RESUMO
Immune-mediated responses are consistently observed in progressing vitiligo at the edge of depigmenting patches. Besides the role of the adaptive immune system, the profile of the innate immune response is now at the center of the stage. We report that plasmacytoid dendritic cells (pDC), which are the major interferon (IFN)-alpha-producing cells, are part of the infiltrate of progressive vitiligo with local production of MxA (a protein induced by IFNα). MxA was associated with expression of the type I IFN-inducible ligand CXCL9 and correlated with the recruitment of CXCR3(+) immune cells. Interestingly, strong MxA expression was observed in perilesional skin in close apposition to remaining melanocytes, surrounded by a prominent T-cell infiltrate. In contrast, MxA was not detectable in lesional skin, suggesting that IFN-α production is an early event in the progression of the disease. Our data highlight a new innate immune pathway leading to progression of vitiligo.
Assuntos
Quimiocina CXCL9/biossíntese , Células Dendríticas/metabolismo , Interferon-alfa/fisiologia , Proteínas de Resistência a Myxovirus/biossíntese , Pele/metabolismo , Transcriptoma , Vitiligo/imunologia , Adolescente , Adulto , Idoso , Doenças Autoimunes/complicações , Quimiocina CXCL9/genética , Quimiotaxia de Leucócito , Células Dendríticas/imunologia , Progressão da Doença , Feminino , Humanos , Imunidade Inata , Inflamação , Masculino , Pessoa de Meia-Idade , Proteínas de Resistência a Myxovirus/genética , Nevo com Halo/etiologia , Receptores CXCR3/análise , Pele/patologia , Subpopulações de Linfócitos T/imunologia , Vitiligo/complicações , Vitiligo/metabolismo , Vitiligo/patologia , Adulto JovemRESUMO
OBJECTIVE: To compare factors associated with halo nevi with nonsegmental vitiligo (NSV) vs NSV alone. DESIGN: Prospective observational study in 553 patients with a confirmed diagnosis of NSV attending a vitiligo clinic between January 1, 2006, and July 1, 2010. SETTING: Vitiligo Clinic at the Department of Dermatology, University Hospital Center of Bordeaux, Bordeaux, France. PATIENTS: The Vitiligo European Task Force questionnaire was informed for each patient attending the clinic with a confirmed diagnosis of NSV after the exclusion of other forms of vitiligo (focal, mucosal, and not classifiable). Thyroid function and antithyroid antibodies were screened if not obtained in the previous year. MAIN OUTCOME MEASURES: Extent of disease and markers of autoimmunity or autoinflammation. RESULTS: Of the 553 patients, 130 had halo nevi-NSV and 423 had NSV. Family history of premature hair graying (odds ratio, 1.74; P < .01) was positively associated with halo nevi-NSV by univariate analysis. Using multivariate analysis, age at onset younger than 18 years, phototype, total body area, localization on the trunk, involvement of hands and feet, and total staging were found to be independent factors. Age at onset younger than 18 years; phototypes I, II, and III; trunk involvement; and staging were positively associated with halo nevi-NSV, whereas this association was negative for total affected area and involvement of hands and feet. CONCLUSIONS: Halo nevi association in NSV affects age at onset and depigmentation pattern and has a stronger link with familial premature hair graying, suggesting that premature hair graying may involve, at least partly, an autoimmune pathway.
Assuntos
Nevo com Halo/complicações , Nevo com Halo/epidemiologia , Vitiligo/complicações , Vitiligo/epidemiologia , Adolescente , Adulto , Idade de Início , Idoso , Senilidade Prematura/genética , Autoimunidade , Criança , Pré-Escolar , Feminino , Cor de Cabelo/genética , Humanos , Lactente , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nevo com Halo/patologia , Estudos Prospectivos , Índice de Gravidade de Doença , Vitiligo/patologia , Adulto JovemRESUMO
A novel series of isoindolo[2,1-a]quinoxaline and indolo[1,2-a]quinoxaline derivatives was synthesized and evaluated in vitro against various human cancer cell lines for antiproliferative activity. These new compounds displayed activity against leukemia and breast cancer cell lines in the 3- to 18-µM concentration range.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Leucemia/tratamento farmacológico , Modelos Moleculares , Estrutura Molecular , Quinoxalinas/química , Relação Estrutura-AtividadeRESUMO
There is a real need to develop new therapeutic strategies for African trypanosomiasis infections. In our study, we developed a new drug delivery system of diminazene (DMZ), a trypanocidal drug registered for veterinary use. This drug candidate presents a limited efficacy, a poor affinity for brain tissue and instability. The development of colloidal formulations based on a porous cationic nanoparticle with an oily core ((70)DGNP(+)), has potentially two advantages: stabilization of the drug and potential targeting of the parasite. We analyzed two processes of drug loading: in process (DMZ was added during the preparation of (70)DGNP(+) at 80 °C) and post-loading (DMZ was mixed with a (70)DGNP(+) solution at room temperature). Poor stability of the drug was observed using the in process technique. When using the post-loading technique over 80% drug entrapment efficiency was obtained at a ratio of DMZ:phospholipids (wt:wt) < 5%. Moreover, DMZ loaded into (70)DGNP(+) was found to be protected against oxidation and was stable for at least six months at 4 °C. Finally, in vitro tests on T.b. brucei showed an increased efficacy of DMZ loaded in (70)DGNP(+).
Assuntos
Diminazena/administração & dosagem , Diminazena/uso terapêutico , Nanopartículas/química , Tripanossomicidas/administração & dosagem , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/veterinária , Animais , Diminazena/farmacologia , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Camundongos , Oxirredução , Fosfolipídeos/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
Attenuation of protein kinases by selective inhibitors is an extremely active field of activity in anticancer drug development. Therefore, Akt, a serine/threonine protein kinase, also known as protein kinase B (PKB), represents an attractive potential target for therapeutic intervention. Recent efforts in the development and biological evaluation of small molecule inhibitors of Akt have led to the identification of novel inhibitors with various heterocycle scaffolds. Based on previous results obtained on the antiproliferative activities of new pyrrolo[1,2-a]quinoxalines, a novel series was designed and synthesized from various substituted phenyl-1H-pyrrole-2-carboxylic acid alkyl esters via a multistep heterocyclization process. These new compounds were tested for their in vitro ability to inhibit the proliferation of the human leukemic cell lines K562, U937, and HL60, and the breast cancer cell line MCF7. The first biological evaluation of our new substituted pyrrolo[1,2-a]quinoxalines showed antiproliferative activity against the tested cell lines. From a general SAR point of view, these preliminary biological results highlight the importance of substitution at the C-4 position of the pyrroloquinoxaline scaffold by a benzylpiperidinyl fluorobenzimidazole group, and also the need for a functionalization on the pyrrole ring.
Assuntos
Benzimidazóis/química , Proliferação de Células/efeitos dos fármacos , Ésteres/química , Ésteres/síntese química , Ésteres/farmacologia , Piperidinas/química , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirróis/química , Pirróis/síntese química , Pirróis/farmacologia , Quinoxalinas/química , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Desenho de Fármacos , Feminino , Humanos , Leucemia/tratamento farmacológico , Leucemia/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND: Chikungunya fever is an emerging arboviral disease characterized by an algo-eruptive syndrome, inflammatory polyarthralgias, or tenosynovitis that can last for months to years. Up to now, the pathophysiology of the chronic stage is poorly understood. CASE PRESENTATION: We report the first case of CHIKV infection with chronic associated rheumatism in a patient who developed progressive erosive arthritis with expression of inflammatory mediators and persistence of specific IgM antibodies over 24 months following infection. CONCLUSIONS: Understanding the specific features of chikungunya virus as well as how the virus interacts with its host are essential for the prevention, treatment or cure of chikungunya disease.
Assuntos
Infecções por Alphavirus/complicações , Anticorpos Antivirais/sangue , Artrite Infecciosa/etiologia , Vírus Chikungunya/imunologia , Imunoglobulina M/sangue , Infecções por Alphavirus/sangue , Infecções por Alphavirus/imunologia , Artrite Infecciosa/sangue , Artrite Infecciosa/imunologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In contrast to young rats, adult rats given i.p. Plasmodium berghei Anka (PbA) control the parasitaemia and repair their anaemia. Here, we investigated whether IgE and CD23/NO immune pathway could be implicated in this age-related resistance of adult rats to PbA. Eight-week-old rats displayed significantly higher levels of plasma total IgE (p=0.01) and soluble CD23 (p=0.003) during the peak of parasitaemia, compared to 4-week-old rats. IgE Fc-binding antibody or aminoguanidine administration to parasitized 8-week-old rats slightly delayed blood parasite clearance or exacerbated anaemia. These data suggest that IgE and CD23/NO could play an important role in the resistance of adult rats experiencing PbA primary intraerythrocytic development.
Assuntos
Envelhecimento/imunologia , Imunoglobulina E/sangue , Malária/imunologia , Óxido Nítrico/metabolismo , Parasitemia/imunologia , Plasmodium berghei/patogenicidade , Receptores de IgE/sangue , Animais , Eritrócitos/parasitologia , Feminino , Malária/parasitologia , Parasitemia/parasitologia , Ratos , Ratos Endogâmicos Lew , Organismos Livres de Patógenos EspecíficosRESUMO
Akt kinases are attractive targets for small molecule drug discovery because of their key role in tumor cell survival/proliferation and their overexpression/activation in many human cancers. Recent efforts in the development and biological evaluation of small molecule inhibitors of Akt have led to the identification of novel Akt kinase inhibitors, based on a quinoxaline or pyrazinone scaffold. A series of new substituted pyrrolo[1,2-a]quinoxaline derivatives, structural analogues of these active quinoxaline or pyrazinone pharmacophores, was synthesized from various substituted 2-nitroanilines or 1,2-phenylenediamine via multistep heterocyclization process. These new compounds were tested for their in vitro ability to inhibit the proliferation of the human leukemic cell lines K562, U937 and HL60, and the breast cancer cell line MCF7. Three of these human cell lines (K562, U937 and MCF7) exhibited an active phosphorylated Akt form. The most promising active pyrroloquinoxalines were found to be 1a that inhibited K562 cell line proliferation with an IC(50) of 4.5 microM, and 1h that inhibited U937 and MCF7 cell lines with IC(50) of 5 and 8 microM, respectively. These two candidates exhibited more potent activities than the reference inhibitor A6730.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Descoberta de Drogas , Humanos , Inibidores de Proteínas Quinases/farmacologia , Pirróis , Relação Estrutura-AtividadeRESUMO
A series of new ursolic and oleanolic acids derivatives was synthesized via ursolic or oleanolic acids, previously extracted from South American Ilex species. These new compounds were tested for in vitro antiparasitic activity on Leishmania amazonensis and Leishmania infantum strains. Some of these compounds showed activity against the promastigote forms of L. amazonensis or L. infantum, with IC(50) ranging from 5 to 12 microM. As expected, most of the compounds showed a significant level of cytotoxicity against monocytes (IC(50) = 2-50 microM). From a structure-activity relationships point of view, these pharmacological results enlightened mainly the importance of an acetylation at position 3 of the oleanolic acid skeleton in the activity against the L. amazonensis strain, and of a bis-(3-aminopropyl)piperazine moiety on the carboxylic function of ursolic acid against the L. infantum strain.
Assuntos
Antiprotozoários/síntese química , Leishmania/efeitos dos fármacos , Ácido Oleanólico/farmacologia , Triterpenos/farmacologia , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Humanos , Concentração Inibidora 50 , Leishmania infantum/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/química , Ácido UrsólicoRESUMO
A series of new 4-(E)-alkenylpyrrolo[1,2-a]quinoxaline derivatives, structural analogues of alkaloid chimanine B, was synthesized in good yields using efficient palladium(0)-catalyzed Suzuki-Miyaura cross-coupling reactions. These new compounds were tested for in vitro antiparasitic activity upon Leishmania amazonensis and Leishmania infantum strains. Biological results showed activity against the promastigote forms of L. amazonensis and L. infantum with IC50 ranging from 0.5 to 7 microM. From a Structure-Activity Relationships point of view, these pharmacological results mainly enlightened the importance of the 4-lateral C6, C7 or C8 alpha-unsaturated trans-alkenyl chain of unsubstituted pyrrolo[1,2-a]quinoxaline moiety.
Assuntos
Antiparasitários/síntese química , Leishmania infantum/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Quinoxalinas/síntese química , Quinoxalinas/uso terapêutico , Animais , Antiparasitários/química , Antiparasitários/uso terapêutico , Concentração Inibidora 50 , Estrutura Molecular , Testes de Sensibilidade Parasitária , Quinoxalinas/química , Testes de ToxicidadeRESUMO
The efficiency of a monomolecular film of (3-glycidoxypropyl) trimethoxysilane (GPTS) on a shear horizontal guided (Love) acoustic wave immunosensor to detect whole Escherichia coli (E. coli) bacteria is demonstrated. Direct anti-E. coli antibodies grafting onto the sensor surface did not lead to a significant bacteria immobilisation, partially attributed to the SiO2 sensor surface roughness. An innovative method has been set up to get around this difficulty and to detect whole bacteria. It consists in grafting goat anti-mouse antibodies (GAM) onto the sensor surface in a first step and introducing E. coli bacteria mixed with anti-E. coli antibodies onto the sensor in a second step. We describe the characteristics of such a technique like sample preparation time (lower than 30 min) and temperature improvements. A 37 degrees C experimental temperature led to the fastest bacteria binding kinetic, reducing the total analysis time. This method enables to keep the specificity of the antibody/antigen interaction and provides significant results in less than 1h. This leads to a detection threshold of 10(6) bacteria/ml in a 500 microl chamber.
Assuntos
Técnicas Biossensoriais/instrumentação , Escherichia coli/isolamento & purificação , Animais , Escherichia coli/imunologia , Imunoensaio/instrumentação , CamundongosRESUMO
An original series of 4-substituted pyrrolo[1,2-a]quinoxaline derivatives, new structural analogues of Galipea species quinoline alkaloids, was synthesized from various substituted 2-nitroanilines via multistep heterocyclizations and tested for in vitro antiparasitic activity upon Leishmania amazonensis and Leishmania infantum strains. Structure-activity relationships enlighten the importance of the 4-substituted alkenyl side chain on the pyrrolo[1,2-a]quinoxaline moiety to modulate the antileishmanial activity.
Assuntos
Antiprotozoários , Leishmania/efeitos dos fármacos , Quinoxalinas , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/farmacologia , Cristalografia por Raios X , Humanos , Interações Hidrofóbicas e Hidrofílicas , Leucócitos Mononucleares/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Quinoxalinas/síntese química , Quinoxalinas/química , Quinoxalinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In Plasmodium falciparum-infected cells or in P. berghei infected mice, increase of reduced glutathione (GSH) levels confers resistance to chloroquine (CQ). GSH is synthesized within the cells through a complex biochemical pathway composed of several well known enzymes, in which glucose-6-phosphate dehydrogenase (G6PD) plays an important role. The physiological hormone dehydroepiandrosterone sulfate (DHEAS) is a potent inhibitor of G6PD activity, and G6PD deficiency is known to exert antimalaria protection. This study aimed to investigate the ability of DHEAS to enhance the antimalarial activity of CQ, via an inhibition of G6PD activity and GSH synthesis. Two P. berghei CQ resistant strains (CQR6 and CQR30) were selected in vivo from the sensitive strain NK65. Drug effects were checked both by monitoring the evolution of parasitaemia and by the survival of infected mice. In addition, intra-parasite levels of GSH and G6PD activity were measured before and after the treatment. Results demonstrate that acquisition of CQ resistance in P. berghei is associated with a significant increase in parasite G6PD activity and GSH level. Combination of CQ with DHEAS or buthionin sulfoximin (BSO, a specific inhibitor of GSH synthesis) significantly increased sensitivity of resistant parasites to CQ and increased the survival period of the infected mice. This reduction of parasitaemia and improvement of the survival of infected mice were associated with intra-parasite depletion of GSH and inhibition of G6PD activity due to DHEAS action. This experimental study suggests that DHEAS could be used to potentiate antimalarial action of CQ, particularly on CQ resistant strains.
Assuntos
Antimaláricos/farmacologia , Cloroquina/farmacologia , Sulfato de Desidroepiandrosterona/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Glucosefosfato Desidrogenase/metabolismo , Glutationa/biossíntese , Plasmodium berghei/efeitos dos fármacos , Animais , Antimaláricos/uso terapêutico , Cloroquina/uso terapêutico , Interações Medicamentosas , Feminino , Dissulfeto de Glutationa , Malária/tratamento farmacológico , Camundongos , Testes de Sensibilidade ParasitáriaRESUMO
Trans-resveratrol was analysed for its apoptotic and growth inhibitory activity in human B-cell lines derived from chronic B-cell malignancies (WSU-CLL and ESKOL), and in leukaemic lymphocytes from patients with B-cell chronic lymphocytic leukaemia (B-CLL). Resveratrol displayed antiproliferative activity on both B-cell lines, as estimated by the decrease in cell recovery and inhibition of thymidine uptake. Furthermore, resveratrol induced apoptosis in the two cell lines as well as in B-CLL patients' cells, as evidenced by the increase in annexin V binding, caspase activation, DNA fragmentation and decrease of the mitochondrial transmembrane potential DeltaPsim. We previously reported that nitric oxide (NO), endogenously released by an iNO synthase (iNOS) spontaneously expressed in these leukaemic cells, contributed to their resistance towards apoptosis. We show here that resveratrol inhibited both iNOS protein expression and in situ NO release in WSU-CLL, ESKOL and B-CLL patients'cells. In addition, Bcl-2 expression was also inhibited by resveratrol. Thus, downregulation of the two anti-apoptotic proteins iNOS and Bcl-2 can contribute to the apoptotic effects of resveratrol in leukaemic B cells from chronic leukaemia. Our data suggest that this drug is of potential interest for the therapy of B-CLL.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Linfócitos B/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Estilbenos/farmacologia , Apoptose , Linfócitos B/metabolismo , Linfócitos B/patologia , Divisão Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Genes bcl-2 , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Resveratrol , Células Tumorais CultivadasRESUMO
The synthesis of new 7-hydroxy-2-substituted-methyl-5H-oxazolo[3,2-a]pyrimidin-5-ones derivatives, designed as structural bicyclic analogues of the iron chelator deferiprone, is described. They were tested for their ability to inhibit proliferation in human Bcr-Abl+ leukemia cells.