Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21.254
Filtrar
1.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502086

RESUMO

In recent years, enzymes have risen as promising therapeutic tools for different pathologies, from metabolic deficiencies, such as fibrosis conditions, ocular pathologies or joint problems, to cancer or cardiovascular diseases. Treatments based on the catalytic activity of enzymes are able to convert a wide range of target molecules to restore the correct physiological metabolism. These treatments present several advantages compared to established therapeutic approaches thanks to their affinity and specificity properties. However, enzymes present some challenges, such as short in vivo half-life, lack of targeted action and, in particular, patient immune system reaction against the enzyme. For this reason, it is important to monitor serum immune response during treatment. This can be achieved by conventional techniques (ELISA) but also by new promising tools such as microarrays. These assays have gained popularity due to their high-throughput analysis capacity, their simplicity, and their potential to monitor the immune response of patients during enzyme therapies. In this growing field, research is still ongoing to solve current health problems such as COVID-19. Currently, promising therapeutic alternatives using the angiotensin-converting enzyme 2 (ACE2) are being studied to treat COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/uso terapêutico , COVID-19/tratamento farmacológico , Terapia Enzimática/métodos , Proteínas Recombinantes/uso terapêutico , Enzima de Conversão de Angiotensina 2/farmacologia , Ensaios Clínicos Fase II como Assunto , Composição de Medicamentos/métodos , Estabilidade Enzimática , Terapia Enzimática/história , Terapia Enzimática/tendências , Meia-Vida , História do Século XX , História do Século XXI , Humanos , Proteínas Recombinantes/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , Resultado do Tratamento , Internalização do Vírus/efeitos dos fármacos
2.
Front Immunol ; 12: 706186, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484202

RESUMO

Background: Sargramostim [recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)] was approved by US FDA in 1991 to accelerate bone marrow recovery in diverse settings of bone marrow failure and is designated on the list of FDA Essential Medicines, Medical Countermeasures, and Critical Inputs. Other important biological activities including accelerating tissue repair and modulating host immunity to infection and cancer via the innate and adaptive immune systems are reported in pre-clinical models but incompletely studied in humans. Objective: Assess safety and efficacy of sargramostim in cancer and other diverse experimental and clinical settings. Methods and Results: We systematically reviewed PubMed, Cochrane and TRIP databases for clinical data on sargramostim in cancer. In a variety of settings, sargramostim after exposure to bone marrow-suppressing agents accelerated hematologic recovery resulting in fewer infections, less therapy-related toxicity and sometimes improved survival. As an immune modulator, sargramostim also enhanced anti-cancer responses in solid cancers when combined with conventional therapies, for example with immune checkpoint inhibitors and monoclonal antibodies. Conclusions: Sargramostim accelerates hematologic recovery in diverse clinical settings and enhances anti-cancer responses with a favorable safety profile. Uses other than in hematologic recovery are less-well studied; more data are needed on immune-enhancing benefits. We envision significantly expanded use of sargramostim in varied immune settings. Sargramostim has the potential to reverse the immune suppression associated with sepsis, trauma, acute respiratory distress syndrome (ARDS) and COVID-19. Further, sargramostim therapy has been promising in the adjuvant setting with vaccines and for anti-microbial-resistant infections and treating autoimmune pulmonary alveolar proteinosis and gastrointestinal, peripheral arterial and neuro-inflammatory diseases. It also may be useful as an adjuvant in anti-cancer immunotherapy.


Assuntos
COVID-19/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunoterapia , Neoplasias/tratamento farmacológico , COVID-19/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , SARS-CoV-2/efeitos dos fármacos
3.
Med Klin Intensivmed Notfmed ; 116(6): 491-498, 2021 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-34463792

RESUMO

BACKGROUND: Severe bleeding under antithrombotic therapy is common and challenging in intensive care medicine; on the one hand, rapid bleeding control must be achieved and, on the other hand, thromboembolic complications must be avoided. AIMS: The paper will provide a brief overview of direct oral anticoagulants, therapeutic options and precise instructions for dealing with severe bleeding. RESULTS: In addition to general measures in direct oral anticoagulant (DOAC)-associated major bleeding, prothrombin complex concentrate (PCC), idarucizumab and andexanet alfa are available as specific antidote therapy. In case of bleeding under heparin therapy, protamine sulfate is available as a possible antidote. CONCLUSIONS: In particular, the importance of andexanet alfa in the treatment of factor Xa inhibitor-associated bleeding requires further investigation.


Assuntos
Fibrinolíticos , Hemorragia , Administração Oral , Anticoagulantes/efeitos adversos , Antídotos/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Fibrinolíticos/efeitos adversos , Hemorragia/tratamento farmacológico , Hemorragia/terapia , Humanos , Proteínas Recombinantes/uso terapêutico
4.
Medicine (Baltimore) ; 100(30): e26711, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397702

RESUMO

OBJECTIVE: Growth hormone (GH) treatment is known to be effective in increasing stature in children with a short stature born small for gestational age (SGA). This multicentre, randomized, open-label, comparative, phase III study aimed to evaluate the efficacy and safety of Growtropin-II (recombinant human GH) and to demonstrate that the growth-promoting effect of Growtropin-II is not inferior to that of Genotropin in children with SGA (NCT ID: NCT02770157). METHODS: Seventy five children who met the inclusion criteria were randomized into 3 groups in a ratio of 2:2:1 (the study group [Growtropin-II, n = 30], control group [Genotropin, n = 30], and 26-week non-treatment group [n = 15]). The study and control groups received subcutaneous injections of Growtropin-II and Genotropin, respectively for 52 weeks, whereas the non-treatment group underwent a non-treatment observation period during weeks 0 to 26 and a dosing period during weeks 27 to 52 and additional dosing till week 78 only in re-consenting children. RESULTS: No significant differences in demographic and baseline characteristics between the groups were observed. The mean ± standard deviation change difference in annualized height velocity (aHV) (study group - control group) was 0.65 ±2.12 cm/year (95% confidence interval [CI], -0.53 to 1.83), whereas the lower limit for the 2-sided 95% CI was -0.53 cm/year. Regarding safety, treatment-emergent adverse events (TEAEs) occurred in 53.33% children in the study group and 43.33% children in the control group; the difference in the incidence of TEAEs between the 2 treatment groups was not statistically significant (P  = .4383). A total of 17 serious adverse events (SAEs) occurred in 13.33% children in the treatment groups, and no significant difference in incidence between groups (P  = .7065) was seen. Two cases of adverse drug reaction (ADR) occurred in 2 children (3.33%): 1 ADR (injection site swelling or pain) occurred in 1 child (3.33%) each in the study and control groups. CONCLUSIONS: This study demonstrates that the change in aHV from the baseline till 52 weeks with Growtropin-II treatment is non-inferior to that with Genotropin treatment in children with short stature born SGA. Growtropin-II is well-tolerated, and its safety profile is comparable with that of Genotropin over a 1-year course of treatment.


Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino
7.
Br J Oral Maxillofac Surg ; 59(7): 757-762, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34266703

RESUMO

Recent studies have indicated the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) to be a viable adjunctive to alveolar cleft reconstruction owing to its osteoinductive capacity. This study aimed to evaluate the efficacy of rhBMP-2 in the treatment of alveolar cleft with autologous bone grafts by precise volumetric analysis. Twenty-six patients (aged 8-14) with unilateral alveolar clefts were enrolled in this comparative study. Patients were divided into two groups: the iliac crest bone graft (ICBG) was placed at the side of the cleft in the control group (ICBG group), and rhBMP-2 was mixed with the ICBG in the rhBMP-2 group (BMP group). Helical computed tomographic images were obtained preoperatively and 12 months postoperatively. The datasets were reconstructed as three-dimensional (3D) images using Mimics software and processed using Geomagic Wrap. The newly formed bone of the alveolar cleft was segmented by identifying the differences between preoperative and postoperative 3D images. In the ICBG group, the volume of newly formed bone ranged from 0.25 to 0.88 cm3, and the mean (SD) bone formation percentage was 42.01% (15.57%). In the BMP group, the volume of newly formed bone ranged from 0.34 to 1.09 cm3, and the bone formation mean (SD) percentage was 55.79% (11.84%). There was a statistically significant difference between the two groups in terms of the postoperative percentage of bone formation (p = 0.022). Thus, rhBMP-2 combined with an autologous bone graft is a promising technique to improve the results of secondary alveolar bone grafting.


Assuntos
Enxerto de Osso Alveolar , Fissura Palatina , Proteína Morfogenética Óssea 2/uso terapêutico , Transplante Ósseo , Fissura Palatina/cirurgia , Computadores , Humanos , Ílio , Proteínas Recombinantes/uso terapêutico , Fator de Crescimento Transformador beta/uso terapêutico
8.
Biomed Environ Sci ; 34(6): 443-453, 2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284852

RESUMO

Objective: To investigate the changes in the cytokine profiles of chronic hepatitis B (CHB) patients undergoing antiviral treatment. Methods: Hepatitis B e antigen (HBeAg)-positive patients were treated with Pegylated interferon (PEG-IFN) and entecavir (ETV). Clinical biochemistry and cytokines were detected at baseline and every 3 months. Results: In all, 200 patients completed 48 weeks of treatment, 100 in the PEG-IFN group and 100 in the ETV group. During 3-6 months of treatment, compared with baseline, the PEG-IFN group showed a significant decrease in interferon-gamma (IFN-γ), interleukin-17A (IL-17A), interleukin-6(IL-6), interleukin-10(IL-10), and transforming growth factor beta (TGF-ß) ( P < 0.001) and a significant increase in interferon-alpha 2(IFN-α2) ( P < 0.001). In the ETV group, IL-10 and TGF-ß1 decreased significantly ( P < 0.001). After 3 months, the levels of IFN-α2, IL-17A, and tumor necrosis factor-alpha(TNF-α) in the PEG-IFN group were significantly higher than those in the ETV group ( P < 0.01). The levels of IL-6 and TGF-ß3 were significantly lower than those in the ETV group ( P < 0.01). After 6 months, the levels of IFN-α2, IFN-γ, and TNF-α in the PEG-IFN group were significantly higher than those in the ETV group ( P < 0.01), while the levels of IL-6 and TGF-ß3 were significantly lower than those in the ETV group ( P < 0.01). Compared with ETV, PEG-IFN had higher HBeAg and HBsAg disappearance rates. Conclusion: During antiviral therapy, a change in the cytokine profile occurred; in the aspect of immune control and functional cure, PEG-IFN was significantly better than ETV.


Assuntos
Antivirais/uso terapêutico , Citocinas/sangue , Guanina/análogos & derivados , Hepatite B Crônica/sangue , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adulto , Antivirais/farmacologia , Feminino , Guanina/farmacologia , Guanina/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Humanos , Interferon-alfa/farmacologia , Masculino , Polietilenoglicóis/farmacologia , Estudos Prospectivos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
9.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34070997

RESUMO

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder based on a mutation in the IDS gene that encodes iduronate 2-sulphatase. As a result, there is an accumulation of glycosaminoglycans-heparan sulphate and dermatan sulphate-in almost all body tissues, which leads to their dysfunction. Currently, the primary treatment is enzyme replacement therapy, which improves the course of the disease by reducing somatic symptoms, including hepatomegaly and splenomegaly. The enzyme, however, does not cross the blood-brain barrier, and no improvement in the function of the central nervous system has been observed in patients with the severe form of the disease. An alternative method of treatment that solves typical problems of enzyme replacement therapy is gene therapy, i.e., delivery of the correct gene to target cells through an appropriate vector. Much progress has been made in applying gene therapy for MPS II, from cellular models to human clinical trials. In this article, we briefly present the history and basics of gene therapy and discuss the current state of knowledge about the methods of this therapy in mucopolysaccharidosis type II.


Assuntos
Glicoproteínas/genética , Mucopolissacaridose II/terapia , Adolescente , Animais , Barreira Hematoencefálica , Sistemas CRISPR-Cas , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Dependovirus/genética , Modelos Animais de Doenças , Portadores de Fármacos , Eletroporação , Terapia de Reposição de Enzimas/métodos , Edição de Genes , Terapia Genética , Vetores Genéticos/efeitos adversos , Vetores Genéticos/uso terapêutico , Glicoproteínas/farmacocinética , Glicoproteínas/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/uso terapêutico , Lactente , Injeções Intraventriculares , Injeções Espinhais , Lentivirus/genética , Camundongos , Mucopolissacaridose II/genética , Estudos Multicêntricos como Assunto , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Retroviridae/genética , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição
10.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066510

RESUMO

Neutrophil extracellular trap (NET) formation, an innate immune system response, is associated with thrombogenesis and vascular endothelial injury. Circulatory disorders due to microvascular thrombogenesis are one of the principal causes of organ damage. NET formation in organs contributes to the exacerbation of sepsis, which is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. We have previously reported that recombinant human soluble thrombomodulin (rTM) reduces lipopolysaccharide (LPS)-induced NET formation in vitro. Here, we aimed to show that thrombomodulin (TM)-mediated suppression of NET formation protects against organ damage in sepsis. Mice were injected intraperitoneally (i.p.) with 10 mg/kg LPS. rTM (6 mg/kg/day) or saline was administered i.p. 1 h after LPS injection. In the LPS-induced murine septic shock model, extracellular histones, which are components of NETs, were observed in the liver and lungs. In addition, the serum cytokine (interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), macrophage chemotactic protein-1 (MCP-1), and interleukin-10 (IL-10)) levels were increased. The administration of rTM in this model prevented NET formation in the organs and suppressed the increase in the levels of all cytokines except IL-1ß. Furthermore, the survival rate improved. We provide a novel role of TM in treating inflammation and NETs in organs during sepsis.


Assuntos
Armadilhas Extracelulares/metabolismo , Fígado/patologia , Pulmão/patologia , Choque Séptico/tratamento farmacológico , Trombomodulina/uso terapêutico , Animais , Citocinas/sangue , Modelos Animais de Doenças , Armadilhas Extracelulares/efeitos dos fármacos , Feminino , Humanos , Lipopolissacarídeos , Fígado/ultraestrutura , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Choque Séptico/sangue , Choque Séptico/induzido quimicamente , Análise de Sobrevida
11.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070642

RESUMO

Urate oxidase initiates the uric acid degradation pathways and is extensively used for protein drug development for gout therapy and serum uric acid diagnosis. We first present the biochemical and structural elucidation of a urate oxidase from the extremophile microorganism Deinococcus radiodurans (DrUox). From enzyme characterization, DrUox showed optimal catalytic ability at 30 °C and pH 9.0 with high stability under physiological conditions. Only the Mg2+ ion moderately elevated its activity, which indicates the characteristic of the cofactor-free urate oxidase family. Of note, DrUox is thermostable in mesophilic conditions. It retains almost 100% activity when incubated at 25 °C and 37 °C for 24 h. In this study, we characterized a thermostable urate oxidase, DrUox with high catalytic efficiency and thermal stability, which strengthens its potential for medical applications.


Assuntos
Proteínas de Bactérias , Deinococcus , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Urato Oxidase , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/uso terapêutico , Deinococcus/enzimologia , Deinococcus/genética , Humanos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico , Urato Oxidase/química , Urato Oxidase/genética , Urato Oxidase/uso terapêutico
12.
Artigo em Russo | MEDLINE | ID: mdl-34156209

RESUMO

The authors report resection of anaplastic convexital meningioma in a middle-aged woman complicated by expected massive blood loss. The most intense bleeding occurred at the final stage of resection and it was impossible to stop it with traditional approaches. The surgeon pressed a standard tachocomb plate moistened with a diluted solution of recombinant activated factor VII (coagil, Russia) to the most bleeding area for 5 minutes. Subsequently, surgeon replaced finger pressure with a permanent napkin. Hemostatic effect of recombinant activated factor VII following its systemic administration is well known and convincingly proven in many surgical areas including neurosurgery. However, we do not know any descriptions of its local application in neurosurgical patients.


Assuntos
Fator VIIa/uso terapêutico , Hemostáticos , Neoplasias Meníngeas , Perda Sanguínea Cirúrgica , Feminino , Humanos , Neoplasias Meníngeas/cirurgia , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Federação Russa
13.
Naunyn Schmiedebergs Arch Pharmacol ; 394(7): 1589-1593, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34151392

RESUMO

In March 2019, the global COVID-19 pandemic caused by the novel SARS-CoV-2 coronavirus began. The first cases of SARS-CoV-2 infection occurred in November 19 in Wuhan, China. Preventive measures taken have not prevented the rapid spread of the virus to countries around the world. To date, there are approximately 3 million deaths, and a massive worldwide vaccination campaign has recently begun. SARS-CoV-2 uses the ACE-2 protein as an intracellular carrier. ACE-2 is a key component of the renin-angiotensin system (RAS), a key regulator of cardiovascular function. Considering the key role of ACE-2 in COVID-19 infection, both as an entry receptor and as a protective role, especially for the respiratory tract, and considering the variations of ACE-2 during the phases of viral infection, it is clear the important role that pharmacological regulation of RAS and ACE-2 may take. In this article, we describe the importance of ACE-2 in COVID-19 infection, the pharmacological aspects of a modulation with RAS-modifying agents, new therapeutic strategies, trying to provide a deep understanding and explanation of the complex mechanisms underlying the relationship between the virus and ACE-2, providing opinions and personal hypotheses on the best strategies of therapeutic intervention.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , COVID-19/enzimologia , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Proteínas Recombinantes/uso terapêutico , SARS-CoV-2/patogenicidade
14.
Sci Rep ; 11(1): 10475, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006961

RESUMO

Infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes COVID-19 disease. Therapeutic antibodies are being developed that interact with the viral spike proteins to limit viral infection of epithelium. We have applied a method to dramatically improve the performance of anti-SARS-CoV-2 antibodies by enhancing avidity through multimerization using simple engineering to yield tetrameric antibodies. We have re-engineered six anti-SARS-CoV-2 antibodies using the human p53 tetramerization domain, including three clinical trials antibodies casirivimab, imdevimab and etesevimab. The method yields tetrameric antibodies, termed quads, that retain efficient binding to the SARS-CoV-2 spike protein, show up to two orders of magnitude enhancement in neutralization of pseudovirus infection and retain potent interaction with virus variant of concern spike proteins. The tetramerization method is simple, general and its application is a powerful methodological development for SARS-CoV-2 antibodies that are currently in pre-clinical and clinical investigation.


Assuntos
SARS-CoV-2/metabolismo , Anticorpos de Cadeia Única/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Reações Antígeno-Anticorpo , COVID-19/tratamento farmacológico , COVID-19/virologia , Ensaio de Imunoadsorção Enzimática , Células HEK293 , Humanos , Testes de Neutralização , Domínios Proteicos , Multimerização Proteica , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/uso terapêutico , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Anticorpos de Cadeia Única/química , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/uso terapêutico , Ressonância de Plasmônio de Superfície , Proteína Supressora de Tumor p53/química
15.
Nat Commun ; 12(1): 3142, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035264

RESUMO

Transthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Cardiomiopatias/tratamento farmacológico , Macrófagos/imunologia , Pré-Albumina/antagonistas & inibidores , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/patologia , Animais , Anticorpos Monoclonais/uso terapêutico , Cardiomiopatias/patologia , Ensaios Clínicos Fase I como Assunto , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Mutação , Miocárdio/patologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Pré-Albumina/genética , Pré-Albumina/metabolismo , Agregados Proteicos/efeitos dos fármacos , Agregados Proteicos/imunologia , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transplante Heterólogo
16.
Mediators Inflamm ; 2021: 9979032, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33967626

RESUMO

Coronaviruses (CoVs) are enveloped and harbor an unusually large (30-32 kb) positive-strand linear RNA genome. Highly pathogenic coronaviruses cause severe acute respiratory syndrome (SARS) (SARS-CoV and SARS-CoV-2) and Middle East respiratory syndrome (MERS) (MERS-CoV) in humans. The coronavirus mouse hepatitis virus (MHV) infects mice and serves as an ideal model of viral pathogenesis, mainly because experiments can be conducted using animal-biosafety level-2 (A-BSL2) containment. Human thymosin beta-4 (Tß4), a 43-residue peptide with an acetylated N-terminus, is widely expressed in human tissues. Tß4 regulates actin polymerization and functions as an anti-inflammatory molecule and an antioxidant as well as a promoter of wound healing and angiogenesis. These activities led us to test whether Tß4 serves to treat coronavirus infections of humans. To test this possibility, here, we established a BALB/c mouse model of coronavirus infection using mouse CoV MHV-A59 to evaluate the potential protective effect of recombinant human Tß4 (rhTß4). Such a system can be employed under A-BSL2 containment instead of A-BSL3 that is required to study coronaviruses infectious for humans. We found that rhTß4 significantly increased the survival rate of mice infected with MHV-A59 through inhibiting virus replication, balancing the host's immune response, alleviating pathological damage, and promoting repair of the liver. These results will serve as the basis for further application of rhTß4 to the treatment of human CoV diseases such as COVID-19.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Vírus da Hepatite Murina , Timosina/uso terapêutico , Animais , Anticorpos Antivirais/sangue , Proteína C-Reativa/análise , Citocinas/sangue , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Vírus da Hepatite Murina/imunologia , RNA Viral/análise , Proteínas Recombinantes/uso terapêutico , Replicação Viral/efeitos dos fármacos
17.
Blood Cells Mol Dis ; 89: 102570, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962291

RESUMO

Hemophilia A and hemophilia B are X-linked inherited bleeding disorders caused by a deficiency of coagulation factor VIII and IX, respectively. Standard of care is prophylactic factor replacement therapy; however, the development of neutralizing antibodies against these factors represents serious complications underlining the need for alternative treatment approaches. Human coagulation factor X has a central role within the blood coagulation system making it an attractive target for the development of alternative treatment strategies for patients with hemophilia. This study focuses on a modified variant of the human coagulation factor X with enhanced hemostatic bypass activity due to insertion of a factor IX derived activation sequence. This molecule design leads to the direct activation of the modified factor X protein by factor XIa allowing it to bypass the need for coagulation factor VIIIa/factor IXa. The modified variant was able to correct in-vitro activated partial prothrombin time of human and murine factor VIII/factor IX deficient plasma. Furthermore, reduced blood loss in factor VIII knock-out mice was observed after intravenous application of the modified factor X variant. In conclusion, these data suggest that the factor X variant described here could potentially serve as a bypassing agent independent of the inhibitor status of hemophilia patients. However, more research is needed to further investigate the potential of this molecule.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fator X/farmacologia , Hemostáticos/farmacologia , Animais , Fator X/uso terapêutico , Feminino , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Hemorragia/sangue , Hemorragia/tratamento farmacológico , Hemostáticos/uso terapêutico , Humanos , Masculino , Camundongos , Tempo de Tromboplastina Parcial , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
18.
J Biol Chem ; 296: 100761, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33971198

RESUMO

Diabetes mellitus (DM) causes injury to tissues and organs, including to the heart and kidney, resulting in increased morbidity and mortality. Thus, novel potential therapeutics are continuously required to minimize DM-related organ damage. We have previously shown that dipeptidyl peptidase III (DPPIII) has beneficial roles in a hypertensive mouse model, but it is unknown whether DPPIII has any effects on DM. In this study, we found that intravenous administration of recombinant DPPIII in diabetic db/db mice for 8 weeks suppressed the DM-induced cardiac diastolic dysfunctions and renal injury without alteration of the blood glucose level. This treatment inhibited inflammatory cell infiltration and fibrosis in the heart and blocked the increase in albuminuria by attenuating the disruption of the glomerular microvasculature and inhibiting the effacement of podocyte foot processes in the kidney. The beneficial role of DPPIII was, at least in part, mediated by the cleavage of a cytotoxic peptide, named Peptide 2, which was increased in db/db mice compared with normal mice. This peptide consisted of nine amino acids, was a digested fragment of complement component 3 (C3), and had an anaphylatoxin-like effect determined by the Miles assay and chemoattractant analysis. The effect was dependent on its interaction with the C3a receptor and protein kinase C-mediated RhoA activation downstream of the receptor in endothelial cells. In conclusion, DPPIII plays a protective role in the heart and kidney in a DM animal model through cleavage of a peptide that is a part of C3.


Assuntos
Cardiomiopatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Animais , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Terapia Enzimática , Coração/fisiopatologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Rim/metabolismo , Rim/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico
19.
Aliment Pharmacol Ther ; 54(2): 176-182, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34048594

RESUMO

BACKGROUND: Hepatitis delta virus (HDV) infection is the most aggressive form of chronic viral hepatitis. Response rates to therapy with 1- to 2-year courses of pegylated interferon alpha (peginterferon) treatment are suboptimal. AIMS: To evaluate the long-term outcomes of patients with chronic hepatitis D after an extended course of peginterferon. METHODS: Patients were followed after completion of trial NCT00023322 and classified based on virological response defined as loss of detectable serum HDV RNA at last follow-up. During extended follow-up, survival and liver-related events were recorded. RESULTS: All 12 patients who received more than 6 months of peginterferon in the original study were included in this analysis. The cohort was mostly white (83%) and male (92%) and ranged in age from 18 to 58 years (mean = 42.6). Most patients had advanced but compensated liver disease at baseline, a median HBV DNA level of 536 IU per mL and median HDV RNA level of 6.86 log10 genome equivalents per mL. The treatment duration averaged 6.1 years (range 0.8-14.3) with a total follow-up of 8.8 years (range 1.7-17.6). At last follow-up, seven (58%) patients had durable undetectable HDV RNA in serum, and four (33%) cleared HBsAg. Overall, one of seven (14%) responders died or had a liver-related event vs four of five (80%) non-responders. CONCLUSIONS: With further follow-up, an extended course of peginterferon therapy was found to result in sustained clearance of HDV RNA and favourable clinical outcomes in more than half of patients and loss of HBsAg in a third.


Assuntos
Hepatite D Crônica , Adolescente , Adulto , Antivirais/efeitos adversos , Feminino , Antígenos de Superfície da Hepatite B , Hepatite D Crônica/tratamento farmacológico , Vírus Delta da Hepatite/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , RNA Viral , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Adulto Jovem
20.
Chem Biol Interact ; 344: 109495, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33961834

RESUMO

Cataracts, a clouding of the eye lens, are a leading cause of visual impairment and are responsible for one of the most commonly performed surgical procedures worldwide. Although generally safe and effective, cataract surgery can lead to a secondary lens abnormality due to transition of lens epithelial cells to a mesenchymal phenotype (EMT) and opacification of the posterior lens capsular bag. Occurring in up to 40% of cataract cases over time, posterior capsule opacification (PCO) introduces additional treatment costs and reduced quality of life for patients. Studies have shown that PCO pathogenesis is driven in part by TGF-ß, signaling through the action of the family of Smad coactivators to effect changes in gene transcription. In the present study, we evaluated the ability of Smad-7, a well characterized inhibitor of TGF-ß -mediated Smad signaling, to suppress the EMT response in lens epithelial cells associated with PCO pathogenesis. Treatment of lens epithelial cells with a cell-permeable form of Smad7 variant resulted in suppressed expression of EMT markers such as alpha smooth muscle actin and fibronectin. A single application of cell-permeable Smad7 variant in the capsular bag of a mouse cataract surgery model resulted in suppression of gene transcripts encoding alpha smooth muscle actin and fibronectin. These results point to Smad7 as a promising biotherapeutic agent for prevention or substantial reduction in the incidence of PCO following cataract surgery.


Assuntos
Opacificação da Cápsula/prevenção & controle , Peptídeos Penetradores de Células/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Produtos do Gene tat/uso terapêutico , Cristalino/efeitos dos fármacos , Proteína Smad7/uso terapêutico , Actinas/metabolismo , Animais , Opacificação da Cápsula/etiologia , Opacificação da Cápsula/patologia , Catarata/complicações , Catarata/patologia , Células Epiteliais/efeitos dos fármacos , Cristalino/patologia , Camundongos Transgênicos , Domínios Proteicos , Proteínas Recombinantes/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...