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1.
Biomed Pharmacother ; 120: 109401, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31622950

RESUMO

Patients with cancer survivors are at increased risk of cardiovascular disease(CVD). Cardio-oncology has developed as a new discipline with the advances in cancer treatment. There are many new challenges for the clinician and a new frontier for research and investigation. There is an urgent need for further study on the prevention of cardiovascular toxicity. Imperatorin (IMP) is a natural form of coumarin and extract from several plants with diver's pharmacokinetic effects, including antioxidant and anti-inflammatory properties. This review focus on the molecular mechanisms and pharmacological effects of Imperatorin maybe provide potential cancer and cardiovascular protection that targets IMP. Further studies are required to elucidate the entire spectrum of cytotoxic activities of these compounds to validate and expand their preclinical and clinical applications and to clarify the potential role of IMP.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Sistema Cardiovascular/efeitos dos fármacos , Furocumarinas/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Antioxidantes/uso terapêutico , Fármacos Cardiovasculares/efeitos adversos , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Furocumarinas/efeitos adversos , Humanos , Mediadores da Inflamação/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
2.
Vox Sang ; 114(6): 595-604, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31297836

RESUMO

BACKGROUND AND OBJECTIVES: Pathogen reduction of donor platelets with amotosalen/UVA has been shown to effectively inactivate pathogens and also contaminating white blood cells (WBCs). We wanted to determine whether WBC inactivation could also decrease alloimmune refractoriness to donor platelets. MATERIALS AND METHODS: Platelets were prepared from a donor dog's whole blood, and the platelets were either transfused without modification [standard (STD) platelets] or treated with amotosalen/UVA under conditions modelling the amotosalen/UVA Blood System for human platelets (APR) using either 4 or 3 J/cm2 of UVA exposure. Platelets were transfused weekly from a single donor dog for 8 weeks or until the recipient dog became refractory to their donor's platelets. Antibody samples were drawn weekly and tested against the donor dog's platelets and WBCs (CD8 and B cells). RESULTS: Only 1/7 (14%) dogs that received STD platelets accepted 8 weeks of donor transfusions. Following APR 4 J/cm2 donor transfusions, 3/9 (33%) recipients accepted their donor's transfusions, but only one recipient remained antibody negative. Following APR 3 J/cm2 donor transfusions, the same dose as used for human platelet transfusions, 7/10 (70%) recipients accepted their donor's transfusions, but only two remained antibody negative. CONCLUSION: As a very high percentage of recipient dogs (70%) accepted APR 3 J/cm2 donor transfusions, these data suggest that preventing alloimmune platelet refractoriness may be another benefit of pathogen reduction using amotosalen/UVA.


Assuntos
Doadores de Sangue , Transfusão de Sangue , Furocumarinas/farmacologia , Raios Ultravioleta , Animais , Cães , Feminino , Furocumarinas/uso terapêutico , Masculino , Modelos Animais , Transfusão de Plaquetas
3.
Biochem Pharmacol ; 166: 56-69, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31075267

RESUMO

Fibromyalgia (FM) is a chronic pain syndrome involving complex interplay of biogenic amines and NMDA receptor mediated hypersensitization of nociceptive pathways. Clinical management of FM is poorly addressed with only a few available therapeutic options. Coumarins are active phenolic molecules of natural origin found to have broad pharmacological activities. Current investigation explores the role of naturally occurring coumarin, imperatorin in mouse model of fibromyalgia. Administration of reserpine (0.5 mg/kg, s.c.) thrice at 24 h intervals induced behavioral and neurochemical alterations characteristic of fibromyalgia. Reserpine was found to induce allodynia quantified using electronic von Frey (e-VF) and pressure application measurement (PAM) test, depression as indicated by an increased duration of immobility in forced swim test (FST), decreased motor coordination and locomotor activity in inclined plane test (IPT) and open field test (OFT) respectively. Cognitive deficits were evident by an increased latency to locate hidden platform in Morris water maze (MWM) and passive avoidance test (PAT). Reserpine treatment was found to cause an increased anxiety as revealed by increased time spent in closed arm of the elevated plus maze (EPM). Furthermore, an up- regulation in NMDA and NFκB expression in the brain and spinal cord was observed in reserpine treated groups. Administration of imperatorin (10 mg/kg, i.p) for a period of 5 days ameliorated all behavioral deficits, biochemical changes and decreased expression of NMDA and NFκB in the brain and spinal cord of treated mice. These findings indicate an interplay of NMDA/NFκB modulation by imperatorin in the reserpine induced fibromyalgia in mice.


Assuntos
Fibromialgia/tratamento farmacológico , Fibromialgia/metabolismo , Furocumarinas/uso terapêutico , N-Metilaspartato/metabolismo , NF-kappa B/metabolismo , Reserpina/toxicidade , Inibidores da Captação Adrenérgica/toxicidade , Animais , Relação Dose-Resposta a Droga , Fibromialgia/induzido quimicamente , Furocumarinas/farmacologia , Camundongos , N-Metilaspartato/agonistas , N-Metilaspartato/antagonistas & inibidores , NF-kappa B/agonistas , NF-kappa B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Resultado do Tratamento
4.
Transfus Med Rev ; 33(1): 29-34, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30021699

RESUMO

Pathogen inactivation (PI) for platelet concentrates (PC) is a fairly recent development in transfusion medicine that is intended to decrease infectious disease transmission from the donor to the receiving patient. Effective inactivation of viruses, bacteria and eukaryotic parasites adds a layer of safety, protecting the blood supply against customary and emerging pathogens. Three PI methods have been described for platelets. These are based on photochemical damage of nucleic acids which prevents replication of most infectious pathogens and contaminating donor leukocytes. Because platelets do not replicate, the collateral damage to platelet function is considered low to non-existing. This is disputable however because photochemistry is not specific for nucleic acids and significantly affects platelet biomolecules as well. The impact of these biomolecular changes on platelet function and hemostasis is not well understood, but is increasingly being studied. The results of these studies can help explain current and future clinical observations with PI platelets, including the impact on transfusion yield and bleeding. This review summarizes the biomolecular effects of PI treatment on platelets. We conclude that despite a comparable principle of photochemical inactivation, all three methods affect platelets in different ways. This knowledge can help blood banks and transfusion specialists to guide their choice when considering the implementation or clinical use of PI treated platelets.


Assuntos
Plaquetas/microbiologia , Preservação de Sangue/métodos , Transfusão de Plaquetas/métodos , Bancos de Sangue , Transfusão de Sangue , Furocumarinas/química , Furocumarinas/uso terapêutico , Hemostasia/efeitos dos fármacos , Humanos , Neoplasias/complicações , Ácidos Nucleicos/química , Riboflavina/química , Transdução de Sinais , Trombocitopenia/complicações , Raios Ultravioleta
5.
Int J Mol Sci ; 19(12)2018 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-30558157

RESUMO

Cancer still remains one of the leading causes of death worldwide. In spite of significant advances in treatment options and the advent of novel targeted therapies, there still remains an unmet need for the identification of novel pharmacological agents for cancer therapy. This has led to several studies evaluating the possible application of natural agents found in vegetables, fruits, or plant-derived products that may be useful for cancer treatment. Bergamottin is a furanocoumarin derived from grapefruits and is also a well-known cytochrome P450 inhibitor. Recent studies have demonstrated potent anti-oxidative, anti-inflammatory, and anti-cancer properties of grapefruit furanocoumarin both in vitro and in vivo. The present review focuses on the potential anti-neoplastic effects of bergamottin in different tumor models and briefly describes the molecular targets affected by this agent.


Assuntos
Inibidores das Enzimas do Citocromo P-450/uso terapêutico , Furocumarinas/uso terapêutico , Neoplasias/terapia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Citrus paradisi/química , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Furocumarinas/química , Furocumarinas/farmacologia , Humanos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos
6.
Crit Care ; 22(1): 271, 2018 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-30367640

RESUMO

Platelet transfusions carry greater risks of infection, sepsis, and death than any other blood product, owing primarily to bacterial contamination. Many patients may be at particular risk, including critically ill patients in the intensive care unit. This narrative review provides an overview of the problem and an update on strategies for the prevention, detection, and reduction/inactivation of bacterial contaminants in platelets. Bacterial contamination and septic transfusion reactions are major sources of morbidity and mortality. Between 1:1000 and 1:2500 platelet units are bacterially contaminated. The skin bacterial microflora is a primary source of contamination, and enteric contaminants are rare but may be clinically devastating, while platelet storage conditions can support bacterial growth. Donor selection, blood diversion, and hemovigilance are effective but have limitations. Biofilm-producing species can adhere to biological and non-biological surfaces and evade detection. Primary bacterial culture testing of apheresis platelets is in routine use in the US. Pathogen reduction/inactivation technologies compatible with platelets use ultraviolet light-based mechanisms to target nucleic acids of contaminating bacteria and other pathogens. These methods have demonstrated safety and efficacy and represent a proactive approach for inactivating contaminants before transfusion to prevent transfusion-transmitted infections. One system, which combines ultraviolet A and amotosalen for broad-spectrum pathogen inactivation, is approved in both the US and Europe. Current US Food and Drug Administration recommendations advocate enhanced bacterial testing or pathogen reduction/inactivation strategies (or both) to further improve platelet safety. Risks of bacterial contamination of platelets and transfusion-transmitted infections have been significantly mitigated, but not eliminated, by improvements in prevention and detection strategies. Regulatory-approved technologies for pathogen reduction/inactivation have further enhanced the safety of platelet transfusions. Ongoing development of these technologies holds great promise.


Assuntos
Contaminação de Medicamentos/prevenção & controle , Transfusão de Plaquetas/normas , Carga Bacteriana/métodos , Furocumarinas/uso terapêutico , Humanos , Fármacos Fotossensibilizantes/uso terapêutico , Transfusão de Plaquetas/efeitos adversos , Transfusão de Plaquetas/métodos , Reação Transfusional/prevenção & controle , Raios Ultravioleta
7.
Int Immunopharmacol ; 63: 110-118, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30077824

RESUMO

Allergic asthma is a chronic inflammatory disease of the airways. T lymphocytes play an important role in the pathogenesis of asthma. The voltage-gated Kv1.3 potassium channel is a target for the preferential inhibition of TEM cells. In this study, we investigate the effects of PAP-1, a selective inhibitor of Kv1.3 channel, on the treatment of the neutrophilic asthma model. PAP-1 (40 mg/kg) was injected intraperitoneally into ovalbumin (OVA)-lipopolysaccharide (LPS)-challenged BALB/c mice. We found that the expression of the Kv1.3 channel in the lung tissues, and the intensity of the Kv current in the asthmatic mice increased clearly compared with those in normal control. PAP-1 significantly reduced airway hyperresponsiveness (AHR), inflammatory cell count in the bronchoalveolar lavage fluids (BALF) and serum, and attenuated airway inflammation in a histological examination of the asthmatic mice. Moreover, PAP-1 inhibited the OVA-LPS-induced imbalance of Th1/Th2, Treg/Th17 lymphocytes, and reduced levels of IL-4 and IL-17, inducing an increase in the production of IFN-γ and IL-10. Furthermore, the activation of the extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) pathway in the lungs of the asthmatic mice was suppressed by PAP-1. We also found that PD-98059, an inhibitor of ERK, had a similar effect with PAP-1 in terms of regulating the imbalance of Th1/Th2, Treg/Th17 cytokines. However, PD-98059 could not further influence cytokine changes when the cells were treated with PAP-1. The results suggest that ERK acts as a downstream regulator of inhibitors of the Kv1.3 channel in neutrophilic asthma. In conclusion, the inhibitor of the Kv1.3 channel has therapeutic potential for treating asthma.


Assuntos
Antiasmáticos/farmacologia , Asma/metabolismo , Furocumarinas/farmacologia , Canal de Potássio Kv1.3/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Animais , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/imunologia , Citocinas/imunologia , Feminino , Furocumarinas/uso terapêutico , Lipopolissacarídeos , Camundongos Endogâmicos BALB C , Ovalbumina
8.
Eur J Pharm Sci ; 124: 114-126, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30153523

RESUMO

8­Methoxypsoralen (8-MOP) in combination with ultraviolet A (PUVA) is a photochemotherapy for management of psoriasis. 8-MOP is a natural compound from Psoralea corylifolia. The present work was undertaken to evaluate the percutaneous absorption of five compounds derived from P. corylifolia, and to further explore the inhibitory effect on psoriasis-like lesions generated by imiquimod stimulation in a mouse model. 8-MOP, psoralen, isopsoralen, psoralidin, and bakuchiol were comparatively tested for in vitro skin permeation, keratinocyte apoptosis, and in vivo antipsoriatic potency. The pig ear skin deposition of 8-MOP, isopsoralen, and bakuchiol at an equimolar dose was 0.47, 0.58, and 0.50 nmol/mg, respectively, which was comparable and higher than that of psoralen (0.25 nmol/mg) and psoralidin (0.14 nmol/mg). Psoralidin and bakuchiol were absorbed into the skin without further penetration across the skin. Besides experimental data of physicochemical properties, the hydrogen bond number, total polarity surface, and stratum corneum lipid docking calculated could explain the correlation of the penetrant structure with the skin permeability. The antiproliferative activity against keratinocytes was stronger for 8-MOP and isopsoralen than the others. Topical application of PUVA by using 8-MOP and isopsoralen on imiquimod-induced plaque significantly reduced transepidermal water loss from 55 to 33 and 38 g/m2/h, respectively. The epidermal thickening elicited by imiquimod (117 µm) was decreased to 62 and 26 µm by 8-MOP and isopsoralen application. IL-6 expression in psoriasiform skin was downregulated by isopsoralen but not 8-MOP. Isopsoralen may be a potential candidate for PUVA therapy.


Assuntos
Benzofuranos/uso terapêutico , Cumarínicos/uso terapêutico , Furocumarinas/uso terapêutico , Terapia PUVA , Fenóis/uso terapêutico , Psoralea , Psoríase/tratamento farmacológico , Animais , Benzofuranos/farmacologia , Cumarínicos/farmacologia , Feminino , Furocumarinas/farmacologia , Imiquimode , Queratinócitos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fenóis/farmacologia , Fotoquimioterapia , Psoríase/induzido quimicamente , Pele/metabolismo , Absorção Cutânea , Suínos , Raios Ultravioleta
9.
Cell Physiol Biochem ; 49(1): 235-244, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30138935

RESUMO

BACKGROUND/AIMS: CD133+ cancer cells display low sensitivity to anti-cancer treatment; thus, combination treatment with adjuvant drugs is required to improve the efficiency of cancer therapy. The aim of this study was to explore the effect of imperatorin, a linear furanocoumarin compound, on γδ T cell-mediated cytotoxicity against CD133+ lung cancer cells. METHODS: CD133+ and CD133- subgroups from A549 and PC9 lung cancer cells were sorted by using flow cytometry. The cytotoxicity of γδ T cells against cancer cells was evaluated by measuring lactate dehydrogenase release. The concentration of tumor necrosis factor-related apoptosis-inducing ligand in the co-culture system was determined by using an enzyme-linked immunosorbent assay. Mitochondrial membrane potential, expression of death receptor 4 (DR4) and DR5 on the cell surface, and rate of apoptosis were measured by flow cytometry. Cytochrome c release and cellular protein expression were detected by western blot analysis. RESULTS: Compared with CD133- cells, CD133+ cells were resistant to γδ T cell-mediated cytotoxicity. However, imperatorin significantly increased the sensitivity of CD133+ lung cancer cells to γδ T cell treatment in vitro and in vivo. Mechanically, we found that myeloid cell leukemia 1 (MCL-1), an important anti-apoptotic protein belonging to the Bcl-2 family, was overexpressed in CD133+ A549 and PC9 cells compared to their corresponding CD133- cells. Co-treatment with imperatorin and γδ T cells suppressed the expression of MCL-1, and thus promoted the mitochondrial apoptosis mediated by γδ T cells in CD133+ A549 and PC9 lung cancer cells. CONCLUSION: Up-regulated MCL-1 in CD133+ lung cancer cells is responsible for their resistance to γδ T cells. Furthermore, the combination of γδ T cells with imperatorin sensitized CD133+ lung cancer cells to γδ T cell-mediated cytotoxicity by targeting MCL-1.


Assuntos
Antígeno AC133/metabolismo , Apoptose/efeitos dos fármacos , Furocumarinas/farmacologia , Linfócitos Intraepiteliais/imunologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Células A549 , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Linhagem Celular Tumoral , Citocromos c/metabolismo , Resistencia a Medicamentos Antineoplásicos , Furocumarinas/uso terapêutico , Humanos , Linfócitos Intraepiteliais/citologia , Linfócitos Intraepiteliais/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/imunologia
10.
Mediators Inflamm ; 2018: 9191743, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29849500

RESUMO

Dysregulated inflammation is increasingly considered as the main cause of many diseases on which NOD1/NF-κB pathway plays an important role. Columbianetin (CBT) is derived from the root of the Chinese herb Radix Angelicae Pubescentis for treating inflammatory diseases. Although the anti-inflammatory effect of CBT has been reported, its anti-inflammatory mechanism was poorly studied. In this study, we explored the anti-inflammatory pathway of CBT in lipopolysaccharide- (LPS-) stimulated human peripheral blood mononuclear cell (PBMC) model. Inflammatory cytokine production in culture supernatant was assessed using ELISA assay, and the possible anti-inflammatory pathway of CBT was screened using qPCR array and enrichment analysis with DAVID6.8. To further confirm the targeted pathway of CBT, we pretreated PBMC with the selective NOD1 inhibitor ML130 and then measured the protein levels of the pathway by Western blotting. The result showed that CBT effectively suppressed the expressions of TNF-α, IL-6, MCP-1, and IL-1ß in a dose-dependent manner and significantly downregulated 19 out of 32 differentially expressed genes, most of which were involved in the NOD1/NF-κB pathway, and also showed that CBT remarkably inhibited LPS-induced NOD1, RIP2, and NF-κB activation. Furthermore, the inhibitory effects of CBT on NOD1/NF-κB pathways were blocked by ML130. These findings indicated that CBT inhibits the production of inflammatory cytokines induced by LPS involved in the downregulation of NOD1/NF-κB pathways.


Assuntos
Furocumarinas/uso terapêutico , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Células Cultivadas , Quimiocina CCL2/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Leucócitos Mononucleares/imunologia , Fator de Necrose Tumoral alfa/metabolismo
11.
Curr Opin Pharmacol ; 41: 20-26, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29679802

RESUMO

DNA crosslinking agents make up a broad class of chemotherapy agents that target rapidly dividing cancer cells by disrupting DNA synthesis. These drugs differ widely in both chemical structure and biological effect. In cells, crosslinking agents can form multiple types of DNA lesions with varying efficiencies. Inter-strand crosslinks (ICLs) are considered to be the most cytotoxic lesion, creating a covalent roadblock to replication and transcription. Despite over 50 years in the clinic, the use of crosslinking agents that specialize in the formation of ICLs remains limited, largely due to high toxicity in patients. Current ICL-based therapeutics have focused on late-stage and drug-resistant tumors, or localized treatments that limit exposure. In this article, we review the development of clinical crosslinking agents, our understanding of how cells respond to different lesions, and the potential to improve ICL-based chemotherapeutics in the future.


Assuntos
Antineoplásicos/uso terapêutico , Reagentes para Ligações Cruzadas/uso terapêutico , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Reagentes para Ligações Cruzadas/farmacologia , DNA/efeitos dos fármacos , Furocumarinas/farmacologia , Furocumarinas/uso terapêutico , Humanos , Mecloretamina/análogos & derivados , Mecloretamina/uso terapêutico , Mitomicinas/farmacologia , Mitomicinas/uso terapêutico
12.
Transfusion ; 58(6): 1506-1515, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29607502

RESUMO

INTRODUCTION: Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare complication after transfusion of components containing viable donor T cells. Gamma irradiation with doses that stop T-cell proliferation is the predominant method to prevent TA-GVHD. Treatment with pathogen inactivation methodologies has been found to also be effective against proliferating white blood cells, including T cells. In this study, T-cell inactivation was compared, between amotosalen/ultraviolet A (UVA) treatment and gamma-irradiation (2500 cGy), using a sensitive limiting dilution assay (LDA) with an enhanced dynamic range. METHODS AND MATERIALS: Matched plasma units (N = 8), contaminated with 1 × 106 peripheral blood mononuclear cells (PBMCs) per mL, were either treated with amotosalen/UVA or gamma irradiation, or retained as untreated control. Posttreatment, cells were cultured under standardized conditions. T-cell proliferation was determined by the incorporation of 3 H-thymidine and correlated with microscopic detection. RESULTS: Range-finding experiments showed that after gamma irradiation (2500 cGy), significant T-cell proliferation could be observed at a 1 × 107 cell culture density, some proliferation at 1 × 106 , and none at 1 × 105 cells/well. Based on these facts, a quantitative comparison was carried out between amotosalen/UVA at the highest challenge of 1 × 107 PBMCs/well, and gamma irradiation at 1 × 106 and 1 × 105 PBMCs/well. Complete inactivation of the T cells after amotosalen/UVA treatment was observed, equivalent to greater than 6.2 log inactivation. Complete inactivation of the T cells was also observed after gamma irradiation when 1 × 105 PBMCs/well were cultured (>4.2 log inactivation). Proliferation was observed when 1 × 106 PBMCs/well were cultured (≤5.2 log inactivation) after gamma irradiation. CONCLUSION: Amotosalen/UVA treatment more effectively inactivates T cells than the current standard of gamma irradiation (2500 cGy) for the prevention of TA-GVHD.


Assuntos
Raios gama , Doença Enxerto-Hospedeiro/prevenção & controle , Linfócitos T/efeitos da radiação , Reação Transfusional/prevenção & controle , Raios Ultravioleta , Transfusão de Sangue , Proliferação de Células/efeitos da radiação , Furocumarinas/farmacologia , Furocumarinas/uso terapêutico , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/efeitos da radiação , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Resultado do Tratamento
13.
Food Funct ; 9(4): 2070-2079, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29577119

RESUMO

Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease associated with a potential imbalance between the growth and death of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs). Imperatorin (IPT) is a naturally occurring furanocoumarin found in umbelliferous vegetables, citrus fruits, and some herbs. The effects of IPT on the proliferation and apoptosis of RA-FLSs and its potential underlying mechanisms have remained unclear. RA-FLSs obtained from RA patients were induced by interleukin-1ß (IL-1ß) and treated with IPT. Cell viability was determined by MTT assay. Apoptotic cell death was analyzed by Annexin V-FITC/PI double staining and Hoechst 33342 staining. The loss in the mitochondrial membrane potential (ΔΨm) was visualized on the basis of JC-1 staining via fluorescence microscopy, and protein expression changes were assessed by western blot, whereas in vivo studies were conducted in male Wistar rats followed by histopathological assessment via TUNEL assay and HE staining of tissues. The results showed that IPT significantly reduced cell viability, accelerated cell apoptosis and decreased matrix metalloproteinases-1/-3 expression in IL-1ß-induced RA-FLSs. Furthermore, IPT exposure was found to disrupt the ΔΨm compared to the IL-1ß-induced treatment. Moreover, IPT increased the release of mitochondrial cytochrome C, the ratio of Bax/Bcl-2, and the cleavage of caspase-9, caspase-3 and poly (ADP-ribose) polymerase. In vivo studies showed that IPT not only significantly reduced the collagen induced arthritis by reducing synovial hyperplasia, and pannus formation but also enhanced the apoptotic index of ankle joint cells. Conclusively, our findings suggest that IPT inhibits cell proliferation and induces apoptosis in RA-FLSs that may be associated with mitochondrial/caspase-mediated signalling pathways.


Assuntos
Apoptose/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Furocumarinas/farmacologia , Sinoviócitos/efeitos dos fármacos , Animais , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Caspases/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Furocumarinas/uso terapêutico , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Ratos Wistar
14.
Actas dermo-sifiliogr. (Ed. impr.) ; 108(7): 637-642, sept. 2017. tab
Artigo em Espanhol | IBECS | ID: ibc-166919

RESUMO

Introducción y objetivo: El vitíligo es una dermatosis autoinmune crónica causada por la destrucción de los melanocitos. Aunque la calidad de vida en pacientes con vitíligo se ha estudiado en diferentes poblaciones, hasta el momento no existen estudios previos sobre el tema en nuestra población. El objetivo de este estudio era determinar la calidad de vida de pacientes con vitíligo mexicanos. Material y método: Se realizó un estudio transversal en la Unidad de Investigación del Centro Dermatológico Dr. Ladislao de la Pascua en la ciudad de México. Se reclutaron adultos con vitíligo, se excluyeron los individuos con otras alteraciones de la pigmentación, diagnóstico de enfermedad neurológica y/o psiquiátrica y en tratamiento farmacológico con sustancias que afectaran su estado mental. Todos los pacientes contestaron los cuestionarios DLQI y VitiQoL y los inventarios de depresión y ansiedad de Beck. Resultados: Se reclutaron 150 pacientes con vitíligo, 68,7% (103) mujeres y 31,3% (47) hombres. La mediana de edad fue de 38 años ± 20 años. En nuestros pacientes el promedio de la puntuación del DLQI fue de 5,2 ± 5,4 y el del VitiQoL fue de 32,1 (DE: 22,7), de los 30 y 90 puntos posibles de cada instrumento, respectivamente. La correlación de los resultados de ambos cuestionarios fue de 0,675, p<0,001. Los pacientes con afectación de genitales reportaron una puntuación mayor en el cuestionario de calidad de vida VitiQoL que aquellos sin afectación de esa zona corporal, 43,5 (DE: 28,4) vs. 28,98 (DE: 20,08), p<0,001. La prevalencia de depresión y ansiedad fue del 34% y 60%, respectivamente. Conclusión: El impacto del vitíligo en la calidad de vida de nuestra muestra de pacientes fue mínimo. El vitíligo en los genitales se asocia a un deterioro de la calidad de vida (AU)


Introduction and objective: Vitiligo is a chronic autoimmune skin disease caused by the destruction of melanocytes. Although quality of life (QOL) in vitiligo has been studied in different countries, it has not yet been investigated in Mexico. The aim of this study was to assess the QOL of Mexican patients with vitiligo. Material and method: We conducted a cross-sectional study at the research unit of Centro Dermatológico Dr. Ladislao de la Pascua in Mexico City. We included adults with vitiligo and excluded those with other pigmentation disorders or a neurological or psychiatric disorder. Patients on psychoactive medications were also excluded. All the patients were administered the Dermatology Life Quality Index (DLQI), a vitiligo-specific quality of life instrument (the VitiQoL), and the Beck Depression and Anxiety Inventories. Results: We studied 150 patients with vitiligo (103 women [68.7%] and 47 men [31.3%]). The median (interquartile range) age was 38 (20) years. The mean (SD) scores on the DLQI and VitiQoL were 5.2 (5.4) and 32.1 (22.7) out of total possible scores of 30 and 90, respectively. The correlation between questionnaire scores was 0.675 (P<.001). Patients with genital involvement scored significantly worse on the VitiQoL than those without lesions in this area (43.95 [28.4]) vs. 28.98 [20.08], P<.001). The prevalence of depression and anxiety was 34% and 60%, respectively. Conclusion: Vitiligo has a minimal impact on the QOL of our patients. QOL was worse in patients with genital lesions (AU)


Assuntos
Humanos , Vitiligo/psicologia , Ansiedade/epidemiologia , Depressão/epidemiologia , Qualidade de Vida , Perfil de Impacto da Doença , Psicometria/estatística & dados numéricos , Estudos Transversais , Inibidores de Calcineurina/uso terapêutico , Corticosteroides/uso terapêutico , Furocumarinas/uso terapêutico
15.
Yakugaku Zasshi ; 137(6): 775-781, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28566583

RESUMO

Nowadays, a lot of food ingredients are marketed as dietary supplements for health. Because the effectiveness and mechanisms of these compounds have not been fully characterized, they might have unknown functions. Therefore, we investigated the effect of several food ingredients (Bergamottin, Chrysin, L-Citrulline and ß-Carotene) known as health foods on adipocyte differentiation by using 3T3-L1 preadipocytes. In this study, we found that Bergamottin, a furanocoumarin isolated from grapefruit juice, promotes adipocyte differentiation. In addition, Bergamottin increases the expression of adiponectin, an anti-inflammatory adipokine, and peroxisome proliferator activated receptor γ (PPARγ), a nuclear receptor regulating adipocyte differentiation. Furthermore, the anti-inflammatory activity of Bergamottin was demonstrated by its inhibition of the activation of nuclear factor-κB (NF-κB), an inflammatory transcription factor. Stimulation of mature 3T3-L1 adipocytes by tumor necrosis factor-α (TNF-α) decreased the expression of the endogeneous NF-κB inhibitor, IκBα. Treatment with Bergamottin further decreased the TNF-α-induced change in IκBα expression, suggesting that Bergamottin mediated the inhibition of NF-κB activation. In addition, Bergamottin decreased the TNF-α-induced increase in the mRNA levels of pro-inflammatory adipokines, monocyte chemoattractant protein-1 and interleukin-6. Taken together, our results show that Bergamottin treatment could inhibit inflammatory activity through promoting adipocyte differentiation, which in turn suggests that Bergamottin has the potential to minimize the risk factors of metabolic syndrome.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Furocumarinas/farmacologia , Mediadores da Inflamação/metabolismo , Fator de Necrose Tumoral alfa/efeitos adversos , Células 3T3-L1 , Adipocinas/metabolismo , Adiponectina/metabolismo , Animais , Citrus paradisi/química , Suplementos Nutricionais , Furocumarinas/isolamento & purificação , Furocumarinas/uso terapêutico , Síndrome Metabólica/prevenção & controle , Camundongos , NF-kappa B/metabolismo , PPAR gama/metabolismo , Fitoterapia
16.
Int Immunopharmacol ; 49: 67-76, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28551494

RESUMO

Isoimperatorin (IMP), an active natural furocoumarin, has numerous pharmacologic effects, including anti-inflammatory, analgesic, antispasmodic, and anticancer activities. This study aimed to evaluate the preventive activity of IMP in an ovalbumin (OVA)-induced murine model of asthma and to investigate its possible molecular mechanisms. Female BALB/c mice were sensitized on days 0 and 14 via intraperitoneal injection of 20µg OVA. On days 21-23 after the initial sensitization, the mice received an airway challenge with OVA (1% w/v in PBS) for 1h; meanwhile, IMP (10 or 30mg/kg once daily) was administered by gavage on days 18-23. Our results revealed that IMP significantly lowered the productions of interleukin (IL)-4, IL-5, IL-13, eotaxin, and immunoglobulin (Ig)E in bronchoalveolar lavage fluid (BALF), plasma, or lung tissues. Histological studies showed that IMP inhibited OVA-induced inflammatory cell infiltration and mucus production in the respiratory tract. In addition, pretreatment with IMP suppressed the activation of p38 mitogen-activated protein kinase (p38 MAPK), extracellular-signal-regulated kinases 1/2 (ERK1/2), and nuclear factor-κB (NF-κB). Together, these results suggest that IMP effectively inhibits airway inflammation and mucus hypersecretion by downregulating the levels of Th2 cytokines and inhibiting NF-κB and MAPK pathways.


Assuntos
Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Furocumarinas/uso terapêutico , Pneumonia/tratamento farmacológico , Células Th2/imunologia , Alérgenos/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Imunoglobulina E/sangue , Camundongos , Camundongos Endogâmicos BALB C , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Muco/metabolismo , NF-kappa B/metabolismo , Ovalbumina/imunologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
J BUON ; 22(6): 1471-1476, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29332340

RESUMO

PURPOSE: The main purpose of the present study was to determine the anticancer properties of imperatorin - a naturally occurring coumarin compound - against SGC-7901 human gastric adenocarcinoma cells and the mouse fibroblast cell line 3T3 (normal cell line). METHODS: Imperatorin effects on apoptosis induction, cell cycle phase distribution and PI3K/Akt/m-TOR signalling pathways were studied. MTT cell viability assay examined the compound's cytotoxic potential, while inverted phase contrast microscopy and fluorescence microscopy techniques were used to study morphological changes induced in SGC-7901 cells by imperatorin. Flow cytometry examined its effects on cell cycle progression while Western blot assay was used to study changes in protein expressions of PI3K/Akt/m-TOR pathway. RESULTS: Imperatorin induced a dose-dependent growth inhibition of the SGC-7901 gastric cancer cells with an IC50 value 62.6 µM, while in case of normal 3T3 mouse fibroblast cells, the drug did not show significant toxicity (IC50 value 195.8 µM), indicating that the drug selectively induced cytotoxicity in gastric cancer cells. The cells became rounded up, shrunken in size and got detached from the monolayer attached to well surface. Cells treated with 10, 75 and 175 µM imperatorin indicated that they began to emit yellow or red fluorescence which is an indication of early or late apoptosis respectively. Imperatorin also induced significant DNA fragmentation along with increasing the fraction of sub-G1 cells, indicating a sub-G1 cell cycle arrest. CONCLUSION: Imperatorin could prove an important lead molecule for the treatment of gastric cancer and deserves further research in vivo against more cell lines.


Assuntos
Adenocarcinoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Furocumarinas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Furocumarinas/farmacologia , Humanos , Camundongos , Transdução de Sinais , Neoplasias Gástricas/patologia
18.
Metab Brain Dis ; 32(1): 259-265, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27670769

RESUMO

Isopsoralen is a type of furocoumarin that exhibits estrogen-like activities. The aim of this study was to determine the estrogen-like neuroprotection of isopsoralen in an animal model of spinal cord injury (SCI). Results indicated that isopsoralen (intraperitoneal injection of 5 and 10 mg/kg per day for two weeks) significantly enhanced the hindlimb locomotor functions of mice with SCI, as revealed in the BMS score and angle of inclined plane tests. Morphological data showed that isopsoralen significantly attenuated the injury of the gray matter of spinal cord and induced the up-regulation of ERα levels. The neuroprotective effects of isopsolaren were blocked by the ERα antagonist MPP (0.3 mg/kg), but not by the ERß receptor antagonist PHTPP (0.3 mg/kg). Isopsolaren treatment increased phosphorylated PI3K and AKT (P-PI3K and P-AKT) in the spinal cord of SCI mice and showed a significant anti-apoptotic activity. These results suggest that isopsoralen performs estrogen-like neuroprotection against SCI-induced apoptosis by activating ERα and regulating the PI3K/AKT pathway.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Furocumarinas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Animais , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/antagonistas & inibidores , Furocumarinas/farmacologia , Antagonistas de Hormônios/farmacologia , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Inflammation ; 39(6): 1876-1882, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27581277

RESUMO

Angelicin, a furocoumarin found in Psoralea corylifolia L. fruit, has been reported to have anti-inflammatory activity. The purpose of this study was to determine the protective effects of angelicin on allergic asthma induced by ovalbumin (OVA) in mice. Mice were sensitized to OVA (on days 0 and 14) and challenged with OVA three times (on days 21 to 23). Angelicin (2.5, 5, 10 mg/kg) was given intraperitoneally 1 h before OVA treatment after the initial OVA sensitization. The production of IL-4, IL-5, and IL-13 in BALF and IgE in the serum were measured by ELISA. Lung histological changes were detected by using hematoxylin and eosin (H&E) stain. The results showed that angelicin significantly inhibited inflammatory cells infiltration into the lungs. Histological studies showed that angelicin significantly attenuated OVA-induced lung injury. Meanwhile, treatment of angelicin dose-dependently inhibited OVA-induced the production of IL-4, IL-5, and IL-13 in BALF and IgE in the serum. Furthermore, angelicin was found to inhibit airway hyperresponsiveness and NF-kB activation. In conclusion, our results suggested that angelicin inhibited allergic airway inflammation and hyperresponsiveness by inhibiting NF-kB activation.


Assuntos
Asma/tratamento farmacológico , Furocumarinas/farmacologia , Inflamação/prevenção & controle , Animais , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/prevenção & controle , Líquido da Lavagem Broncoalveolar/química , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Furocumarinas/uso terapêutico , Imunoglobulina E/sangue , Inflamação/dietoterapia , Pulmão/patologia , Camundongos , NF-kappa B/antagonistas & inibidores , Ovalbumina
20.
Dermatol Online J ; 22(5)2016 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-27617516

RESUMO

BACKGROUND: Tumor stage mycosis fungoides (MF) is a subtype of cutaneous T-cell lymphoma (CTCL). Tumor stage MF is rarely curable. Treatment is aimed towards controlling the disease and minimizing side effects from therapy. OBJECTIVE: To characterize clinicopathologic features of tumor stage MF and the impact of clinical characteristics and treatment modalities on patient outcome. METHODS: A retrospective chart review was conducted on 39 patients with tumor stage MF followed at Vanderbilt University between July 1995 and July 2010. RESULTS: The median age of diagnosis was 61 years (IQR: 54-70). Sixty-nine percent of the patients were male (27/39). The median follow-up time was 13.6 months (IQR: 5.5-35.9). Among the patients younger than 60 years at the time of initial diagnosis (n = 19), median overall survival (OS) was 7.0 years (95% CI: 2.1-17.9), compared with 3.3 years (95% CI: 2.4-9.3) in patients who were 60 years or older at initial diagnosis. Ten patients with T1/T2 stage at diagnosis had median OS of 5.0 years (95% CI 3.2-7.0). Twenty-eight patients with T3 stage at diagnosis had median OS of 5.8 years (95% CI 2.4-14.2). Median OS for patients with large cell transformation (LCT) and without LCT was 3.3 and 7.7 years, respectively. LIMITATIONS: This is a retrospective study with the bias of a tertiary-care referral center. CONCLUSION: Although LCT and older age at diagnosis were not statistically significant negative prognostic indicators of OS, there was a trend towards statistical significance for LCT. Clinical stage at diagnosis may not affect OS in patients who develop tumor stage MF.


Assuntos
Micose Fungoide/mortalidade , Neoplasias Cutâneas/mortalidade , Fatores Etários , Idoso , Anticarcinógenos/uso terapêutico , Antineoplásicos/uso terapêutico , Bexaroteno , Transformação Celular Neoplásica , Progressão da Doença , Feminino , Furocumarinas/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Micose Fungoide/patologia , Micose Fungoide/terapia , Estadiamento de Neoplasias , Prognóstico , Radioterapia/métodos , Estudos Retrospectivos , Pele/patologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Centros de Atenção Terciária , Tetra-Hidronaftalenos/uso terapêutico , Terapia Ultravioleta/métodos
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