample is not routinely performed. METHODS: We present a patient with COVID-19, whose respiratory swabs became negative but fecal sample remained positive for SARS-CoV-2 RNA. RESULTS: Stool sample collected on 27th of February was still positive for SARS-CoV-2 RNA, 24 days after the first negative respiratory swab. CONCLUSIONS: Based on the experience from the 2003 SARS epidemic, we recommend that fecal RNA testing of SARS-CoV-2 should be incorporated into the discharge criteria to minimize the risk of transmission from the gastrointestinal tract.


Assuntos
/virologia , Convalescença , Fezes/virologia , Alta do Paciente/normas , RNA Viral/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , /isolamento & purificação , Adulto , Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , Infecções Assintomáticas , /tratamento farmacológico , Quimioterapia Combinada , Reações Falso-Negativas , Feminino , Humanos , Nasofaringe/virologia , Faringe/virologia , Timalfasina/uso terapêutico
5.
Int J Mol Sci ; 22(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374407

RESUMO

Thymosin α1 (Tα1) is an immunostimulatory peptide for the treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and used as an immune enhancer, which also offers prospects in the context of COVID-19 infections and cancer. Manufacturing of this N-terminally acetylated 28-residue peptide is demanding, and its short plasma half-life limits in vivo efficacy and requires frequent dosing. Here, we combined the PASylation technology with enzymatic in situ N-acetylation by RimJ to produce a long-acting version of Tα1 in Escherichia coli at high yield. ESI-MS analysis of the purified fusion protein indicated the expected composition without any signs of proteolysis. SEC analysis revealed a 10-fold expanded hydrodynamic volume resulting from the fusion with a conformationally disordered Pro/Ala/Ser (PAS) polypeptide of 600 residues. This size effect led to a plasma half-life in rats extended by more than a factor 8 compared to the original synthetic peptide due to retarded kidney filtration. Our study provides the basis for therapeutic development of a next generation thymosin α1 with prolonged circulation. Generally, the strategy of producing an N-terminally protected PASylated peptide solves three major problems of peptide drugs: (i) instability in the expression host, (ii) rapid degradation by serum exopeptidases, and (iii) low bioactivity because of fast renal clearance.


Assuntos
Adjuvantes Imunológicos/farmacocinética , Timalfasina/farmacocinética , Acetilação , Acetiltransferases/metabolismo , Adjuvantes Imunológicos/genética , Adjuvantes Imunológicos/farmacologia , Animais , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Feminino , Meia-Vida , Espectrometria de Massas , Microscopia Eletrônica de Varredura , Neoplasias/tratamento farmacológico , Peptídeos/química , Proteólise , Ratos , Ratos Wistar , Proteínas Recombinantes de Fusão/sangue , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/ultraestrutura , Proteínas Ribossômicas/metabolismo , Timalfasina/sangue , Timalfasina/química , Timalfasina/genética , Viroses/tratamento farmacológico
6.
Int Immunopharmacol ; 88: 106873, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32795897

RESUMO

BACKGROUND: COVID-19 characterized by refractory hypoxemia increases patient mortality because of immunosuppression effects. This study aimed to evaluate the efficacy of immunomodulatory with thymosin α1 for critical COVID-19 patients. METHODS: This multicenter retrospective cohort study was performed in 8 government-designated treatment centers for COVID-19 patients in China from Dec. 2019 to Mar. 2020. Thymosin α1 was administrated with 1.6 mg qd or q12 h for >5 days. The primary outcomes were the 28-day and 60-day mortality, the secondary outcomes were hospital length of stay and the total duration of the disease. Subgroup analysis was carried out according to clinical classification. RESULTS: Of the 334 enrolled COVID-19 patients, 42 (12.6%) died within 28 days, and 55 (16.5%) died within 60 days of hospitalization. There was a significant difference in the 28-day mortality between the thymosin α1 and non-thymosin α1-treated groups in adjusted model (P = 0.016), without obvious differences in the 60-day mortality and survival time in the overall cohort (P > 0.05). In the subgroup analysis, it was found that thymosin α1 therapy significantly reduced 28-day mortality (Hazards Ratios HR, 0.11, 95% confidence interval CI 0.02-0.63, P=0.013) via improvement of Pa02/FiO2 (P = 0.036) and prolonged the hospital length of stay (P = 0.024) as well as the total duration of the disease (P=0.001) in the critical type patients, especially those aged over 64 years, with white blood cell >6.8×109/L, neutrophil >5.3×109/L, lymphocyte < 0.73 × 109/L, PaO2/FiO2 < 196, SOFA > 3, and acute physiology and chronic health evaluation (APACHE) II > 7. CONCLUSION: These results suggest that treatment with thymosin α1 can markedly decrease 28-day mortality and attenuate acute lung injury in critical type COVID-19 patients.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Cuidados Críticos/métodos , Pneumonia Viral/tratamento farmacológico , Timalfasina/uso terapêutico , APACHE , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Idoso , Betacoronavirus , China/epidemiologia , Estudos de Coortes , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Timalfasina/administração & dosagem , Timalfasina/efeitos adversos
7.
Medicine (Baltimore) ; 99(31): e21429, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756149

RESUMO

RATIONALE: The COVID-19 cases increased very fast in January and February 2020. The mortality among critically ill patients, especially the elder ones, is relatively high. Considering many patients died of severe inflammation response, it is urgent to develop effective therapeutic strategies for these patients. The human umbilical cord mesenchymal stem cells (hUCMSCs) have shown good capabilities to modulate the immune response and repair the injured tissue. Therefore, investigating the potential of hUCMSCs to the treatment of COVID-19 critically ill patients is necessary. PATIENT CONCERNS: A 65-year-old woman felt fatigued and had a fever with body temperature of 38.2C, coughed up white foaming sputum. After 1 day, she had chest tightness with SPO2 of 81%, and blood pressure of 160/91 mm Hg. DIAGNOSE: According to the guideline for the diagnosis and treatment of 2019 novel coronavirus infected pneumonia (Trial 4th Edition), COVID-19 was diagnosed, based on the real-time RT-PCR test of SARS-CoV-2. INTERVENTIONS: After regular treatment for 12 days, the inflammation symptom of the patient was still very severe and the potential side effects of corticosteroid were observed. Then, allogenic hUCMSCs were given 3 times (5 × 10 cells each time) with a 3-day interval, together with thymosin α1 and antibiotics daily injection. OUTCOMES: After these treatments, most of the laboratory indexes and CT images showed remission of the inflammation symptom. The patient was subsequently transferred out of ICU, and the throat swabs test reported negative 4 days later. LESSONS: These results indicated the clinical outcome and good tolerance of allogenic hUCMSCs transfer.


Assuntos
Betacoronavirus , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Infecções por Coronavirus/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Pneumonia Viral/terapia , Idoso , Antibacterianos/uso terapêutico , Terapia Combinada , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Feminino , Humanos , Pandemias , Pneumonia Viral/virologia , Timalfasina/uso terapêutico , Resultado do Tratamento
9.
Chin J Traumatol ; 23(4): 190-195, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32690231

RESUMO

COVID-19 is known for its magical infectivity, fast transmission and high death toll based on the large number of infected people. From the perspective of the clinical manifestation, autopsy examination and pathophysiology, the essence of COVID-19 should be viewed as a sepsis induced by viral infection, and has the essential characteristics as sepsis induced by other pathogens. Therefore, in addition to etiological and supportive treatment, immunomodulatory therapy is also appropriate to severe COVID-19. Although there is still a lack of consensus on immunotherapy for sepsis so far, relatively rich experiences have been accumulated in the past decades, which will help us in the treatment of severe COVID-19. This article will elaborate immunotherapy of sepsis, though it may not be consistent.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Fatores Imunológicos/uso terapêutico , Pneumonia Viral/complicações , Sepse/etiologia , Corticosteroides/uso terapêutico , Glicoproteínas/uso terapêutico , Humanos , Pandemias , Sepse/tratamento farmacológico , Timalfasina/uso terapêutico
11.
Brasília; s.n; 19 jun. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1100432

RESUMO

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 9 artigos e 6 protocolos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Avaliação da Tecnologia Biomédica , Imunoglobulinas/uso terapêutico , Metilprednisolona/uso terapêutico , Heparina/uso terapêutico , Cefoperazona/uso terapêutico , Cloroquina/uso terapêutico , Ritonavir/uso terapêutico , Oseltamivir/uso terapêutico , Lopinavir/uso terapêutico , Moxifloxacina/uso terapêutico , Timalfasina/uso terapêutico , Hidroxicloroquina/uso terapêutico
12.
s.l; s.n; ene. 2020. ilus, tab.
Não convencional em Espanhol | LILACS, BRISA/RedTESA | ID: biblio-1095041

RESUMO

OBJETIVO: Se sugiere no utilizar Timosina alfa-1 como terapia adyuvante en el tratamiento del câncer. TECNOLOGÍA EVALUADA: El sistema inmunitario juega un rol fundamental en las propias defensas del organismo contra las células cancerosas. El timo juega un papel central en esta situación y modifica los linfocitos T, una clase de linfocitos. Los estudios de péptidos tímicos hallaron numerosos efectos sobre el sistema inmunitario. Existen dos grupos de péptidos tímicos disponibles para el tratamiento, a saber: los extractos purificados de timo animal (mayormente de terneros) y los péptidos de timo producidos de forma sintética. Se cree que los extractos de timo purificados (pTE, por sus siglas en inglés) y los péptidos tímicos sintéticos (sTP, por sus siglas en inglés) mejoran el sistema inmunitario de los pacientes con cáncer para poder luchar contra el crecimiento de células tumorales y resistir las infecciones por la inmunodepresión inducida por la enfermedad y el tratamiento antineoplásico. METODOLOGÍA: Este estudio incluyó 26 ensayos (2736 pacientes). Veinte ensayos investigaron los Pte (timoestimulina o timosina fracción 5) y seis ensayos investigaron los sTP (timopentina o timosina α1). 4 estudios evaluaron el uso de Timosina alfa-1 en pacientes con cáncer Cheng 2004; Gish 2009; Maio 2010; Schulof 1985. Veintiún ensayos informaron los resultados de la SG, seis los de la SLE, 14 los de la RT, nueve los de los EA y diez los de seguridade de los pTE y los sTP. El agregado de pTE no produjo beneficios en la SG (CR 1,00; IC del 95%: 0,79 a 1,25); la SLE (CR 0,97; IC del 95%: 0,82 a 1,16); ni en la RT (CR 1,07; IC del 95%: 0,92 a 1,25). La heterogeneidad de estos resultados fue de moderada a alta. Para la timosina α1el CR agrupado de la SG fue de 1,21 (IC del 95%: 0,94 a 1,56; p = 0,14), con una baja heterogeneidad; y de 3,37 (IC del 95%: 0,66 a 17,30; p = 0,15) para la SLE, con heterogeneidad moderada. Los pTE redujeron el riesgo de complicaciones infecciosas graves (CR 0,54; IC del 95%: 0,38 a 0,78; p = 0,0008; I2 = 0%). El CR de la neutropenia grave en los pacientes tratados con timoestimulina fue de 0,55 (IC del 95%: 0,25 a 1,23; p = 0,15). La tolerabilidad de los pTE y los sTP fue adecuada. La mayoría de ensayos tenían al menos un riesgo de sesgo moderado. RECOMENDACIONES Y JUICIOS: En general, no se hallaron pruebas de que el agregado de pTE al tratamento antineoplásico reduzca el riesgo de mortalidad o la progresión de la enfermedad, ni que mejore la tasa de respuestas tumorales al tratamiento antineoplásico. Se sugiere no utilizar Timosina alfa-1 como terapia adyuvante en el tratamiento del câncer.


Assuntos
Humanos , Timalfasina/uso terapêutico , Neoplasias/tratamento farmacológico , Avaliação da Tecnologia Biomédica , Análise Custo-Eficiência
13.
Prep Biochem Biotechnol ; 50(3): 281-291, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31718419

RESUMO

The use of interferon α-2 in combination with thymosin α-1 shows higher anti-cancer effect in comparison when both are used individually because of their synergistic effects. In this study we produced an important human interferon α-2-thymosin α-1 (IFNα2-Tα1) fusion protein with probable pharmaceutical properties coupled to its high-level expression, characterization, and study of its biological activity. The IFNα2-Tα1 fusion gene was constructed by over-lap extension PCR and expressed in Escherichia coli expression system. The expression of IFNα2-Tα1 fusion protein was optimized to higher level and its maximum expression was obtained in modified terrific broth medium when lactose was used as inducer. The fusion protein was refolded into its native biologically active form with maximum yield of 83.14% followed by purification with ∼98% purity and 69% final yield. A band of purified IFNα2-Tα1 fusion protein equal to ∼23 kDa was observed on 12 % SDS-PAGE gel. The integrity of IFNα2-Tα1 fusion protein was confirmed by western blot analysis and secondary structure was assessed by CD spectroscopy. When IFNα2-Tα1 fusion protein was subjected to its biological activity analysis it was observed that it exhibits both IFNα2 & Tα1 activities as well as significantly higher anticancer activity as compared to IFNα-2 alone.


Assuntos
Interferon-alfa , Proteínas Recombinantes de Fusão , Timalfasina , Escherichia coli/química , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Interferon-alfa/química , Interferon-alfa/genética , Interferon-alfa/isolamento & purificação , Interferon-alfa/farmacologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/farmacologia , Timalfasina/química , Timalfasina/genética , Timalfasina/isolamento & purificação , Timalfasina/farmacologia
14.
Front Immunol ; 10: 1841, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447849

RESUMO

Intestinal inflammatory disorders, such as inflammatory bowel disease (IBD), are associated with increased pro-inflammatory cytokine secretion in the intestines. Furthermore, intestinal inflammation increases the risk of enteric cancer, which is a common malignancy globally. Native anti-inflammatory peptides are a class of anti-inflammatory agents that could be used in the treatment of several intestinal inflammation conditions. However, potential cytotoxicity, and poor anti-inflammatory activity have prevented their development as anti-inflammatory agents. Therefore, in this study, we designed and developed a novel hybrid peptide for the treatment of intestinal inflammation. Eight hybrid peptides were designed by combining the active centers of antimicrobial peptides, including LL-37 (13-36), YW12D, innate defense regulator 1, and cathelicidin 2 (1-13) with thymopentin or the active center of thymosin alpha 1 (Tα1) (17-24). The hybrid peptide, LL-37-Tα1 (LTA), had improved anti-inflammatory activity with minimal cytotoxicity. LTA was screened by molecule docking and in vitro experiments. Likewise, its anti-inflammatory effects and mechanisms were also evaluated using a lipopolysaccharide (LPS)-induced intestinal inflammation murine model. The results showed that LTA prevented LPS-induced impairment in the jejunum epithelium tissues and infiltration of leukocytes, which are both histological markers of inflammation. Additionally, LTA decreased the levels of tumor necrosis factor-alpha, interferon-gamma, interleukin-6, and interleukin-1ß. LTA increased the expression of zonula occludens-1 and occludin, and reduced permeability and apoptosis in the jejunum of LPS-treated mice. Additionally, its anti-inflammatory effect is associated with neutralizing LPS, binding to the Toll-like receptor 4-myeloid differentiation factor 2 (TLR4/MD-2) complex, and modulating the nuclear factor-kappa B signal transduction pathway. The findings of this study suggest that LTA may be an effective therapeutic agent in the treatment of intestinal inflammation.


Assuntos
Anti-Inflamatórios/uso terapêutico , Desenho de Fármacos , Desenvolvimento de Medicamentos , Inflamação/tratamento farmacológico , Enteropatias/tratamento farmacológico , Animais , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Citocinas/antagonistas & inibidores , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , NF-kappa B/fisiologia , Peptídeos/uso terapêutico , Células RAW 264.7 , Timalfasina/uso terapêutico , Junções Íntimas/efeitos dos fármacos
15.
Ann Clin Lab Sci ; 49(3): 368-371, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31308037

RESUMO

OBJECTIVE: This study aims to investigate the changes in CD3+, CD4+ and CD8+ expression in cells in peripheral blood of silicosis patients, and observe the immunoregulatory effect of thymalfasin. METHODS: A total of 80 silicosis patients were enrolled in the study, randomly divided into two groups: treatment group and control group (n=40, each group). In addition, 40 healthy adults, who underwent physical examinations in our hospital, were enrolled into the health examination group. Patients in the control group and treatment group were given anti-infection treatment, according to their conditions. Patients in the treatment group additionally received thymalfasin. Then, the number of peripheral blood T lymphocyte subsets in subjects in all three groups before and after treatment was measured. RESULTS: (1) Before treatment, CD3+, CD4+ and CD8+ levels in cells were significantly lower in the treatment group and control group than in the health examination group, and the differences were statistically significant (P<0.05). (2) In the treatment group, the number of CD4+ cells in peripheral blood was significantly higher after one week of treatment, when compared to that before treatment, and the difference was statistically significant (P<0.05). CONCLUSION: In silicosis patients, CD3+, CD4+ and CD8+ cells in peripheral blood are decreased, and thymalfasin can significantly increase CD4+ cells in peripheral blood of silicosis patients.


Assuntos
Antígenos CD/metabolismo , Silicose/sangue , Silicose/tratamento farmacológico , Timalfasina/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Silicose/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Timalfasina/farmacologia
16.
Sci Rep ; 9(1): 10310, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311979

RESUMO

Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is the most frequent mutation causing cystic fibrosis (CF). F508del-CFTR is misfolded and prematurely degraded. Recently thymosin a-1 (Tα-1) was proposed as a single molecule-based therapy for CF, improving both F508del-CFTR maturation and function by restoring defective autophagy. However, three independent laboratories failed to reproduce these results. Lack of reproducibility has been ascribed by the authors of the original paper to the use of DMSO and to improper handling. Here, we address these potential issues by demonstrating that Tα-1 changes induced by DMSO are fully reversible and that Tα-1 peptides prepared from different stock solutions have equivalent biological activity. Considering the negative results here reported, six independent laboratories failed to demonstrate F508del-CFTR correction by Tα-1. This study also calls into question the autophagy modulator cysteamine, since no rescue of mutant CFTR function was detected following treatment with cysteamine, while deleterious effects were observed when bronchial epithelia were exposed to cysteamine plus the antioxidant food supplement EGCG. Although these studies do not exclude the possibility of beneficial immunomodulatory effects of thymosin α-1, they do not support its utility as a corrector of F508del-CFTR.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Deleção de Sequência , Timalfasina/farmacologia , Animais , Autofagia , Células Cultivadas , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Células MCF-7 , Cultura Primária de Células , Transporte Proteico/efeitos dos fármacos
17.
Int Immunopharmacol ; 74: 105662, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31220695

RESUMO

Thymosin alpha 1 (Tα1) is an immunomodulatory polypeptide secreted from the thymus. Tα1 has a wide range of biological functions, such as immunomodulation and endocrine regulation. Tα1 also displays antiviral and antitumor activities. Tα1 has been successfully used in clinical adjuvant therapy for solid tumors to improve the immune response of patients undergoing chemotherapy and radiotherapy. However, the half-life of Tα1 in the body is short, so frequent administration is required to maintain efficacy. In order to improve the pharmacokinetic profile of Tα1, we linked the mutated CH3 (mCH3) fragment of IgG1 (human) to the C-terminus of Tα1 to produce a long-acting fusion protein, Tα1-mCH3. The half-life of Tα1-mCH3 (47 h) was substantially increased compared with that of the parent molecule Tα1 (3 h). In vivo studies indicated that mCH3 fusion retained the original biological activity of Tα1, and Tα1-mCH3 showed slightly better immunomodulatory effect than Ta1. In the 4 T1 and B16F10 tumor xenograft models, Tα1-mCH3 induced a greater abundance of CD4+ and CD8+ T-cells in tumor tissues compared with Ta1. Tα1-mCH3 exhibited better effect in promoting the production of IL-2 and IFN-γ compared with Tα1. Therefore, Tα1-mCH3 more efficiently inhibited the growth of 4 T1 and B16F10 tumors than Tα1. In conclusion, fusion with mCH3 is an attractive strategy to lengthen the half-life and increase the activity of Tα1.


Assuntos
Antineoplásicos , Fragmentos de Imunoglobulinas , Imunoglobulina G , Neoplasias/tratamento farmacológico , Proteínas Recombinantes de Fusão , Timalfasina , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Citocinas/imunologia , Feminino , Meia-Vida , Fragmentos de Imunoglobulinas/genética , Fragmentos de Imunoglobulinas/uso terapêutico , Imunoglobulina G/genética , Imunoglobulina G/uso terapêutico , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/uso terapêutico , Timalfasina/farmacocinética , Timalfasina/uso terapêutico
18.
Environ Toxicol ; 34(8): 941-949, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31067016

RESUMO

This research was conducted to investigate the biochemical effects of thymosin alpha-1 using human lung cancer cells (A549). The A549 cells were treated with different concentrations of Thα1 for 24 h and the growth, inhibition of cells was determined. Thα1 revealed anti-proliferative effect at 24 and 48 µg/ml after 24 h. Furthermore, it indicated antioxidant properties by significantly enhancing the activity of catalase (12 µg/ml), superoxide dismutase (6 and 12 µg/ml), and glutathione peroxidase (3, 6 and 12 µg/ml) and reducing the production of cellular ROS. Our results showed that Thα1 inhibits the migration of A549 cells in a concentration-dependent manner after 24 and 48 h. Moreover, the effect of Thα1 on apoptosis was investigated by Hoechst 33342 staining and cell cycle analysis. Results demonstrated no significant effect on the induction of apoptosis in A549 cells. In conclusion, our results showed the antioxidant properties of Thα1 on A549 cancer cells.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Timalfasina/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Catalase/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
19.
Bioorg Chem ; 87: 743-752, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30974297

RESUMO

In this research, the antioxidant property of thymosin alpha-1 (Thα1) peptide was investigated through various antioxidant methods. Thα1 showed 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity (IC50 = 20 µM) and its 2,2-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) scavenging reached 45.33% at 80 µM (IC50 = 85 µM). In addition, hydroxyl and superoxide radical scavenging of Thα1 peptide exhibited a concentration-depended manner. The IC50 values of hydroxyl and superoxide radical scavenging were estimated to be 82 µM and 20 µM, respectively. The effect of Thα1 on eliminating superoxide radicals was higher (62.23%) than other antioxidant assays. Moreover, the antioxidant activity of Thα1 peptide was evaluated by measuring cellular reactive oxygen species (ROS). Results indicated that Thα1 decreased the generation of ROS level in 1321 N1 human neural asterocytoma cells. The inhibitory effect of Thα1 on angiotensin-converting enzyme (ACE) was determined. The kinetic parameters (Km and Vmax) and the inhibition pattern were examined. Based on the Lineweaver-Burk plot, Thα1 displayed a mixed inhibition pattern. The IC50 and Ki values of Thα1 were 0.8 µM and 3.33 µM, respectively. Molecular modeling suggested that Thα1 binds to ACE-domains with higher affinity binding to N-domain with the binding energy of -22.87 kcal/mol. Molecular docking indicated that Thα1 interacted with ACE enzyme (N- and C-domains) due to electrostatic, hydrophobic, and hydrogen forces. Our findings suggested that Thα1 possess a multifunctional peptide with dual antioxidant and ACE-inhibitory properties. Further researches are needed to investigate the antioxidant and anti-hypertensive effect of Thα1 both in vitro and in vivo.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antioxidantes/farmacologia , Peptidil Dipeptidase A/metabolismo , Timalfasina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Antioxidantes/química , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Picratos/antagonistas & inibidores , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Ácidos Sulfônicos/antagonistas & inibidores , Timalfasina/química
20.
Transplant Proc ; 51(2): 556-560, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30879589

RESUMO

Mucormycosis is an uncommonly encountered fungal infection in solid-organ transplantation, occurring most often gastrointestinally. The most common and fatal infectious disease is cytomegalovirus (CMV) pneumonia, which may result in acute respiratory distress syndrome (ARDS), with rapid onset. Early diagnosis, active treatment, and rational reduction of immunosuppressants are crucial for successful kidney transplantation. We performed successful treatment for both mucormycosis and CMV pneumonia and adjusted the tacrolimus dose accordingly. The case we describe was that of a 47-year-old woman with history of renal transplantation 1 month earlier. She presented with chest pain and gastrointestinal bleeding and was diagnosed with gastric mucormycosis and a secondary episode of hospital-acquired pneumonia. Preemptive therapy, which included liposomal amphotericin B and posaconazole, was adminstered when voriconazole proved to be unhelpful and before histologic reports of gastric mucormycosis. Moreover, CMV re-activation was confirmed by CMV antibody detection, and we administered gancyclovir and thymosin α1 but reduced the strength of the immunosuppressive drugs. Fourteen days after the aforementioned therapy, the patient began to recover and she was discharged on day 81 postoperatively. We conclude that preemptive treatment is critical for severe infection in renal transplant recipients, especially with the rarely seen gastric mucormycosis and with ARDS. In addition, immunoregulated agents, such as asthymosin α1, are also of great value in renal transplant recipients in the setting of opportunistic pathogen infections.


Assuntos
Infecções por Citomegalovirus/imunologia , Hospedeiro Imunocomprometido , Transplante de Rim/efeitos adversos , Mucormicose/imunologia , Infecções Oportunistas/imunologia , Anti-Infecciosos/uso terapêutico , Citomegalovirus , Feminino , Ganciclovir/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Pessoa de Meia-Idade , Pneumonia/imunologia , Pneumonia/microbiologia , Gastropatias/imunologia , Gastropatias/microbiologia , Timalfasina/uso terapêutico
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