Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.811
Filtrar
1.
J Spec Oper Med ; 20(3): 128-134, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32969018

RESUMO

Future expeditionary missions are expected to occur in more remote austere environments where combat medics and casualties may have to wait up to 7 days before resupply or safe evacuation. Currently, there is no effective fluid therapy for hemorrhagic shock (HS) at the point-of-injury and continuum-of-care over this extended period. We have been developing a small-volume IV or IO ALM therapy for noncompressible HS and have shown in preclinical models that it extends survival to 3 days, reduces abdominal bleeding by 60%, blunts inflammation, corrects coagulopathy, preserves platelet function, and prevents immunodeficiency. The ALM-survival phenotype is associated with an upregulation of the master genes of metabolism and mitochrondrial biogenesis in heart and brain and a downregulation in the periphery. Future translational studies will investigate the timing and nature of the "switch" and extend survival to 7 days. We will also discuss some of the controversies of ALM resuscitation in pigs, present our Systems Hypothesis of Trauma (SHOT), and discuss future clinical safety trials before field use.


Assuntos
Choque Hemorrágico , Adenosina/uso terapêutico , Animais , Hidratação , Lidocaína/uso terapêutico , Magnésio/uso terapêutico , Ressuscitação , Choque Hemorrágico/terapia , Suínos
2.
Int J Biol Sci ; 16(13): 2382-2391, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760206

RESUMO

COVID-19 is a public health emergency that has rapidly spread to over 200 countries and regions, and no effective treatment has been established to date. Severe and critical cases have been associated with higher mortality due to acute respiratory distress syndrome (ARDS) and cytokine storm. Based on the novelty and recent emergence of COVID-19, no effective treatment regimen has been identified, thus prompting clinicians to engage in drug repurposing to address the immediate therapeutic need. This study focused on the molecular target angiotensin-converting enzyme 2 (ACE2) of SARS-CoV-2 and screened a group of ACE2 agonists by bioinformatics. Glucocorticoids are a type of ACE2 activator. We verified the efficacy of nine chemicals on regulating ACE2 expression in human GES-1, an upper digestive tract epithelial cell line, and THP-1, a human monocyte cell line, and found that several glucocorticoids imparted activating effects on ACE2 in both cell lines. The drugs triciribine and kinetin riboside activate ACE2 expression or inhibit IL-6 production in macrophages to some extent. In addition, we compared the efficacies of several glucocorticoids. Hydrocortisone showed the strongest effect on ACE2 activation, followed by prednisolone, dexamethasone, and methylprednisolone. We retrospectively analyzed the therapeutic efficacy of nine severe or critical patients from a cohort of 90 COVID-19 cases, who received medium to small doses of glucocorticoids from our integrated medical team in Wuhan. Seven out of nine patients revealed significant improvement in clinical parameters and chest CT images. This study provides experimental and clinical evidence that medium-to-low-dose glucocorticoids may play a protective role in the respiratory and digestive systems by activating ACE2 and suppressing cytokine storm.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Glucocorticoides/uso terapêutico , Interleucina-6/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Adenosina/uso terapêutico , Adulto , Idoso , Antivirais/uso terapêutico , Betacoronavirus , Linhagem Celular , Linhagem Celular Tumoral , Infecções por Coronavirus/metabolismo , Citocinas/metabolismo , Células Epiteliais/virologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hidrocortisona/uso terapêutico , Cinetina/uso terapêutico , Macrófagos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Monócitos/virologia , Pandemias , Pneumonia Viral/metabolismo , Estudos Retrospectivos , Ribonucleosídeos/uso terapêutico , Transcriptoma
3.
s.l; IETSI; 25 abr. 2020.
Não convencional em Espanhol | LILACS, BRISA/RedTESA | ID: biblio-1096567

RESUMO

INTRODUCCIÓN: Remdesivir (RDV) es un nucleótido que es metabolizado intracelularmente a un análogo de trifosfato de adenosina que inhibe a las polimerasas virales ARN y tiene actividad contra el virus del ébola y los coronavirus (SARS-CoV y MERS-CoV). El RDV esta siendo desarrollado por Gilead Sciences, Inc. (Gilead) y su formulación es de administracion intravenosa. El planteamiento del uso de RDV como tratamiento del COVID-19 está basada en su actividad en vitro (Wang 2020) y en estudios de modelos animales contra SARS-CoV (Sheahan 2017) y MERS-CoV (de Wit 2020). Los recientes resultados de una prueba in vitro realizado en el CDC de China en colaboración con Gilead mostró que RDV tiene actividad antiviral contra SARS-CoV-2 en células Vero (EC50=0.137 µM; datos preliminares) (Wang 2020). Estos resultados tomados en conjunto con la experiencia de uso en humanos infectados con ébola, han dado pie a la investigación de sus efectos en pacientes con COVID-19. MÉTODOS: Se realizó una busqueda de reportes, comunicaciones (pre proof, pre print), noticias acerca del uso remdesivir en el tratamiento del COVID-19 en los siguientes buscadores o paginas de internet: 1. Pubmed. 2. EMBASE. 3. Scopus. 4. Web of Science. 5. Cochrane. 6. www.medrxiv.org (pre-prints). 7. Google Scholar. 8. Twitter. RESULTADOS: Se identificó un reporte de casos publicado en una revista, cuatro estudios en fase de reclutamiento y uno culminado, pero sin publicación en una revista con revision por pares. CONCLUSIONES. El RDV es un nucleótido en investigación que ha mostrado tener una actividad in vitro en contra del SARS-CoV-2 y actividad in vivo (estudios en animales) contra SARS-CoV y MERS-CoV. Sin embargo, la experiencia clínica en pacientes con COVID-19 es aún anecdótica. A la fecha, solo se dispone de una serie de casos altamente seleccionada por el fabricante auspiciador del estudio, quien se encargó de recoger, analizar y escribir el manuscrito. En esta serie de casos, se observó que un poco menos de la mitad de los pacientes pudieron ser retirados de la ventilación invasiva y un poco menos de la mitad de los pacientes pudieron salir de alta. Sin embargo, una alta proporción de los pacientes que fueron dados de alta habían estado recibiendo oxígeno por vía no invasiva (es decir, no eran casos graves). Además, casi la cuarta parte (23%) de los pacientes padeció de un evento adverso serio. Recientemente, el NIH ha publicado una guía de tratamiento de pacientes con COVID19 en la que señala que debido a falta de información no puede emitir una recomendación a favor o en contra del uso de RDV. Múltiples ensayos clínicos que evaluaran el tratamiento de COVID 19 con RDV están en progreso, varios de los cuales son auspiciados por el fabricante, por lo que se espera que sus resultados informen sobre la eficacia y seguridad de este medicamento en este contexto clínico. Con todo ello, a juzgar por la evidencia científica al momento encontrada, no es posible sostener técnicamente una recomendación a favor del remdesivir para pacientes COVID-19 o subgrupos de los mismos. La comunidad médica y científica internacional se encuentran a la espera de la publicación formal de los ensayos clínicos actualmente en proceso para poder diferenciar los efectos clínicos que puedan atribuirse causalmente al uso de remdesivir, especialmente en lo referente a si los potenciales daños del uso de este medicamento son menores a los beneficios clínicamente relevantes desde la perspectiva del pacientes que pueda tener.


Assuntos
Humanos , Adenosina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Nucleotídeos/uso terapêutico , Avaliação da Tecnologia Biomédica , Análise Custo-Benefício
4.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(3): 173-176, 2020 Mar 12.
Artigo em Chinês | MEDLINE | ID: mdl-32164081

RESUMO

The new coronavirus pneumonia (NCP), also named as COVID-19 by WHO on Feb 11 2020, is now causing a severe public health emergency in China since. The number of diagnosed cases is more than 40,000 until the submission of this manuscript. Coronavirus has caused several epidemic situations world widely, but the present contagious disease caused by 2019 new coronavirus is unprecedentedly fulminating. The published cohorts of 2019 new coronavirus (n-Cov) are single-center studies, or retrospective studies. We here share the therapeutic experiences of NCP treatment with literature review. Combination of Ribavirin and interferon-α is recommended by the 5(th) edition National Health Commission's Regimen (Revised Edition) because of the effect on Middle East respiratory syndrome (MERS), and the effectiveness of Lopinavir/Ritonavir and Remdisivir needs to be confirmed by randomized controlled trial (RCT), given the situation of no specific antivirus drug on NCP is unavailable. Systemic glucocorticosteroid is recommended as a short term use (1~2 mg·kg(-1)·d(-1), 3~5 d) by the 5(th) edition National Health Commission's Regimen (Revised Edition) yet RCTs are expected to confirm the effectiveness. Inappropriate application of antibiotics should be avoided, especially the combination of broad-spectrum antibiotics, for the NCP is not often complicated with bacterial infection.


Assuntos
Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais , Infecções por Coronavirus/tratamento farmacológico , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Lopinavir/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ribonucleotídeos/uso terapêutico , Ritonavir/uso terapêutico , Adenosina/uso terapêutico , Alanina/uso terapêutico , Antibacterianos/uso terapêutico , China , Quimioterapia Combinada , Humanos , Estudos Retrospectivos
5.
Acta Cir Bras ; 34(12): e201901204, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32074166

RESUMO

PURPOSE: To examine the therapeutic effect of external adenosine on an acetic acid-induced acute ulcerative colitis model in rats. METHODS: Thirty male mature rats were divided into three groups as control, acute colitis (AC) and AC+adenosine group (AC+AD). AC was induced by rectal administration of 4% acetic acid (AA). 5mg/kg/day adenosine was performed i.p for 4 weeks to AC+AD group. Rectum and colon were excised for microscopic and histopathological histopathologic evaluations, and immunohistochemical analysis of nuclear factor kappa B (NF-kB). Blood samples were collected for biochemical detection of TNF-α, Pentraxin-3 and malondialdehyde (MDA) levels. RESULTS: AC group had generalized hyperemia and hemorrhage with increased macroscopic and histopathological scores compared with control (P <0.0001) while adenosine treatment decreased these scores significantly (P <0.001), with reduced distribution of disrupted epithelium, leukocyte infiltrates, and focal hemorrhage. AC group showed significantly increased immunoexpression of NF-kB in rectum, plasma and tissue levels of TNF-α, plasma Pentraxin-3 and MDA levels (P <0.0001) while adenosine reduced these levels (P < 0.05). CONCLUSION: Adenosine appears to promote healing of colon and rectum exposed to AA-induced AC, suggesting a boosting effect of adenosine on the intestinal immune system to cure ulcerative colitis.


Assuntos
Adenosina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Ácido Acético , Doença Aguda , Animais , Proteína C-Reativa/análise , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Masculino , Malondialdeído/sangue , NF-kappa B/análise , Ratos Sprague-Dawley , Reto/patologia , Valores de Referência , Reprodutibilidade dos Testes , Componente Amiloide P Sérico/análise , Substâncias Reativas com Ácido Tiobarbitúrico , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise
6.
Yakugaku Zasshi ; 140(1): 15-22, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-31902879

RESUMO

The development of serious lung diseases, such as pulmonary fibrosis, is associated with several drugs. A recent study has shown that the epithelial-mesenchymal transition (EMT) plays an essential role in the development of pulmonary fibrosis. However, the mechanisms underlying drug-induced EMT in alveolar epithelial cells have not been characterized. The present study showed that methotrexate (MTX), a drug known to cause lung injury, induced EMT-like phenotypic changes in an A549 cell model of the alveolar epithelium. We also found that the transforming growth factor (TGF)-ß1-mediated signaling pathway was associated with MTX-induced EMT. In addition, our results showed that certain secreted factors and microRNAs, a class of small noncoding RNAs, may be involved in MTX-induced EMT. The effects of COA-Cl, a novel synthetic small molecule, on TGF-ß1-induced EMT were evaluated to determine the therapeutic potential of COA-Cl against drug-induced lung injury. COA-Cl significantly suppressed TGF-ß1-induced EMT-like phenotypic changes, as evidenced by the inhibition of EMT-related transcription factors. Furthermore, MTX-induced EMT was completely suppressed by co-treatment with folic acid. Thus, these compounds may be promising therapeutic agents against drug-induced lung injury. In conclusion, the present study elucidated mechanisms underlying drug-induced EMT and highlighted a potential novel therapeutic approach to drug-induced lung diseases.


Assuntos
Lesão Pulmonar/induzido quimicamente , Metotrexato/efeitos adversos , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/uso terapêutico , Animais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ácido Fólico/administração & dosagem , Ácido Fólico/uso terapêutico , Humanos , Lesão Pulmonar/tratamento farmacológico , MicroRNAs , Terapia de Alvo Molecular , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta1/fisiologia
7.
Cell Mol Life Sci ; 77(8): 1623-1643, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31378829

RESUMO

The pathophysiology of type 2 diabetes mellitus (T2D) is characterized by reduced or absent insulin receptor (INSR) responsiveness to its ligand, elevated hepatic glucose output and impaired glucose uptake in peripheral tissues, particularly skeletal muscle. Treatments to reduce hyperglycemia and reestablish normal insulin signaling are much sought after. Any agent which could be orally administered to restore INSR function, in an insulin-independent manner, would have major implications for the management of this global disease. We have discovered a non-peptidyl small molecule, adenosine, 5'-Se-methyl-5'-seleno-, 2',3'-diacetate [referred to as non-peptidyl compound #43 (NPC43)], which restores INSR signaling in the complete absence of insulin. Initial screening of numerous compounds in human HepG2 liver cells revealed that NPC43 significantly inhibited glucose production. The compound was potently anti-hyperglycemic and anti-hyperinsulinemic in vivo, in insulin-resistant T2D Leprdb/db mice, following either acute or chronic treatment by oral gavage and intraperitoneal injection, respectively. The compound acted at the level of INSR and activated it in both liver and skeletal muscle of Leprdb/db mice. In cell culture, the compound activated INSR in both liver and skeletal muscle cells; furthermore, it cooperated with insulin to depress glucose-6-phosphatase catalytic subunit (G6pc) expression and stimulate glucose uptake, respectively. Our results indicated that the compound directly interacted with INSRα, triggering appropriate phosphorylation and activation of the receptor and its downstream targets. Unlike insulin, NPC43 did not activate insulin-like growth factor 1 receptor in either liver or skeletal muscle. We believe this compound represents a potential oral and/or injectable insulin replacement therapy for diabetes and diseases associated with insulin resistance.


Assuntos
Adenosina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Receptor de Insulina/metabolismo , Adenosina/análogos & derivados , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Células Hep G2 , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Hipoglicemiantes/química , Insulina/metabolismo , Resistência à Insulina , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organosselênicos/química , Compostos Organosselênicos/uso terapêutico
8.
Int Immunopharmacol ; 76: 105899, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31518916

RESUMO

The function of histone methyltransferase enhancer of zeste homolog 2 (EZH2) in sepsis remains unknown. We reported here that the expression of EZH2 and H3K27me3 was significantly upregulated in the circulation of septic patients, whereas patients who survived presented downregulated the expression of EZH2 on CD14+ monocytes. We further identified increased expression of EZH2 in the circulation, peritoneal fluid, and septic lungs from CLP mice. 3-DZNeP treated CLP mice improved mortality and protected from organ injury. EZH2 inhibition not only suppressed the activation of inflammatory cells and release of cytokines in the circulation and infectious sites, but also promoted bacteria clearance and replenished the circulating monocyte and neutrophil pool from bone marrow. Blockage of EZH2 also suppressed the progression of lung injury and alleviated inflammation by decreasing the pulmonary cell apoptosis, reducing inflammatory cells infiltration and cytokines release through inhibition of the STAT3 signaling pathway and recovery of PPARγ activation. In addition, EZH2 inhibitor blunted macrophage M1 polarization by SOCS3/STAT1 pathway. Overall, these data suggest that EZH2 could be a potential biomarker predicting clinical outcome and a new target for therapeutic interference in sepsis.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Sepse/imunologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carga Bacteriana , Citocinas/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Histona Desmetilases com o Domínio Jumonji/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Fagocitose , Sepse/tratamento farmacológico , Sepse/microbiologia , Sepse/patologia
9.
Drugs R D ; 19(4): 319-328, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31452117

RESUMO

BACKGROUND: Pulmonary arterial hypertension is a hemodynamic disorder. Signs and symptoms are generally difficult to recognize because they are non-specific. The current treatment for pulmonary arterial hypertension offers no cure or prevention; therefore, it is important to explore treatment avenues for novel pulmonary arterial hypertension treatments. In this study, we tested the hypothesis: pulmonary vasodilator responses of adenosine are dependent on the activation of L-type calcium channels, independent of the synthesis of nitric oxide from L-arginine, activation of adenosine triphosphate-sensitive potassium channels, and the release of cyclooxygenase products. METHODS: We performed an isolated lobar lung preparation in mongrel cats. The thromboxane A2 analog U-46619 was used to increase lobar arterial pressure to a high steady level. We recorded responses to adenosine and other vasodepressor agents in the pulmonary vascular bed of a cat under conditions of controlled pulmonary blood flow and constant left atrial pressure. RESULTS: These data show that adenosine has significant vasodepressor activity in the pulmonary vascular bed of the cat. The data suggest that pulmonary vasodilator responses to adenosine are partially dependent on the activation of adenosine 1 and 2 receptor pathways, and independent of the activation of cyclooxygenase activation, adenosine triphosphate-sensitive K + channels, or synthesis of nitric oxide in the pulmonary vascular bed of the cat. CONCLUSIONS: Vasodepressor effects of adenosine are species specific, and this species specificity will impact the development of future testing and treatments for pulmonary arterial hypertension. Clinical studies are warranted to see if adenosine moieties could play a therapeutic role in patients with pulmonary arterial hypertension and/or other pulmonary pathogeneses.


Assuntos
Adenosina/uso terapêutico , Canais de Cálcio Tipo L/metabolismo , Hipertensão Pulmonar/tratamento farmacológico , Vasodilatadores/uso terapêutico , Animais , Gatos , Modelos Animais de Doenças , Feminino , Hipertensão Pulmonar/metabolismo , Masculino , Óxido Nítrico/metabolismo , Canais de Potássio/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptor A1 de Adenosina/metabolismo , Receptores A2 de Adenosina/metabolismo , Transdução de Sinais
10.
Curr Pharm Des ; 25(26): 2792-2807, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31333097

RESUMO

BACKGROUND: Adenosine mediates various physiological and pathological conditions by acting on its four P1 receptors (A1, A2A, A2B and A3 receptors). Omnipresence of P1 receptors and their activation, exert a wide range of biological activities. Thus, its modulation is implicated in various disorders like Parkinson's disease, asthma, cardiovascular disorders, cancer etc. Hence these receptors have become an interesting target for the researchers to develop potential therapeutic agents. Number of molecules were designed and developed in the past few years and evaluated for their efficacy in various disease conditions. OBJECTIVE: The main objective is to provide an overview of new chemical entities which have crossed preclinical studies and reached clinical trials stage following their current status and future prospective. METHODS: In this review we discuss current status of the drug candidates which have undergone clinical trials and their prospects. RESULTS: Many chemical entities targeting various subtypes of P1 receptors are patented; twenty of them have crossed preclinical studies and reached clinical trials stage. Two of them viz adenosine and regadenoson are approved by the Food and Drug Administration. CONCLUSION: This review is an attempt to highlight the current status, progress and probable future of P1 receptor ligands which are under clinical trials as promising novel therapeutic agents and the direction in which research should proceed with a view to come out with novel therapeutic agents.


Assuntos
Agonistas do Receptor Purinérgico P1/uso terapêutico , Antagonistas de Receptores Purinérgicos P1/uso terapêutico , Adenosina/uso terapêutico , Asma/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Receptores Purinérgicos P1
11.
Am J Emerg Med ; 37(10): 1990.e1-1990.e2, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31358381

RESUMO

Left ventricular non-compaction (LVNC) is a cardiomyopathy with altered ventricular wall anatomy. This condition is characterized by the presence of prominent left ventricular trabeculae, a thin compacted layer, and deep intertrabecular recesses that are continuous with the left ventricular cavity and separated from the epicardial coronary. Left ventricular non-compaction can present with acute heart failure, arrhythmias, or sudden cardiac death. We present a case of a common cardiac arrhythmia in the emergency department with a work up consistent with LVNC being the underlying etiology.


Assuntos
Arritmias Cardíacas/etiologia , Dispneia/etiologia , Taquicardia Supraventricular/etiologia , Disfunção Ventricular Esquerda/complicações , Adenosina/uso terapêutico , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/fisiopatologia , Dispneia/fisiopatologia , Serviço Hospitalar de Emergência , Humanos , Masculino , Pessoa de Meia-Idade , Taquicardia Supraventricular/fisiopatologia , Recusa do Paciente ao Tratamento , Disfunção Ventricular Esquerda/fisiopatologia
12.
Int Arch Allergy Immunol ; 180(2): 120-127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256157

RESUMO

BACKGROUND: Allergen immunotherapy (AIT) is the only etiological and potentially curative therapy for allergic rhinitis (AR). OBJECTIVES: We sought to investigate the role of epigenetic regulator enhancer of zeste homolog 2 (EZH2) in the activation of dendritic cells (DCs) in AIT. METHOD: In this study, EZH2 expression in circulating myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) were evaluated using flow cytometry. Clinical information from 56 AR patients receiving AIT was collected, including 30 subjects with subcutaneous immunotherapy (SCIT) and 26 subjects with sublingual immunotherapy (SLIT). In vitro, the effect of EZH2 inhibitor, 3 Deazaneplanocin A (DZNep), on the phenotypic and functional activation of monocyte-derived DCs (moDCs) was evaluated. RESULTS: EZH2 expression in circulating mDCs and pDCs were both negatively correlated to treatment time of AIT (r = -0.39, p = 0.003 and r = -0.47, p = 0.0002, respectively). Furthermore, there was a higher correlation between EZH2 expression and AIT treatment time in the SCIT group compared to that of the SLIT group in mDCs (r = -0.42, p = 0.02 vs. r = -0.23, p = 0.26)and pDCs (r = -0.52, p = 0.003 vs. r = -0.33, p = 0.10). In vitro, the co-stimulatory molecules on moDCs, such as CD80, CD86, and CD83, were significantly inhibited by DZNep in a dose-dependent manner. The -DC-driven T-cell proliferation was suppressed by DZNep (MD = 22.88, 95% CI 7.809-37.96, p < 0.05). CONCLUSIONS: Our study shows that EZH2, which is required in the activation of DCs, mediates the epigenetic modification in AIT and stresses the importance of patient adherence during AIT.


Assuntos
Adenosina/análogos & derivados , Células Dendríticas/imunologia , Dessensibilização Imunológica/métodos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Rinite Alérgica/imunologia , Adenosina/uso terapêutico , Adulto , Proliferação de Células/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Epigênese Genética/genética , Epigênese Genética/imunologia , Feminino , Humanos , Interleucina-10/análise , Interleucina-6/análise , Masculino , Cooperação do Paciente , Rinite Alérgica/patologia , Adulto Jovem
13.
J Trauma Acute Care Surg ; 87(3): 606-613, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31162330

RESUMO

BACKGROUND: Noncompressible torso hemorrhage is a leading cause of traumatic death. Our aim was to examine survival time and the expression of key master genes of cellular metabolism after 3% NaCl adenosine, lidocaine, and Mg (ALM) bolus and 4 hours 0.9% NaCl/ALM "drip" in a rat model of uncontrolled hemorrhagic shock. METHODS: Male Sprague-Dawley rats (425 ± 8 g) were anesthetized and randomly assigned to saline controls (n = 10) or ALM therapy (n = 10). Hemorrhage was induced by liver resection (60% left lateral lobe). After 15 minutes, a single intravenous bolus of 3% NaCl ± ALM (0.7 mL/kg) was administered (Phase 1), and after 60 minutes, a 0.9% NaCl ± ALM stabilization "drip" (0.5 mL/kg per hour) was infused for 4 hours (Phase 2) with 72 hours monitoring. Mean arterial pressure and lactate were measured. After 72 hours (or high moribund score), tissues were freeze-clamped and stored at -80°C. Total RNA was extracted in heart, brain, and liver, and the relative expressions of amp-k, mtCO3, PGC-1α, and sirt-1 genes were determined. RESULTS: Kaplan-Meier survival curves showed that controls had a mean survival time of 22.6 ± 4.5 hours, and ALM animals, 72 ± 0 hours (p < 0.05). Death in controls was accompanied by approximately sevenfold increase in lactate, while ALM animals maintained lactates similar to baseline over 72 hours. The relative expression of amp-k, PGC-1α, and sirt-1 in heart and brain was 1.5-fold and 2.7-fold higher in the ALM group compared with controls (p < 0.05), with the exception of mitochondrial encoded cytochrome C oxidase III pseudogene 1 in heart, which was 19-fold higher. In contrast, amp-k, sirt-1, and mtCO3 gene expression in liver was significantly 29-41% lower in the ALM group compared with controls, and PGC-1α was 75% lower. CONCLUSION: Small-volume ALM therapy led to 3.3-times longer survival time compared with saline controls after hemorrhagic shock. A hallmark of the ALM-survival phenotype in heart and brain was an upregulation of amp-k, PGC-1α, sirt-1, and mtCO3 to presumably "boost" mitochondrial function and ATP production, and a contrasting downregulation in liver. These central-peripheral differences in gene expression require further investigation.


Assuntos
Adenosina/uso terapêutico , Hidratação/métodos , Lidocaína/uso terapêutico , Magnésio/uso terapêutico , Choque Hemorrágico/terapia , Adenosina/administração & dosagem , Animais , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Lidocaína/administração & dosagem , Magnésio/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Choque Hemorrágico/tratamento farmacológico , Choque Hemorrágico/metabolismo , Choque Hemorrágico/mortalidade , Fatores de Tempo
14.
Int Immunopharmacol ; 72: 479-486, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31051404

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative method for blood cancers and other blood disorders, but is limited by the development of graft-versus-host disease (GVHD). GVHD results in inflammatory damage to the host liver, gastrointestinal tract and skin, resulting in high rates of morbidity and mortality in HSCT recipients. Activation of the A2A receptor has been previously demonstrated to reduce disease in allogeneic mouse models of GVHD. This study aimed to investigate the effect of A2A activation on disease development in a humanised mouse model of GVHD. Immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (IL)-2 receptor γnull (NSG) mice injected with human (h) peripheral blood mononuclear cells (hPBMCs), were treated with either the A2A agonist CGS 21680 or control vehicle. Contrary to the beneficial effect of A2A activation in allogeneic mouse models, CGS 21680 increased weight loss, and failed to reduce the clinical score or increase survival in this humanised mouse model of GVHD. Moreover, CGS 21680 reduced T regulatory cells and increased serum human IL-6 concentrations. Conversely, CGS 21680 reduced serum human tumour necrosis factor (TNF)-α concentrations and leukocyte infiltration into the liver, indicating that A2A activation can, in part, reduce molecular and histological GVHD in this model. Notably, CGS 21680 also prevented healthy weight gain in NSG mice not engrafted with hPBMCs suggesting that this compound may be suppressing appetite or metabolism. Therefore, the potential benefits of A2A activation in reducing GVHD in HSCT recipients may be limited and confounded by adverse impacts on weight, decreased T regulatory cell frequency and increased IL-6 production.


Assuntos
Agonistas do Receptor A2 de Adenosina/uso terapêutico , Adenosina/análogos & derivados , Doença Enxerto-Hospedeiro/tratamento farmacológico , Fenetilaminas/uso terapêutico , Adenosina/efeitos adversos , Adenosina/uso terapêutico , Agonistas do Receptor A2 de Adenosina/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Camundongos , Fenetilaminas/efeitos adversos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
16.
Pharmacol Biochem Behav ; 181: 110-116, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31054946

RESUMO

Repetitive behaviors are diagnostic for autism spectrum disorder (ASD) and commonly observed in other neurodevelopmental disorders. Currently, there are no effective pharmacological treatments for repetitive behavior in these clinical conditions. This is due to the lack of information about the specific neural circuitry that mediates the development and expression of repetitive behavior. Our previous work in mouse models has linked repetitive behavior to decreased activation of the subthalamic nucleus, a brain region in the indirect and hyperdirect pathways in the basal ganglia circuitry. The present experiments were designed to further test our hypothesis that pharmacological activation of the indirect pathway would reduce repetitive behavior. We used a combination of adenosine A1 and A2A receptor agonists that have been shown to alter the firing frequency of dorsal striatal neurons within the indirect pathway of the basal ganglia. This drug combination markedly and selectively reduced repetitive behavior in both male and female C58 mice over a six-hour period, an effect that required both A1 and A2A agonists as neither alone reduced repetitive behavior. The adenosine A1 and A2A receptor agonist combination also significantly increased the number of Fos transcripts and Fos positive cells in dorsal striatum. Fos induction was found in both direct and indirect pathway neurons suggesting that the drug combination restored the balance of activation across these complementary basal ganglia pathways. The adenosine A1 and A2A receptor agonist combination also maintained its effectiveness in reducing repetitive behavior over a 7-day period. These findings point to novel potential therapeutic targets for development of drug therapies for repetitive behavior in clinical disorders.


Assuntos
Agonistas do Receptor A1 de Adenosina/uso terapêutico , Agonistas do Receptor A2 de Adenosina/uso terapêutico , Adenosina/análogos & derivados , Comportamento Compulsivo/tratamento farmacológico , Fenetilaminas/uso terapêutico , Comportamento Estereotipado/efeitos dos fármacos , Adenosina/administração & dosagem , Adenosina/química , Adenosina/uso terapêutico , Agonistas do Receptor A1 de Adenosina/administração & dosagem , Agonistas do Receptor A1 de Adenosina/química , Agonistas do Receptor A2 de Adenosina/administração & dosagem , Agonistas do Receptor A2 de Adenosina/química , Análise de Variância , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/citologia , Quimioterapia Combinada , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Neurônios/metabolismo , Óleo de Amendoim/química , Óleo de Amendoim/farmacologia , Fenetilaminas/administração & dosagem , Fenetilaminas/química , Fenótipo , Proteínas Proto-Oncogênicas c-fos/metabolismo
17.
Antiviral Res ; 167: 104-109, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31051186

RESUMO

Zika virus (ZIKV) infection during pregnancy has been associated with adverse outcomes and birth defects such as microcephaly in newborn children. Congenital malformations associated with ZIKV are believed to occur via direct infection of the fetus. Unfortunately, there are no licensed therapeutic or preventative tools to block maternal-fetal transmission of ZIKV. In this study, we developed a mouse model of ZIKV infection that specifically establishes vertical maternal-fetal transmission of ZIKV in 40-60% of fetuses when the dams acquire ZIKV infection during pregnancy. This mouse model somewhat mirrors the experience in humans at the peak of the epidemic in the Americas. Using this model, we demonstrate that a well-documented directly acting antiviral (DAA) compound that targets flaviviral RNA synthesis can completely prevent fetal infection when the treatment is started at the time of infection. Notably, we show that the treatment commenced at the time of peak viremia is still able to reduce the risk of fetal infection concomitant with significant reduction in placental viral load. Our results show for the first time the potential for clinical development of antiviral drugs for preventing vertical maternal-fetal transmission of ZIKV.


Assuntos
Adenosina/análogos & derivados , Antivirais/uso terapêutico , Transmissão Vertical de Doença Infecciosa , Malformações do Sistema Nervoso/virologia , Infecção por Zika virus , Adenosina/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Feto/anormalidades , Feto/virologia , Humanos , Camundongos , Microcefalia/virologia , Malformações do Sistema Nervoso/tratamento farmacológico , Malformações do Sistema Nervoso/prevenção & controle , Gravidez , Complicações Infecciosas na Gravidez , Carga Viral/efeitos dos fármacos , Zika virus/isolamento & purificação , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/transmissão
18.
J Trauma Acute Care Surg ; 87(1): 68-75, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30985476

RESUMO

BACKGROUND: Adenosine, lidocaine, and magnesium (ALM) is a cardioplegic agent shown to improve survival by improving cardiac function, tissue perfusion, and coagulopathy in animal models of shock. We hypothesized prehospital ALM treatment in hemorrhagic shock would improve survival compared to current Tactical Combat Casualty Care (TCCC) resuscitation beyond the golden hour. METHODS: Swine were randomized to: (1) TCCC, (2) 2 mL·kg vehicle control (VC), (3) 2 mL·kg ALM + drip, (4) 4 mL·kg ALM + drip, 5) 4 mL·kg ALM + delayed drip at 0.5 mL·kg·h, 6) 4 mL/kg VC, 7) 4 mL·kg ALM for 15 minutes + delayed drip at 3 mL·kg·h. Animals underwent pressure controlled hemorrhage to mean arterial pressure (MAP) of 30 mm Hg (S = 0). Treatment was administered at T = 0. After 120 minutes of simulated prehospital care (T = 120) blood product resuscitation commenced. Physiologic variables were recorded and laboratories were drawn at specified time points. RESULTS: Tactical Combat Casualty Care demonstrated superior survival to all other agents. The VC and ALM groups had lower MAPs and systolic blood pressures compared with TCCC. Except for the VC groups, lactate levels remained similar with correction of base deficit after prehospital resuscitation in all groups. Kidney function and liver function remained comparable across all groups. Compared with baseline values, TCCC demonstrated significant hypocoagulability. CONCLUSION: Adenosine, lidocaine, and magnesium, as administered in this study, are inferior to current Hextend-based resuscitation for survival from prolonged hemorrhagic shock in this model. In survivors, ALM groups had lower systolic blood pressures and MAPs, but provided a protective effect on coagulopathy as compared to TCCC. Adenosine, lidocaine, and magnesium do not appear to be a suitable low volume replacement to current TCCC resuscitation. The reduced coagulopathy compared to TCCC warrants future studies of ALM, perhaps as a therapeutic adjunct.


Assuntos
Adenosina/uso terapêutico , Soluções Cardioplégicas/uso terapêutico , Serviços Médicos de Emergência/métodos , Lidocaína/uso terapêutico , Magnésio/uso terapêutico , Medicina Militar/métodos , Ressuscitação/métodos , Choque Hemorrágico/terapia , Ferimentos e Lesões/terapia , Adenosina/administração & dosagem , Animais , Soluções Cardioplégicas/administração & dosagem , Modelos Animais de Doenças , Lidocaína/administração & dosagem , Magnésio/administração & dosagem , Masculino , Ressuscitação/mortalidade , Choque Hemorrágico/mortalidade , Suínos , Ferimentos e Lesões/mortalidade
19.
J Dermatol Sci ; 94(1): 205-212, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30954335

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is characterized by fibrosis of the skin and internal organs. Although transforming growth factor (TGF)-ß1-induced connective tissue growth factor (CTGF/CCN2) expression has been presented in SSc fibrosis, the therapeutic potential of targeting CTGF in SSc has not been fully explored. COA-Cl is a novel nucleic acid analog, which is reported to have pleiotropic beneficial biologic effects. OBJECTIVE: We examine the effects of COA-Cl on TGF-ß1-induced CTGF expression in normal human dermal fibroblast (NHDF). We also examined the effects of COA-Cl on CTGF expression in a mouse SSc model of angiotensin II (Ang II)-induced skin fibrosis. METHODS: NHDF was cultured for in vitro experiments. For in vivo experiments, C57BL/6J mice were treated with Ang II for 14 days by subcutaneous osmotic pump. Quantitative real-time polymerase chain reaction, western blot analysis, immunohistochemical staining and immunofluorescence staining were performed to examine the expression levels of CTGF and phosphorylation levels of Smad2/3, ERK1/2 and Akt. RESULTS: COA-Cl attenuated the TGF-ß1-induced expression of both CTGF mRNA and protein in NHDF. Although COA-Cl did not alter the TGF-ß1-induced phosphorylation of Smad2/3 or ERK1/2, it reduced the TGF-ß1-induced phosphorylation levels of Akt in NHDF. Notably, COA-Cl dephosphorylated the Akt of lysates of TGF-ß1-treated NHDF. COA-Cl reduced the levels of CTGF mRNA, CTGF protein, dermal thickness, collagen content and Akt phosphorylation in the skin of mice SSc model. CONCLUSION: These results imply that the inhibition of TGF-ß1-induced CTGF expression by COA-Cl may be a therapeutic approach for SSc.


Assuntos
Adenosina/análogos & derivados , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Escleroderma Sistêmico/tratamento farmacológico , Pele/patologia , Fator de Crescimento Transformador beta1/metabolismo , Adenosina/farmacologia , Adenosina/uso terapêutico , Angiotensina II/toxicidade , Animais , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/patologia , Humanos , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Escleroderma Sistêmico/patologia , Pele/efeitos dos fármacos
20.
Curr Med Chem ; 26(25): 4786-4798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30836908

RESUMO

BACKGROUND: Preeclapmsia (PE) is characterized by early onset symptoms such as elevated blood pressure, proteinuria and edema in the pregnant woman, and may result in seizures in the affected female. Currently, there are no therapeutic drugs available to treat this condition, but there are interventions to regulate the symptoms based on the gestational period of the fetus, although the largely favored option is delivery of the fetus and placenta. OBJECTIVE: A search for biomolecules associated with PE was conducted so as to identify diagnostic markers and therapeutic leads. RESULTS: The literature search resulted in the identification of biomolecules such as Corin and Placental Protein 13 (PP13), among others that are associated with PE. Thereby, giving an insight into the various mechanistic pathways involved in the causation of PE. However, it is also evident that PE cannot be solely attributed to any single mechanism but is due to an interplay of different factors that have led to the development of this disease condition. CONCLUSION: The identified biomarkers would ultimately help in understanding this complex disease and perhaps lead to the discovery of potential effective molecular targets for clinical trials, thereby providing a valuable therapeutic option for affected pregnant women.


Assuntos
Adenosina/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Vasodilatadores/uso terapêutico , Animais , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/metabolismo , Gravidez
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA