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1.
Int J Nanomedicine ; 14: 7743-7758, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571874

RESUMO

Purpose: Peptide drugs have been used in therapy various diseases. However, the poor bioavailability of peptide drugs for oral administration has limited their clinical applications, on account of the acidic environment and digestive enzymes inside the human gastrointestinal tract. To enhance stability in the human gastrointestinal tract, bioavailability, and targeted drug delivery of peptide drugs through oral administration, a vitamin B12-modified amphiphilic sodium alginate derivative (CSAD-VB12) was synthesized. Materials and methods: A vitamin B12-modified amphiphilic sodium alginate derivative (CSAD-VB12) was synthesized via the N,N'-dicyclohexylcarbodiimide active method at room temperature, and then characterized using FTIR and 1H NMR spectroscopy. Insulin was used as a model peptide drug and the insulin-loaded CSAD-VB12 (CSAD-VB12/insulin) nanoparticles with negative zeta potentials were prepared in PBS (pH=7.4). Scanning electron microscopy was used to observe CSAD-VB12/insulin as spherical nanoparticles. The CSAD-VB12 derivatives and CSAD-VB12/insulin nanoparticles displayed nontoxicity towards the human colon adenocarcinoma (Caco-2) cells by CCK-8 test. Caco-2 cell model was used to measure the apparent permeability (Papp) of insulin, CSAD/insulin and CSAD-VB12/insulin. Furthermore, confocal was used to confirm the endocytosis of intestinal enterocytes. Type 1 diabetes mice were used to evaluate the intestinal absorption and retention effect of test nanoparticles. Results: They were observed as spherical nanoparticles in the size of 30-50 nm. The CSAD-VB12 derivatives and CSAD-VB12/insulin nanoparticles displayed nontoxicity towards the human colon adenocarcinoma (Caco-2) cells. Comparing with insulin and the CSAD/insulin nanoparticles, the CSAD-VB12/insulin nanoparticles exhibited higher permeation ability through intestinal enterocytes in the Caco-2 cell model. Oral administration of the CSAD-VB12/insulin nanoparticles to Type 1 diabetic mice yields higher intestinal retention effect, targeted absorption, and outstanding efficacy. Conclusion: CSAD-VB12 derivatives enhance the small intestinal absorption efficacy and retention of peptide by oral administration, which indicated that it could be a promising candidate for oral peptide delivery in the prospective clinical application.


Assuntos
Alginatos/química , Sistemas de Liberação de Medicamentos , Peptídeos/administração & dosagem , Preparações Farmacêuticas/administração & dosagem , Vitamina B 12/química , Administração Oral , Alginatos/síntese química , Animais , Células CACO-2 , Morte Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Insulina/administração & dosagem , Insulina/farmacologia , Insulina/uso terapêutico , Absorção Intestinal/efeitos dos fármacos , Masculino , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier , Vitamina B 12/síntese química
2.
BMC Bioinformatics ; 20(1): 456, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492094

RESUMO

*: Background In the search for therapeutic peptides for disease treatments, many efforts have been made to identify various functional peptides from large numbers of peptide sequence databases. In this paper, we propose an effective computational model that uses deep learning and word2vec to predict therapeutic peptides (PTPD). *: Results Representation vectors of all k-mers were obtained through word2vec based on k-mer co-existence information. The original peptide sequences were then divided into k-mers using the windowing method. The peptide sequences were mapped to the input layer by the embedding vector obtained by word2vec. Three types of filters in the convolutional layers, as well as dropout and max-pooling operations, were applied to construct feature maps. These feature maps were concatenated into a fully connected dense layer, and rectified linear units (ReLU) and dropout operations were included to avoid over-fitting of PTPD. The classification probabilities were generated by a sigmoid function. PTPD was then validated using two datasets: an independent anticancer peptide dataset and a virulent protein dataset, on which it achieved accuracies of 96% and 94%, respectively. *: Conclusions PTPD identified novel therapeutic peptides efficiently, and it is suitable for application as a useful tool in therapeutic peptide design.


Assuntos
Biologia Computacional/métodos , Aprendizado Profundo , Peptídeos/uso terapêutico , Bases de Dados de Ácidos Nucleicos , Descoberta de Drogas
3.
Mol Biol (Mosk) ; 53(4): 541-560, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31397431

RESUMO

The human respiratory syncytial virus (RSV) is one of the most common viral pathogens that affects the lower respiratory tract and could be a reason of bronchiolitis and/or pneumonia. Currently, there are no available effective ways of treating the RSV infection. Attempts to develop preventive vaccine have been unsuccessful. The only therapeutic agent used for RSV treatment is virazole (ribavirin); however, it induces adverse effects. Medications based on neutralizing monoclonal antibodies, such as IGIV (Respigam), palivizumab (Synagis), and MEDI-524 (Numab), are under clinical trials; however, their use will be limited by their high cost. One of the promising approaches for antiviral therapy is the use of natural peptides (defensins and cathelicidins), or their synthetic analogs. The majority of currently described antiviral peptides are developed against the human immunodeficiency virus, the herpes simplex virus, and the influenza virus. At the same time, a body of experimental data evidencing anti-RSV activity of peptides has been accumulated. The main advantages of peptide drugs are their wide spectrum of antiviral activity and low toxicity. However, there are obstacles in implementing peptide-based drugs in clinical practice. Due to their low resistance to the action of serum proteases, most authors consider peptides promising only for local application. Given that RSV affects the epithelium of the respiratory tract, where the protease activity is lower than in the systemic circulation, it is possible to develop locally active peptide drugs, for example, as inhalation forms. Their stability could also be increased by the synthesis of dendrimer peptides and by the development of recombinant peptides as precursor proteins. Anti-RSV peptides can be divided into several groups: (1) attachment and/or fusion blockers; (2) peptides displaying direct virucidal activity, disrupting the viral envelope. Such peptides, which suppress early stages of the viral life cycle, are considered prophylactic agents. However, for several peptides, their immunoregulatory properties have been described, which opens the possibility for therapeutic use. This review summarizes the information on the antiviral properties of such peptides and mechanisms of their action and describes the prospects of the future development of antiviral peptides.


Assuntos
Antivirais/farmacologia , Peptídeos/farmacologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Antivirais/uso terapêutico , Humanos , Peptídeos/uso terapêutico
4.
Chem Commun (Camb) ; 55(69): 10226-10229, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31380870

RESUMO

A formulation of self-assembled peptido-nanomicelles has been developed for a combinational treatment of SDT, PDT and chemotherapy to nasopharyngeal carcinoma. In vitro cellular tests and in vivo mice therapy proved effective for targeted tumor growth inhibition. These merits provided a novel approach to non-invasive cancer treatments.


Assuntos
Corantes Fluorescentes/uso terapêutico , Carcinoma Nasofaríngeo/terapia , Peptídeos/uso terapêutico , Rosa Bengala/uso terapêutico , Animais , Linhagem Celular Tumoral , Terapia Combinada/métodos , Corantes Fluorescentes/administração & dosagem , Humanos , Camundongos Nus , Micelas , Carcinoma Nasofaríngeo/patologia , Peptídeos/administração & dosagem , Fotoquimioterapia/métodos , Rosa Bengala/administração & dosagem , Terapia por Ultrassom/métodos
5.
Anticancer Res ; 39(7): 3487-3492, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262872

RESUMO

BACKGROUND/AIM: Despite intensive chemotherapy, the survival rates for high-risk neuroblastoma, most of which have MYCN amplification, remain low. Overexpression of N-myc oncoprotein promotes expression of cancer-associated properties. We recently found that combination of all-trans retinoic acid (ATRA) with the ß1-integrin-activating peptide TNIIIA2 attenuated cancer-associated properties of neuroblastoma cells through N-Myc degradation. However, ATRA has serious side-effects and there are concerns about late adverse effects. The aim of this study was to examine the effects of the combination of acyclic retinoid (ACR) with TNIIIA2 on neuroblastoma. MATERIALS AND METHODS: The effects of ACR and TNIIIA2 were examined by neuroblastoma cell proliferation and survival assays as well as by using a neuroblastoma xenograft model. The levels of N-Myc and cancer-associated malignant properties were assayed by western blot and colony formation assay, respectively. RESULTS: Combining ACR, which is clinically safe, with TNIIIA2 induced proteasomal degradation of N-Myc and reduction of neuroblastoma cell malignant properties. An in vivo experiment showed therapeutic potential. CONCLUSION: ACR-TNIIIA2 combination treatment may be efficacious and clinical safe chemotherapy for high-risk neuroblastoma.


Assuntos
Antineoplásicos/uso terapêutico , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/tratamento farmacológico , Peptídeos/uso terapêutico , Tenascina/uso terapêutico , Tretinoína/análogos & derivados , Animais , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Peptídeos/farmacologia , Fenótipo , Tenascina/farmacologia , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Carga Tumoral/efeitos dos fármacos
6.
Int J Nanomedicine ; 14: 4817-4831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308660

RESUMO

Background: In vitro (1R,3S)-1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxyl-Lys(Pro-Ala-Lys)-Arg-Gly-Asp-Val (MTCA-KKV) adheres activated platelets, targets P-selectin and GPIIb/IIIa. This led to the development of MTCA-KKV as thrombus targeting nano-medicine. Methods: MTCA-KKV was characterized by nano-feature, anti-thrombotic activity, thrombolytic activity, thrombus target and targeting release. Results: In vivo 0.01 µmol/kg of MTCA-KKV formed nano-particles less than 100 nm in diameter, targeted thrombus, released anti-thrombotic and thrombolytic pharmacophores, prevented thrombosis and dissolved blood clots. Conclusion: Based on the profiles of targeting thrombus, targeting release, inhibiting thrombosis and dissolving blood clots MTCA-KKV is a promising nano-medicine.


Assuntos
Coagulação Sanguínea , Carbolinas/química , Carbolinas/uso terapêutico , Nanopartículas/química , Peptídeos/uso terapêutico , Trombose/sangue , Trombose/tratamento farmacológico , Administração Oral , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Carbolinas/administração & dosagem , Eritrócitos/efeitos dos fármacos , Humanos , Leucócitos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Masculino , Nanopartículas/ultraestrutura , Selectina-P/metabolismo , Peptídeos/farmacologia , Adesividade Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier
7.
Urologiia ; (3): 31-35, 2019 Jul.
Artigo em Russo | MEDLINE | ID: mdl-31356010

RESUMO

BACKGROUND: chronic prostatitis is a common disease that significantly influence on the quality of life. AIM: Our aim was to assess the prevalence of particular domains of UPOINT classification and determine the efficiency of prostate-selective cytomedins in complex therapy of chronic prostatitis with the predominance of organic component. MATERIALS AND METHODS: a total of 96 patients aged from 24 to 48 years were treated in City clinical hospital named after D.D. Pletnev in 2017-2018 yy. with a previously diagnosed chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The mean duration of the disease was 18.0+/-6.2 months. The total NIH-CPSI score was 24+/-7.3 (pain score 9+/-4.9, urinary score 7+/-2,7, quality of life 8+/-2.3), Qmax was 16+/-4.2 ml/s, prostate volume - 34+/-12 cc. Leukocyturia in post-massage urine was found in 52 patients (54%). Positive urine culture after prostate massage or positive bacterial semen study were found in 22 patients (23%). Prostate-specific therapy consisted of 20 days of rectal suppositories Vitaprost-forte followed by oral therapy by Vitaprost tablet of the same duration. RESULTS: Follow-up examination of 72 patients (75%) was performed after 3 months of therapy. The total NIH-CSPI score decreased to 15.6+/-5.1 (pain score 6.3+/-3.8, urinary score 4.6+/-2.2, quality of life 4.7+/-2), Qmax was 16+/-3.8 ml/s and mean prostate volume was 24+/-6 cc. The normalization of laboratory parameters was achieved in all cases. CONCLUSION: using the UPOINT classification allows to optimize the treatment of patients with chronic prostatitis. Use of prostate-specific cytomedins (Vitaprost) is highly effective in case of prostatic involvement according to the UPOINT classification.


Assuntos
Peptídeos , Prostatite , Adulto , Doença Crônica , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pélvica/etiologia , Peptídeos/uso terapêutico , Prostatite/complicações , Prostatite/tratamento farmacológico , Qualidade de Vida , Síndrome , Adulto Jovem
8.
West J Emerg Med ; 20(4): 587-600, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31316698

RESUMO

Angioedema is defined by non-dependent, non-pitting edema that affects several different sites and is potentially life-threatening due to laryngeal edema. This narrative review provides emergency physicians with a focused overview of the evaluation and management of angioedema. Two primary forms include histamine-mediated and bradykinin-mediated angioedema. Histamine-mediated forms present similarly to anaphylaxis, while bradykinin-mediated angioedema presents with greater face and oropharyngeal involvement and higher risk of progression. Initial evaluation and management should focus on evaluation of the airway, followed by obtaining relevant historical features, including family history, medications, and prior episodes. Histamine-mediated angioedema should be treated with epinephrine intramuscularly, antihistaminergic medications, and steroids. These medications are not effective for bradykinin-mediated forms. Other medications include C1-INH protein replacement, kallikrein inhibitor, and bradykinin receptor antagonists. Evidence is controversial concerning the efficacy of these medications in an acute episode, and airway management is the most important intervention when indicated. Airway intervention may require fiberoptic or video laryngoscopy, with preparation for cricothyrotomy. Disposition is dependent on patient's airway and respiratory status, as well as the sites involved.


Assuntos
Angioedema/etiologia , Angioedema/terapia , Serviço Hospitalar de Emergência , Manuseio das Vias Aéreas , Algoritmos , Anti-Inflamatórios não Esteroides/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Bradicinina/análogos & derivados , Bradicinina/metabolismo , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Broncodilatadores/uso terapêutico , Epinefrina/uso terapêutico , Glucocorticoides/uso terapêutico , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Peptídeos/uso terapêutico , Plasma , Urticária/etiologia
9.
Int J Nanomedicine ; 14: 4059-4069, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213815

RESUMO

Background and purpose: Traumatic brain injury (TBI) is a major disease without effective treatment. Recently, Tat-NR2B9c peptide emerged as a promising neuroprotective agent, but limited in clinical translation by it low brain penetrability. We synthesized Tat-NR2B9c loaded self-assembled activatable protein nanoparticles, termed TN-APNPs, and demonstrated that TN-APNPs enhanced the delivery of Tat-NR2B9c to the brain lesion in stroke. Herein we developed a novel approach to further engineering TN-APNPs for targeted delivery of Tat-NR2B9c to the injured brain with enhanced efficiency through conjugation of CAQK or CCAQK, a short peptide. Methods: Short peptide-conjugated TN-APNPs were synthesized by conjugated with CAQK or CCAQK via a click condensation reaction with CBT, then analyzed by dynamic light scattering, transmission electron microscopy and thrombin responsive assay. Characterization of short peptide-conjugated TN-APNPs were investigated by using cell excitotoxicity assay and transwell blood-brain-barrier model in vitro, and pharmacokinetics, IVIS imaging system and confocal analysis in TBI-bearing mice. Evaluation of therapeutic effects were analyzed by H&E staining, Elevated Plus Maze analysis and Rotarod test. Results: CAQK-conjugated TN-APNPs (C-TN-APNPs) and CCAQK-conjugated TN-APNPs (CC-TN-APNPs) were spherical in morphology and 30 nm in diameter. In vitro studies revealed that TN-APNPs, C-TN-APNPs and CC-TN-APNPs were responsive to thrombin cleavage, reduced the cytotoxicity of Tat-NR2B9c, and increased BBB permeability of Tat-NR2B9c. CC-TN-APNPs demonstrated the better circulation time, better targeting ability and penetrating efficiency to the injured brain, and better therapeutic benefits in vivo studies. Conclusion: This study demonstrated CC-TN-APNPs as a promising therapeutic for clinical management of TBI.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Nanopartículas/química , Peptídeos/uso terapêutico , Animais , Lesões Encefálicas Traumáticas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/metabolismo , Portadores de Fármacos/química , Humanos , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/ultraestrutura , Peptídeos/síntese química , Peptídeos/farmacologia , Teste de Desempenho do Rota-Rod , Trombina/uso terapêutico
10.
Carbohydr Polym ; 220: 30-42, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31196548

RESUMO

Low molecular weight heparin (LMWH) is a natural sulfated glycosaminoglycan with the affinity to proangiogenic factors, rendering it a promising agent for tumor therapy. Inspired by DOX binding to the helix of DNA, mitochondrial damage KLA peptide derivative (mKLA) and anti-angiogenic LMWH-chrysin conjugate (LC) are constructed to simulate the double strands for doxorubicin (DOX) binding (LKD nanocomplex). Initiated and "locked" by DOX, mKLA and LC temporarily aggregate by π-π stacks, electrostatic and hydrophobic interactions in aqueous condition with self-amplified DOX loading (19.07 ± 1.08 wt%). During endosome-lysosome trafficking, DOX protonated by H+ could "unlock" the LKD nanocomplex to disassemble, which enables mKLA and DOX to damage mitochondria and nucleus DNA respectively, and LMWH could also inhibit angiogenesis. Based on the strong inhibition of tumors at all stages in vivo, we hold that LKD nanocomplex provides a new opportunity based on smart construction of carbohydrate materials for clinically advanced cancer patients.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Doxorrubicina/uso terapêutico , Heparina de Baixo Peso Molecular/química , Nanoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Peptídeos/uso terapêutico , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , DNA/química , Doxorrubicina/química , Doxorrubicina/farmacologia , Flavonoides/química , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Nanoconjugados/química , Peptídeos/química , Peptídeos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cell Mol Life Sci ; 76(20): 3969-3985, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31218451

RESUMO

Cardiovascular diseases represent one of the most important health problems of developed countries. One of the main actors involved in the onset and development of cardiovascular diseases is the increased production of reactive oxygen species that, through lipid peroxidation, protein oxidation and DNA damage, induce oxidative stress and cell death. Basic and clinical research are ongoing to better understand the endogenous antioxidant mechanisms that counteract oxidative stress, which may allow to identify a possible therapeutic targeting/application in the field of stress-dependent cardiovascular pathologies. In this context, increasing attention is paid to the glutathione/glutathione-peroxidase and to the thioredoxin/thioredoxin-reductase systems, among the most potent endogenous antioxidative systems. These key enzymes, belonging to the selenoprotein family, have a well-established function in the regulation of the oxidative cell balance. The aim of the present review was to highlight the role of selenoproteins in cardiovascular diseases, introducing the emerging cardioprotective role of endoplasmic reticulum-resident members and in particular one of them, namely selenoprotein T or SELENOT. Accumulating evidence indicates that the dysfunction of different selenoproteins is involved in the susceptibility to oxidative stress and its associated cardiovascular alterations, such as congestive heart failure, coronary diseases, impaired cardiac structure and function. Some of them are under investigation as useful pathological biomarkers. In addition, SELENOT exhibited intriguing cardioprotective effects by reducing the cardiac ischemic damage, in terms of infarct size and performance. In conclusion, selenoproteins could represent valuable targets to treat and diagnose cardiovascular diseases secondary to oxidative stress, opening a new avenue in the field of related therapeutic strategies.


Assuntos
Cardiotônicos/uso terapêutico , Doenças Cardiovasculares/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Peptídeos/uso terapêutico , Selenocisteína/metabolismo , Selenoproteínas/genética , Animais , Antioxidantes/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/terapia , Regulação da Expressão Gênica , Glutationa Peroxidase/metabolismo , Humanos , Terapia de Alvo Molecular/métodos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Selenoproteínas/agonistas , Selenoproteínas/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismo
12.
Protein Pept Lett ; 26(9): 664-675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31215368

RESUMO

Bioactive peptides are short chain of amino acids (usually 2-20) that are linked by amide bond in a specific sequence which have some biological effects in animals or humans. These can be of diverse origin like plant, animal, fish, microbe, marine organism or even synthetic. They are successfully used in the management of many diseases. In recent years increased attention has been raised for its effects and mechanism of action in various disease conditions like cancer, immunity, cardiovascular disease, hypertension, inflammation, diabetes, microbial infections etc. Bioactive peptides are more bioavailable and less allergenic when compared to total proteins. Food derived bioactive peptides have health benefits and its demand has increased tremendously over the past decade. This review gives a view on last two years research on potential bioactive peptides derived from food which have significant therapeutic effects.


Assuntos
Produtos Biológicos/uso terapêutico , Alimentos , Peptídeos/uso terapêutico , Animais , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Doenças do Sistema Imunitário/tratamento farmacológico , Infecção/tratamento farmacológico , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Peptídeos/química , Peptídeos/metabolismo
13.
Curr Med Chem ; 26(30): 5664-5683, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31250748

RESUMO

Targeting angiogenesis in the microenvironment of a tumor can enable suppression of tumor angiogenesis and delivery of anticancer drugs into the tumor. Anti-angiogenesis targeted delivery systems utilizing passive targeting such as Enhanced Permeability and Retention (EPR) and specific receptor-mediated targeting (active targeting) should result in tumor-specific targeting. One targeted anti-angiogenesis approach uses peptides conjugated to nanoparticles, which can be loaded with anticancer agents. Anti-angiogenesis agents can suppress tumor angiogenesis and thereby affect tumor growth progression (tumor growth arrest), which may be further reduced with the targetdelivered anticancer agent. This review provides an update of tumor vascular targeting for therapeutic and diagnostic applications, with conventional or long-circulating nanoparticles decorated with peptides that target neovascularization (anti-angiogenesis) in the tumor microenvironment.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Nanopartículas/química , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neovascularização Patológica/diagnóstico , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Humanos , Estrutura Molecular , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/uso terapêutico
14.
Cancer Sci ; 110(8): 2378-2385, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31218770

RESUMO

The prognosis of advanced pancreatic adenocarcinoma is still extremely poor. This study sought to determine the efficacy of, and immunological response to, peptide vaccination therapy in patients with this disease. In this multicenter randomized phase II study, patients with advanced pancreatic adenocarcinoma after gemcitabine and/or tegafur/gimeracil/oteracil were randomly assigned to 3 groups that each received a 2-step treatment course. In Step 1, the groups received treatments of: (i) survivin 2B peptide (SVN-2B) plus interferon-ß (IFNß); (ii) SVN-2B only; or (iii) placebo until the patients show progression. In Step 2, all patients who consented to participate received 4 treatments with SVN-2B plus IFNß. The primary endpoint was progression-free survival (PFS) after initiation of Step 1 treatment. Secondary endpoints included immunological effects assessed by analysis of PBMCs after Step 1. Eighty-three patients were randomly assigned to receive SVN-2B plus IFNß (n = 30), SVN-2B (n = 34), or placebo (n = 19). No significant improvement in PFS was observed. Survivin 2B-specific CTLs were found to be increased in the SVN-2B plus IFNß group by tetramer assay. Among patients who participated in Step 2, those who had received SVN-2B plus IFNß in Step 1 showed better overall survival compared with those who had received placebo in Step 1. Patients vaccinated with SVN-2B plus IFNß did not have improved PFS, but showed significant immunological reaction after vaccination. Subgroup analysis suggested that a longer SVN-2B plus IFNß vaccination protocol might confer survival benefit. (Clinical trial registration number: UMIN 000012146).


Assuntos
Adenocarcinoma/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Interferon beta/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos/uso terapêutico , Survivina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Vacinação/métodos , Vacinas de Subunidades/uso terapêutico
15.
J Immunoassay Immunochem ; 40(4): 439-447, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31204576

RESUMO

The beneficial effects promoted from the use of biomolecular substances into the formulations of personal care products are considered useful ingredients in cosmetic and therapeutic applications. Innovations in cosmetics are based on new bioactive formulations such as vitamins, oils, peptides, and protein hydrolysates. In skin care, the monomeric amino acids such as serine, threonine, alanine are common ingredients in cosmetics as they function as natural moisturizing factors which act as water-binding molecules. Amino acids and their salts e.g., arginine, glycine, etc. are also used as hair- and skin-conditioning agents in cosmetic formulations. The peptides are composed of short chain of amino acids and are used in cosmetics due to their numerous pathophysiological properties including anti-aging. There is growing interest in bioactive peptides in products for stimulating collagen and elastin synthesis in skin and improve surface healing. The main benefit of using proteins in cosmeceuticals is to improve the hydration of skin. Proteins increase the dehydration in the skin which helps to reduce wrinkles and improves the functions of the skin barrier. This review article describes the peptides, proteins that are most frequently used in cosmeceuticals and their potential benefits and practical use in cosmetic science and skincare.


Assuntos
Cosmecêuticos/química , Cosmecêuticos/farmacologia , Peptídeos/análise , Proteínas/análise , Rejuvenescimento/fisiologia , Higiene da Pele/métodos , Pele/efeitos dos fármacos , Animais , Cosmecêuticos/uso terapêutico , Técnicas Cosméticas , Humanos , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Proteínas/farmacologia , Proteínas/uso terapêutico , Pele/imunologia , Pele/patologia
16.
Nephrol Nurs J ; 46(3): 315-290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31199098

RESUMO

The number, volume, and timing of oral medications prescribed to treat secondary hyperparathyroidism can add to the burden of disease management for both the patient and the nurse. Administering intravenous (IV) medication when possible has the potential of reducing the burden of medication management. Data on the use of IV calcimimetic etelcalcetide has shown improvement in blood calcium, phosphorus, and parathyroid hormone levels. IV administration of etelcalcetide at the end of each hemodialysis session may reduce the pill burden for patients and has the potential to help improve disease management within an environment that supports person-centered care.


Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Hiperparatireoidismo Secundário , Enfermagem em Nefrologia , Peptídeos , Calcimiméticos , Cálcio , Humanos , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/enfermagem , Peptídeos/uso terapêutico , Diálise Renal
18.
Molecules ; 24(12)2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208037

RESUMO

BACKGROUND: While phase III clinical trials for the treatment of Alzheimer's disease (AD) keep failing regardless of the target, more and more data suggest that the toxic protein assemblies of amyloid-beta protein (Aß) and tubulin binding protein (TAU) behave like prions. Irrespective of the question of whether AD is theoretically or practically contagious, the presence of a self-replicating toxic etiologic agent in the brains of AD patients must have decisive consequences for drug development programs and clinical trial designs. OBJECTIVES: We intend to challenge the hypothesis that the underlying etiologic agent of AD is behaving prion-like. We want to discuss whether the outcome of clinical trials could have been predicted based on this hypothesis, and whether compounds that directly disassemble the toxic prion could be more beneficial for AD treatment. METHOD: We collected publicly accessible pre-clinical efficacy data of Aß targeting compounds that failed or still are in phase III clinical trials. We describe the desired properties of an anti-prion compound and compare it the properties of past and current phase III drug candidates. RESULTS: We could not find convincing and reproducible pre-clinical efficacy data of past and current phase III drug candidates on cognition other than in preventive treatment settings. The desired properties of an anti-Aß-prionic compound are fulfilled by the drug candidate RD2, which has been developed to directly disassemble toxic Aß oligomers. CONCLUSION: RD2 is the first anti-prion drug candidate. It is able to enhance cognition and impede neurodegeneration in three different transgenic AD mouse models, even under truly non-preventive conditions and even when applied orally. In addition, it is safe in humans.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos/uso terapêutico , Proteínas Priônicas/antagonistas & inibidores , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Ensaios Clínicos como Assunto , Humanos , Peptídeos/química , Peptídeos/farmacologia , Proteínas Priônicas/metabolismo , Agregados Proteicos , Agregação Patológica de Proteínas , Multimerização Proteica , Resultado do Tratamento
19.
Nat Cell Biol ; 21(6): 778-790, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160710

RESUMO

Phosphorylation networks intimately regulate mechanisms of response to therapies. Mapping the phospho-catalytic profile of kinases in cells or tissues remains a challenge. Here, we introduce a practical high-throughput system to measure the enzymatic activity of kinases using biological peptide targets as phospho-sensors to reveal kinase dependencies in tumour biopsies and cell lines. A 228-peptide screen was developed to detect the activity of >60 kinases, including ABLs, AKTs, CDKs and MAPKs. Focusing on BRAFV600E tumours, we found mechanisms of intrinsic resistance to BRAFV600E-targeted therapy in colorectal cancer, including targetable parallel activation of PDPK1 and PRKCA. Furthermore, mapping the phospho-catalytic signatures of melanoma specimens identifies RPS6KB1 and PIM1 as emerging druggable vulnerabilities predictive of poor outcome in BRAFV600E patients. The results show that therapeutic resistance can be caused by the concerted upregulation of interdependent pathways. Our kinase activity-mapping system is a versatile strategy that innovates the exploration of actionable kinases for precision medicine.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Neoplasias Colorretais/tratamento farmacológico , Melanoma/tratamento farmacológico , Proteína Quinase C-alfa/genética , Proteínas Proto-Oncogênicas c-pim-1/genética , Adulto , Idoso , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/química , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases/genética , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Peptídeos/química , Peptídeos/uso terapêutico , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico
20.
Int J Nanomedicine ; 14: 2573-2589, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040673

RESUMO

Background: In the past few years, significant progress has been made in inhibiting neovascularization at the tumor site, cutting off the nutrient supply of the tumor, and inhibiting tumor growth and metastasis. However, many proteins/peptides have the disadvantage of poor stability, short half-life, and uncertain targeting ability. Chemical modification can be used to overcome these disadvantages; many polyethylene glycol-modified proteins/peptides have been approved by US FDA. The purpose of this study was to obtain a novel anti-angiogenic chondroitin sulfate (CS)-peptide nanoparticle conjugate with efficient anti-neovascularization and tumor targeting ability and an acceptable half-life. Materials and methods: The CS-ES2-AF nanoparticle conjugate was synthesized and characterized using 1H-nuclear magnetic resonance spectroscopy, transmission electron microscopy, and particle size and zeta potential analyzer. The anti-angiogenic ability was studied using MTT, migration, tube formation, and chick chorioallantoic membrane assays. The targeting ability of CS-ES2-AF was studied by ELISA, surface plasmon resonance, and bioimaging. The pharmacokinetics was also studied. Results: The CS-ES2-AF could self-assemble into stable nanoparticles in aqueous solution, which significantly enhances its anti-neovascularization activity, tumor targeting more explicit, and prolongs its half-life. Conclusion: CS is an effective protein/peptide modifier, and CS-ES2-AF displayed good potential in tumor targeting therapy.


Assuntos
Inibidores da Angiogênese/farmacologia , Sulfatos de Condroitina/farmacologia , Nanopartículas/química , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/uso terapêutico , Animais , Movimento Celular , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacocinética , Sulfatos de Condroitina/uso terapêutico , Membrana Corioalantoide/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/ultraestrutura , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Tamanho da Partícula , Peptídeos/uso terapêutico , Espectroscopia de Prótons por Ressonância Magnética , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto
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