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1.
Medicine (Baltimore) ; 99(6): e19064, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32028428

RESUMO

BACKGROUND: This meta-analysis is to evaluate the efficacy and safety of bivalirudin in patients with ST-elevation myocardial infarction (STEMI). METHODS: PubMed, Cochrane Library, Embase, CNKI, CBMdisc, and VIP database were searched. Randomized controlled trial (RCT) was selected and the meta-analysis was conducted by RevMan 5.1. The primary efficacy endpoint was the incidence of major adverse cardiovascular events (MACE) and the primary safety endpoint was the incidence of major bleeding. Secondary efficacy endpoints were myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST), stock, mortality, and thrombocytopenia. The pooled risk ratios (RRs) with the corresponding 95% confidence intervals (CI) were used to assess the efficacy and safety of bivalirudin vs heparin. RESULTS: Seven RCTs met the inclusion criteria, and 16,640 patients were included. We found that bivalirudin associated with lower risk of mortality (RR = 1.05; 95% CI = 0.74-1.49; P = .03; I = 2%), major bleeding (RR = 0.64; 95% CI = 0.54-0.75; P < .00001; I = 70%) and thrombocytopenia (RR = 0.39; 95% CI = 0.25-0.61; P < .0001; I = 0) compared with heparin. However, the use of bivalirudin increase the risk of MI(RR = 1.37; 95% CI = 1.10-1.71; P = .004; I = 25%) and ST(RR = 1.61; 95% CI = 1.05-2.47; P = .03; I = 70%) and has similar risk of MACE (RR = 1.00; 95% CI = 0.90-1.11; P = .97; I = 16%), TVR (RR = 1.43; 95% CI = 0.92-2.22; P = .11; I = 46%) and stock (RR = 1.43; 95% CI = 0.92-2.22; P = .11; I = 46%) compared with heparin used in STEMI patients. CONCLUSION: Bivalirudin associated with lower risk of mortality, major bleeding and thrombocytopenia compared with heparin. However, the use of bivalirudin increase the risk of MI and ST and has similar risk of MACE, TVR and stock compared with heparin used in STEMI patients.


Assuntos
Antitrombinas/uso terapêutico , Doença das Coronárias/cirurgia , Heparina/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Intervenção Coronária Percutânea , Heparina/efeitos adversos , Hirudinas/efeitos adversos , Humanos , Fragmentos de Peptídeos/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Trombose/etiologia , Trombose/prevenção & controle , Resultado do Tratamento
2.
Life Sci ; 246: 117404, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32035128

RESUMO

AIMS: The study aims to investigate the effect of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of fibrinolytic process, on blood glucose in type 2 diabetes mellitus (T2DM) and its mechanism. MATERIALS AND METHODS: We developed a highly potent and highly specific PAI-1 inhibitor, named PAItrap3, based on the inactivated urokinase. Meanwhile, a single point mutation of PAItrap3 (i.e., PAItrapNC) was parallelly prepared as negative control. PAItrap3 was intravenously injected into type 2 diabetic (T2D) mice and its effect on metabolic system was evaluated by measuring the levels of blood glucose, PAI-1, and tumor necrosis factor alpha (TNF-α) in T2D mice. KEY FINDINGS: PAItrap3 significantly reduced the high blood glucose level and PAI-1 level in streptozotocin-induced T2D mice. PAItrapNC did not have any hypoglycemic effect at all on T2D mice. Mechanistically, both PAI-1 and TNF-α levels were attenuated by the administration of PAItrap3. In addition, we observed that PAItrap3 reduced the amount of fat droplets in adipocytes. SIGNIFICANCE: These findings provide clear evidence for PAI-1 to participate in inflammation and obesity mediated hyperglycemia, and open up a new prospect for the treatment of T2DM by PAI-1 inhibition.


Assuntos
Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico , Adipócitos/efeitos dos fármacos , Animais , Masculino , Inibidor 1 de Ativador de Plasminogênio/sangue
3.
Life Sci ; 241: 117174, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31843531

RESUMO

Hypertrophic scar is a dermal fibroproliferative disorder characterized by excess collagen deposition. There are many existing treatment modalities, but none works perfectly in all individuals. Recently, evidence is increasing that peptides can play crucial roles in the prevention or treatment of hypertrophic scar. The peptides may be derived from growth factors, hormones, and intracellular products of proteolysis. In vitro and in vivo studies have revealed that a number of peptides, usually topically applied, have beneficial effects on fibroblasts in rat, mouse, hamster, pig and rabbit scar models. The length of such peptides typically ranges between 10 and 15 amino acids (aa). Peptides may reduce scar progenitors, prevent excessive scarring, decrease scar growth, speed re-epithelialization and promote scar maturation through multiple mechanisms. They may target TGF-ß signaling, fibroblast function or collagen modulation, inflammation, renin angiotensin system, gap junction and other pathways. However, there is a paucity of evidence regarding specific binding sites for these peptides in scar models. Here, we review current research progress on the roles of peptides and underlying mechanisms in hypertrophic scar. We also discuss the clinical potential of peptides as therapeutic agents in scarring. Finally, the functions of several peptide-related compounds in hypertrophic scar are summarized.


Assuntos
Cicatriz Hipertrófica/prevenção & controle , Hormônios/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fragmentos de Peptídeos/uso terapêutico , Animais , Cicatriz Hipertrófica/metabolismo , Humanos
4.
Eur J Pharmacol ; 861: 172593, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31401154

RESUMO

We focused on the cyclophosphamide-induced hemorrhagic cystitis (100 mg/kg/day intraperitoneally throughout three days) as a particular NO-system disturbance, and therapy possibilities. We demonstrated that it may be attenuated by subsequent administration of the NOS substrate L-arginine (100 mg/kg/day intraperitoneally), aggravated by NOS-blocker L-NAME (5 mg/kg/day intraperitoneally), all influenced by the stable gastric pentadecapeptide BPC 157 (10 µg/kg/day, 10 ng/kg/day, intraperitoneally or perorally, in drinking water). Regularly, cyclophosphamide dose- and time-dependently induced severe hemorrhagic cystitis lesions, gross lesions, and corresponding urothelial necrosis, vesical edema, erosion, hemorrhage, inflammation, and ulceration, microscopically. The bladder wet weight dramatically increased. Functionally, already after first cyclophosphamide administration, there is an increased leak point pressure. Until the second cyclophosphamide administration, L-arginine consistently attenuated regular cyclophosphamide-induced severe hemorrhagic cystitis lesions, grossly and microscopically, but not functionally. L-NAME aggravated these lesions and eradicated beneficial effect of L-arginine when combined. BPC 157 administration after cyclophosphamide, given in either dose or in either regimen markedly attenuated all cyclophosphamide lesions, grossly, microscopically. The increase of the bladder wet weight was consistently attenuated. Functionally, increased leak point pressure was reversed to the values noted in normal rats. The similar findings were noted in rats that received BPC 157 together with L-NAME or L-arginine, given alone or combined. Thus, the lesions are NO-related based on the administration of L-NAME as well as administration of L-arginine, and their mutual interaction, and counteraction by BPC 157 application. Likewise, we reveal new therapeutic possibilities, emphasizing stable gastric pentadecapeptide BPC 157 and L-arginine, versus L-NAME in rats underwent cyclophosphamide-induced cystitis.


Assuntos
Arginina/farmacologia , Ciclofosfamida/efeitos adversos , Cistite/complicações , Cistite/tratamento farmacológico , Hemorragia/complicações , NG-Nitroarginina Metil Éster/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteínas/farmacologia , Animais , Antiulcerosos/farmacologia , Antiulcerosos/uso terapêutico , Arginina/uso terapêutico , Feminino , NG-Nitroarginina Metil Éster/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Proteínas/uso terapêutico , Ratos , Ratos Wistar
5.
J Pept Sci ; 25(8): e3197, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31264321

RESUMO

Platelet-activating factor (PAF) is known as an important mediator of anaphylaxis and, therefore, may possibly serve as a direct target for anti-anaphylactic drugs. We recently reported that a synthetic N-terminally biotinylated peptide, BP21, alleviates hypothermia and vascular hyperpermeability during anaphylactic reactions in a mouse model of anaphylaxis via the direct binding of a Tyr-Lys-Asp-Gly sequence in the peptide to PAF. In this study, we investigated the effect of BP21 on in vivo anaphylactic hypotension. Results showed that BP21 significantly inhibited anaphylactic hypotension in a dose-dependent manner, with peak severity being reached within 20 minutes. Adrenaline, which is the recommended first line treatment for anaphylactic patients, did not inhibit anaphylactic hypothermia. The combined administration of BP21 with adrenaline inhibited both hypotension and hypothermia, even at both low doses, more effectively compared with solo administration of BP21 or adrenaline. These results suggested that BP21 could potentially be a novel anti-anaphylactic agent for targeting PAF in vivo.


Assuntos
Anafilaxia/tratamento farmacológico , Biotina/análogos & derivados , Proteínas Hemolisinas/uso terapêutico , Hipotensão/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Animais , Biotina/química , Biotina/metabolismo , Biotina/uso terapêutico , Biotinilação , Proteínas Hemolisinas/química , Proteínas Hemolisinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Estrutura Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo
6.
Med Sci Monit ; 25: 5482-5492, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31337746

RESUMO

BACKGROUND The recombinant avirulent Newcastle disease virus (NDV) LaSota strain expressing the rabies virus glycoprotein (rL-RVG) can induce much greater apoptosis than can NDV in gastric carcinoma cells, but the mechanisms involved remains unclear. MATERIAL AND METHODS The 2 gastric carcinoma cell lines were divided into the rL-RVG group, the NDV group, and the PBS group. MTT assay was used to detect and analyze cell viability. siRNA for alpha7-nAChR, alpha7-nAChR antagonist, or alpha7-nAChR agonist, AKT antagonist, and p-AKT agonist were used for pretreatment. The protein expressions of RVG, NDV, alpha7-nAChR, cleaved caspase-3, p-AKT, PI3K, Bcl-2, and Bax proteins were detected by Western blot assay. Immunofluorescence was used to detect expressions of alpha7-nAChR proteins. Light microscopy, flow cytometry, and TUNEL assay were used to assess apoptosis. RESULTS The results showed that 2 virus concentrations over 10³ dilution caused greater cell proliferation inhibition. rL-RVG treatment increased the expression of alpha7-nAChR, cleaved caspase-3, and Bax protein but decreased the expression of p-AKT, PI3K, and Bcl-2 protein. When the groups were pretreated with alpha7-nAChR antagonist, the alpha7-nAChR, cleaved caspase-3, and Bax protein expression increased, but the expression of p-AKT, PI3K, and Bcl-2 protein was clearly decreased. However, the results in the alpha7-nAChR agonist group were the opposite. When treated with the AKT antagonist, the result was the same as in the rL-RVG treatment group. The result in the AKT agonist group was the opposite of that in the AKT antagonist group. Compared with the NDV group, the results of light microscopy, FCM, and TUNEL assay showed that alpha7-nAChR antagonist significantly affected the apoptosis of gastric cancer cells in the rL-RVG group. CONCLUSIONS rL-RVG leads to much greater apoptosis through the alpha7-nAChR/PI3K/AKT pathway.


Assuntos
Glicoproteínas/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Neoplasias Gástricas/terapia , Proteínas Virais/uso terapêutico , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Humanos , Vírus da Doença de Newcastle/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Vírus da Raiva , Transdução de Sinais , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Proteína X Associada a bcl-2/metabolismo
7.
Int J Med Sci ; 16(7): 1032-1041, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341417

RESUMO

AP25 is an anti-tumor peptide with a high affinity for integrins. It exerts its anti-tumor activity by inhibiting angiogenesis and by directly inhibiting the growth of tumor cells. Its half-life time in vivo is only about 50 minutes, which limits its clinical application. In order to prolong the half-life time of AP25 while preserving its anti-tumor activity, several fusion proteins of AP25 and IgG4 Fc were designed and expressed; their anti-tumor activity and pharmacokinetics properties were evaluated. Firstly, four AP25-Fc fusion protein sequences were designed, and the corresponding proteins were expressed and purified. Based on the results of HUVEC migration inhibition assay, HUVEC and tumor cell proliferation inhibition assay and yields of expression by HEK293 cells, the fusion protein designated PSG4R was selected for further evaluation. The anti-tumor effect of PSG4R was then evaluated in vivo on HCT-116 nude mice xenograft model. And the pharmacokinetics properties of PSG4R were investigated in rats. The results showed that PSG4R could inhibit the growth of xenografts of human colon cancer cell line HCT-116 in nude mice by intravenous administration of 40 mg/kg once every two days. The half-life time of PSG4R was 56.270 ± 15.398 h. This study showed that the construction of AP25-Fc fusion protein could significantly prolong the half-life of AP25 while retaining its anti-tumor activity, which provides a new direction for new drug development of AP25.


Assuntos
Endostatinas/farmacologia , Imunoconjugados/farmacologia , Imunoglobulina G/farmacologia , Neoplasias/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Administração Intravenosa , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Endostatinas/genética , Endostatinas/uso terapêutico , Feminino , Células HCT116 , Células HEK293 , Meia-Vida , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunoconjugados/genética , Imunoconjugados/uso terapêutico , Imunoglobulina G/genética , Imunoglobulina G/uso terapêutico , Masculino , Camundongos , Modelos Animais , Neoplasias/patologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/uso terapêutico , Ratos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Biomed Environ Sci ; 32(6): 419-426, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262387

RESUMO

OBJECTIVE: Silicosis, caused by inhalation of silica dust, is the most serious occupational disease in China and the aim of present study was to explore the protective effect of Ang (1-7) on silicotic fibrosis and myofibroblast differentiation induced by Ang II. METHODS: HOPE-MED 8050 exposure control apparatus was used to establish the rat silicosis model. Pathological changes and collagen deposition of the lung tissue were examined by H.E. and VG staining, respectively. The localizations of ACE2 and α-smooth muscle actin (α-SMA) in the lung were detected by immunohistochemistry. Expression levels of collagen type I, α-SMA, ACE2, and Mas in the lung tissue and fibroblasts were examined by western blot. Levels of ACE2, Ang (1-7), and Ang II in serum were determined by ELISA. Co-localization of ACE2 and α-SMA in fibroblasts was detected by immunofluorescence. RESULTS: Ang (1-7) induced pathological changes and enhanced collagen deposition in vivo. Ang (1-7) decreased the expressions of collagen type I and α-SMA and increased the expressions of ACE2 and Mas in the silicotic rat lung tissue and fibroblasts stimulated by Ang II. Ang (1-7) increased the levels of ACE2 and Ang (1-7) and decreased the level of Ang II in silicotic rat serum. A779 enhanced the protective effect of Ang (1-7) in fibroblasts stimulated by Ang II. CONCLUSION: Ang (1-7) exerted protective effect on silicotic fibrosis and myofibroblast differentiation induced by Ang II by regulating ACE2-Ang (1-7)-Mas axis.


Assuntos
Angiotensina II/sangue , Angiotensina I/uso terapêutico , Pulmão/metabolismo , Miofibroblastos/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Silicose/prevenção & controle , Actinas/metabolismo , Angiotensina I/sangue , Angiotensina I/farmacologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Pulmão/patologia , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Silicose/metabolismo , Silicose/patologia
9.
J Vasc Surg ; 70(1): 274-284.e5, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31230646

RESUMO

OBJECTIVE: The direct thrombin inhibitor bivalirudin (BIV) was shown to be superior to unfractionated heparin (UFH) in percutaneous coronary interventions for reducing procedural blood loss. The aim of this study was to compare outcome profiles of BIV and UFH in peripheral endovascular procedures (PEPs) by synthesizing the currently available data. METHODS: Following the PRISMA statement, we conducted a comprehensive literature search using Medline, Cochrane CENTRAL, PubMed, EMBASE, CINAHL Google scholar, and clinicaltrials.gov. We recruited randomized, controlled trials and well-conducted observational studies that compared UFH and BIV in PEPs requiring anticoagulation, excluding endovascular cardiac procedures and coronary interventions. Random-effects meta-analyses were conducted to compare the outcome profiles of these two agents. RESULTS: Thirteen articles containing 17 studies involving a total of 21,057 patients were enrolled. Of these, 2 were randomized controlled trials, 2 were prospective cohort studies, and 10 were retrospective studies. There were no significant differences between BIV and UFH in terms of procedural success rates, major and minor perioperative bleeding, transfusion, perioperative transient ischemic attack, or hemorrhagic strokes. However, compared with UFH, BIV had significantly lower odds ratios (OR) of perioperative mortality (OR, 0.58; 95% confidence interval [CI], 0.40-0.86), major adverse cardiovascular events (OR, 0.65; 95% CI, 0.51-0.83), net adverse clinical events (OR, 0.75; 95% CI, 0.63-0.88), perioperative myocardial infarction (OR, 0.73; 95% CI, 0.55-0.98), major vascular complications (OR, 0.59; 95% CI, 0.39-0.91), and minor vascular complications (OR, 0.58; 95% CI, 0.40-0.84). CONCLUSIONS: Compared with UFH, PEPs using BIV had comparable procedural success rates and odds of perioperative transient ischemic attack and hemorrhagic stroke. However, procedures with BIV had a lower but nonsignificant odds of perioperative bleeding and transfusion. Depending on the procedures conducted, the patients who received BIV will have reduced or comparable odds of perioperative mortality, myocardial infarction, major adverse cardiovascular events, net adverse clinical events, and major and minor vascular complications. Therefore, BIV may be chosen solely as an alternative procedural anticoagulant to UFH for PEPs.


Assuntos
Anticoagulantes/uso terapêutico , Antitrombinas/uso terapêutico , Procedimentos Endovasculares , Heparina/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Doenças Vasculares Periféricas/terapia , Anticoagulantes/efeitos adversos , Antitrombinas/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Hemorragia/induzido quimicamente , Heparina/efeitos adversos , Hirudinas/efeitos adversos , Humanos , Ataque Isquêmico Transitório/etiologia , Infarto do Miocárdio/etiologia , Estudos Observacionais como Assunto , Segurança do Paciente , Fragmentos de Peptídeos/efeitos adversos , Doenças Vasculares Periféricas/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento
10.
Thromb Haemost ; 119(9): 1539-1545, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31226721

RESUMO

Despite dual antiplatelet therapy patients undergoing percutaneous coronary intervention (PCI) continue to experience periprocedural ischemic events. In addition, all currently used antithrombotic drugs increase the bleeding risk. Thus, there is an unmet clinical need for antithrombotic strategies with improved efficacy and no increase in bleeding. Revacept is a novel, lesion-directed antithrombotic drug that does not interfere with the function of circulating platelets. This dimeric fusion protein of the extracellular domain of glycoprotein VI (the major platelet collagen receptor) and the human Fc-fragment inhibits collagen-mediated platelet adhesion and subsequent aggregation at the site of vascular injury. The randomized, double-blinded, phase II ISAR-PLASTER trial is based on extensive preclinical evaluation of Revacept and a favorable first-in-man trial. A total of 332 patients with stable coronary artery disease undergoing elective PCI will be randomized to either Revacept 160 mg, Revacept 80 mg, or placebo administered as single intravenous infusion directly before the intervention, on top of standard dual antiplatelet therapy and either heparin or bivalirudin, based on local practice and current guidelines. The primary endpoint is the composite of death or myocardial injury (defined as increase in high sensitivity troponin T ≥ 5 times the upper limit of normal) at 48 hours. The safety endpoint is bleeding of class 2 or higher according to the Bleeding Academic Research Consortium at 30 days. This phase II randomized, double blind trial will assess for the first time the efficacy and safety of Revacept-a lesion-directed inhibitor of platelet adhesion-in patients undergoing elective PCI.


Assuntos
Plaquetas/fisiologia , Doença da Artéria Coronariana/terapia , Fibrinolíticos/uso terapêutico , Glicoproteínas/uso terapêutico , Hemorragia/etiologia , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Infarto do Miocárdio/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/mortalidade , Método Duplo-Cego , Procedimentos Cirúrgicos Eletivos , Feminino , Fibrinolíticos/efeitos adversos , Alemanha , Glicoproteínas/efeitos adversos , Hemorragia/mortalidade , Heparina/uso terapêutico , Hirudinas , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Fragmentos de Peptídeos/uso terapêutico , Intervenção Coronária Percutânea , Placebos , Agregação Plaquetária/efeitos dos fármacos , Proteínas Recombinantes/uso terapêutico , Análise de Sobrevida , Adulto Jovem
11.
Int J Mol Sci ; 20(13)2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252620

RESUMO

Psoriasis is a chronic inflammatory skin disease characterized by excessive growth of keratinocytes and hyperkeratosis in the epidermis. An abnormality of the non-lesional epidermis at an early stage of psoriasis is involved in triggering inflammatory cell infiltration into the dermis. Integrin α5ß1 acts as a receptor for fibronectin and has been found to be overexpressed in non-lesional psoriatic epidermis. To investigate whether α5ß1 integrin has a potential as a drug target for psoriasis treatment, the α5ß1 integrin-binding peptide, C16, was used to obstruct the HaCat keratinocyte cellular responses induced by fibronectin (Fn) in culture and psoriasis-like skin inflammation induced in mice by imiquimod (IMQ). The C16 exhibited antagonistic activity against α5ß1 integrin in HaCat cells, with evidence of suppression of the Fn-mediated proliferative, cytoskeletal, and inflammatory responses. Topical treatment with C16 greatly reduced the IMQ-induced epidermal hyperplasia, infiltration of neutrophils/macrophages, and expression of pro-inflammatory mediators in mouse skin. The C16SP (C16-derived short peptide; DITYVRLKF) also exhibited antagonistic activity, suppressing α5ß1 integrin activity in culture, and reducing IMQ-induced skin inflammation. Taken together, this study provides the first evidence that α5ß1 integrin may be a potential drug target for psoriasis. The synthetic C16 peptide may serve as an agent for psoriasis therapy.


Assuntos
Anti-Inflamatórios/uso terapêutico , Laminina/química , Fragmentos de Peptídeos/uso terapêutico , Psoríase/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Linhagem Celular , Feminino , Fibronectinas/farmacologia , Humanos , Imiquimode/toxicidade , Integrina alfa5beta1/antagonistas & inibidores , Integrina alfa5beta1/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Ligação Proteica , Psoríase/etiologia
12.
Int J Mol Med ; 44(2): 523-534, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173192

RESUMO

The T7 peptide, an active fragment of full­length tumstatin [the non­collagenous 1 domain of the type IV collagen α3 chain, α3 (IV) NC1], has exhibited potential antitumor effects in several types of cancer cells. However, the mechanism underlying its action against human hepatocellular carcinoma (HCC) remains unclear. The present study aimed to investigate the role of autophagy in T7 peptide­induced cytotoxicity in HCC cells in vitro and in vivo. The results revealed that the T7 peptide significantly reduced cell viability and induced cell cycle arrest in HCC cells. The T7 peptide induced apoptosis in HCC cells through upregulation of Bax, Fas, and Fas ligand, and through upregulation of the anti­apoptotic protein Bcl­2. In addition, treatment with the T7 peptide induced protective autophagy in HCC cells. Blocking autophagy by 3­methyladenineor bafilomycin A1 enhanced T7 peptide­induced apoptosis. Furthermore, co­treatment with MK­2206 (an Akt specific inhibitor) or rapamycin (an inhibitor of mTOR) enhanced T7 peptide­induced autophagy, whereas co­treatment with insulin (an activator of the Akt/mTOR signaling pathway) alleviated T7 peptide­induced autophagy, which suggested that the T7 peptide may induce autophagy activation via inhibition of the Akt/mTOR signaling pathway. Taken together, the present results demonstrated that suppression of autophagy potentiated the cytotoxic effects of the T7 peptide, and suggested that the T7 peptide may serve as a potential alternative compound for HCC therapy.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Colágeno Tipo IV/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Animais , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Colágeno Tipo IV/uso terapêutico , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/uso terapêutico
13.
Neuropharmacology ; 155: 104-112, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31128121

RESUMO

Galanin (1-15) [GAL(1-15)] participates in mood regulation and depression. GAL(1-15) is also able to enhance the antidepressant effects induced by Fluoxetine (FLX) in the forced swimming test through interaction between GALR1-GALR2 and 5-HT1A receptors that induced changes in the binding characteristics and mRNA of the 5-HT1AR in the hippocampus. Since the medial prefrontal cortex (mPFC) is a core region for the interaction between emotional processing and cognition with a high density of 5-HT1AR and GALR1 and GALR2, we have analyzed the binding characteristics and mRNA levels of 5-HT1AR in the mPFC after GAL(1-15)-FLX administration in the rats. GAL(1-15) increased the Kd and the Bmax of the 5HT1AR agonist binding in the mPFC as well as the mRNA levels of 5-HT1AR in mPFC. Moreover, GAL(1-15) reversed the effects of memory impairment induced by FLX(10 mg/kg) in the Novel Object Recognition task. GALR2 was involved in these effects, since the specific GALR2 antagonist M871 blocked GAL(1-15) mediated actions at behavioral level. On the contrary GAL(1-15) did not reverse the effect of FLX in the Object Location Memory task. In conclusion, our results describe an interactions between GAL(1-15) and FLX in the mPFC involving interactions at the 5-HT1AR receptor level in the plasma membrane with changes at the transcriptional level with implications also at functional level. The GALR1-GALR2-5-HT1A heteroreceptor could be postulated to be used to reverse some of the adverse effects of FLX on memory processes.


Assuntos
Fluoxetina/metabolismo , Galanina/metabolismo , Fragmentos de Peptídeos/metabolismo , Córtex Pré-Frontal/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Inibidores de Captação de Serotonina/metabolismo , Animais , Interações de Medicamentos/fisiologia , Fluoxetina/toxicidade , Galanina/farmacologia , Galanina/uso terapêutico , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Neuropeptídeos/metabolismo , Neuropeptídeos/farmacologia , Neuropeptídeos/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Inibidores de Captação de Serotonina/toxicidade
14.
Rev Mal Respir ; 36(4): 442-446, 2019 Apr.
Artigo em Francês | MEDLINE | ID: mdl-31006580

RESUMO

Severe asthma required high dose of corticosteroids combined with biotherapies to control more or less asthma symptoms and lead to the decrease of patients' quality of life on long term. Recent studies show that hypoallergenic peptides derived from allergen can prevent airway hyperresponsiveness, decrease Th2 response and also allergen-specific IgE in mouse models of allergic asthma. Even if some peptides mechanisms remain unknown, their fast efficacy with low doses of allergens make peptide immunotherapy a new promising approach in allergic asthma.


Assuntos
Alérgenos/química , Asma/terapia , Dessensibilização Imunológica/métodos , Peptídeos/uso terapêutico , Alérgenos/imunologia , Alérgenos/uso terapêutico , Animais , Asma/imunologia , Humanos , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Peptídeos/imunologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/terapia
15.
Exp Eye Res ; 184: 24-29, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30980815

RESUMO

The purpose of the study is to evaluate the protective properties of PEDF peptide fragments on rd10 mouse models of retinal degeneration ex vivo. Human recombinant PEDF and synthetic peptides were used. Rd10 retinal explants as well as wild-type retinal explants treated with zaprinast to mimic the rd10 photoreceptor cell death were employed. PEDF protein was intravitreally administered into rd10 mice. Outer nuclear layer thickness measurements in retinal sections, TUNEL labeling in retinal explants, western blots and immunofluorescence with retinal samples were performed. PEDF protein levels in the RPE of rd10 mice decreased with age (P15 - P25). Levels of PEDF receptor PEDF-R declined in the photoreceptor inner segments from rd10 relative to wild-type mice at P25. PEDF administration increased the outer nuclear layer thickness of rd10 retinas in vivo and decreased the number of TUNEL+ nuclei of photoreceptors in rd10 retinal explant cultures, both relative to untreated controls. Peptides containing the PEDF neurotrophic region decreased the number of TUNEL+ photoreceptors in both rd10 and zaprinast-induced cell death ex vivo models, while peptides without the neurotrophic region and/or lacking affinity for PEDF-R were ineffective in protecting photoreceptors. Thus, retinal explants are a valuable system to evaluate PEDF activity. Short peptides with the photoreceptor-protective property of PEDF may prove useful for the development of therapeutic agents for photoreceptor protection in retinal degenerations.


Assuntos
Proteínas do Olho/uso terapêutico , Fatores de Crescimento Neural/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Degeneração Retiniana/tratamento farmacológico , Serpinas/uso terapêutico , Animais , Western Blotting , Sobrevivência Celular , Modelos Animais de Doenças , Técnica Indireta de Fluorescência para Anticorpo , Marcação In Situ das Extremidades Cortadas , Injeções Intravítreas , Camundongos , Camundongos Endogâmicos C57BL , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patologia , Proteínas Recombinantes , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia
16.
Int J Biol Macromol ; 133: 58-66, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30981773

RESUMO

Nanoparticle-based pulmonary delivery of protein therapeutics provides a promising approach for improving protein bioavailability to treat either local or systemic diseases, however high-efficient nanocarrier is a great challenge. Here, biomimetic phosphorylcholine-chitosan nanoparticles (PCCs-NPs) taking advantages of both zwitterionic phosphorylcholine and chitosan were developed as a pulmonary protein delivery platform. msFGFR2c, a potential therapeutic protein for lung fibrosis as model was loaded into PCCs-NPs via ionic gelation. The obtained msFGFR2c/PCCs-NPs inhibited α-SMA expression in fibroblasts induced by TGF-ß1, slightly more effective than naked msFGFR2c. After orotracheal administration to bleomycin-induced pulmonary fibrosis model rats, msFGFR2c/PCCs-NPs resulted in a significant antifibrotic efficacy, with reduction in inflammatory cytokines and α-SMA expression, remarkable attenuation of lung fibrosis score and collagen deposition, and significant increase in survival rate, while naked msFGFR2c exhibited a poor efficacy. The in vitro and in vivo results strongly indicated that PCCs-NPs may be a promising nanocarrier for pulmonary protein delivery.


Assuntos
Bleomicina/efeitos adversos , Quitosana/química , Pulmão/metabolismo , Nanopartículas/química , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/uso terapêutico , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêutico , Animais , Linhagem Celular , Portadores de Fármacos/química , Feminino , Humanos , Pulmão/efeitos dos fármacos , Fosforilcolina/química , Fibrose Pulmonar/induzido quimicamente , Ratos , Ratos Wistar
18.
Neurobiol Dis ; 127: 87-100, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30818065

RESUMO

Multiple Sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by autoimmune and neurodegenerative pathologies for which there is no cure and no defined etiology. Although several, modestly effective, disease modifying drugs are available to treat MS, there are presently no treatments that offer neuroprotection and prevent clinical progression. Therapies are needed that control immune homeostasis, prevent disease progression, and stimulate regeneration in the CNS. Components of the renin-angiotensin-system (RAS) have recently been identified as chemical mediators in the CNS and in neurological disease. Here we show the beneficial effect of therapeutic treatment with the Mas receptor agonist and metabolite of the protective arm of RAS, angiotensin 1-7 (A(1-7)), in the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Therapeutic treatment with A(1-7) caused a dose-dependent reduction both in clinical disease severity and progression, and was dependent on Mas receptor activation. Further analysis of the most optimal dose of A(1-7) treatment revealed that the reductions in clinical disease course were associated with decreased immune infiltration and demyelination, axonal loss and oxidative stress in the spinal cord. In addition A(1-7) treatment was also associated with increases in circulating alternatively activated monocytes/macrophages.


Assuntos
Angiotensina I/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Angiotensina I/administração & dosagem , Animais , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Relação Dose-Resposta a Droga , Encefalomielite Autoimune Experimental/diagnóstico , Encefalomielite Autoimune Experimental/metabolismo , Masculino , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Índice de Gravidade de Doença , Resultado do Tratamento
19.
Thromb Res ; 177: 59-69, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30851630

RESUMO

ACS patients undergoing percutaneous coronary intervention (PCI) when treated with bivalirudin and clopidogrel had increased frequency of early stent thrombosis. 24 patients referred for intervention with planned bivalirudin therapy, not previously treated with a P2Y12 inhibitor and not receiving heparins or αIIbß3 inhibitors were randomized to treatment with either clopidogrel (600 mg) or prasugrel (60 mg). Platelet aggregation (PA) was measured by light transmission aggregometry (LTA) of platelet-rich plasma in response to ADP, PAR1/PAR4 thrombin receptor agonists and collagen at baseline and at 1, 2, 4 and 16 h following the cessation of bivalirudin infusion. Prasugrel-mediated inhibition of PA was significantly greater than that of clopidogrel at all time points for ADP as well as PAR1. There was an unanticipated, significantly greater protection of PAR4-mediated platelet aggregation only detected with prasugrel and not observed with clopidogrel. We further examined the effect of the hyperreactive PAR4 Thr120 variant in the protease-activated receptor 4 (PAR4), single nucleotide polymorphism (SNP) rs773902 on aggregation protection. The PAR4 protective effect with prasugrel was lost in individuals carrying the PAR4 Thr120 variant, and not in Ala120 homozygote. PAR1, ADP and collagen inhibition was not significantly affected in the hyperreactive PAR4 Thr120 variant. We documented that the P2Y12 ADP receptor-mediated regulation of the strength of the high-affinity conformation of αIIbß3 as detected by PAC-1 ab, and in control of platelet adhesiveness through Rap1 GTPase protein activation. Importantly, the PAR4 Thr120 variant resulted in the increased rate and magnitude of Rap1 activation. Human platelet PAR4 mediated-activation of αIIbß3 was phospholipase C beta (PLCß)-dependent and unlike mouse platelet PI3K-independent. These data identify a PAR4-dependent inhibitory mechanism for the prasugrel-mediated platelet inhibition, not seen with clopidogrel that could explain the reduction in stent thrombosis documented in clinical trials with prasugrel.


Assuntos
Antitrombinas/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Trombose/prevenção & controle , Idoso , Feminino , Hirudinas , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Receptores Purinérgicos P2Y12/metabolismo , Receptores de Trombina/metabolismo , Proteínas Recombinantes/uso terapêutico , Stents/efeitos adversos , Trombose/etiologia , Trombose/metabolismo
20.
Cell Tissue Res ; 377(2): 153-159, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30915550

RESUMO

There is a current need for a therapy that can alleviate the social and economic burden that presents itself with debilitating and recurring musculoskeletal soft tissue injuries and disorders. Currently, several therapies are emerging and undergoing trials in animal models; these focus on the manipulation and administration of several growth factors implicated with healing. However, limitations include in vivo instability, reliance on biocompatible and robust carriers and restricted application procedures (local and direct). The aim of this paper is therefore to critically review the current literature surrounding the use of BPC 157, as a feasible therapy for healing and functional restoration of soft tissue damage, with a focus on tendon, ligament and skeletal muscle healing. Currently, all studies investigating BPC 157 have demonstrated consistently positive and prompt healing effects for various injury types, both traumatic and systemic and for a plethora of soft tissues. However, to date, the majority of studies have been performed on small rodent models and the efficacy of BPC 157 is yet to be confirmed in humans. Further, over the past two decades, only a handful of research groups have performed in-depth studies regarding this peptide. Despite this, it is apparent that BPC 157 has huge potential and following further development has promise as a therapy to conservatively treat or aid recovery in hypovascular and hypocellular soft tissues such as tendon and ligaments. Moreover, skeletal muscle injury models have suggested a beneficial effect not only for disturbances that occur as a result of direct trauma but also for systemic insults including hyperkalamia and hypermagnesia. Promisingly, there are few studies reporting any adverse reactions to the administration of BPC 157, although there is still a need to understand the precise healing mechanisms for this therapy to achieve clinical realisation.


Assuntos
Ligamentos , Músculo Esquelético , Fragmentos de Peptídeos/farmacologia , Proteínas/farmacologia , Traumatismos dos Tendões/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Humanos , Ligamentos/efeitos dos fármacos , Ligamentos/lesões , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/lesões , Fragmentos de Peptídeos/uso terapêutico , Proteínas/uso terapêutico
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