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1.
Nat Commun ; 11(1): 3890, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753636

RESUMO

Inhibiting thrombosis without generating bleeding risks is a major challenge in medicine. A promising solution may be the inhibition of coagulation factor XII (FXII), because its knock-out or inhibition in animals reduced thrombosis without causing abnormal bleeding. Herein, we have engineered a macrocyclic peptide inhibitor of activated FXII (FXIIa) with sub-nanomolar activity (Ki = 370 ± 40 pM) and a high stability (t1/2 > 5 days in plasma), allowing for the preclinical evaluation of a first synthetic FXIIa inhibitor. This 1899 Da molecule, termed FXII900, efficiently blocks FXIIa in mice, rabbits, and pigs. We found that it reduces ferric-chloride-induced experimental thrombosis in mice and suppresses blood coagulation in an extracorporeal membrane oxygenation (ECMO) setting in rabbits, all without increasing the bleeding risk. This shows that FXIIa activity is controllable in vivo with a synthetic inhibitor, and that the inhibitor FXII900 is a promising candidate for safe thromboprotection in acute medical conditions.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Fator XIIa/antagonistas & inibidores , Peptídeos Cíclicos/efeitos dos fármacos , Trombose/prevenção & controle , Animais , Cloretos/efeitos adversos , Clonagem Molecular , Modelos Animais de Doenças , Descoberta de Drogas , Oxigenação por Membrana Extracorpórea/métodos , Fator XII/antagonistas & inibidores , Feminino , Compostos Férricos/efeitos adversos , Humanos , Pulmão , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coelhos , Proteínas Recombinantes/farmacologia , Suínos
2.
Cardiovasc Ther ; 2020: 1389312, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32788926

RESUMO

Inflammation plays a major role in the development of myocardial ischemia-reperfusion (IR) injury. Recombinant human brain natriuretic peptide (rhBNP), a man-made version of a peptide that is elevated in heart failure, exhibits anti-inflammatory effects in various tissues. However, its role in myocardial IR injury remains unclear. In this study, we demonstrate that treatment with rhBNP provided protection for mice against myocardial IR injury as manifested by reduced infarct size and well-preserved myocardial, attenuated inflammatory infiltration and CD4+ T cell proliferation function, and inhibited expression of proinflammatory related genes. Furthermore, mechanistic studies revealed that rhBNP inhibited Jurkat T proliferation by promoting PI3K/AKT/mTOR phosphorylation. Collectively, our data suggest that the administration of rhBNP during IR injury could expand our understanding of the cardioprotective effects of rhBNP.


Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/enzimologia , Peptídeo Natriurético Encefálico/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Células Jurkat , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/imunologia , Miocárdio/patologia , Fosforilação , Proteínas Recombinantes/farmacologia , Transdução de Sinais
3.
Science ; 369(6507)2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32855309

RESUMO

Neuronal synapses undergo structural and functional changes throughout life, which are essential for nervous system physiology. However, these changes may also perturb the excitatory-inhibitory neurotransmission balance and trigger neuropsychiatric and neurological disorders. Molecular tools to restore this balance are highly desirable. Here, we designed and characterized CPTX, a synthetic synaptic organizer combining structural elements from cerebellin-1 and neuronal pentraxin-1. CPTX can interact with presynaptic neurexins and postsynaptic AMPA-type ionotropic glutamate receptors and induced the formation of excitatory synapses both in vitro and in vivo. CPTX restored synaptic functions, motor coordination, spatial and contextual memories, and locomotion in mouse models for cerebellar ataxia, Alzheimer's disease, and spinal cord injury, respectively. Thus, CPTX represents a prototype for structure-guided biologics that can efficiently repair or remodel neuronal circuits.


Assuntos
Proteína C-Reativa/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Vias Neurais/efeitos dos fármacos , Precursores de Proteínas/farmacologia , Receptores de AMPA/metabolismo , Proteínas Recombinantes/farmacologia , Sinapses/efeitos dos fármacos , Doença de Alzheimer/terapia , Animais , Proteína C-Reativa/química , Proteína C-Reativa/uso terapêutico , Ataxia Cerebelar/terapia , Modelos Animais de Doenças , Células HEK293 , Hipocampo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/uso terapêutico , Domínios Proteicos , Precursores de Proteínas/química , Precursores de Proteínas/uso terapêutico , Receptores de Glutamato/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêutico , Coluna Vertebral/efeitos dos fármacos , Coluna Vertebral/fisiologia
4.
Int J Nanomedicine ; 15: 4275-4288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606677

RESUMO

Purpose: Selenium nanoparticles (Se NPs) are promising antibacterial agents to tackle the growing problem of antimicrobial resistance. The aim of this study was to fabricate Se NPs with a net positive charge to enhance their antibacterial efficacy. Methods: Se NPs were coated with a positively charged protein - recombinant spider silk protein eADF4(κ16) - to give them a net positive surface charge. Their cytotoxicity and antibacterial activity were investigated, with negatively charged polyvinyl alcohol coated Se NPs as a control. Besides, these eADF4(κ16)-coated Se NPs were immobilized on the spider silk films, and the antibacterial activity of these films was investigated. Results: Compared to the negatively charged polyvinyl alcohol coated Se NPs, the positively charged eADF4(κ16)-coated Se NPs demonstrated a much higher bactericidal efficacy against the Gram-negative bacteria E. coli, with a minimum bactericidal concentration (MBC) approximately 50 times lower than that of negatively charged Se NPs. Cytotoxicity testing showed that the eADF4(κ16)-coated Se NPs are safe to both Balb/3T3 mouse embryo fibroblasts and HaCaT human skin keratinocytes up to 31 µg/mL, which is much higher than the MBC of these particles against E. coli (8 ± 1 µg/mL). In addition, antibacterial coatings were created by immobilising the eADF4(κ16)-coated Se NPs on positively charged spider silk films and these were shown to retain good bactericidal efficacy and overcome the issue of low particle stability in culture broth. It was found that these Se NPs needed to be released from the film surface in order to exert their antibacterial effects and this release can be regulated by the surface charge of the film, such as the change of the spider silk protein used. Conclusion: Overall, eADF4(κ16)-coated Se NPs are promising new antibacterial agents against life-threatening bacteria.


Assuntos
Antibacterianos/farmacologia , Nanopartículas/química , Proteínas Recombinantes/farmacologia , Selênio/farmacologia , Seda/farmacologia , Células 3T3 , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Contagem de Colônia Microbiana , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Nanopartículas/ultraestrutura , Tamanho da Partícula
5.
Bratisl Lek Listy ; 121(8): 571-579, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726120

RESUMO

OBJECTIVE: The main objective of the present study was to investigate the possible osteostimulatory action of recombinant human matrix metalloproteinase-2 (rhMMP-2) implanted in a bone defect made in calvaria of rats, bounded to the monoolein as carrier. METHODS: Forty-four adult male Wistar rats (about 600 g body weight) underwent surgery in order to create a spherical defect in parietal bone on the right side of the median sagittal suture by using 4 mm diameter of a trephine drill. Animals were divided into three groups: no treatment (control, C), treatment with rhMMP-2 diluted in monoolein liquid crystal (rhMMP-2) and negative control with monoolein (M). The groups were divided into two experimental times, 2- and 4-weeks of experimental time. RESULTS: The rate of new-formed bone, estimated by the number of points on new-formed cancellous bone, was in enhanced rhMMP-2 group in both periods in comparison to C or M groups. CONCLUSION: There was no difference in bone neoformation between second to fourth week within groups. In the present study, monoolein alone had a negative role in the post-operative surgery, but monoolein associated with +rhMMP-2 had a positive role on releasing rhMMP-2 and enhance the rate of new-formed bone (Tab. 1, Fig. 5, Ref. 71).


Assuntos
Regeneração Óssea , Glicerídeos , Metaloproteinase 2 da Matriz , Proteínas Recombinantes , Adulto , Animais , Glicerídeos/farmacologia , Glicerídeos/uso terapêutico , Humanos , Masculino , Metaloproteinase 2 da Matriz/farmacologia , Ratos , Ratos Wistar , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
6.
PLoS Biol ; 18(7): e3000564, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32701952

RESUMO

Amyloids are protein aggregates with a highly ordered spatial structure giving them unique physicochemical properties. Different amyloids not only participate in the development of numerous incurable diseases but control vital functions in archaea, bacteria and eukarya. Plants are a poorly studied systematic group in the field of amyloid biology. Amyloid properties have not yet been demonstrated for plant proteins under native conditions in vivo. Here we show that seeds of garden pea Pisum sativum L. contain amyloid-like aggregates of storage proteins, the most abundant one, 7S globulin Vicilin, forms bona fide amyloids in vivo and in vitro. Full-length Vicilin contains 2 evolutionary conserved ß-barrel domains, Cupin-1.1 and Cupin-1.2, that self-assemble in vitro into amyloid fibrils with similar physicochemical properties. However, Cupin-1.2 fibrils unlike Cupin-1.1 can seed Vicilin fibrillation. In vivo, Vicilin forms amyloids in the cotyledon cells that bind amyloid-specific dyes and possess resistance to detergents and proteases. The Vicilin amyloid accumulation increases during seed maturation and wanes at germination. Amyloids of Vicilin resist digestion by gastrointestinal enzymes, persist in canned peas, and exhibit toxicity for yeast and mammalian cells. Our finding for the first time reveals involvement of amyloid formation in the accumulation of storage proteins in plant seeds.


Assuntos
Amiloide/metabolismo , Ervilhas/metabolismo , Proteínas de Armazenamento de Sementes/metabolismo , Sementes/metabolismo , Amiloide/ultraestrutura , Detergentes/farmacologia , Escherichia coli/metabolismo , Íons , Pancreatina/metabolismo , Ervilhas/efeitos dos fármacos , Pepsina A/metabolismo , Agregados Proteicos , Domínios Proteicos , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia , Saccharomyces cerevisiae/metabolismo , Proteínas de Armazenamento de Sementes/química , Proteínas de Armazenamento de Sementes/farmacologia , Proteínas de Armazenamento de Sementes/ultraestrutura
7.
PLoS One ; 15(7): e0235784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658899

RESUMO

Soft tissue is composed of cells surrounded by an extracellular matrix that is made up of a diverse array of intricately organized proteins. These distinct components work in concert to maintain homeostasis and respond to tissue damage. During tissue repair, extracellular matrix proteins and their degradation products are known to influence physiological processes such as angiogenesis and inflammation. In this study we developed a discovery platform using a decellularized extracellular matrix biomaterial to identify new chemotrophic factors derived from the extracellular matrix. An in vitro culture of RAW.264 macrophage cells with the biomaterial ovine forestomach matrix led to the identification of a novel ~12 kDa chemotactic factor, termed 'MayDay', derived from the N-terminal 31-188 sequence of decorin. The recombinant MayDay protein was shown to be a chemotactic agent for mesenchymal stromal cells in vitro and in vivo. We hypothesize that the macrophage-induced cleavage of decorin, via MMP-12, leads to the release of the chemotactic molecule MayDay, that in turn recruits cells to the site of damaged tissue.


Assuntos
Fatores Quimiotáticos/farmacologia , Decorina/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Células Cultivadas , Fatores Quimiotáticos/química , Quimiotaxia/efeitos dos fármacos , Decorina/química , Células-Tronco Mesenquimais/citologia , Camundongos , Fragmentos de Peptídeos/química , Células RAW 264.7 , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia , Ovinos
9.
Nat Commun ; 11(1): 2832, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504029

RESUMO

Human amyloids have been shown to interact with viruses and interfere with viral replication. Based on this observation, we employed a synthetic biology approach in which we engineered virus-specific amyloids against influenza A and Zika proteins. Each amyloid shares a homologous aggregation-prone fragment with a specific viral target protein. For influenza we demonstrate that a designer amyloid against PB2 accumulates in influenza A-infected tissue in vivo. Moreover, this amyloid acts specifically against influenza A and its common PB2 polymorphisms, but not influenza B, which lacks the homologous fragment. Our model amyloid demonstrates that the sequence specificity of amyloid interactions has the capacity to tune amyloid-virus interactions while allowing for the flexibility to maintain activity on evolutionary diverging variants.


Assuntos
Amiloide/farmacologia , Antivirais/farmacologia , Genética Reversa/métodos , Biologia Sintética/métodos , Amiloide/genética , Amiloide/uso terapêutico , Animais , Antivirais/uso terapêutico , Modelos Animais de Doenças , Cães , Feminino , Células HEK293 , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/genética , Vírus da Influenza A/patogenicidade , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Células Madin Darby de Rim Canino , Camundongos , Polimorfismo Genético , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Proteínas Virais/genética , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Zika virus/genética , Zika virus/patogenicidade , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/virologia
10.
Cell Host Microbe ; 27(6): 870-878, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: covidwho-436439

RESUMO

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Without approved antiviral therapeutics or vaccines to this ongoing global threat, type I and type III interferons (IFNs) are currently being evaluated for their efficacy. Both the role of IFNs and the use of recombinant IFNs in two related, highly pathogenic coronaviruses, SARS-CoV and MERS-CoV, have been controversial in terms of their protective effects in the host. In this review, we describe the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses and discuss the potential use of IFNs as a treatment strategy for COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Interferon Tipo I/imunologia , Interferons/imunologia , Pneumonia Viral/imunologia , Animais , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Evasão da Resposta Imune , Interferon Tipo I/genética , Interferon Tipo I/farmacologia , Interferons/genética , Interferons/farmacologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteínas Recombinantes/farmacologia , Transdução de Sinais
11.
Cell Host Microbe ; 27(6): 870-878, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: covidwho-594357

RESUMO

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Without approved antiviral therapeutics or vaccines to this ongoing global threat, type I and type III interferons (IFNs) are currently being evaluated for their efficacy. Both the role of IFNs and the use of recombinant IFNs in two related, highly pathogenic coronaviruses, SARS-CoV and MERS-CoV, have been controversial in terms of their protective effects in the host. In this review, we describe the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses and discuss the potential use of IFNs as a treatment strategy for COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Interferon Tipo I/imunologia , Interferons/imunologia , Pneumonia Viral/imunologia , Animais , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Evasão da Resposta Imune , Interferon Tipo I/genética , Interferon Tipo I/farmacologia , Interferons/genética , Interferons/farmacologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteínas Recombinantes/farmacologia , Transdução de Sinais
12.
Cell Host Microbe ; 27(6): 870-878, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: covidwho-381944

RESUMO

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Without approved antiviral therapeutics or vaccines to this ongoing global threat, type I and type III interferons (IFNs) are currently being evaluated for their efficacy. Both the role of IFNs and the use of recombinant IFNs in two related, highly pathogenic coronaviruses, SARS-CoV and MERS-CoV, have been controversial in terms of their protective effects in the host. In this review, we describe the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses and discuss the potential use of IFNs as a treatment strategy for COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Interferon Tipo I/imunologia , Interferons/imunologia , Pneumonia Viral/imunologia , Animais , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Evasão da Resposta Imune , Interferon Tipo I/genética , Interferon Tipo I/farmacologia , Interferons/genética , Interferons/farmacologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteínas Recombinantes/farmacologia , Transdução de Sinais
13.
Antiviral Res ; 179: 104811, 2020 07.
Artigo em Inglês | MEDLINE | ID: covidwho-133419

RESUMO

There is an urgent need to identify antivirals to curtail the COVID-19 pandemic. Herein, we report the sensitivity of SARS-CoV-2 to recombinant human interferons α and ß (IFNα/ß). Treatment with IFN-α or IFN-ß at a concentration of 50 international units (IU) per milliliter reduces viral titers by 3.4 log or over 4 log, respectively, in Vero cells. The EC50 of IFN-α and IFN-ß treatment is 1.35 IU/ml and 0.76 IU/ml, respectively, in Vero cells. These results suggest that SARS-CoV-2 is more sensitive than many other human pathogenic viruses, including SARS-CoV. Overall, our results demonstrate the potential efficacy of human Type I IFN in suppressing SARS-CoV-2 infection, a finding which could inform future treatment options for COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Interferon Tipo I/farmacologia , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Animais , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Imunidade Inata , Interferon-alfa/farmacologia , Interferon beta/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Proteínas Recombinantes/farmacologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Células Vero , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
14.
Eur Heart J Acute Cardiovasc Care ; 9(3): 209-214, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: covidwho-165340

RESUMO

Therapeutic options for coronavirus disease 2019 are desperately needed to respond to the ongoing severe acute respiratory syndrome coronavirus 2 pandemic. Both antiviral drugs and immunomodulators might have their place in the management of coronavirus disease 2019. Unfortunately, no drugs have been approved yet to treat infections with human coronaviruses. As it will take years to develop new therapies for severe acute respiratory syndrome coronavirus 2, the current focus is on the repurposing of drugs that have been approved or are in development for other conditions. Several clinical trials have already been conducted or are currently ongoing to evaluate the efficacy of such drugs. Here, we discuss the potential of these therapies for the treatment of coronavirus disease 2019.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Betacoronavirus/efeitos dos fármacos , Cloroquina/toxicidade , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Administração Intravenosa , Alanina/administração & dosagem , Alanina/farmacologia , Alanina/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Antivirais/uso terapêutico , Cloroquina/efeitos adversos , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Pandemias , Pneumonia Viral/epidemiologia , Pirazinas/farmacologia , Pirazinas/uso terapêutico , RNA Viral/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
15.
Anticancer Res ; 40(5): 2515-2523, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366396

RESUMO

BACKGROUND/AIM: Dedifferentiated liposarcoma (DDLPS) is associated with a poor survival rate even with multi-modality treatment. In the present study, we evaluated the efficacy of recombinant methioninase (rMETase) combined with tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R against a doxorubicin-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: A recurrent high-grade DDLPS from the right retroperitoneum of a patient was grown orthotopically in the retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomly divided into the following groups: Control, no treatment; doxorubicin monotherapy; rMETase monotherapy; S. typhimurium A1-R monotherapy; S. typhimurium A1-R and rMETase combination therapy. Tumor length and width were measured before and after treatment. RESULTS: On day 14 after treatment, all treatments significantly inhibited DDLPS PDOX tumor growth compared to the untreated control except for doxorubicin monotherapy. rMETase combined with S. typhimurium A1-R was significantly more effective and regressed tumor volume compared to either rMETase or S. typhimurium A1-R alone. The relative body weight did not significantly differ between days 0 and 14 for individual groups. CONCLUSION: The combination of rMETase and S. typhimurium A1-R has important clinical potential for this recalcitrant sarcoma.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Liases de Carbono-Enxofre/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lipossarcoma/patologia , Salmonella typhimurium/fisiologia , Animais , Terapia Combinada , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Lipossarcoma/tratamento farmacológico , Camundongos , Proteínas Recombinantes/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Eur Heart J Acute Cardiovasc Care ; 9(3): 209-214, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32363880

RESUMO

Therapeutic options for coronavirus disease 2019 are desperately needed to respond to the ongoing severe acute respiratory syndrome coronavirus 2 pandemic. Both antiviral drugs and immunomodulators might have their place in the management of coronavirus disease 2019. Unfortunately, no drugs have been approved yet to treat infections with human coronaviruses. As it will take years to develop new therapies for severe acute respiratory syndrome coronavirus 2, the current focus is on the repurposing of drugs that have been approved or are in development for other conditions. Several clinical trials have already been conducted or are currently ongoing to evaluate the efficacy of such drugs. Here, we discuss the potential of these therapies for the treatment of coronavirus disease 2019.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Betacoronavirus/efeitos dos fármacos , Cloroquina/toxicidade , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Administração Intravenosa , Alanina/administração & dosagem , Alanina/farmacologia , Alanina/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Antivirais/uso terapêutico , Cloroquina/efeitos adversos , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Pandemias , Pneumonia Viral/epidemiologia , Pirazinas/farmacologia , Pirazinas/uso terapêutico , RNA Viral/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
17.
Antiviral Res ; 179: 104811, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32360182

RESUMO

There is an urgent need to identify antivirals to curtail the COVID-19 pandemic. Herein, we report the sensitivity of SARS-CoV-2 to recombinant human interferons α and ß (IFNα/ß). Treatment with IFN-α or IFN-ß at a concentration of 50 international units (IU) per milliliter reduces viral titers by 3.4 log or over 4 log, respectively, in Vero cells. The EC50 of IFN-α and IFN-ß treatment is 1.35 IU/ml and 0.76 IU/ml, respectively, in Vero cells. These results suggest that SARS-CoV-2 is more sensitive than many other human pathogenic viruses, including SARS-CoV. Overall, our results demonstrate the potential efficacy of human Type I IFN in suppressing SARS-CoV-2 infection, a finding which could inform future treatment options for COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Interferon Tipo I/farmacologia , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Animais , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Imunidade Inata , Interferon-alfa/farmacologia , Interferon beta/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Proteínas Recombinantes/farmacologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Células Vero , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
18.
Stroke ; 51(6): 1886-1890, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32404037

RESUMO

Background and Purpose- Previous experimental studies found that the infusion of human purified nascent HDL (high-density lipoprotein) significantly reduced infarct volume and hemorrhagic transformation rate by decreasing neutrophil recruitment. ApoA1-M (apolipoprotein A1-Milano) is a natural variant of human ApoA1 that confers protection against atherosclerosis. Recombinant ApoA1-M has been formulated as a complex with phospholipids to mimic the properties of nascent HDL. The aim of this study was to assess the impact of intravenous ApoA1-M in a transient middle cerebral artery occlusion stroke model in rats. Methods- In a first experiment, rats were subjected to 120-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused immediately or 4 hours after occlusion. In a second experiment, rats were subjected to 240-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused with or without recombinant tPA (tissue-type plasminogen activator) immediately after recanalization. Primary outcome criteria were the infarct volume and hemorrhagic transformation rate measured at 24 hours. Platelets, coagulation, and neutrophil activation biomarkers were measured in brain homogenates and plasma. Additional in vitro experiments studied the effects of ApoA1-M on platelet aggregation and platelet-neutrophil interactions. Results- The infusion of ApoA1-M immediately or 4 hours after 120-minute transient middle cerebral artery occlusion significantly reduced the infarct volume compared with saline (P=0.034 and P=0.036, respectively). Compared with tPA alone, co-administration of ApoA1-M and tPA showed similar rates of hemorrhagic transformation. ApoA1-M had no significant inhibition effect on neutrophil activation biomarkers. Platelet activation was slightly decreased in rats treated with ApoA1-M compared with saline. In vitro, the incubation of human and rat platelet-rich plasma with ApoA1-M significantly reduced ADP-induced platelet aggregation (P=0.001 and P=0.02, respectively). Conclusions- ApoA1-Milano significantly decreased the infarct volume through an inhibition of platelet aggregation but did not reduce hemorrhagic transformation and neutrophils activation as expected after previous experimental studies with nascent HDL. Visual Overview- An online visual overview is available for this article.


Assuntos
Apolipoproteína A-I/farmacologia , Aterosclerose/prevenção & controle , Infarto da Artéria Cerebral Média/prevenção & controle , Animais , Aterosclerose/sangue , Aterosclerose/patologia , Biomarcadores/sangue , Plaquetas/metabolismo , Plaquetas/patologia , Modelos Animais de Doenças , Humanos , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/patologia , Masculino , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Agregação Plaquetária/efeitos dos fármacos , Ratos , Proteínas Recombinantes/farmacologia
19.
Proc Natl Acad Sci U S A ; 117(23): 13000-13011, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32434918

RESUMO

Extensive studies in prostate cancer and other malignancies have revealed that l-methionine (l-Met) and its metabolites play a critical role in tumorigenesis. Preclinical and clinical studies have demonstrated that systemic restriction of serum l-Met, either via partial dietary restriction or with bacterial l-Met-degrading enzymes exerts potent antitumor effects. However, administration of bacterial l-Met-degrading enzymes has not proven practical for human therapy because of problems with immunogenicity. As the human genome does not encode l-Met-degrading enzymes, we engineered the human cystathionine-γ-lyase (hMGL-4.0) to catalyze the selective degradation of l-Met. At therapeutically relevant dosing, hMGL-4.0 reduces serum l-Met levels to >75% for >72 h and significantly inhibits the growth of multiple prostate cancer allografts/xenografts without weight loss or toxicity. We demonstrate that in vitro, hMGL-4.0 causes tumor cell death, associated with increased reactive oxygen species, S-adenosyl-methionine depletion, global hypomethylation, induction of autophagy, and robust poly(ADP-ribose) polymerase (PARP) cleavage indicative of DNA damage and apoptosis.


Assuntos
Cistationina gama-Liase/farmacologia , Metionina/antagonistas & inibidores , Mutagênese Sítio-Dirigida , Neoplasias da Próstata/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Cistationina gama-Liase/genética , Cistationina gama-Liase/isolamento & purificação , Cistationina gama-Liase/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Ensaios Enzimáticos , Humanos , Masculino , Metionina/sangue , Metionina/metabolismo , Camundongos , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/sangue , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Testes de Toxicidade Aguda , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(1): 27-33, 2020 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376548

RESUMO

OBJECTIVE: To investigate the molecular mechanism of recombinant methioninase (rMETase) in promoting apoptosis of gastric cancer cells. METHODS: Gastric cancer SGC-7901 cells were treated with rMETase (final concentration of 1.25 and 2.50 mmmol/L) for 72 h, and the changes in the cell viability were detected using CCK-8 method and the cell morphology changes were observed under an inverted microscope. Plate colony formation assay was used to evaluate colony formation ability of the cells, and flow cytometry was performed to analyze the changes in cell apoptosis and cell cycles. Glucose and lactate levels in the culture medium were determined using a colorimetric method and ATP concentration was detected using a fluorescence microplate reader; Western blotting was used to assess the effect of rMETase on PI3K/Akt pathway, glucose transporter-1 (GLUT-1), glycolysis- related proteins and apoptotic proteins in SGC-7901 cells. RESULTS: rMETase significantly inhibited the proliferation and clonal formation, promoted cell apoptosis, and induced cell cycle arrest in S phase in SGC-7901 cells (P < 0.05). With the increase of rMETase concentration, the cells showed obviously decreased glucose intake accompanied by decreased glycolysis and ATP concentration (P < 0.001). The results of Western blotting showed that the expressions of PI3K, p-Akt/t-Akt, GLUT-1, and the key glycolytic enzymes HK2, PFKM, LDHA, antiapoptosis protein Bcl-2 were all downregulated and the pro-apoptotic proteins Bax and caspase-3 were up-regulated in response to rMETase treatment in SGC-7901 cells (P < 0.01). CONCLUSIONS: rMETase can inhibit aerobic glycolysis, induce apoptosis and inhibit the proliferation of SGC-7901 cells by inhibiting the activity of PI3K/Akt/GLUT-1 pathway, suggesting its potential as a therapeutic agent for gastric cancer.


Assuntos
Apoptose , Liases de Carbono-Enxofre/farmacologia , Transdução de Sinais , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transportador de Glucose Tipo 1/metabolismo , Glicólise , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes/farmacologia
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