Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.197
Filtrar
1.
Internist (Berl) ; 60(10): 1043-1058, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31501913

RESUMO

Therapeutic regimens using monoclonal antibodies have been implemented in clinical daily practice for various gastroenterological diseases, for therapeutic strategies in gastrointestinal (GI) oncology, and infectious diseases of the gastrointestinal tract. The main indications remain the therapy of chronic inflammatory bowel disease and in GI oncology. A new field has opened for targeted therapy with monoclonal antibodies of recurrent Clostridium difficile infection. In the nomenclature of monoclonal antibodies, the endings of the substances indicate the production or degree of "humanization" of the respective antibodies ("umab": fully human, recombinant antibody; "ximab": chimeric antibody with variable murine domain). For chronic inflammatory bowel disease, monoclonal antibodies has been developed to interfere with molecular targets of the inflammatory cascade in the underlying pathogenesis (tumor necrosis factor­α, interleukin-12 and -23; α4ß7-integrins). The development of targeted therapies in the treatment of GI malignancies, monoclonal antibodies has been developed to interfere with substantial pathways of proliferation and apoptosis as well as neoplastic vascularization and neovascularization (e.g., vascular endothelial growth factor [VEGF] and VEGF receptor antibodies, epidermal growth factor receptor antibodies, HER2/neu antibodies). In the current review, we provide a summary of the current applications of monoclonal antibodies in the therapeutic treatment of gastroenterological diseases.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Gastroenteropatias/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos , Colite Ulcerativa/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Receptores ErbB/efeitos dos fármacos , Gastroenterologia , Humanos , Fatores Imunológicos/farmacologia , Camundongos , Receptores de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular
2.
Expert Opin Drug Saf ; 18(10): 925-948, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31429602

RESUMO

Introduction: In the last 20 years the armamentarium for multiple sclerosis (MS) treatment has been enriched from an increasingly wider variety of new drugs in order to reach a better control of the disease with a better patient compliance. Areas covered: With this great variety of therapeutic options, physicians may face new and major challenges. The huge amount of data from pilot studies and real-life settings showed that the first-line therapies have a better safety profile. On the other hand, the risks associated with newer drugs, with more selective mechanism of action and targeting specific pathways of MS pathophysiology, are not yet fully established. In particular, real-life use of these advanced drugs has raised important safety issues as long-term effects and potential risks are not yet known and remain to be carefully evaluated. Expert opinion: No time like the present, the physician faces new and major challenges in order to choose the best available therapy for MS. With the increasing number of drugs for treating MS and the lack of safety data, observational studies and post-marketing surveillance activities are crucial in order to improve the knowledge about the safety profile of these drugs and the therapeutic management in clinical practice settings.


Assuntos
Fatores Imunológicos/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Vigilância de Produtos Comercializados , Animais , Desenho de Drogas , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Adesão à Medicação , Esclerose Múltipla Recidivante-Remitente/fisiopatologia
3.
Medicine (Baltimore) ; 98(27): e16100, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277110

RESUMO

BACKGROUND: Rotavirus (RV) can cause vomiting and diarrhea in infants and children, and could be treated clinically with immunoglobulin Y (IgY), which is an immunoglobulin extracted from chicken yolk. There is no systematic evaluation of immunoglobulin in the treatment of rotavirus enteritis. Therefore, we systematically evaluated rotavirus enteritis with oral immunoglobulin Y therapy using meta-analysis. METHODS: We conducted a systematic search in CNKI, WANFANG DATA, VIP, PubMed, and the Cochrane Library databases (up to April 30, 2018). Using Revman 5.3 software for meta-analysis. RESULTS: A total of 2626 subjects with rotavirus diarrhea from 17 randomized clinical trials were included in the meta-analysis. Of these, 1347 subjects received oral immunoglobulin Y and 1279 subjects received conventional treatment. The results of the meta-analysis indicated that the total number of effective cases and effective rates of immunoglobulin Y in treatment of rotavirus enteritis in infants and children was statistically different from that in the control group (odds ratio [OR] = 3.87, 95% confidence interval [CI] (3.17, 4.74), P < .00001) and (OR = 3.63, 95% CI [2.75, 4.80], P < .00001). CONCLUSIONS: Immunoglobulin Y is effective in the treatment of infantile rotavirus enteritis. Oral immunoglobulin Y can be widely used in the treatment of rotavirus enteritis in clinic.


Assuntos
Diarreia Infantil/tratamento farmacológico , Imunoglobulinas/administração & dosagem , Fatores Imunológicos/administração & dosagem , Infecções por Rotavirus/tratamento farmacológico , Administração Oral , Estudos de Casos e Controles , Criança , Enterite/tratamento farmacológico , Humanos , Imunoglobulinas/farmacologia , Fatores Imunológicos/farmacologia , Lactente , Recém-Nascido , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
J Agric Food Chem ; 67(32): 9070-9078, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31343168

RESUMO

In this study, an immunologically active novel microparticulate mushroom ß-glucan (PRA-1p) was prepared using an alkali-soluble glucan PRA-1 by an emulsification and cross-linking method. PRA-1 was a hyperbranched (1→3),(1→6)-ß-d-glucan with a degree of branching of 0.89, isolated from the sclerotia of Polyporus rhinocerus. PRA-1 had a rod-like conformation, while PRA-1p exhibited a monodisperse and homogeneous spherical conformation with a diameter ranging from 0.3 to 2.0 µm in water. PRA-1p significantly induced nitric oxide and reactive oxygen species production as well as morphological changes of murine macrophages (RAW 264.7 cells) and upregulated their phagocytic activity. Furthermore, PRA-1p treatment markedly enhanced the secretion of cytokines, including cutaneous T cell-attracting chemokine 27, granulocyte-colony-stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, macrophage inflammatory protein 2, regulated on activation, normal T cell expressed and secreted, soluble tumor necrosis factor receptor 1, and tissue inhibitors of metalloproteinases. Activation of RAW 264.7 cells triggered by PRA-1p was associated with activation of inducible nitric oxide synthase, nuclear factor κB, extracellular signal-regulated kinase, and protein kinase B. This work suggests that novel PRA-1p derived from the mushroom sclerotia of P. rhinocerus has potential application as an immunostimulatory agent.


Assuntos
Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polyporus/química , beta-Glucanas/química , beta-Glucanas/farmacologia , Animais , Quimiocina CCL27/genética , Quimiocina CCL27/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fatores Imunológicos/isolamento & purificação , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , Óxido Nítrico/imunologia , Fagocitose/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Polyporus/imunologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , beta-Glucanas/isolamento & purificação
5.
Carbohydr Polym ; 219: 368-377, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151536

RESUMO

A water-soluble polysaccharide was isolated from Tornabea scutellifera and fractionated using a DAEA Sepharose FF column to evaluate its capacity to stimulate natural killer (NK) cells and macrophages. Neutral sugars (71.8-93.5%) constituted the major part of crude polysaccharides and fractions (TSF1 and TSF2) with relatively lower levels of proteins (0.4-20.3%) and uronic acids (0.8-4.9%). The weight average molecular weights (Mw) of 152.7-537.3 × 103 g/mol were measured for isolated polysaccharides. The polysaccharides were composed of glucose (14.4-44.0%), galactose (23.2-43.2%), mannose (28.5-34.2%) and rhamnose (2.6-13.9%) units connected through (1→2)-Galp, (1→2,6)-Galp, (1→4)-Glcp, (1→6)-Glcp, (1→3)-Rhap, (1→2)-Rhap and (1→4)-Manp residues. TSF2 polysaccharide effectively induced RAW264.7 murine macrophages to release nitric oxide, TNF-α, IL-1ß and IL-6, and activated NK cells to produce TNF-α, INF-γ, granzyme-B, perforin, NKG2D and FasL through NF-κB and MAPKs signaling pathways. Overall results suggested that polysaccharides from T. scutellifera could be potent immunostimulatory compounds inducing both macrophages and NK cells.


Assuntos
Ascomicetos/metabolismo , Citocinas/metabolismo , Fatores Imunológicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Óxido Nítrico/metabolismo , Polissacarídeos/farmacologia , Animais , Galactose/química , Glucose/química , Irã (Geográfico) , Células Matadoras Naturais , Manose/química , Camundongos , Polissacarídeos/química , Células RAW 264.7 , Ramnose/química , Ácidos Urônicos/metabolismo
6.
Eur J Med Chem ; 178: 13-29, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31173968

RESUMO

The oncogenic Epstein-Barr virus (EBV) evades the immune system through limiting the expression of its highly antigenic and essential genome maintenance protein, EBNA1, to the minimal level to ensure viral genome replication, thereby also minimizing the production of EBNA1-derived antigenic peptides. This regulation is based on inhibition of translation of the virally-encoded EBNA1 mRNA, and involves the interaction of host protein nucleolin (NCL) with G-quadruplex (G4) structures that form in the glycine-alanine repeat (GAr)-encoding sequence of the EBNA1 mRNA. Ligands that bind to these G4-RNA can prevent their interaction with NCL, leading to disinhibition of EBNA1 expression and antigen presentation, thereby interfering with the immune evasion of EBNA1 and therefore of EBV (M.J. Lista et al., Nature Commun., 2017, 8, 16043). In this work, we synthesized and studied a series of 20 cationic bis(acylhydrazone) derivatives designed as G4 ligands. The in vitro evaluation showed that most derivatives based on central pyridine (Py), naphthyridine (Naph) or phenanthroline (Phen) units were efficient G4 binders, in contrast to their pyrimidine (Pym) counterparts, which were poor G4 binders due to a significantly different molecular geometry. The influence of lateral heterocyclic units (N-substituted pyridinium or quinolinium residues) on G4-binding properties was also investigated. Two novel compounds, namely PyDH2 and PhenDH2, used at a 5 µM concentration, were able to significantly enhance EBNA1 expression in H1299 cells in a GAr-dependent manner, while being significantly less toxic than the prototype drug PhenDC3 (GI50 > 50 µM). Antigen presentation, RNA pull-down and proximity ligation assays confirmed that the effect of both drugs was related to the disruption of NCL-EBNA1 mRNA interaction and the subsequent promotion of GAr-restricted antigen presentation. Our work provides a novel modular scaffold for the development of G-quadruplex-targeting drugs acting through interference with G4-protein interaction.


Assuntos
Hidrazonas/farmacologia , Evasão da Resposta Imune/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Fosfoproteínas/metabolismo , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Linhagem Celular Tumoral , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Quadruplex G , Herpesvirus Humano 4/genética , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Ligantes , Camundongos , RNA Mensageiro/genética
7.
Eur J Med Chem ; 178: 243-258, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185414

RESUMO

To address the multifactorial nature of Alzheimer's Disease (AD), a multi-target-directed ligand approach was herein developed. As a follow-up of our previous studies, a small library of newly designed 2-arylbenzofuran derivatives was evaluated towards cholinesterases and cannabinoid receptors. The two most promising compounds, 8 and 10, were then assessed for their neuroprotective activity and for their ability to modulate the microglial phenotype. Compound 8 emerged as able to fight AD from several directions: it restored the cholinergic system by inhibiting butyrylcholinesterase, showed neuroprotective activity against Aß1-42 oligomers, was a potent and selective CB2 ligand and had immunomodulatory effects, switching microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. Derivative 10 was a potent CB2 inverse agonist with promising immunomodulatory properties and could be considered as a tool for investigating the role of CB2 receptors and for developing potential immunomodulating drugs addressing the endocannabinoid system.


Assuntos
Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Células CHO , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cricetulus , Desenho de Drogas , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Ligação Proteica , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
8.
BMC Neurol ; 19(1): 116, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176355

RESUMO

BACKGROUND: STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS. METHODS: Patients aged 18-65 years had an RRMS diagnosis < 3 years prior to screening, an Expanded Disability Status Scale (EDSS) score ≤ 4.0, and anti-JCV antibody negative status. Magnetic resonance imaging was performed at baseline and yearly thereafter. Cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were evaluated at 2 years. NEDA (no 24-week-confirmed EDSS worsening, no relapses, no gadolinium-enhancing lesions, and no new/newly enlarging T2-hyperintense lesions) was evaluated over 2 years. The Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Score (MSIS-29) were assessed at baseline and 1 and 2 years. Statistical analysis used summary statistics and frequency distributions. RESULTS: The study population (N = 222) had early RRMS, with mean (standard deviation [SD]) time since diagnosis of 1.6 (0.77) years and mean (SD) baseline EDSS score of 2.0 (1.13). NEDA was achieved in 105 of 187 patients (56.1%) during year 1 and 120 of 163 (73.6%) during year 2. Over 2 years, 76 of 171 patients (44.4%) attained overall NEDA. Probabilities of 24-week-confirmed EDSS worsening and improvement were 14.1% and 28.4%, respectively. After 2 years, patients exhibited significant improvements from baseline in SDMT (n = 158; mean [SD]: 4.3 [11.8]; p < 0.001) and MSIS-29 physical (n = 153; mean [SD]: - 3.9 [14.7]; p = 0.001), psychological (n = 152; mean [SD]: - 2.0 [7.9]; p < 0.001), and quality-of-life (n = 153; mean [SD]: - 6.0 [21.3]; p < 0.001) scores. CONCLUSIONS: These results support natalizumab's effectiveness over 2 years, during which nearly half of early RRMS patients achieved NEDA. During year 2, nearly 75% of patients exhibited NEDA. Over 2 years, patients continued to experience significant cognitive and quality-of-life benefits. These results are limited by the lack of a comparator group to determine the extent of a placebo effect. TRIAL REGISTRATION: clinicaltrials.gov, NCT01485003 , registered 5 December 2011.


Assuntos
Fatores Imunológicos/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/farmacologia , Avaliação de Resultados (Cuidados de Saúde) , Adulto , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Natalizumab/administração & dosagem , Fatores de Tempo
9.
Microbes Environ ; 34(2): 206-214, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31167991

RESUMO

Lactic acid bacteria (LAB) exert beneficial health effects by regulating immune responses. Brassica rapa L., known as Nozawana, is commonly consumed as a lactic acid-fermented food called nozawana-zuke. Few studies have investigated changes in the bacterial community and cytokine production activities during the fermentation of B. rapa L. In order to obtain more detail information, we herein conducted a study on fresh B. rapa L. fermented for 28 d. An amplicon analysis of the 16S rRNA gene revealed that Lactobacillales predominated during fermentation, and the microbiota became less diverse on day 7 or later. Fermented B. rapa L. promoted the production of interferon (IFN)-γ and interleukin (IL)-10 by mouse spleen cells more than non-fermented vegetables. Lactobacillus curvatus was the predominant species during fermentation, followed by L. plantarum and L. brevis. L. sakei was occasionally detected. A correlation analysis showed that IFN-γ concentrations positively correlated with the numbers of L. curvatus and L. plantarum, while those of IL-10 correlated with the numbers of L. sakei in addition to these 2 species. Significantly higher levels of IFN-γ and IL-10 were induced by fermented B. rapa L. when isolated Lactobacillus strains were added as starter cultures. These results suggest that the Lactobacillus species present in fermented B. rapa L. are beneficial for manufacturing vegetables with immunomodulatory effects.


Assuntos
Brassica rapa/imunologia , Brassica rapa/microbiologia , Alimentos Fermentados/microbiologia , Microbiologia de Alimentos , Fatores Imunológicos/farmacologia , Microbiota/fisiologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Biodiversidade , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , DNA Bacteriano/genética , Lactobacillus/classificação , Lactobacillus/genética , Lactobacillus/isolamento & purificação , Lactobacillus/metabolismo , Masculino , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genética , Especificidade da Espécie , Baço/efeitos dos fármacos , Baço/metabolismo
10.
Chin J Nat Med ; 17(4): 252-263, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31076129

RESUMO

Astragalus membranaceus may be a potential therapy for childhood asthma but its driving mechanism remains elusive. The main components of A. membranaceus were identified by HPLC. The children with asthma remission were divided into two combination group (control group, the combination of budesonide and terbutaline) and A. membranaceus group (treatment group, the combination of budesonide, terbutaline and A. membranaceus). The therapeutic results were compared between two groups after 3-month therapy. Porcine peripheral blood mononuclear cells (PBMCs) were isolated from venous blood by using density gradient centrifugation on percoll. The levels of FoxP3, EGF-ß, IL-17 and IL-23 from PBMCs and serum IgE were measured. The relative percentage of Treg/Th17 cells was determined using flow cytometry. The main components of A. membranaceus were calycosin-7-O-glucoside, isoquercitrin, ononin, calycosin, quercetin, genistein, kaempferol, isorhamnetin and formononetin, all of which may contribute to asthma therapy. Lung function was significantly improved in the treatment group when compared with a control group (P < 0.05). The efficacy in preventing the occurrence of childhood asthma was higher in the treatment group than the control group (P < 0.05). The levels of IgE, IL-17 and IL-23 were reduced significantly in the treatment group when compared with the control group, while the levels of FoxP3 and TGF-ß were increased in the treatment group when compared with the control group (P < 0.05). A. membranaceus increased the percentage of Treg cells and reduced the percentage of Th17 cells. A. membranaceus is potential natural product for improving the therapeutic efficacy of combination therapy of budesonide and terbutaline for the children with asthma remission by modulating the balance of Treg/Th17 cells.


Assuntos
Asma/tratamento farmacológico , Astragalus propinquus/química , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Fatores Imunológicos/administração & dosagem , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Asma/imunologia , Budesonida/administração & dosagem , Células Cultivadas , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Humanos , Fatores Imunológicos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Masculino , Suínos , Linfócitos T Reguladores/citologia , Terbutalina/administração & dosagem , Células Th17/citologia , Resultado do Tratamento
11.
Molecules ; 24(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083328

RESUMO

Organosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, Ferula EOs, asafoetida, and other plant and food extracts. Traditionally, garlic (Allium sativum) is used to boost the immune system; however, the mechanisms involved in the putative immunomodulatory effects of garlic are unknown. We investigated the effects of garlic EO and 22 organosulfur compounds on human neutrophil responses. Garlic EO, allyl propyl disulfide, dipropyl disulfide, diallyl disulfide, and allyl isothiocyanate (AITC) directly activated Ca2+ flux in neutrophils, with the most potent being AITC. Although 1,3-dithiane did not activate neutrophil Ca2+ flux, this minor constituent of garlic EO stimulated neutrophil reactive oxygen species (ROS) production. In contrast, a close analog (1,4-dithiane) was unable to activate neutrophil ROS production. Although 1,3-dithiane-1-oxide also stimulated neutrophil ROS production, only traces of this oxidation product were generated after a 5 h treatment of HL60 cells with 1,3-dithiane. Evaluation of several phosphatidylinositol-3 kinase (PI3K) inhibitors with different subtype specificities (A-66, TGX 221, AS605240, and PI 3065) showed that the PI3K p110δ inhibitor PI 3065 was the most potent inhibitor of 1,3-dithiane-induced neutrophil ROS production. Furthermore, 1,3-dithiane enhanced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), glycogen synthase kinase 3 α/ß (GSK-3α/ß), and cAMP response element binding (CREB) protein in differentiated neutrophil-like HL60 cells. Density functional theory (DFT) calculations confirmed the reactivity of 1,3-dithiane vs. 1,4-dithiane, based on the frontier molecular orbital analysis. Our results demonstrate that certain organosulfur compounds can activate neutrophil functional activity and may serve as biological response modifiers by augmenting phagocyte functions.


Assuntos
Fatores Imunológicos/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Compostos Orgânicos/farmacologia , Compostos de Enxofre/farmacologia , Compostos Alílicos/farmacologia , Antioxidantes/metabolismo , Dissulfetos/farmacologia , Alho/química , Células HL-60 , Compostos Heterocíclicos/farmacologia , Humanos , Proteínas Quinases Ativadas por Mitógeno , Neutrófilos/metabolismo , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Quinoxalinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sulfetos/farmacologia , Tiazolidinedionas/farmacologia
12.
Carbohydr Polym ; 216: 270-281, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047067

RESUMO

The fine structure and chain conformation of a heteropolysaccharide (PCIPS3) from mycelium of Paecilomyces cicadae were investigated via the analysis of HPLC, IR, methylation, NMR spectroscopy and multiangle light scattering. It was determined to be a 2.23 × 104 g/mol heteropolysaccharide primarily composed of glucose, galactose and mannose in a molar ratio of 23.8:2.1:1.0. The PCIPS3 backbone consisted of 1,4-linked α-d-Glcp and 1,4-linked 6-O-Me-α-d-Glcp residues, which were occasionally interrupted by branched ß-Galf residues through 1,6-linkage. Moreover, the α (0.60) from Mark-Houwink-Sakurada (MHS) equation suggested that PCIPS3 adopted a flexible chain conformation in 0.1 mol/L NaNO3 at 25 °C. The worm-like chains model parameters for PCIPS3 were estimated as following: ML = 437 nm-1, q = 0.46 nm and 0.79 nm, which were further evidenced by AFM. Furthermore, PCIPS3 showed excellent scavenging capacities of 2,2-diphenyl-1-picrylhydrazyl radical, superoxide radical, hydroxyl radical, ORAC radical and moderate immunomodulatory activity.


Assuntos
Depuradores de Radicais Livres/farmacologia , Polissacarídeos Fúngicos/farmacologia , Fatores Imunológicos/farmacologia , Paecilomyces/química , Animais , Configuração de Carboidratos , Sobrevivência Celular/efeitos dos fármacos , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/isolamento & purificação , Depuradores de Radicais Livres/toxicidade , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/isolamento & purificação , Polissacarídeos Fúngicos/toxicidade , Radical Hidroxila/química , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/toxicidade , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Camundongos , Peróxidos/química , Células RAW 264.7 , Superóxidos/química , Fator de Necrose Tumoral alfa/metabolismo
13.
J Immunol Res ; 2019: 6384278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093512

RESUMO

Triple-negative breast cancer (TNBC) is one of the most aggressive tumors, with poor prognosis and high metastatic capacity. The aggressive behavior may involve inflammatory processes characterized by deregulation of molecules related to the immunological responses in which interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) are involved. It is known that calcitriol, the active vitamin D metabolite, modulates the synthesis of immunological mediators; however, its role in the regulation of IL-1ß and TNF-α in TNBC has been scarcely studied. In the present study, we showed that TNBC cell lines SUM-229PE and HCC1806 expressed vitamin D, IL-1ß, and TNF-α receptors. Moreover, calcitriol, its analogue EB1089, IL-1ß, and TNF-α inhibited cell proliferation. In addition, we showed that synthesis of both IL-1ß and TNF-α was stimulated by calcitriol and its analogue. Interestingly, the antiproliferative activity of calcitriol was significantly abrogated when the cells were treated with anti-IL-1ß receptor 1 (IL-1R1) and anti-TNF-α receptor type 1 (TNFR1) antibodies. Furthermore, the combination of calcitriol with TNF-α resulted in a greater antiproliferative effect than either agent alone, in the two TNBC cell lines and an estrogen receptor-positive cell line. In summary, this study demonstrated that calcitriol exerted its antiproliferative effects in part by inducing the synthesis of IL-1ß and TNF-α through IL-1R1 and TNFR1, respectively, in TNBC cells, highlighting immunomodulatory and antiproliferative functions of calcitriol in TNBC tumors.


Assuntos
Calcitriol/farmacologia , Proliferação de Células/efeitos dos fármacos , Interleucina-1beta/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Fator de Necrose Tumoral alfa/imunologia , Calcitriol/análogos & derivados , Linhagem Celular Tumoral , Feminino , Humanos , Fatores Imunológicos/farmacologia , Interleucina-1beta/genética , Receptores Tipo I de Interleucina-1/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Fator de Necrose Tumoral alfa/farmacologia
14.
Korean J Parasitol ; 57(2): 83-92, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31104400

RESUMO

Based on the reactive oxygen species (ROS) regulatory properties of diphenyleneiodonium (DPI), we investigated the effects of DPI on host-infected T. gondii proliferation and determined specific concentration that inhibit the intracellular parasite growth but without severe toxic effect on human retinal pigment epithelial (ARPE-19) cells. As a result, it is observed that host superoxide, mitochondria superoxide and H2O2 levels can be increased by DPI, significantly, followed by suppression of T. gondii infection and proliferation. The involvement of ROS in anti-parasitic effect of DPI was confirmed by finding that DPI effect on T. gondii can be reversed by ROS scavengers, N-acetyl-L-cysteine and ascorbic acid. These results suggest that, in ARPE-19 cell, DPI can enhance host ROS generation to prevent T. gondii growth. Our study showed DPI is capable of suppressing T. gondii growth in host cells while minimizing the un-favorite side-effect to host cell. These results imply that DPI as a promising candidate material for novel drug development that can ameliorate toxoplasmosis based on ROS regulation.


Assuntos
Antiprotozoários/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/parasitologia , Fatores Imunológicos/farmacologia , Oniocompostos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Toxoplasma/crescimento & desenvolvimento , Antiprotozoários/toxicidade , Linhagem Celular , Células Epiteliais/fisiologia , Humanos , Fatores Imunológicos/toxicidade , Oniocompostos/toxicidade , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/parasitologia , Toxoplasma/efeitos dos fármacos
15.
Int J Nanomedicine ; 14: 2383-2395, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040663

RESUMO

Background: The inflammatory basis of diabetes mellitus directed the researchers' attention to the immune system for better management and prevention of complications. Metoclopramide (MCA; the only US Food and Drug Administration-approved for gastroparesis) has the ability to restore immune function through increasing prolactin secretion. This study aimed to test the effect of BSA/MCA nanoparticles (NPs) on modulating immune response. Methods: BSA/MCA NPs were fabricated by desolvation and evaluated in vitro via measuring loading efficiency, particle size, and surface charge. The selected formula was further evaluated via differential scanning calorimetry and release behavior. Then, NPs were injected into rats (25 mg MCA/kg/week) for 3 weeks to be evaluated histopathologically and immunologically via measuring proinflammatory cytokines, such as IL1ß, IL6, and TNFα, in addition to measuring regulatory T-cell frequency. Results: MCA was successfully loaded on BSA, achieving high encapsulation efficiency reaching 63±2%, particles size of 120-130 nm with good polydispersity, and a negative surface charge indicating that entire positively charged drug was encapsulated inside NPs. Differential scanning calorimetry thermography of selected NPs showed an obvious interaction between components and cross-linking of BSA molecules using glutaraldehyde, resulting in sustained release of MCA (around 50% within 3 days). MCA NPs significantly restored the immune response via decreasing proinflammatory cytokines and increasing regulatory T-cell frequency when compared to control and free MCA (drug not loaded in NPs)-treated groups. Histopathological examination of this MCA NPs-treated group did not show the characteristic lesions of diabetes, and apoptosis nearly disappeared. Conclusion: BSA/MCA NPs could be considered a new modality for treatment of gastro-paresis, in addition to management of diabetes itself and preventing its complications via an MCA-immunomodulatory effect.


Assuntos
Citocinas/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/imunologia , Fatores Imunológicos/farmacologia , Mediadores da Inflamação/metabolismo , Metoclopramida/farmacologia , Nanopartículas/química , Linfócitos T Reguladores/imunologia , Animais , Apoptose/efeitos dos fármacos , Varredura Diferencial de Calorimetria , Citocinas/sangue , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Masculino , Nanopartículas/ultraestrutura , Tamanho da Partícula , Ratos Wistar , Soroalbumina Bovina/química , Eletricidade Estática , Linfócitos T Reguladores/efeitos dos fármacos
16.
Carbohydr Polym ; 217: 79-89, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31079688

RESUMO

Several scientific evidences have revealed probiotics implications on human health. A wide range of lactic acid bacteria (LAB) have been extensively studied for their ability to produce extracellular polysaccharides (EPSs), which are repeating units of mono/oligosaccharides with various chemical compositions and properties. Despite the conventional belief regarding probiotics that states bacteria must be alive to exert their beneficial effects, mounting evidence opened up new perspectives on health-promoting effects of bacterial-derived molecules/metabolites. Employing EPSs seems safer alternative in complicated disorders like cancer and immune related diseases. EPSs have potential applications in textiles, cosmetology, wastewater treatment, food, and pharmaceutical industries, but little is known about their function therefore the present review aims to discuss the health-promoting properties of EPSs produced by LAB. Antioxidant, antiviral, antitumor and immunomodulating activity, with focus on the mechanisms involved, are discussed in the study. Ever-growing number of researches indicate that EPSs beneficiary effects have a promising future ahead.


Assuntos
Antineoplásicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactobacillales/química , Polissacarídeos Bacterianos/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sequência de Carboidratos , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Polissacarídeos Bacterianos/química , Polissacarídeos Bacterianos/farmacologia
17.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 43-47, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078151

RESUMO

The immune system is an important physiological defense system. Its balance and stability are closely related to the body's health. Once the immune system loses its dynamic balance, the immune response will be blocked, which will lead to the occurrence of various diseases. Hesperetin is a kind of natural flavonoids extracted from citrus fruits of Rutaceae and it has many pharmacological activities. However, its water solubility and liposolubility are poor, and it is easy to be quickly metabolized in vivo, so it is difficult to maintain high blood drug concentration. Therefore, its derivative (HES) was found by structural modification. In this study, THP-1 cells were used as experimental model to investigate the immunomodulatory effect of HES in vitro. The results showed that HES participates in immune response by enhancing phagocytosis of macrophages to promote the release of NO, IL-6 and IL-1ß, and enhancing immunity by up-regulating the expression of Bcl-2 and Bcl-XL proteins. This study provides a theoretical and practical basis for the development of HES as an immunomodulator in the future.


Assuntos
Hesperidina/farmacologia , Fatores Imunológicos/farmacologia , Macrófagos/imunologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Hesperidina/química , Humanos , Fatores Imunológicos/química , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Óxido Nítrico/biossíntese , Fagocitose/efeitos dos fármacos , Células THP-1 , Proteína bcl-X/metabolismo
18.
Nat Chem ; 11(6): 521-532, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31086302

RESUMO

The chemical diversification of natural products provides a robust and general method for the creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.


Assuntos
Antineoplásicos/farmacologia , Azulenos/farmacologia , Morte Celular/efeitos dos fármacos , Diterpenos/farmacologia , Piridazinas/farmacologia , Tiorredoxinas/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Azulenos/síntese química , Azulenos/química , Linhagem Celular Tumoral , Cisteína/química , Diterpenos/síntese química , Diterpenos/química , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos SCID , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-Atividade , Tiorredoxinas/química
19.
Expert Opin Ther Pat ; 29(5): 339-351, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31064237

RESUMO

INTRODUCTION: Boron-containing compounds induce effects on immune responses. Such effects are interesting to the biomedical field for the development of therapeutic tools to modulate the immune system. AREAS COVERED: The scope of BCC use to modify immune responses is expanding, mainly with regard to inflammatory diseases. The information was organized to demonstrate the breadth of reported effects. BCCs act as modulators of innate and adaptive immunity, with the former including regulation of cluster differentiation and cytokine production. In addition, BCCs exert effects on inflammation induced by infectious and noninfectious agents, and there are also reports regarding their effects on mechanisms involving hypersensitivity and transplants. Finally, the authors discuss the beneficial effects of BCCs on pathologies involving various targets and mechanisms. EXPERT OPINION: Some BCCs are currently used as drugs in humans. The mechanisms by which these BCCs modulate immune responses, as well as the required structure-activity relationship for each observed mechanism of action, should be clarified. The former will allow for the development of improved immunomodulatory drugs with extensive applications in medicine. Patenting trends involve claims concerning the synthesis and actions of identified molecules with a defined profile regarding cytokines, cell differentiation, proliferation, and antibody production.


Assuntos
Compostos de Boro/farmacologia , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Imunidade Adaptativa/efeitos dos fármacos , Animais , Formação de Anticorpos/efeitos dos fármacos , Compostos de Boro/química , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/química , Inflamação/imunologia , Patentes como Assunto , Relação Estrutura-Atividade
20.
Croat Med J ; 60(2): 87-98, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31044580

RESUMO

Increasing evidence suggests that B cells contribute both to the regulation of normal autoimmunity and to the pathogenesis of immune mediated diseases, including multiple sclerosis (MS). B cells in MS are skewed toward a pro-inflammatory profile, and contribute to MS pathogenesis by antibody production, antigen presentation, T cells stimulation and activation, driving autoproliferation of brain-homing autoreactive CD4+ T cells, production of pro-inflammatory cytokines, and formation of ectopic meningeal germinal centers that drive cortical pathology and contribute to neurological disability. The recent interest in the key role of B cells in MS has been evoked by the profound anti-inflammatory effects of rituximab, a chimeric monoclonal antibody (mAb) targeting the B cell surface marker CD20, observed in relapsing-remitting MS. This has been reaffirmed by clinical trials with less immunogenic and more potent B cell-depleting mAbs targeting CD20 - ocrelizumab, ofatumumab and ublituximab. Ocrelizumab is also the first disease-modifying drug that has shown efficacy in primary-progressive MS, and is currently approved for both indications. Another promising approach is the inhibition of Bruton's tyrosine kinase, a key enzyme that mediates B cell activation and survival, by agents such as evobrutinib. On the other hand, targeting B cell cytokines with the fusion protein atacicept increased MS activity, highlighting the complex and not fully understood role of B cells and humoral immunity in MS. Finally, all other approved therapies for MS, some of which have been designed to target T cells, have some effects on the frequency, phenotype, or homing of B cells, which may contribute to their therapeutic activity.


Assuntos
Antígenos CD20/imunologia , Linfócitos B/fisiologia , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/imunologia , Rituximab/uso terapêutico , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Humanos , Fatores Imunológicos/farmacologia , Esclerose Múltipla/tratamento farmacológico , Proteínas Recombinantes de Fusão , Rituximab/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA