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1.
Food Chem ; 308: 125601, 2020 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-31670190

RESUMEN

The aim of this work was to analyse the hypotensive effect of amaranth protein/peptides on spontaneously hypertensive rats (SHR). The mechanism of action of these peptides was studied in vivo and ex vivo. We also tested the effect of protection against gastrointestinal digestion (GID) exerted by an O:W emulsion on the integrity of the antihypertensive peptides. All samples tested produced a decrease in blood pressure (SBP). The animals treated with emulsion (GE) and emulsion + peptide (GE+VIKP) showed the most significant reduction in the SBP (42 ±â€¯2 mmHg and 35 ±â€¯2 mmHg, respectively). The results presented suggest that after GID, a variety of peptides with biological activities were released or were resistant to this process. These peptides play a role in the regulation of the SBP by acting on plasma ACE, plasma renin and the vascular system. These results support the use of amaranth protein/peptides in the elaboration of functional foods for hypertensive individuals.


Asunto(s)
Amaranthus/química , Antihipertensivos/farmacología , Hipertensión/tratamiento farmacológico , Péptidos/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Masculino , Péptidos/uso terapéutico , Proteínas de Plantas/farmacología , Proteínas de Plantas/uso terapéutico , Ratas , Ratas Endogámicas SHR
2.
Int J Nanomedicine ; 14: 7743-7758, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31571874

RESUMEN

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.


Asunto(s)
Alginatos/química , Sistemas de Liberación de Medicamentos , Péptidos/administración & dosificación , Preparaciones Farmacéuticas/administración & dosificación , Vitamina B 12/química , Administración Oral , Alginatos/síntesis química , Animales , Células CACO-2 , Muerte Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Femenino , Humanos , Insulina/administración & dosificación , Insulina/farmacología , Insulina/uso terapéutico , Absorción Intestinal/efectos de los fármacos , Masculino , Ratones , Nanopartículas/química , Nanopartículas/ultraestructura , Péptidos/farmacología , Péptidos/uso terapéutico , Espectroscopía de Protones por Resonancia Magnética , Espectroscopía Infrarroja por Transformada de Fourier , Vitamina B 12/síntesis química
3.
BMC Bioinformatics ; 20(1): 456, 2019 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-31492094

RESUMEN

*: 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.


Asunto(s)
Biología Computacional/métodos , Aprendizaje Profundo , Péptidos/uso terapéutico , Bases de Datos de Ácidos Nucleicos , Descubrimiento de Drogas
4.
Mol Biol (Mosk) ; 53(4): 541-560, 2019.
Artículo en Ruso | MEDLINE | ID: mdl-31397431

RESUMEN

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.


Asunto(s)
Antivirales/farmacología , Péptidos/farmacología , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Antivirales/uso terapéutico , Humanos , Péptidos/uso terapéutico
5.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-31404991

RESUMEN

Burns are physically debilitating and potentially fatal injuries. Two marine biomaterials, carboxymethyl chitosan (CMC) and collagen peptides (COP), have emerged as promising burn dressings. In this paper, sponges of carboxymethyl chitosan grafted with collagen peptide (CMC-COP) were prepared by covalent coupling and freeze drying. Scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy were then used to characterize the prepared sponges. To evaluate the wound healing activity of the CMC-COP sponges, in vitro tests including cell viability scratch wound healing and scald wound healing experiments were performed in rabbits. Appearance studies revealed the porous nature of sponges and FTIR spectroscopy demonstrated the successful incorporation of COP into CMC. The in vitro scratch assay showed that treatment with CMC-COP sponges (at 100 µg/mL) had significant effects on scratch closure. For burn wounds treated with CMC-COP, regeneration of the epidermis and collagen fiber deposition was observed on day 7, with complete healing of the epidermis and wound on days 14 and 21, respectively. Based on the pathological examination by hematoxylin and eosinstaining, the CMC-COP group demonstrated pronounced wound healing efficiencies. These results confirmed that the CMC-COP treatment enhanced cell migration and promoted skin regeneration, thereby highlighting the potential application of these sponges in burn care.


Asunto(s)
Vendajes , Quemaduras/terapia , Quitosano/análogos & derivados , Colágeno/uso terapéutico , Cicatrización de Heridas , Animales , Línea Celular , Quitosano/uso terapéutico , Femenino , Masculino , Péptidos/uso terapéutico , Conejos , Cicatrización de Heridas/efectos de los fármacos
6.
Molecules ; 24(15)2019 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-31370142

RESUMEN

Hypertension is considered a major public health issue due to its high prevalence and subsequent risk of cardiovascular and kidney diseases. Thus, the search for new antihypertensive compounds remains of great interest. Snake venoms provide an abundant source of lead molecules that affect the cardiovascular system, which makes them prominent from a pharmaceutical perspective. Such snake venom components include bradykinin potentiating peptides (proline-rich oligopeptides), natriuretic peptides, phospholipases A2, serine-proteases and vascular endothelial growth factors. Some heparin binding hypotensive factors, three-finger toxins and 5' nucleotidases can also exert blood pressure lowering activity. Great advances have been made during the last decade regarding the understanding of the mechanism of action of these hypotensive proteins. Bradykinin potentiating peptides exert their action primarily by inhibiting the angiotensin-converting enzyme and increasing the effect of endogenous bradykinin. Snake venom phospholipases A2 are capable of reducing blood pressure through the production of arachidonic acid, a precursor of cyclooxygenase metabolites (prostaglandins or prostacyclin). Other snake venom proteins mimic the effects of endogenous kallikrein, natriuretic peptides or vascular endothelial growth factors. The aim of this work was to review the current state of knowledge regarding snake venom components with potential antihypertensive activity and their mechanisms of action.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipotensión/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/química , Animales , Antihipertensivos/química , Bradiquinina/química , Bradiquinina/uso terapéutico , Humanos , Péptidos/química , Péptidos/uso terapéutico , Venenos de Serpiente/química
7.
Int J Pharm ; 569: 118625, 2019 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-31425817

RESUMEN

Bioactive peptides are attractive candidates for drug development. QAW is a tripeptide that is obtained from an anti-inflammatory protein-Annexin A1 (ANXA1). Previous studies showed that QAW alleviated inflammation in experimental colitis and inflammatory bowel disease via NF-κB inhibition. This study establishes adjuvant-induced arthritis (AIA) mouse models and explores the anti-inflammatory efficacy of QAW in AIA mice. To enhance the targeting, responsiveness, and efficacy of QAW to inflammation, QAW (Q) is modified with a cell penetrating peptide (T), a matrix metalloproteases-2/9 (MMP-2/9) digestive peptide (M), and an inflammation targeting peptide-RGD (R). The designed RMTQ demonstrates enhanced delivery to cytoplasm, higher reduction of pro-inflammatory factors, and better efficacy than QAW. The anti-inflammatory efficacy of RMTQ is similar to that of DEX in this study whereas RMTQ treatment shows a higher safety than that of DEX. In sum, this study demonstrates that RMTQ can be a potential therapeutic for inflammatory arthritis.


Asunto(s)
Antiinflamatorios/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , Péptidos/uso terapéutico , Animales , Antiinflamatorios/farmacología , Femenino , Ratones , Péptidos/farmacología , Células RAW 264.7
8.
Chem Commun (Camb) ; 55(69): 10226-10229, 2019 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-31380870

RESUMEN

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.


Asunto(s)
Colorantes Fluorescentes/uso terapéutico , Carcinoma Nasofaríngeo/terapia , Péptidos/uso terapéutico , Rosa Bengala/uso terapéutico , Animales , Línea Celular Tumoral , Terapia Combinada/métodos , Colorantes Fluorescentes/administración & dosificación , Humanos , Ratones Desnudos , Micelas , Carcinoma Nasofaríngeo/patología , Péptidos/administración & dosificación , Fotoquimioterapia/métodos , Rosa Bengala/administración & dosificación , Terapia por Ultrasonido/métodos
9.
World J Gastroenterol ; 25(25): 3196-3206, 2019 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-31333311

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is the third most common malignancy of the digestive tract and the fifth leading cause of cancer-related mortality in China. Sporamin, a Kunitz-type trypsin inhibitor isolated from sweet potato, is a potential anti-cancer agent with activities against a number of malignant tumor cells in vitro. The liver secretes a myriad of endocrine factors that may facilitate the growth and transformation of tumors in the development of CRC. AIM: To investigate the effects of sporamin on liver morphology and biomarkers of xenografted CRC in the liver of athymic BALB/c mice. METHODS: Twenty-seven male BALB/c nude mice were randomly divided into control, vehicle, and sporamin groups. Mice in the latter two groups were intraperitoneally xenografted with LoVo colorectal carcinoma cells and intragastrically infused with saline or sporamin (0.5 g/kg body weight/d), respectively, for 3 wk. Hematoxylin and eosin (HE) staining of the sections was performed to observe morphological changes in hepatic tissue and real-time fluorescent quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to measure the expression of ß-catenin and vascular endothelial growth factor (VEGF) in the liver. RESULTS: Sporamin significantly reduced the number and weight of tumor nodules formed in the abdominal cavity. Compared with the vehicle group, the mean tumor weight (± SD) in the sporamin group was significantly reduced (0.44 ± 0.10 g vs 0.26 ± 0.15 g) and the total number of tumors decreased from 93 to 55. HE staining showed that enlargement of the nucleus and synthesis of proteins within hepatocytes, as well as infiltration of inflammatory cells into the liver, were attenuated by sporamin. Immunohistochemical staining and ELISA showed that the concentrations of ß-catenin and VEGF in the liver were significantly reduced by sporamin. Compared with the vehicle group, the expression of ß-catenin measured in integrated optical density units per area was reduced in the sporamin group (47.29 ± 9.10 vs 26.14 ± 1.72; P = 0.003). Expression of VEGF was also reduced after sporamin intervention from 20.78 ± 2.06 in the vehicle group to 15.80 ± 1.09 in the sporamin group (P = 0.021). Compared with the vehicle group, the concentration of ß-catenin decreased from 134.42 ± 22.04 pg/mL to 109.07 ± 9.65 pg/mL after sporamin intervention (P = 0.00002). qPCR indicated that compared to the vehicle group, relative mRNA expression of ß-catenin and VEGF in the liver of mice in the sporamin-treated group was significantly reduced to 71% ± 1% (P = 0.000001) and 23% ± 7% (P = 0.00002), respectively, of the vehicle group levels. CONCLUSION: Sporamin down-regulates the expression and secretion of ß-catenin and VEGF in the liver, which subsequently inhibits the transcription of downstream genes involved in cancer progression and angiogenesis.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Péptidos/farmacología , Proteínas de Plantas/farmacología , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neovascularización Patológica/patología , Péptidos/uso terapéutico , Proteínas de Plantas/uso terapéutico , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismo
10.
Cell Mol Biol (Noisy-le-grand) ; 65(5): 24-31, 2019 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-31304902

RESUMEN

This study was carried out to evaluate the preventive and curative effects of Pilose antler against osteoporosis due to kidney deficiency, and investigate its potential mechanism of action. A model of osteoporosis due to kidney deficiency was established in rats using bilateral ovariectomy. Pilose antler polypeptide (PAP), Pilose antler polysaccharide (PAP'), and their mixture (PAP+PAP') were separately administered to the rats for 12 weeks, with progynova and xianlingubao tablets (XLGB) as the positive control groups. We determined the bone mineral density (BMD) and uterus Index of the rats. Osteoblastic bone metabolism-related indices in serum and bone tissue were measured with ELISA. Western blotting and RT-PCR were used to investigate the protein and mRNA expressions of Bmp-2, Smad1, Smad5, Runx2 in bone tissue. The morphology of bone tissue was determined using immunohistochemical methods. Compared with control group, PAP, PAP', PAP+PAP' increased BMD and regulated bone metabolism indices in serum and bone tissue. Treatment with Pilose antler up-regulated the mNRA and protein expressions of Bmp-2, Smad1, Smad5 and Runx2. Immunohistochemical staining showed that Bmp-2, Smad1, Smad5 and Runx2 were stained brown, indicating that all of them were positive. There were abnormal changes in the protein expressions of Bmp-2, Smad1, Smad5 and Runx2 in bone tissue, which may be an important mechanism underlying the development of kidney deficiency osteoporosis. Moreover, PAP, PAP' and PAP+PAP' had some preventive effects on osteoporosis, probably via the activation of the Bmp-2/Smad1 and Smad5/Runx2 signaling pathways through induction of high expressions of their mRNAs and proteins.


Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Osteoporosis/etiología , Péptidos/farmacología , Sustancias Protectoras/farmacología , Insuficiencia Renal/complicaciones , Animales , Densidad Ósea , Proteína Morfogenética Ósea 2/metabolismo , Huesos/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/uso terapéutico , Femenino , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Osteoporosis/prevención & control , Ovariectomía/efectos adversos , Péptidos/administración & dosificación , Péptidos/uso terapéutico , Polisacáridos/administración & dosificación , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/uso terapéutico , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo , Útero/patología
11.
West J Emerg Med ; 20(4): 587-600, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31316698

RESUMEN

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.


Asunto(s)
Angioedema/etiología , Angioedema/terapia , Servicio de Urgencia en Hospital , Manejo de la Vía Aérea , Algoritmos , Antiinflamatorios no Esteroideos/uso terapéutico , Factores de Coagulación Sanguínea/uso terapéutico , Bradiquinina/análogos & derivados , Bradiquinina/metabolismo , Bradiquinina/uso terapéutico , Antagonistas del Receptor de Bradiquinina B2/uso terapéutico , Broncodilatadores/uso terapéutico , Epinefrina/uso terapéutico , Glucocorticoides/uso terapéutico , Histamina/metabolismo , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Péptidos/uso terapéutico , Plasma , Urticaria/etiología
12.
Anticancer Res ; 39(7): 3487-3492, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31262872

RESUMEN

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.


Asunto(s)
Antineoplásicos/uso terapéutico , Proteína Proto-Oncogénica N-Myc/metabolismo , Neuroblastoma/tratamiento farmacológico , Péptidos/uso terapéutico , Tenascina/uso terapéutico , Tretinoina/análogos & derivados , Animales , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Neuroblastoma/metabolismo , Neuroblastoma/patología , Péptidos/farmacología , Fenotipo , Tenascina/farmacología , Tretinoina/farmacología , Tretinoina/uso terapéutico , Carga Tumoral/efectos de los fármacos
13.
EBioMedicine ; 45: 630-645, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31257147

RESUMEN

Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle degeneration, caused by the absence of dystrophin. Exon skipping by antisense oligonucleotides (ASOs) has recently gained recognition as therapeutic approach in DMD. Conjugation of a peptide to the phosphorodiamidate morpholino backbone (PMO) of ASOs generated the peptide-conjugated PMOs (PPMOs) that exhibit a dramatically improved pharmacokinetic profile. When tested in animal models, PPMOs demonstrate effective exon skipping in target muscles and prolonged duration of dystrophin restoration after a treatment regime. Herein we summarize the main pathophysiological features of DMD and the emergence of PPMOs as promising exon skipping agents aiming to rescue defective gene expression in DMD and other neuromuscular diseases. The listed PPMO laboratory findings correspond to latest trends in the field and highlight the obstacles that must be overcome prior to translating the animal-based research into clinical trials tailored to the needs of patients suffering from neuromuscular diseases.


Asunto(s)
Distrofia Muscular de Duchenne/terapia , Enfermedades Neuromusculares/terapia , Oligonucleótidos Antisentido/uso terapéutico , Péptidos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Distrofina , Exones/genética , Terapia Genética , Humanos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/genética , Enfermedades Neuromusculares/genética , Oligonucleótidos Antisentido/genética , Péptidos/genética
14.
Int J Nanomedicine ; 14: 4817-4831, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31308660

RESUMEN

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.


Asunto(s)
Coagulación Sanguínea , Carbolinas/química , Carbolinas/uso terapéutico , Nanopartículas/química , Péptidos/uso terapéutico , Trombosis/sangre , Trombosis/tratamiento farmacológico , Administración Oral , Animales , Coagulación Sanguínea/efectos de los fármacos , Plaquetas/efectos de los fármacos , Carbolinas/administración & dosificación , Eritrocitos/efectos de los fármacos , Humanos , Leucocitos/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Masculino , Nanopartículas/ultraestructura , Selectina-P/metabolismo , Péptidos/farmacología , Adhesividad Plaquetaria/efectos de los fármacos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Ratas Sprague-Dawley , Espectroscopía Infrarroja por Transformada de Fourier
15.
ACS Appl Mater Interfaces ; 11(33): 29604-29618, 2019 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-31361112

RESUMEN

Diabetes and its complications have become a global challenge of public health. Herein, we aimed to develop a long-acting delivery system of lixisenatide (Lixi), a glucose-dependent antidiabetic peptide, based on an injectable hydrogel for the synchronous treatment of type 2 diabetes mellitus (T2DM) and associated complications. Two triblock copolymers, poly(ε-caprolactone-co-glycolic acid)-poly(ethylene glycol)-poly(ε-caprolactone-co-glycolic acid) and poly(d,l-lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(d,l-lactic acid-co-glycolic acid) possessing temperature-induced sol-gel transitions, were synthesized by us. Compared to the two single-component hydrogels, their 1/1 mixture hydrogel not only maintained the temperature-induced gelation but also exhibited a steadier degradation profile in vivo. Both in vitro and in vivo release studies demonstrated that the mixture hydrogel provided the sustained release of Lixi for up to 9 days, which was attributed to balanced electrostatic interactions between the positive charges in the peptide and the negative charges in the polymer carrier. The hypoglycemic efficacy of Lixi delivered from the mixture hydrogel after a single subcutaneous injection into diabetic db/db mice was comparable to that of twice-daily administrations of Lixi solution for up to 9 days. Furthermore, three successive administrations of the abovementioned gel system within a month significantly increased the plasma insulin level, lowered glycosylated hemoglobin, and improved the pancreatic function of the animals. These results were superior or equivalent to those of twice-daily injections of Lixi solution for 30 days, but the number of injections was markedly reduced from 60 to 3. Finally, an improvement in hyperlipidemia, augmentation of nerve fiber density, and enhancement of motor nerve conduction velocity in the gel formulation-treated db/db mice indicated that the sustained delivery of Lixi arrested and even ameliorated diabetic complications. These findings suggested that the Lixi-loaded mixture hydrogel has great potential for the treatment of T2DM with significant improvements in the health and quality of life of patients.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Péptidos/administración & dosificación , Péptidos/uso terapéutico , Animales , Rastreo Diferencial de Calorimetría , Dicroismo Circular , Preparaciones de Acción Retardada , Complicaciones de la Diabetes/sangre , Complicaciones de la Diabetes/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Femenino , Hemoglobina A Glucada/metabolismo , Hidrogeles/química , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Calidad de Vida , Ratas
16.
Urologiia ; (3): 31-35, 2019 Jul.
Artículo en Ruso | MEDLINE | ID: mdl-31356010

RESUMEN

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.


Asunto(s)
Péptidos , Prostatitis , Adulto , Enfermedad Crónica , Humanos , Masculino , Persona de Mediana Edad , Dolor Pélvico/etiología , Péptidos/uso terapéutico , Prostatitis/complicaciones , Prostatitis/tratamiento farmacológico , Calidad de Vida , Síndrome , Adulto Joven
17.
Biomed Pharmacother ; 116: 109046, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31174091

RESUMEN

This study was conducted to purify the angiotensin converting enzyme (ACE) inhibitory peptides from beef myofibrillar proteins by using inexpensive enzymes alkaline-AK and papain. Different molecular weight peptides (<3 and <10 kDa) were obtained using ultrafiltration. The <3 kDa peptides obtained by alkaline-AK (AK3K) digestion showed the highest ACE inhibitory activity (74.29%) as compared to other alkaline-AK peptides, and a strong antihypertensive effect of AK3K was observed in the spontaneously hypertensive rat (SHR) model. The AK3K treatment groups (400 and 800 mg/kg body weight) exhibited a decrease in systolic blood pressure (SBP) by 28 and 35 mmHg, respectively in the SHR model. The study demonstrated that the ACE inhibitory peptide obtained from beef myofibrillar proteins had the sequence Leu-Ile-Val-Gly-Ile-Ile-Arg-Cys-Val, and could be possibly used for lowering the SBP.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/aislamiento & purificación , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Proteínas Musculares/metabolismo , Miofibrillas/metabolismo , Péptidos/aislamiento & purificación , Péptidos/uso terapéutico , Carne Roja , Secuencia de Aminoácidos , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Especificidad de Órganos , Oxidación-Reducción , Péptidos/química , Ratas Endogámicas SHR , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo
18.
Molecules ; 24(12)2019 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-31208037

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos/uso terapéutico , Proteínas Priónicas/antagonistas & inhibidores , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Animales , Ensayos Clínicos como Asunto , Humanos , Péptidos/química , Péptidos/farmacología , Proteínas Priónicas/metabolismo , Agregado de Proteínas , Agregación Patológica de Proteínas , Multimerización de Proteína , Resultado del Tratamiento
19.
Nat Cell Biol ; 21(6): 778-790, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31160710

RESUMEN

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.


Asunto(s)
Proteínas Quinasas Dependientes de 3-Fosfoinosítido/genética , Neoplasias Colorrectales/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Proteína Quinasa C-alfa/genética , Proteínas Proto-Oncogénicas c-pim-1/genética , Adulto , Anciano , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Indoles/química , Estimación de Kaplan-Meier , Sistema de Señalización de MAP Quinasas/genética , Masculino , Melanoma/genética , Melanoma/patología , Persona de Mediana Edad , Péptidos/química , Péptidos/uso terapéutico , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Sulfonamidas/uso terapéutico
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