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1.
Int J Mol Sci ; 18(7)2017 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-28657598

RESUMO

In this study, we investigated the role of a matricellular protein galectin-9 (Gal-9) in pleural effusion related to tuberculosis (TB). Plasma and pleural fluid of a patient with extrapulmonary TB were analyzed for cytokine content by ELISA and Luminex. Peripheral blood mononuclear cells (PBMCs) and pleural fluid cells (PFCs) were examined for interferon-γ (IFN-γ) secretion by the enzyme-linked immunospot (ELISPOT) assay or IFN-γ ELISA, for apoptosis and necrosis by Cell Death Detection ELISA, and also underwent cell sorting. The results indicate that compared to plasma, pleural fluid had increased levels of IFN-γ (1.6 vs. 55.5 pg/mL), IL-10, IL-12p40, vascular endothelial growth factor (VEGF), and Gal-9 (3.0 vs. 936.0 pg/mL), respectively. PFCs culture supernatant exhibited higher concentration of Gal-9 compared to PBMCs in culture, consistent with enriched Gal-9 staining in the granuloma that is in closer vicinity to PFCs compared to PBMCs. PFCS displayed higher IFN-γ secretion after stimulation with TB antigens ESAT-6/CFP-10. Furthermore, in PFCs, Gal-9 alone could stimulate IFN-γ synthesis in culture or ELISPOT, which was inhibited by a Gal-9 antagonist lactose, and which may promote apoptosis and necrosis. These findings suggest that Gal-9 could modulate immune responses and participate in immunopathology of pleural effusion during TB.


Assuntos
Galectinas/metabolismo , Interferon gama/metabolismo , Tuberculose/metabolismo , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino
2.
PLoS One ; 10(7): e0132835, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26181635

RESUMO

BACKGROUND: Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is known as an anti-platelet drug and acts directly on platelets. Cilostazol has been shown to exhibit vascular protection in ischemic diseases. Although vascular endothelium-derived prostaglandin I2 (PGI2) plays an important role in vascular protection, it is unknown whether cilostazol directly stimulates PGI2 synthesis in endothelial cells. Here, we elucidate the mechanism of cilostazol-induced PGI2 stimulation in endothelial cells. METHODS AND RESULTS: Human aortic endothelial cells (HAECs) were stimulated with cilostazol and PGI2 accumulation in the culture media was measured. Cilostazol increased PGI2 synthesis via the arachidonic acid pathway. Cilostazol-induced intracellular calcium also promoted PGI2 synthesis via the inositol 1,4,5-trisphosphate receptor. Using RNAi, silencing of PDE3B abolished the induction effect of cilostazol on PGI2 synthesis and intracellular cAMP accumulation. Inhibition of the exchange protein, which was directly activated by cyclic AMP 1 (Epac-1) and its downstream signal the Ras-like small GTPase (Rap-1), abolished cilostazol-induced PGI2 synthesis, but this did not take place via protein kinase A (PKA). Inhibition of downstream signaling, such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) γ, and phospholipase C (PLC) ε, suppressed cilostazol-induced PGI2 synthesis. CONCLUSIONS: The PDE3/Epac-1/Rap-1 signaling pathway plays an important role in cilostazol-induced PGI2 synthesis. Namely, stimulation of HAECs with cilostazol induces intracellular calcium elevation via the Rap-1/PLCε/IP3 pathway, along with MAPK activation via direct activation by Epac-1/Rap-1 and indirect activation by Epac-1/Rap-1/PI3Kγ, resulting in synergistically induced PGI2 synthesis.


Assuntos
Células Endoteliais/efeitos dos fármacos , Epoprostenol/agonistas , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Inibidores da Fosfodiesterase 3/farmacologia , Proteínas de Ligação a Telômeros/metabolismo , Tetrazóis/farmacologia , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Ácido Araquidônico/metabolismo , Cálcio/metabolismo , Linhagem Celular , Cilostazol , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Epoprostenol/biossíntese , Regulação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Receptores de Inositol 1,4,5-Trifosfato , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoinositídeo Fosfolipase C/genética , Fosfoinositídeo Fosfolipase C/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Complexo Shelterina , Transdução de Sinais , Proteínas de Ligação a Telômeros/genética
4.
J Phys Chem A ; 113(44): 12056-62, 2009 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-19803511

RESUMO

Ionization and fragmentation were studied on alkylphenols with long alkyl chains (p-(C6H4)(OH)(C(n)H(2n+1)), n = 1,3,5,8,9) and, for reference, on alkylbenzenes ((C6H5)(C(n)H(2n+1)), n = 1,3,5,7,9) by intense femtosecond laser pulses, typically with 43 fs duration at 0.8 microm and 140 fs at 1.3 microm in an intensity range of 10(14) W cm(-2). The major products were the corresponding molecular and C7 fragment ions from the alkylphenols and alkylbenzenes. The molecular ion yields decreased from nearly 1 (n = 1) to 0.3-0.5 (n = 9) when the carbon number in the alkyl chain increased for both excitation wavelengths. Higher yields of the molecular ions were observed at a longer wavelength of 1.3 microm. The long wavelengths in the range of 1.3-1.5 microm were used to determine whether or not -OH absorption had any increase in fragment ions. No effect was observed by vibrational overtone excitation of the -OH group in this wavelength range. Direct dissociation by cation absorption is the most plausible explanation of the present fragmentation results. Other possible mechanisms were discussed, including a statistical model, an effect of electron rescattering, a multiactive electron model, and dissociation from the superexcited state. In the case of cyclohexane, nonresonant wavelength excitation with a pulse of 1.3 microm (150 fs) effectively suppressed fragmentation more than excitation by a resonant but short-duration pulse (0.8 microm, 15 fs).

6.
J Pharm Sci ; 98(5): 1775-87, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-18781650

RESUMO

The purpose of the present study was to examine whether the intestinal absorption of low-permeability drugs could be improved by utilization of the intestinal influx transporter PEPT1. We investigated whether peptide derivatives of poorly absorbable nonamino acid-like drugs might be substrates of PEPT1, using rebamipide (Reb) as a model drug. We synthesized several peptide derivatives of rebamipide and examined their inhibitory effect on the uptake of [(3)H]Gly-Sar by PEPT1-expressing HeLa cells. Some of the peptide derivatives inhibited PEPT1-mediated uptake of [(3)H]Gly-Sar. Next, uptake of the inhibitory peptide derivatives was evaluated in PEPT1-expressing Xenopus oocytes and HeLa cells. Ser(Reb)-Gly exhibited significantly increased uptake by PEPT1-expressing cells in comparison with that by mock cells. The permeability of Ser(Reb)-Gly across a Caco-2 cell monolayer was significantly higher than that of rebamipide itself, and the transport was decreased in the presence of PEPT1 substrates. Further, a rat intestinal perfusion study revealed increased absorption of Ser(Reb)-Gly compared with rebamipide. These results demonstrate that the addition of a dipeptide moiety to a poorly absorbable nonpeptide/nonamino acid-like drug can result in absorption via the intestinal transporter PEPT1, though there is some selectivity as regards the structure of the added peptide moiety.


Assuntos
Alanina/análogos & derivados , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Absorção Intestinal/fisiologia , Peptídeos/química , Quinolonas/administração & dosagem , Quinolonas/farmacocinética , Simportadores/metabolismo , Alanina/administração & dosagem , Alanina/farmacocinética , Animais , Disponibilidade Biológica , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Dipeptídeos/química , Glutamina/química , Células HeLa , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Mucosa Intestinal/metabolismo , Intestinos/irrigação sanguínea , Oócitos/metabolismo , Técnicas de Patch-Clamp , Transportador 1 de Peptídeos , Peptídeos/síntese química , Ratos , Fluxo Sanguíneo Regional , Dodecilsulfato de Sódio , Taurina , Xenopus
7.
Biochim Biophys Acta ; 1780(3): 497-503, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18241678

RESUMO

Peptides which mimic functional activities of glycosphingolipids were prepared by a technology of phage-displayed peptide library using monoclonal antibodies against glycosphingolipids. These peptides were named glyco-replica peptides. Peptides prepared with anti-GD1alpha antibody by this technology were found to contain WHW as common motif, and they showed suppressive activity not only on adhesion between hepatic sinusoidal endothelial cells and lymphosarcoma RAW117-H10 cells, but also on metastasis of the tumor cell to the liver and lung. The WHW motif seems to be important to mimic the functional activity of the ganglioside GD1alpha. Next, we prepared GD3-replica peptides using a monoclonal antibody against GD3 (4F6). A peptide, GD3-P4 with highest affinity to 4F6 was used to immunize mice to examine if the mice show their immune response to raise antibodies against GD3. We confirmed the immune response and succeeded in the production of a monoclonal antibody (3D2) against GD3. The monoclonal antibody 3D2 showed specific binding to GD3 on a thin-layer chromatography plate and also melanoma tissues. Interestingly, the amino acid sequence of the CDR regions of light and heavy chains showed high similarity with those of the original GD3 monoclonal antibody (4F6) used for the preparation of GD3-replica peptide. The technology of the phage-displayed peptide library was applied to in vivo bio-panning study using an angiogenesis experimental model. The obtained peptides were found to show strong binding property to the neo-vasculature system and to be quite useful to carry an anti-tumor drug to the tumor tissue. Based on these experimental results, we discuss about some applications of this method to drug discovery.


Assuntos
Desenho de Fármacos , Glicômica/métodos , Biblioteca de Peptídeos , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Adesão Celular/efeitos dos fármacos , Gangliosídeo G(M1)/análogos & derivados , Gangliosídeo G(M1)/farmacologia , Gangliosídeos/imunologia , Glicoesfingolipídeos/química , Glicoesfingolipídeos/metabolismo , Humanos , Melanoma/irrigação sanguínea , Melanoma/imunologia , Melanoma/patologia , Camundongos , Dados de Sequência Molecular , Metástase Neoplásica , Neovascularização Patológica , Peptídeos/química , Peptídeos/imunologia , Peptídeos/farmacologia
8.
J Med Chem ; 51(3): 388-91, 2008 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-18197613

RESUMO

Reported herein are the design, biological activities, and biophysical properties of a novel HIV-1 membrane fusion inhibitor. alpha-Helix-inducible X-EE-XX-KK motifs were applied to design an enfuvirtide analogue 2 that exhibited highly potent anti-HIV activity against wild-type HIV-1, enfuvirtide-resistant HIV-1 strains, and an HIV-2 strain in vitro. Indispensable residues for bioactivity of enfuvirtide, including the residues interacting with the N-terminal heptad repeat and the C-terminal hydrophobic residues, were identified.


Assuntos
Proteína gp41 do Envelope de HIV/síntese química , Inibidores da Fusão de HIV/síntese química , HIV-1/efeitos dos fármacos , Fragmentos de Peptídeos/síntese química , Sequência de Aminoácidos , Farmacorresistência Viral , Enfuvirtida , Proteína gp41 do Envelope de HIV/química , Proteína gp41 do Envelope de HIV/farmacologia , Inibidores da Fusão de HIV/química , Inibidores da Fusão de HIV/farmacologia , HIV-1/fisiologia , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Ligação Proteica , Estrutura Secundária de Proteína , Relação Estrutura-Atividade
9.
J Chem Phys ; 127(10): 104314, 2007 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-17867754

RESUMO

Methane derivatives of CH(3)-X (X: H, F, Cl, Br, I, and CN) were ionized and fragmented by an intense femtosecond laser with a 40 fs pulse at 0.8 microm in intensities of 10(13)-10(15) W cm(-2). The curves of the ionization yields of CH(3)-X versus laser intensities have been found to be fitted with an atomic ionization theory (the theory of Perelomov, Popov, and Terent'ev) that has been established to reproduce experimental results well for rare gas atoms. The saturation intensities have been reproduced within a factor of 1.6 of the calculated ones. For molecules with low ionization potentials such as amines, another atomic ionization theory (the theory of Ammosov, Delone, and Krainov) reproduced the saturation intensities. The atomiclike ionization behavior of molecules indicates that the fragmentation occurs after the ionization. The fragmentation mechanisms after the ionization of some molecular ions are discussed.

10.
J Chem Phys ; 126(10): 104304, 2007 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-17362065

RESUMO

The authors compared circularly and linearly polarized lights in the ionization and fragmentation of anthracene, using 800 nm femtosecond laser pulses at intensities of 10(13)-10(15) W cm-2. Singly and doubly charged intact molecular ions as well as numerous fragment ions were observed in the mass spectra, which were investigated as a function of laser intensity and polarization. At comparable intensities above the saturation threshold for complete ionization, the fragmentation pathways are enhanced with a circularly polarized field compared to a linearly polarized field. Resonant excitation of the molecular cation through the 2Au<--2Bg transition is proposed to be the initial step to ion fragmentation. The circularly polarized field interacts with a larger fraction of the randomly oriented molecules than the linearly polarized field, and this is considered to be the reason for the enhanced fragmentation brought about by circularly polarized light.

11.
Thromb Res ; 119(3): 319-29, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-16566959

RESUMO

Recent progress in the understanding of thrombus formation has suggested an important role for glycoprotein (GP) VI in this process. To clarify the exact role in detail, it is necessary to use specific, high affinity inhibitory antibodies. However, possibly due to the conserved structure of GPVI among species, it has been difficult to obtain potent antibodies. In this study, we developed highly potent anti-human GPVI monoclonal antibodies using GPVI knockout mice for immunization. Fab fragments of these antibodies, named OM1 and OM2, potently inhibit collagen-induced platelet aggregation. The IC(50) values for OM1 and OM2 are 0.6+/-0.05 and 1.7+/-0.5 microg/mL, respectively, showing potency greater than, or equal to that of abciximab (1.7+/-0.3 microg/mL), an anti-GPIIb/IIIa antibody. Fab fragments of OM1 and OM2 also potently inhibit collagen-induced ATP release, thromboxane A(2) formation, and platelet adhesion to immobilized collagen under static and flow conditions. Interestingly, platelet aggregation induced with collagen-related peptide was potently inhibited by OM2 but not OM1, indicating that OM1 recognizes an epitope that is different from collagen-related peptide-binding site on GPVI. These results suggest that OM1 and OM2 may be useful tools to understand the role of GPVI in thrombus formation. Furthermore, these antibodies have the potential to be developed as a new class of therapeutic tool.


Assuntos
Anticorpos Monoclonais/farmacologia , Fragmentos Fab das Imunoglobulinas/farmacologia , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/imunologia , Animais , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos/imunologia , Plaquetas/citologia , Plaquetas/metabolismo , Células COS , Chlorocebus aethiops , Humanos , Imunização , Fragmentos Fab das Imunoglobulinas/imunologia , Camundongos , Camundongos Knockout , Adesividade Plaquetária/imunologia , Agregação Plaquetária/imunologia , Glicoproteínas da Membrana de Plaquetas/deficiência
12.
J Phys Chem A ; 110(25): 7763-71, 2006 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-16789760

RESUMO

We examined the femtosecond nonresonant ionization of organic amines with vertical ionization potentials as low as 5.95 eV. The quantitative evaluation of suppressed ionization relative to the single active electron approximation model was done by comparing the saturation intensity, I(sat), in experiments and theory. ADK theory was found to be useful in predicting the ionization yield in the I(sat) scale within a factor of 2, even for molecules with very low ionization potentials. The degree of suppression was, however, smaller than that of benzene. The localization of electrons on the nitrogen atom was found to affect the ionization behavior under the strong laser field. The delocalized pi electrons in benzene could not follow the laser field adiabatically, while those in localized molecular orbitals could. In addition, the growth of a tunneling barrier due to the screening effect in amines may be relatively smaller than that in benzene.

13.
FEBS Lett ; 580(5): 1398-404, 2006 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-16458892

RESUMO

GD3-replica peptides were obtained from a phage peptide library and an anti-GD3 monoclonal antibody (Mab) (4F6), and anti-GD3 Mabs were generated by immunizing a peptide GD3P4. A Mab, 3D2 was found to recognize GD3 by immunohistochemical approaches. Amino acid analysis of heavy and light chain variable regions of 4F6 and 3D2 showed that the respective chains had the same length, and only a few different amino acid substitutions were found. The present data indicate that the immunogenic GD3P4 is processed in a certain size and exposed on the antigen-presenting cells with a molecular shape quite similar to that of the GD3 epitope in 4F6.


Assuntos
Anticorpos Monoclonais/química , Formação de Anticorpos , Gangliosídeos/imunologia , Peptídeos/imunologia , Aminoácidos/análise , Animais , Anticorpos Monoclonais/biossíntese , Apresentação de Antígeno , Sequência de Bases , Imunização , Cadeias Pesadas de Imunoglobulinas , Cadeias Leves de Imunoglobulina , Região Variável de Imunoglobulina , Camundongos , Mimetismo Molecular , Dados de Sequência Molecular , Biblioteca de Peptídeos
14.
J Med Chem ; 46(14): 3033-44, 2003 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-12825942

RESUMO

A series of 6-(4-amino-1-piperidinyl)carbonyl-2(1H)-quinolinones, and their open form derivatives, were synthesized and evaluated for their ability to stimulate femoral artery blood flow (FBF) in the canine hindlimb. All members of this series stimulated FBF, and subsequent experiments revealed that selected members of this series produced minimal changes in coronary blood flow or systemic blood pressure. Compound 25 was the most promising agent in this respect, and clinical trials are now ongoing to evaluate the effectiveness of this drug as a novel treatment for intermittent claudication and Raynaud's phenomenon.


Assuntos
Membro Posterior/irrigação sanguínea , Piperidinas/síntese química , Vasodilatadores/síntese química , Animais , Artérias , Pressão Sanguínea/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Cães , Fêmur/irrigação sanguínea , Técnicas In Vitro , Piperidinas/química , Piperidinas/farmacologia , Quinolonas/síntese química , Quinolonas/química , Quinolonas/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Relação Estrutura-Atividade , Vasodilatadores/química , Vasodilatadores/farmacologia
15.
Biol Pharm Bull ; 25(7): 904-6, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12132666

RESUMO

Novel peptides homing to angiogenic vessels were recently isolated from a phage-displayed random pentade-capeptide library, and peptides having WRP sequence showed tumor growth suppression. In this study, we observed that another novel sequence, PVVLFPLH, suppressed tumor growth in vivo. Through the study of tumor growth suppression by the 5-mer peptides derived from this sequence, we determined the epitope sequence to be LFPLH. LFPLH, but not the shuffled peptide FHLLP, suppressed the migration of vascular endothelial growth factor-stimulated human umbilical vein endothelial cells. Interestingly, growth suppression of LFPLH against the cells as well as tumor cells was not observed in vitro. Therefore LFPLH may function to induce tumor dormancy through inhibition of angiogenesis.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Peptídeos/uso terapêutico , Sarcoma Experimental/tratamento farmacológico , Inibidores da Angiogênese/química , Animais , Divisão Celular/efeitos dos fármacos , Endotélio Vascular/citologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/uso terapêutico , Biblioteca de Peptídeos , Peptídeos/química , Sarcoma Experimental/irrigação sanguínea , Veias Umbilicais/citologia
16.
Oncogene ; 21(17): 2662-9, 2002 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-11965539

RESUMO

Cancer chemotherapy targeted to angiogenic vessels is expected to cause indirect tumor regression through the damage of the neovasculature without the induction of drug resistance. To develop a tool for neovasculature-specific drug delivery, we isolated novel peptides homing to angiogenic vessels formed by a dorsal air sac method from a phage-displayed peptide library. Three distinct phage clones that markedly accumulated in murine tumor xenografts presented PRPGAPLAGSWPGTS-, DRWRPALPVVLFPLH- or ASSSYPLIHWRPWAR-peptide respectively. After the determination of the epitope sequences of these peptides, we modified liposomes with epitope penta-peptides. Liposome modified with APRPG-peptide showed high accumulation in murine tumor xenografts, and APRPG-modified liposome encapsulating adriamycin effectively suppressed experimental tumor growth. Finally, specific binding of APRPG-modified liposome to human umbilical endothelial cells, and that of PRP-containing peptide to angiogenic vessels in human tumors, i.e., islet cell tumor and glioblastoma, were demonstrated. The present study indicates the usefulness of APRPG-peptide as a tool for anti-neovascular therapy, a novel modality of cancer treatment.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Melanoma Experimental/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Peptídeos/uso terapêutico , Sarcoma Experimental/irrigação sanguínea , Sequência de Aminoácidos , Animais , Antibióticos Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Injeções Subcutâneas , Lipossomos/metabolismo , Linfocinas/farmacologia , Masculino , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Dados de Sequência Molecular , Neovascularização Patológica/patologia , Biblioteca de Peptídeos , Sarcoma Experimental/patologia , Tomografia Computadorizada de Emissão
17.
FEBS Lett ; 510(3): 206-10, 2002 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-11801255

RESUMO

Novel peptides homing to angiogenic vessels were recently isolated from a phage-displayed random pentadecapeptide library. One of the isolated peptides, ASSSYPLIHWRPWAR, significantly suppressed the migration of VEGF-stimulated human umbilical vein endothelial cells. Dendoric ASSSYPLIHWRPWAR-peptide suppressed the formation of new blood vessels in dorsal air sac model mice. Furthermore, ASSSYPLIHWRPWAR-peptide and the fragment peptides containing WRP, which is revealed to be an epitope sequence, significantly suppressed the tumor growth, although 15-mer shuffled peptide derived from ASSSYPLIHWRPWAR and pentapeptides with alanine substitution of each residue of WRP did not. Taken together, ASSSYPLIHWRPWAR-peptide may cause tumor dormancy through inhibition of angiogenesis, and the WRP sequence may be the minimal and essential sequence for this activity.


Assuntos
Inibidores da Angiogênese/farmacologia , Endotélio Vascular/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Peptídeos/farmacologia , Sarcoma Experimental/tratamento farmacológico , Sequência de Aminoácidos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/química , Animais , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fatores de Crescimento Endotelial/farmacologia , Endotélio Vascular/citologia , Epitopos , Humanos , Injeções Subcutâneas , Linfocinas/farmacologia , Melanoma Experimental/irrigação sanguínea , Camundongos , Dados de Sequência Molecular , Transplante de Neoplasias , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Biblioteca de Peptídeos , Peptídeos/administração & dosagem , Peptídeos/química , Sarcoma Experimental/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
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