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1.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675055

RESUMO

Growing evidence of the microbiome's role in human health and disease has emerged since the creation of the Human Microbiome Project. Recent studies suggest that alterations in microbiota composition (dysbiosis) may play an essential role in the occurrence, development, and prognosis of prostate cancer (PCa), which remains the second most frequent male malignancy worldwide. Current advances in biological technologies, such as high-throughput sequencing, transcriptomics, and metabolomics, have enabled research on the gut, urinary, and intra-prostate microbiome signature and the correlation with local and systemic inflammation, host immunity response, and PCa progression. Several microbial species and their metabolites facilitate PCa insurgence through genotoxin-mediated mutagenesis or by driving tumor-promoting inflammation and dysfunctional immunosurveillance. However, the impact of the microbiome on PCa development, progression, and response to treatment is complex and needs to be fully understood. This review addresses the current knowledge on the host-microbe interaction and the risk of PCa, providing novel insights into the intraprostatic, gut, and urinary microbiome mechanisms leading to PCa carcinogenesis and treatment response. In this paper, we provide a detailed overview of diet changes, gut microbiome, and emerging therapeutic approaches related to the microbiome and PCa. Further investigation on the prostate-related microbiome and large-scale clinical trials testing the efficacy of microbiota modulation approaches may improve patient outcomes while fulfilling the literature gap of microbial-immune-cancer-cell mechanistic interactions.


Assuntos
Microbioma Gastrointestinal , Microbiota , Neoplasias da Próstata , Masculino , Humanos , Microbiota/fisiologia , Neoplasias da Próstata/terapia , Neoplasias da Próstata/patologia , Microbioma Gastrointestinal/fisiologia , Próstata/patologia , Inflamação , Disbiose
2.
Int J Mol Sci ; 21(24)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352687

RESUMO

Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Metilação de DNA , Mutação , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Adulto , Idoso , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Prognóstico , Regiões Promotoras Genéticas , Estudos Retrospectivos , Taxa de Sobrevida
3.
J Neuroinflammation ; 15(1): 205, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30001736

RESUMO

BACKGROUND: Parkinson's disease (PD) affects an estimated 7 to 10 million people worldwide, and only symptomatic treatments are presently available to relieve the consequences of brain dopaminergic neurons loss. Neuronal degeneration in PD is the consequence of neuroinflammation in turn influenced by peripheral adaptive immunity, with CD4+ T lymphocytes playing a key role. CD4+ T cells may however acquire proinflammatory phenotypes, such as T helper (Th) 1 and Th17, as well as anti-inflammatory phenotypes, such as Th2 and the T regulatory (Treg) one, and to what extent the different CD4+ T cell subsets are imbalanced and their functions dysregulated in PD remains largely an unresolved issue. METHODS: We performed two cross-sectional studies in antiparkinson drug-treated and drug-naïve PD patients, and in age- and sex-matched healthy subjects. In the first one, we examined circulating Th1, Th2, Th17, and in the second one circulating Treg. Number and frequency of CD4+ T cell subsets in peripheral blood were assessed by flow cytometry and their functions were studied in ex vivo assays. In both studies, complete clinical assessment, blood count and lineage-specific transcription factors mRNA levels in CD4+ T cells were independently assessed and thereafter compared for their consistency. RESULTS: PD patients have reduced circulating CD4+ T lymphocytes, due to reduced Th2, Th17, and Treg. Naïve CD4+ T cells from peripheral blood of PD patients preferentially differentiate towards the Th1 lineage. Production of interferon-γ and tumor necrosis factor-α by CD4+ T cells from PD patients is increased and maintained in the presence of homologous Treg. This Th1-biased immune signature occurs in both drug-naïve patients and in patients on dopaminergic drugs, suggesting that current antiparkinson drugs do not affect peripheral adaptive immunity. CONCLUSIONS: The complex phenotypic and functional profile of CD4+ T cell subsets in PD patients strengthen the evidence that peripheral adaptive immunity is involved in PD, and represents a target for the preclinical and clinical assessment of novel immunomodulating therapeutics.


Assuntos
Citocinas/metabolismo , Doença de Parkinson/imunologia , Doença de Parkinson/patologia , Células Th1/patologia , Células Th17/patologia , Células Th2/patologia , Idoso , Linfócitos T CD4-Positivos , Estudos Transversais , Citocinas/genética , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/sangue , RNA Mensageiro/metabolismo
5.
Inflamm Res ; 64(2): 127-35, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25561369

RESUMO

OBJECTIVES: Adrenergic modulation of immunity has been extensively characterized, however, few information exist regarding polymorphonuclear leukocytes (PMN), despite their key role in immunity and inflammation. We investigated the effect of adrenergic agents on human PMN migration, CD11b and CD18 expression, reactive oxygen species (ROS) and interleukin (IL)-8 production, and on adrenoceptor (AR) expression. METHODS: Migration was measured by the Boyden chamber assay, CD11b/CD18 expression was assessed by flow cytometry, intracellular ROS were detected by spectrofluorimetry, and IL-8 was quantitated by standard ELISA assay. AR mRNA levels were measured by real-time PCR and PMN morphology was studied by scanning electron microscopy. RESULTS: Adrenaline(A), noradrenaline and the ß-AR agonist isoprenaline reduced N-formyl-Met-Leu-Phe (fMLP)-induced migration, CD11b/CD18 expression, and ROS production, without affecting IL-8. The effect of A on CD11b was antagonized by yohimbine and propranolol, and increased by prazosin. The effect on ROS production was completely abolished by propranolol. PMN expressed α(1A)-, α(1B)-, α(1D)-, α(2A)-, α(2C)-, ß(1)-, ß(2)-, and ß(3)-AR mRNA. A prevented fMLP-induced morphological changes of PMN. CONCLUSIONS: Adrenergic agents reduced PMN responses mainly through ß-AR, although α-AR may contribute at least to CD11b expression. AR-operated pathways in PMN should be investigated in disease conditions and in the response to therapeutic agents.


Assuntos
Antagonistas Adrenérgicos/farmacologia , Neutrófilos/efeitos dos fármacos , Antígeno CD11b/metabolismo , Antígenos CD18/metabolismo , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Expressão Gênica , Humanos , Interleucina-8/metabolismo , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/citologia , Neutrófilos/metabolismo , Neutrófilos/fisiologia , Prazosina/farmacologia , Propranolol/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores Adrenérgicos/genética , Ioimbina/farmacologia
6.
Phytother Res ; 28(8): 1232-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24458921

RESUMO

Bergamot (Citrus aurantium L. subsp. bergamia) essential oil (BEO) is used in folk medicine as an antiseptic and anthelminthic and to facilitate wound healing. Evidence indicates that BEO has substantial antimicrobial activity; however its effects on immunity have never been examined. We studied the effects of BEO on reactive oxygen species (ROS) production in human polymorphonuclear leukocytes (PMN) and the role of Ca(2+) in the functional responses evoked by BEO in these cells. Results show that BEO increased intracellular ROS production in human PMN, an effect that required the contribution of extracellular (and, to a lesser extent, of intracellular) Ca(2+) . Bergamot essential oil also significantly increased ROS production induced by the chemotactic peptide N-formyl-Met-Leu-Phe and reduced the response to the protein kinase C activator phorbol myristate acetate. In conclusion, this is the first report showing the ability of BEO to increase ROS production in human PMN. This effect could both contribute to the activity of BEO in infections and in tissue healing as well as underlie an intrinsic proinflammatory potential. The relevance of these findings for the clinical uses of BEO needs careful consideration.


Assuntos
Neutrófilos/efeitos dos fármacos , Óleos Voláteis/farmacologia , Óleos de Plantas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Cálcio/metabolismo , Citrus/química , Humanos , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Acetato de Tetradecanoilforbol/farmacologia
7.
Neuroimmunomodulation ; 19(5): 283-92, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22472872

RESUMO

OBJECTIVE: We investigated dopaminergic inhibition of CD4+CD25(high) regulatory T lymphocytes (Treg) in relapsing-remitting multiple sclerosis (MS) patients treated with interferon (IFN)-ß. METHODS: MS patients were prospectively studied at baseline and during 1 year of IFN-ß, and compared with healthy controls (HCs). Treg were separated by immunomagnetic sorting and the effect of dopamine (DA) on Treg was assessed in coculture experiments with homologous effector T lymphocytes (Teff). Tyrosine hydroxylase (TH), dopaminergic receptors (DR) D3 and D5, and forkhead box protein P3 (FoxP3) mRNA were assessed by real-time PCR. Circulating CD4+ T cell subsets were assessed by flow cytometry. RESULTS: In coculture experiments, Treg inhibition of Teff proliferation was reduced by DA in HCs and completely abolished in MS patients at baseline. However, in patients after 12 months of IFN-ß, Teff proliferation was impaired and DA had no more effect on Treg. In comparison to cells from HCs, Treg from MS patients at baseline had increased mRNA for DR D5 and TH (but not for DR D3). During treatment with IFN-ß, both DR D5 and TH mRNA decreased down to values lower than those of cells from HCs. In comparison to HCs, MS patients had a higher frequency of circulating Treg, both at baseline and after IFN-ß, while FoxP3 mRNA levels in Treg were similar in patients and HCs and did not show major changes during IFN-ß. CONCLUSIONS: Dopaminergic inhibition of Treg in MS patients is suppressed during IFN-ß treatment. Treg play a key role in the suppression of autoimmunity, thus the effect may have a therapeutic repercussion.


Assuntos
Antígenos CD4/metabolismo , Dopamina/farmacologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Esclerose Múltipla Recidivante-Remitente/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Adulto , Análise de Variância , Proliferação de Células/efeitos dos fármacos , Avaliação da Deficiência , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Fito-Hemaglutininas , RNA Mensageiro , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismo , Receptores de Dopamina D5/genética , Receptores de Dopamina D5/metabolismo , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
8.
Cancers (Basel) ; 14(16)2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-36010943

RESUMO

The main hypothesis of this study is that gene expression profiles (GEPs) integrating both tumor antigenicity and a pre-existing adaptive immune response can be used to generate distinct immune-related signatures of BRAF mutant colorectal cancers (BRAF-CRCs) to identify actionable biomarkers predicting response to immunotherapy. GEPs of 89 immunotherapy-naïve BRAF-CRCs were generated using the Pan-Cancer IO 360 gene expression panel and the NanoString nCounter platform and were correlated with microsatellite instability (MSI) status and with CD8+ tumor-infiltrating lymphocyte (TIL) content. Hot/inflamed profiles were found in 52% of all cases, and high scores of Tumor Inflammation Signature were observed in 42% of the metastatic BRAF-CRCs. A subset of MSI tumors showed a cold profile. Antigen Processing Machinery (APM) signature was not differentially expressed in MSI tumors compared with MSS cases. By contrast, the APM signature was significantly upregulated in CD8+ BRAF-CRCs versus CD8- tumors. Our study demonstrates that a significant fraction of BRAF-CRCs may be a candidate for immunotherapy and that the simultaneous analysis of MSI status and CD8+ TIL content increases accuracy in identifying patients who can potentially benefit from immune checkpoint inhibitors. GEPs may be very useful in expanding the spectrum of patients with BRAF-CRCs who can benefit from immune checkpoint blockade.

9.
Phytother Res ; 23(4): 540-5, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19067389

RESUMO

Plants are the main source of molecules with antioxidant and radical scavenging properties that aid the natural defence systems of cells and may be involved in the preservation of human health, particularly preventing all the physiopathological conditions where oxidative damage is a hallmark. Achillea collina Becker ex Rchb. is a medicinal plant of the Achillea millefolium aggregate (yarrow) traditionally used, particularly in mountain areas, as an infusion or alcohol extract for its digestive, antiinflammatory, analgesic, antipyretic and wound healing properties. The aim of this study was to investigate the antioxidant capacity and cytoprotective activity against oxidative stress of infusions obtained from the leaves and inflorescences of Achillea collina Becker ex Rchb., assessed by chemical (free radical scavenging activity by DPPH and Folin Ciocalteu assay) and biological assays (in vitro model of cytotoxicity and lipid peroxidation in PC12 cells line). Infusions of leaves had the highest antioxidant properties and cytoprotective activity. The antioxidant capacity was significantly correlated with the total phenolic content but not with the cytoprotective profile. Achillea collina Becker ex Rchb. has good antioxidant and cytoprotective properties, suggesting further investigations on its chemical composition and potential health value, particularly for traditionally prepared infusions of leaves.


Assuntos
Achillea/química , Antioxidantes/farmacologia , Citoproteção , Estresse Oxidativo , Extratos Vegetais/farmacologia , Animais , Flores/química , Peroxidação de Lipídeos , Células PC12 , Fenóis/farmacologia , Folhas de Planta/química , Plantas Medicinais/química , Ratos
10.
Biomed Pharmacother ; 111: 91-98, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30579257

RESUMO

Red clover (Trifolium pratense L., Fabaceae; RCL), a perennial plant rich in isoflavones, is a natural alternative for menopausal symptoms, as well as antiaging and antioxidant. Isoflavone preparations usually contain aglycones and ß-glycosides. Aglycones, the active moieties, are absorbed slowly and unevenly due to reduced water solubility and biotransformation from ß-glycosides. NeoSol™RCL40 is a novel RCL isoflavone aglycones preparation based on active solubilization technologies. In the present study, NeoSol™RCL40 was shown to induce solubilization of isoflavones and to increase estrogenic and antioxidative effects in comparison to a standard RCL extract (RCLE). NeoSol™RCL40 was prepared from RCLE using as host molecules either 2-pyrrolidone, 1-ethenyl homopolymer (PVP), γ-cyclodextrin, or maltodextrin. Solubilisation assays, performed by means of HPLC-UV, showed that solubilization of isoflavone aglycones was highest with RCLE processed with PVP, which was therefore selected for functional assays. In comparison to RCLE, NeoSol™RCL40 containing the same amount of isoflavone aglycones displayed 3.4 times higher estrogenicity in MCF-7 cell, 1.9-2.0 higher antioxidant activity in the DPPH and in the FRAP assay, and was cytoprotective in PC12 cells. As a whole, results support the ability of NeoSol™RCL40 to promote isoflavones solubilization leading to increased biological activity. NeoSol™RCL40 is therefore an interesting novel preparation providing improved availability of active isoflavones aglycones.


Assuntos
Antioxidantes/farmacologia , Iridoides/farmacologia , Isoflavonas/farmacologia , Extratos Vegetais/farmacologia , Trifolium , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Iridoides/química , Iridoides/isolamento & purificação , Isoflavonas/química , Isoflavonas/isolamento & purificação , Células MCF-7 , Células PC12 , Componentes Aéreos da Planta , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Solubilidade
11.
J Ethnopharmacol ; 116(3): 501-7, 2008 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-18280072

RESUMO

AIM OF THE STUDY: Achyrocline satureioides (Lam.) D.C. is a South American native medicinal herb known by the popular name of "Marcela". Its infusion is widely utilized for the treatment of several digestive ailments, as an anti-inflammatory preparation, as a sedative and anti-atherosclerotic. Circumstantial evidence suggests that extracts of Achyrocline satureioides may have immunomodulatory properties. The present study was therefore devised to investigate the in vitro effects Achyrocline satureioides infusion on human peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes (PMNs). MATERIALS AND METHODS: Experiments were performed on cells isolated from venous blood obtained from healthy donors. PBMC proliferation and cytokine production were assessed by standard ELISA methods. Reactive oxygen species (ROS) production by PMNs was evaluated by spectrofluorimetry. RESULTS: In PBMCs, Achyrocline satureioides infusion in the 0.06-0.24microg/ml quercetin equivalent (QE) concentration range concentration-dependently reduced PHA-induced proliferation and production of interferon (IFN)-gamma and interleukin (IL)-4. Lower concentrations of the infusion (0.006-0.03microg/ml QE), which were ineffective on cell proliferation, significantly increased the production of both IFN-gamma and IL-4 and decreased the ratio IFN-gamma/IL-4. In PMNs, Achyrocline satureioides infusion slightly increased the spontaneous generation of ROS only at concentrations > or =0.06microg/ml QE. On the contrary, in the 0.0012-0.03microg/ml QE concentration range the infusion profoundly inhibited fMLP-induced ROS generation as well as spontaneous and fMLP-induced IL-8 production. CONCLUSIONS: The present results provide evidence that Achyrocline satureioides infusion may exert several immunomodulatory effects, in line with its traditional use as an anti-inflammatory agent in many disease conditions. Further studies are warranted to better characterize such effects and to assess their therapeutic relevance.


Assuntos
Achyrocline/química , Fatores Imunológicos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Fatores Imunológicos/efeitos adversos , Leucócitos Mononucleares/citologia , Extratos Vegetais/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo
12.
J Leukoc Biol ; 104(3): 603-614, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29668114

RESUMO

This study tests the hypothesis that in isolated human polymorphonuclear leukocytes (PMN) adrenergic ligands can affect neutrophil extracellular trap (NET) formation. We have previously shown that, in PMN, adrenaline (A), through the activation of adrenergic receptors (AR), reduces stimulus-dependent cell activation; we have, therefore, planned to investigate if AR are involved in NET production. PMN were obtained from venous blood of healthy subject. The ability of adrenergic ligands to affect reactive oxygen species (ROS) production, NET production, and cell migration was investigated in cells cultured under resting conditions or after activation with N-formyl-methionyl-leucyl-phenylalanine (fMLP), LPS, or IL-8. Stimuli-induced NET production measured as ROS, microscopic evaluation, and elastase production was reverted by A and this effect was blocked by the selective ß2 -AR antagonist ICI-118,551. The stimulus-induced ROS generation and migration was prevented by A and by isoprenaline (ISO), and these effects were counteracted only by ICI-118,551 and not by the other two selective ligands for the ß1 and ß3 -AR. Finally, the presence of the ß-ARs on PMN was confirmed, by means of microscopy and flow cytometry. The data of the present study suggest that adrenergic compounds, through the interaction of mainly ß2 -AR, are able to affect neutrophil functions. These data are suggestive of a possible therapeutic role of ß2 -AR ligands (in addition to their classical use), promoting the possible therapeutic relevance of adrenergic system in the modulation of innate immunity proposing their possible use as anti-inflammatory drugs.


Assuntos
Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Células Cultivadas , Armadilhas Extracelulares/imunologia , Humanos , Neutrófilos/imunologia , Receptores Adrenérgicos beta 2/imunologia
14.
Sci Rep ; 6: 33738, 2016 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-27652978

RESUMO

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra pars compacta, α-synuclein (α-syn)-rich intraneuronal inclusions (Lewy bodies), and microglial activation. Emerging evidence suggests that CD4+ T lymphocytes contribute to neuroinflammation in PD. Since the mainstay of PD treatment is dopaminergic substitution therapy and dopamine is an established transmitter connecting nervous and immune systems, we examined CD4+ T naive and memory lymphocytes in PD patients and in healthy subjects (HS), with specific regard to dopaminergic receptor (DR) expression. In addition, the in vitro effects of α-syn were assessed on CD4+ T naive and memory cells. Results showed extensive association between DR expression in T lymphocytes and motor dysfunction, as assessed by UPDRS Part III score. In total and CD4+ T naive cells expression of D1-like DR decrease, while in T memory cells D2-like DR increase with increasing score. In vitro, α-syn increased CD4+ T memory cells, possibly to a different extent in PD patients and in HS, and affected DR expression with cell subset-specific patterns. The present results support the involvement of peripheral adaptive immunity in PD, and may contribute to develop novel immunotherapies for PD, as well as to better use of current dopaminergic antiparkinson drugs.

15.
Data Brief ; 9: 376-381, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27699190

RESUMO

This data article presents a dataset of mRNA levels for dopaminergic receptors, adrenoceptors and for tyrosine hydoxylase, the rate-limiting enzyme in the synthesis of catecholamines, in peripheral blood mononuclear cells as well as in CD4+ T effector and regulatory cells from subjects with clinically isolated syndromes (CIS), which is a first episode of neurological disturbance(s) suggestive of multiple sclerosis. CIS subjects are divided into two groups according to their eventual progression, after 12 months from CIS, to clinically established multiple sclerosis. The data reported are related to the article entitled "Dopaminergic receptors and adrenoceptors in circulating lymphocytes as putative biomarkers for the early onset and progression of multiple sclerosis" (M. Cosentino, M. Zaffaroni, M. Legnaro, R. Bombelli, L. Schembri, D. Baroncini, A. Bianchi, R. Clerici, M. Guidotti, P. Banfi, G. Bono, F. Marino, 2016) [1].

16.
J Neuroimmunol ; 298: 82-9, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27609280

RESUMO

Clinically isolated syndrome (CIS) is a first, usually recovering, episode of neurological disturbance(s) suggestive of multiple sclerosis (MS). CIS subjects might benefit from early disease-modifying drugs, provided that those at high risk of developing MS can be identified. Gene expression for dopaminergic receptors (DR) and adrenoceptors (AR) is dysregulated in lymphocytes of MS patients and is affected by treatment with interferon (IFN)-ß. In particular, lymphocyte DR D5 mRNA might be a marker of IFN-ß response in MS patients. No information exists so far in CIS subjects. We investigated DR and AR gene expression in peripheral blood mononuclear cells (PBMC) and in CD4+ T effector (Teff) and regulatory (Treg) cells from CIS subjects, and assessed their relationship with MS progression after 12months. Expression of several DR and AR are upregulated in PBMC, Teff and Treg from CIS subjects. DR D3 and α2A-AR mRNA in PBMC, and DR D5 mRNA in Treg correlate with the risk of MS at 12months. Results show the involvement of dopaminergic and adrenergic pathways in CIS as well as in MS pathogenesis, supporting the evaluation of dopaminergic and adrenergic agents in MS.


Assuntos
Linfócitos/metabolismo , Esclerose Múltipla/patologia , Receptores Adrenérgicos/metabolismo , Receptores Dopaminérgicos/metabolismo , Regulação para Cima/fisiologia , Adulto , Catecolaminas/urina , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/urina , RNA Mensageiro/metabolismo , Receptores Adrenérgicos/genética , Receptores Dopaminérgicos/genética , Transdução de Sinais/fisiologia , Estatísticas não Paramétricas , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Adulto Jovem
17.
J Neuroimmunol ; 162(1-2): 112-21, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15833366

RESUMO

Interferon (IFN)-gamma plays a pivotal role in the pathogenesis of multiple sclerosis (MS), while IFN-beta may be able to modify the clinical course of the disease, eventually also by counterbalancing IFN-gamma-mediated effects. Catecholamines (CA) exert important effects on the immune response, both as transmitters between the nervous and the immune system, as well as autocrine/paracrine mediators in immune cells, and several lines of evidence support their involvement in MS. In particular, dysregulated production of CA seems to occur in peripheral blood mononuclear cells (PBMCs) of MS patients. We assessed the effects of IFN-beta and IFN-gamma on endogenous CA in PBMCs. In cultured PBMCs stimulated with phytohaemagglutinin (PHA), IFN-beta increased CA production and induced CA release in the culture medium, while IFN-gamma decreased both CA production and the expression of mRNA for the CA-synthesizing enzyme tyrosine hydroxylase. Coincubation with both IFNs prevented the inhibitory effect of IFN-gamma, as well as the stimulatory effect of IFN-beta. IFNs are the first physiological compounds shown to affect endogenous CA in PBMCs: in view of the role of CA-dependent mechanisms in the immune response, these findings may help to better understand the mechanisms of action of IFN-beta as an immunomodulatory drug in MS.


Assuntos
Catecolaminas/metabolismo , Interferon beta/farmacologia , Interferon gama/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Northern Blotting , Células Cultivadas , Cromatografia Líquida de Alta Pressão/métodos , Interações Medicamentosas , Eletroquímica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/metabolismo , Fito-Hemaglutininas/farmacologia , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
18.
J Neuroimmunol ; 125(1-2): 125-33, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11960648

RESUMO

Although it is now established that immunocompetent cells produce catecholamines (CA), which in turn may act as autocrine/paracrine mediators, little is known about the mechanisms regulating CA production in these cells. In the present study, evidence is provided that stimulation of human cultured peripheral blood mononuclear cells (PBMCs) with phytohaemagglutinin (PHA) induces the expression of tyrosine hydroxylase (TH) mRNA and subsequently increases intracellular CA levels through protein kinase C (PKC) activation and the contribution of intracellular Ca(++)-dependent mechanisms. Increased production of CA in PHA-stimulated PBMCs suggests a preferential involvement of catecholaminergic pathways in the functional modulation of activated cells. These findings may help to better define the role of immunocompetent cell-derived CA in the neuroimmune network.


Assuntos
Cálcio/metabolismo , Catecolaminas/biossíntese , Ácido Egtázico/análogos & derivados , Leucócitos Mononucleares/enzimologia , Fito-Hemaglutininas/farmacologia , Proteína Quinase C/metabolismo , Células Cultivadas , Quelantes/farmacologia , Ácido Egtázico/farmacologia , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/imunologia , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Proteína Quinase C/antagonistas & inibidores , RNA Mensageiro/análise , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
19.
J Neuroimmunol ; 133(1-2): 233-40, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12446028

RESUMO

Sympathoadrenergic mechanisms may play a role in multiple sclerosis (MS). We examined catecholamine (CA) levels and production and tyrosine hydroxylase (TH) expression in peripheral blood mononuclear cells (PBMCs) from MS patients, and the correlation between CA production and apoptosis in PBMCs. PBMCs from MS patients had increased norepinephrine (NE) levels. However, phytohaemagglutinin (PHA)-stimulated PBMCs from MS patients with active disease synthesized less dopamine (DA) than cells from both healthy controls and patients with inactive disease. PBMCs from patients with inactive disease showed lower expression of TH. Pharmacological inhibition of TH in cultured PBMCs stimulated with PHA reduced the percentage of apoptotic cells. Since a failure of activation-induced apoptosis in immune cells may be involved in MS, it is suggested that altered CA production by PBMCs may be implicated in such dysregulation.


Assuntos
Apoptose/imunologia , Catecolaminas/biossíntese , Leucócitos Mononucleares/imunologia , Ativação Linfocitária/imunologia , Esclerose Múltipla/imunologia , Tirosina 3-Mono-Oxigenase/metabolismo , Adulto , Catecolaminas/imunologia , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Leucócitos Mononucleares/enzimologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/enzimologia , Neuroimunomodulação/imunologia , Sistema Nervoso Simpático/imunologia , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , alfa-Metiltirosina/farmacologia
20.
Biochem Pharmacol ; 67(5): 865-73, 2004 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15104239

RESUMO

Activation of human peripheral blood mononuclear cells (PBMC) triggers endogenous production of catecholamines (CA) through protein kinase (PK) C-dependent induction of tyrosine hydroxylase (TH; EC 1.14.16.2), the first and rate-limiting enzyme in the synthesis of CA. Since CA themselves are major mediators of the neural input to the immune system, we have examined their ability to affect PKC-induced TH mRNA expression and CA production in human isolated PBMC. In T- and B-lymphocytes (but not in monocytes) the PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA) (but not its inactive analogue 4alpha-phorbol-12,13-didecanoate) induced TH mRNA expression which was followed by an increase in the amount of intracellular CA. Coincubation of human PBMC with dopamine (DA) (but not with norepinephrine or epinephrine) inhibited TPA-induced TH mRNA expression. The effect of DA was concentration-dependent and was mimicked by the dopaminergic D1-like receptor agonist SKF-38393 but not by the D2-like receptor agonist bromocriptine. The D1-like antagonist SCH-23390 shifted to the right the concentration-response curves of both DA and SKF-38393, while neither the D2-like antagonist domperidone, nor the alpha1-adrenoceptor antagonist prazosin, the alpha2-adrenoceptor antagonist yohimbine, or the beta-adrenoceptor antagonist propranolol affected to any significant extent the inhibitory effect of DA. SKF-38393 also significantly reduced TPA-induced increase of intracellular CA, an effect which was antagonized by SCH-23390. It is thus suggested that in human T- and B-lymphocytes PKC activation leads to TH mRNA expression and subsequent increase of intracellular CA, which can be inhibited by D1-like receptor activation. Inhibition of intracellular CA production in human PBMC promotes cell survival through reduction of activation-induced apoptosis, and dopaminergic modulation of TH expression and intracellular CA content may thus represent a novel mechanism in the cross-talk between the nervous and the immune system as well as among immune system cells.


Assuntos
Catecolaminas/metabolismo , Linfócitos/metabolismo , Proteína Quinase C/metabolismo , Receptores de Dopamina D1/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Dopamina/farmacologia , Epinefrina/farmacologia , Humanos , Técnicas In Vitro , Linfócitos/efeitos dos fármacos , Linfócitos/enzimologia , Norepinefrina/farmacologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores de Dopamina D2/metabolismo , Tirosina 3-Mono-Oxigenase/genética
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