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1.
Nature ; 574(7776): 63-68, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31554967

RESUMO

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.


Assuntos
Receptor gp130 de Citocina/metabolismo , Citocinas/síntese química , Citocinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Ligação Competitiva , Citocinas/química , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Drogas , Fígado Gorduroso/prevenção & controle , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Incretinas/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Obesidade/metabolismo , Pâncreas/metabolismo , Fosfoproteínas/metabolismo , Engenharia de Proteínas , Receptores de Interleucina-6/metabolismo , Transdução de Sinais , Ganho de Peso/efeitos dos fármacos
2.
Br J Anaesth ; 123(5): 610-617, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31542162

RESUMO

BACKGROUND: Traumatic brain injury (TBI) is associated with reduced cerebral blood flow and impaired autoregulation after TBI, which may lead to poor outcome. Clinical evidence has implicated neurological injuries and associated neuroinflammation as causes of cardiac dysfunction. Studies on newborn pigs show an association of elevated catecholamines with a sex-dependent impairment of cerebral autoregulation after TBI. One strategy to decrease sympathetic hyperactivity is pharmacological intervention with beta blockade. We tested the hypothesis that propranolol would prevent the impairment of cerebral autoregulation and tissue changes after TBI via inhibition of interleukin-6 (IL-6) upregulation. METHODS: Using newborn pigs of both sexes equipped with a closed cranial window, TBI was induced via lateral fluid percussion injury. Propranolol was administered at 1 h post-TBI. Analyses included cerebral autoregulation (pial artery reactivity) before and 4 h post-TBI, CSF IL-6 analysed (enzyme-linked immunosorbent assay), and histopathology at 4 h post-TBI. RESULTS: Propranolol administration prevented impairment of hypotensive dilation in both male and female newborn pigs after fluid percussion injury, which was paralleled by reduced upregulation of IL-6 in the CSF. Moreover, propranolol prevented neuronal cell death in cornu amonis (CA)1 and CA3 hippocampus equivalently in male and female pigs after TBI. Papaverine-induced dilation was unchanged by TBI and propranolol. CONCLUSIONS: These data indicate that sympathetic hyperactivity noted after TBI can be limited by propranolol administration to result in improved brain outcome post-injury via block of IL-6 upregulation, and this effect is irrespective of sex.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Propranolol/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Animais Recém-Nascidos , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Modelos Animais de Doenças , Feminino , Hipocampo/fisiologia , Homeostase/fisiologia , Masculino , Neurônios/efeitos dos fármacos , Suínos , Regulação para Cima/efeitos dos fármacos
3.
Eur J Med Chem ; 175: 114-128, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31077997

RESUMO

In order to discover novel anti-inflammatory agents, total thirty-seven new resveratrol-based flavonol derivatives were designed and synthesized. All compounds have been screened for their anti-inflammatory activity by evaluating their inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Their toxicity was also assessed in vitro. Structure-activity relationships (SARs) have been concluded, and finally 2-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)-3-hydroxy-4H-chromen-4-one was found to be the most active scaffold with low toxicity. This compound could significantly decrease productions of NO, IL-6 and TNF-α with IC50 values of 1.35, 1.12 and 1.92 µM, respectively in RAW 264.7 macrophages. Preliminary mechanism studies indicated that it could inhibit the expression of TLR4 protein, resulting in activation of the NF-ĸB cell signaling pathway. The in vivo anti-inflammatory activity of this compound could reduce pulmonary inflammation by mouse model of LPS-induced acute lung injury (ALI). We believe these findings would further support studies of rational design of more efficient acute lung injury regulatory inhibitors.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Flavonoides/síntese química , Flavonoides/farmacologia , Interleucina-6/antagonistas & inibidores , Óxido Nítrico/antagonistas & inibidores , Resveratrol/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios/toxicidade , Flavonoides/química , Flavonoides/toxicidade , Técnicas In Vitro , Concentração Inibidora 50 , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
J Microbiol Biotechnol ; 29(6): 856-862, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31091864

RESUMO

A series of thienopyrimidine compounds (6Aa-g and 6Ba-d) were synthesized and characterized by NMR spectroscopy and mass spectrometry. These compounds (6Aa-g and 6Ba-d) potently inhibited STAT3 expression induced by IL-6 in a dose-dependent manner with IC50 values of 5.73-0.32 µM. Among the prepared thienopyrimidine derivatives, 6Aa, 6Ab, 6Ba and 6Bc significantly suppressed the phosphorylation of STAT3 and ERK1/2 stimulated by IL-6 in Hep3B cells. Furthermore, the synthesized compounds might be useful remedies for the treatment of inflammatory diseases by inhibiting the action of IL-6.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Anti-Inflamatórios/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/farmacologia , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas , Pirimidinas/química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
5.
Mol Cancer ; 18(1): 68, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30927911

RESUMO

BACKGROUND: Although the tumor stroma in solid tumors like gastric cancer (GC) plays a crucial role in chemo-resistance, specific targets to inhibit the interaction between the stromal and cancer cells have not yet been utilized in clinical practice. The present study aims to determine whether cancer-associated fibroblasts (CAFs), a major component of the tumor stroma, confer chemotherapeutic resistance to GC cells, and to discover potential targets to improve chemo-response in GC. METHODS: To identify CAF-specific proteins and signal transduction pathways affecting chemo-resistance in GC cells, secretome and transcriptome analyses were performed. We evaluated the inhibiting effect of CAF-specific protein in in vivo and in vitro models and investigated the expression of CAF-specific protein in human GC tissues. RESULTS: Secretome and transcriptome data revealed that interleukin-6 (IL-6) is a CAF-specific secretory protein that protects GC cells via paracrine signaling. Furthermore, CAF-induced activation of the Janus kinase 1-signal transducer and activator of transcription 3 signal transduction pathway confers chemo-resistance in GC cells. CAF-mediated inhibition of chemotherapy-induced apoptosis was abrogated by the anti-IL-6 receptor monoclonal antibody tocilizumab in various experimental models. Clinical data revealed that IL-6 was prominently expressed in the stromal portion of GC tissues, and IL-6 upregulation in GC tissues was correlated with poor responsiveness to chemotherapy. CONCLUSIONS: Our data provide plausible evidence for crosstalk between GC cells and CAFs, wherein IL-6 is a key contributor to chemoresistance. These findings suggest the potential therapeutic application of IL-6 inhibitors to enhance the responsiveness to chemotherapy in GC.


Assuntos
Fibroblastos Associados a Câncer/citologia , Fluoruracila/administração & dosagem , Interleucina-6/genética , RNA Interferente Pequeno/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Camundongos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Immunity ; 50(4): 1007-1023, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995492

RESUMO

Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in immunity, tissue regeneration, and metabolism. Rapid production of IL-6 contributes to host defense during infection and tissue injury, but excessive synthesis of IL-6 and dysregulation of IL-6 receptor signaling is involved in disease pathology. Therapeutic agents targeting the IL-6 axis are effective in rheumatoid arthritis, and applications are being extended to other settings of acute and chronic inflammation. Recent studies reveal that selective blockade of different modes of IL-6 receptor signaling has different outcomes on disease pathology, suggesting novel strategies for therapeutic intervention. However, some inflammatory diseases do not seem to respond to IL-6 blockade. Here, we review the current state of IL-6-targeting approaches in the clinic and discuss how to apply the growing understanding of the immunobiology of IL-6 to clinical decisions.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Inflamação/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Ensaios Clínicos como Assunto , Receptor gp130 de Citocina/antagonistas & inibidores , Receptor gp130 de Citocina/imunologia , Humanos , Inflamação/imunologia , Interleucina-6/biossíntese , Interleucina-6/deficiência , Interleucina-6/imunologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Knockout , Receptores de Interleucina-6/imunologia , Ribonucleases/deficiência , Fator de Transcrição STAT3/fisiologia , Proteína 1 Supressora da Sinalização de Citocina/fisiologia , Proteína 3 Supressora da Sinalização de Citocinas/fisiologia
7.
Immunity ; 50(4): 812-831, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995501

RESUMO

Since the molecular cloning of interleukin-6 (IL-6) in 1986, many other cytokines have been found to share the same signal transducer, gp130, in their receptor complexes. Thus, the IL-6 family of cytokines now consists of ten members. Although some of the family members' functions are redundant as a result of the expression of gp130, there are also functional distinctions between members. The mechanisms that determine functional redundancies and distinctions are not completely understood. Yet, research has clarified the role of IL-6 family cytokines in autoimmune diseases and has led to effective therapies that target them. Here, we review the IL-6 family of cytokines in autoimmune diseases, with a particular focus on the prototypical member IL-6, from the viewpoints of their structure, signaling, and biological features and discuss possible mechanisms of their functional pleiotropy.


Assuntos
Citocinas/fisiologia , Pleiotropia Genética , Família Multigênica/fisiologia , Animais , Doenças Autoimunes/imunologia , Citocinas/genética , Regulação da Expressão Gênica , Inflamação/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-6/fisiologia , Camundongos , Subunidades Proteicas , Receptores de Citocinas/fisiologia , Receptores de Interleucina-6/fisiologia , Transdução de Sinais , Relação Estrutura-Atividade
8.
Pharmazie ; 74(3): 175-178, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30961685

RESUMO

Upregulation of pro-inflammatory cytokine interleukin (IL)-6 is observed in gastric cancer tissue, and high IL-6 serum levels predict a poor prognosis of gastric cancer patients. The IL-6/STAT3 pathway has been confirmed to play essential roles in the process of carcinogenesis, including gastric cancer. Thus, blockade of the IL-6/STAT3 pathway may be a potentially effective therapeutic option for gastric cancer. Micheliolide (MCL), a guaianolide sesquiterpene lactone, possesses anti-inflamma tory properties and can attenuate the IL-6 level. In addition, MCL has been widely reported to possess anti-tumor activity. But the anti-cancer effect of MCL on gastric cancer is unclear. In this study, we detected the effects of MCL on gastric cancer cell proliferation and apoptosis by performing MTT, colony formation, TUNEL and western blot assays, and found that MCL inhibited gastric cancer cell proliferation and promoted apoptosis in vitro. We further investigated the molecular mechanism by which MCL played an efficient role against gastric cancer, and found that the IL-6/STAT3 pathway is involved in the anti-cancer effect of MCL on gastric cancer. In vivo experiments further confirmed this conclusion. Taken together, MCL inhibits gastric cancer growth in vitro and in vivo via blockade of IL-6/STAT3 pathway.


Assuntos
Interleucina-6/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Sesquiterpenos de Guaiano/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação , Distribuição Aleatória , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Phytochemistry ; 163: 23-32, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30986687

RESUMO

The 95% ethanol extract and its EtOAc and n-BuOH fractions obtained from the leaves and twigs of Schefflera rubriflora C. J. Tseng & G. Hoo showed significant inhibitory activities (33.6%, 35.7% and 40.6%, respectively) against croton oil-induced ear inflammation in mice. Bioactivity-guided isolation and separation gave eight previously undescribed terpenes or terpene glycosides. Structural elucidation was based on UV, IR, and NMR spectroscopy, MS, experimental and calculated ECD data, and Mosher's method. To identify anti-inflammatory components from the extract, all the compounds were evaluated for tumor necrosis factor-α (TNF-α) and interleukine-6 (IL-6) inhibitory activities. Four undescribed compounds inhibited mRNA expression of TNF-α and IL-6 with IC50 values of 15.3-52.4 µM.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Araliaceae/química , Interleucina-6/antagonistas & inibidores , Extratos Vegetais/farmacologia , Terpenos/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Células Cultivadas , Óleo de Cróton , Relação Dose-Resposta a Droga , Orelha , Edema/induzido quimicamente , Edema/tratamento farmacológico , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Conformação Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Células RAW 264.7 , Relação Estrutura-Atividade , Terpenos/química , Terpenos/isolamento & purificação , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
BMC Cancer ; 19(1): 224, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30866863

RESUMO

BACKGROUND: Our previous works have demonstrated that 8-bromo-7-methoxychrysin suppressed stemness of human hepatocellular carcinoma (HCC) cell line SMMC-7721 induced by condition medium from hepatic stellate cell line LX-2 that was activated by liver cancer stem-like cells (LCSCs). However, whether and whereby BrMC inhibits the stemness induced by co-culture of LCSCs and LX-2 cells remains to be investigated. METHODS: The second-generation spheres by sphere culture were identified and used as SMMC-7721-and MHCC97H-derived LCSLCs. SMMC-7721-and MHCC97-derived LCSCs/LX-2 cells transwell co-culture system was treated with BrMC and its lead compound chrysin. The concentrations of IL-6, IL-8, HGF and PDGF in condition medium from co-culture were measured by enzyme-linked immunosorbent assay (ELISA). The stemness of SMMC-7721 cells was evaluated by sphere formation assay and western blot analysis for expression levels of cancer stem cell markers (CD133 and CD44).The expression levels of cancer-associated fibroblast markers (FAP-α and α-SMA) were employed to evaluate pathologic activation of LX-2 cells. Addition of IL-6 and/or HGF or deletion of IL-6 and/or HGF was conducted to investigate the mechanisms for BrMC and chrysin treatment in SMMC-7721-derived LCSLCs co-cultured with LX-2cells. RESULTS: The co-culture of LCSLCs with LX-2 cells increased sphere formation capability as well as expression of CD133 and CD44 in SMMC-7721 cells, meanwhile, upregulated expression of FAP-α in LX-2 cells. ELISA indicated that the concentrations of IL-6 and HGF were significantly elevated in Co-CM than that of condition media from co-cultured SMMC-7721 cells/LX-2 cells. Treatment of BrMC and chrysin with co-cultures of SMMC-7721- and MHCC97H-derived LCSLCs and LX-2 cells effectively inhibited the above responses. Moreover, addition of IL-6 and/or HGF induced stemness of SMMC-7721 cells and activation of LX-2 cells, conversely, deletion of IL-6 and/or HGF suppressed those. Furthermore, the inhibitory effects of BrMC and chrysin on stemness of SMMC-7721 cells and activation of LX-2 cells were attenuated by addition of IL-6 or HGF, and enhanced by deletion of IL-6 or HGF. CONCLUSIONS: Our results suggest IL-6 and HGF may be the key communication molecules for the interaction between LCSLCs and HSCs, and BrMC and chrysin could block these effects and be the novel therapeutic candidates for HCC management.


Assuntos
Carcinoma Hepatocelular/metabolismo , Flavonoides/farmacologia , Células Estreladas do Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Feminino , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Interleucina-8/antagonistas & inibidores , Interleucina-8/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
Int J Mol Sci ; 20(6)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909508

RESUMO

Bisphosphonates are one of the most widely used synthetic pyrophosphate analogues for the treatment of bone resorbing diseases such as osteoporosis, multiple myeloma, and bone metastases. Although the therapeutic usefulness of bisphosphonates mainly depends on their anti-osteoclastogenic effect, a severe side-effect of bisphosphonates called bisphosphonate-related osteonecrosis of the jaw (BRONJ) could not be explained by the anti-osteoclastogenic effect of bisphosphonates. In the present study, we have evaluated the changes in osteoclastogenesis- or osteoblastogenesis-supporting activities of osteocytes induced by bisphosphonates. Zoledronate, a nitrogen-containing bisphosphonate, markedly increased both the receptor activator of nuclear factor kB ligand (RANKL) as well as sclerostin in osteocyte-like MLO-Y4 cells, which were functionally revalidated by osteoclast/osteoblast generating activities of the conditioned medium obtained from zoledronate-treated MLO-Y4 cells. Of note, the zoledronate treatment-induced upregulation of the RANKL expression was mediated by autocrine interleukin-6 (IL-6) and subsequent activation of the signal transducer and activator of transcription 3 (STAT3) pathway. These results were evidenced by the blunted RANKL expression in the presence of a Janus activated kinase (JAK2)/STAT3 inhibitor, AG490. Also, the osteoclastogenesis-supporting activity was significantly decreased in zoledronate-treated MLO-Y4 cells in the presence of IL-6 neutralizing IgG compared to that of the control IgG. Thus, our results show previously unanticipated effects of anti-bone resorptive bisphosphonate and suggest a potential clinical importance of osteocytes in BRONJ development.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Interleucina-6/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteócitos/metabolismo , Ligante RANK/metabolismo , Ácido Zoledrônico/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Biomarcadores , Comunicação Celular , Linhagem Celular , Expressão Gênica , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Janus Quinase 2/metabolismo , Camundongos , Modelos Biológicos , Osteogênese/efeitos dos fármacos , Ligante RANK/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Fitoterapia ; 135: 1-4, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30914332

RESUMO

Two novel 8,15-seco C19-diterpenoid alkaloids, nagarines A (1) and B (2), were isolated from the roots of Aconitum nagarum Stapf (Ranunculaceae), a folk herbal medicine used to treat rheumatism and arthritis in Southwestern China, Northern Burma and Northeastern India. They are the first C19-diterpenoid alkaloids possessing unprecedented opened D ring formed by the cleavage of the bond between C-8 and C-15. Compounds 1 and 2 showed certain inhibition activities of interleukin-6 in LPS-activated RAW 264.7 cells with IC50 values of 72.63 ±â€¯0.39 µM and 52.98 ±â€¯0.50 µM, respectively.


Assuntos
Aconitum/química , Alcaloides/química , Artrite/tratamento farmacológico , Diterpenos/química , Doenças Reumáticas/tratamento farmacológico , Alcaloides/farmacologia , Animais , Diterpenos/farmacologia , Interleucina-6/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Medicina Tradicional , Camundongos , Estrutura Molecular , Raízes de Plantas/química , Células RAW 264.7
13.
Drug Des Devel Ther ; 13: 681-694, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30858698

RESUMO

Purpose: Budesonide (Bud) is a nonhalogenated glucocorticoid with high anti-inflammatory potency and low systemic side effects. However, the poor water solubility of Bud affects its dissolution and release behavior, thus influencing its anti-inflammatory effect. This study was aimed at synthesizing and evaluating novel conjugates of Bud, hoping to increase the anti-inflammatory activity of Bud by improving its water solubility. Materials and methods: Seven novel Bud conjugates (3a-3g) were designed and synthesized in this study. Besides, the equilibrium solubility, cell viability, in vitro and in vivo anti-inflammatory activity, and the hydrolysis behavior of the conjugates in different pH solutions, rat and human plasma, and rat lung homogenate were studied in detail. Results: As compared to Bud, the equilibrium solubility of 3a, 3c, and 3e was significantly increased; 3a, 3b, and 3c significantly inhibited the interleukin-6 production in lipopolysaccharide-induced A549 cells; 3a and 3e could significantly decrease the xylene-induced ear edema; and 3a and 3c were gradually and slowly hydrolyzed into Bud in the alveolar fluid and lung homogenate and broken down quickly in plasma. Conclusion: The amino acid ester compounds budesonide-21-glycine ester (3a) and budesonide-21-alanine ester (3c) were selected as potential conjugates of Bud. This study would provide a theoretical and an experimental basis for the in vivo process of glucocorticoids and the treatment of inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Budesonida/síntese química , Budesonida/farmacologia , Otopatias/tratamento farmacológico , Edema/tratamento farmacológico , Células A549 , Animais , Anti-Inflamatórios não Esteroides/química , Budesonida/química , Sobrevivência Celular/efeitos dos fármacos , Otopatias/induzido quimicamente , Edema/induzido quimicamente , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xilenos
14.
J Neuroinflammation ; 16(1): 26, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30732627

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly. The neovascular (wet) form of AMD can be treated with intravitreal injections of different anti-vascular endothelial growth factor (VEGF) agents. Placental growth factor (PGF) is another member of the VEGF family of cytokines with pro-angiogenic and pro-inflammatory effects. Here, we aimed to compare single and combined inhibition of VEGF-A and PGF in the laser-induced mouse model of choroidal neovascularization (CNV) with a focus on the effects on retinal mononuclear phagocytes. METHODS: CNV was induced in C57BL/6J mice using a YAG-Laser. Immediately after laser damage antibodies against VEGF-A (aVEGF), anti-PGF (aPGF), aVEGF combined with aPGF, aflibercept, or IgG control were injected intravitreally in both eyes. Three and 7 days after laser damage, the vascular leakage was determined by fluorescence angiography. Lectin staining of retinal and RPE/choroidal flat mounts was used to monitor CNV. In situ mRNA co-expression of Iba1, VEGF and PGF were quantified using in situ hybridization. Retinal and RPE/choroidal protein levels of VEGF and PGF as well as the pro-inflammatory cytokines IL-6, IL1-beta, and TNF were determined by ELISA. RESULTS: Early (day 3) and intermediate (day 7) vascular leakage and CNV were significantly inhibited by PGF and VEGF-A co-inhibition, most effectively with the trap molecule aflibercept. While VEGF-A blockage alone had no effects, trapping PGF especially with aflibercept prevented the accumulation of reactive microglia and macrophages in laser lesions. The lesion-related mRNA expression and secretion of VEGF-A and PGF by mononuclear phagocytes were potently suppressed by PGF and partially by VEGF-A inhibition. Protein levels of IL-6 and IL1-beta were strongly reduced in all treatment groups. CONCLUSIONS: Retinal inhibition of PGF in combination with VEGF-A prevents vascular leakage and CNV possibly via modulating their own expression in mononuclear phagocytes. PGF-related, optimized strategies to target inflammation-mediated angiogenesis may help to increase efficacy and reduce non-responders in the treatment of wet AMD patients.


Assuntos
Monócitos/metabolismo , Neovascularização Patológica/prevenção & controle , Fator de Crescimento Placentário/antagonistas & inibidores , Doenças Retinianas/prevenção & controle , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Plexo Corióideo/patologia , Citocinas/metabolismo , Feminino , Interleucina-1/antagonistas & inibidores , Interleucina-1/biossíntese , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Neovascularização Patológica/patologia , Fator de Crescimento Placentário/biossíntese , RNA Mensageiro/biossíntese , Retina/patologia , Doenças Retinianas/patologia , Fator A de Crescimento do Endotélio Vascular/biossíntese
15.
Circ Res ; 124(3): 437-450, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30702995

RESUMO

The recognition that atherosclerosis is a complex chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anticytokine therapies targeting specific IL (interleukin) signaling pathways could serve as powerful adjuncts to lipid lowering in the prevention and treatment of cardiovascular disease. Cytokines involved in human atherosclerosis can be broadly classified as proinflammatory and proatherogenic (such as IL-1, IL-6, and TNF [tumor necrosis factor]) or as anti-inflammatory and antiatherogenic (such as IL-10 and IL-1rA). The recent CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) has shown that specific targeting of IL-1ß can significantly reduce cardiovascular event rates without lipid or blood pressure lowering. In CANTOS, the magnitude of benefit of this cytokine-targeted approach to atherosclerosis treatment was associated to the magnitude of reduction of the central signaling cytokine IL-6 and the downstream clinical biomarker high-sensitivity CRP (C-reactive protein). By contrast, in the recent CIRT (Cardiovascular Inflammation Reduction Trial), low-dose methotrexate neither reduced IL-1ß, IL-6, or high-sensitivity CRP nor lowered cardiovascular event rates. Taken together, these 2 contemporary trials provide proof of principle that focused cytokine inhibition, not broad-spectrum anti-inflammatory therapy, is likely to be crucial for atheroprotection. This review provides an overview of cytokines in atherosclerosis, the potential benefits and risks associated with targeted anticytokine therapies, and a look to the future of clinical practices addressing residual inflammatory risk.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Aterosclerose/tratamento farmacológico , Proteína C-Reativa/antagonistas & inibidores , Doenças Cardiovasculares/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Trombose/tratamento farmacológico , Animais , Aterosclerose/complicações , Antígenos CD40/antagonistas & inibidores , Ligante de CD40/antagonistas & inibidores , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Modelos Animais de Doenças , Hematopoese , Humanos , Inflamassomos/antagonistas & inibidores , Interleucina-18/antagonistas & inibidores , Metotrexato/uso terapêutico , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/prevenção & controle , Trombose/etiologia , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores
16.
PLoS One ; 14(2): e0212063, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30807577

RESUMO

MicroRNAs (miRNAs) are small non-coding RNA molecules that play an important role in the regulation of gene expression related to inflammatory responses. Human adipose stem cells are characterized by pluripotent differentiation potential and isolated from adipose tissues. These cells regulate inflammation mainly by interacting with immune cells and affecting the secretion of immune factors; details of this interaction are currently unknown. In the current study, we successfully established an acute inflammation model and a chronic inflammation model involving adipose stem cells. We used high-throughput miRNA microarray analysis to identify miRNAs that were significantly (p < 0.05) differentially expressed during both acute and chronic inflammation. Lipopolysaccharide (LPS) significantly (p < 0.05) reduced the expression of miR-223-3P and miR-2909, while promoting the production of pro-inflammatory cytokines, interleukin (IL) 6, IL-1ß, and tumor necrosis factor (TNF)-α via the Toll-like receptor (TLR) 4/TLR2/nuclear factor (NF)-κB/signal transducer and activator of transcription (STAT) 3 signaling pathway in human adipose stem cells. Further, miR-223-3P expression was significantly (p < 0.05) reduced in human adipose stem cells during activation by IL-6 stimulation. The inducible down-regulation of miR-223-3P resulted in the activation of STAT3, which was directly targeted by miR-223-3P. STAT3 directly targeted TLR4 and TLR2, promoting the production of the pro-inflammatory cytokine, IL-6, and formed a positive feedback loop to regulate IL-6 levels. Similarly, TNF-α significantly (p < 0.05) increased the expression of miR-223-3p, with LPS and TLR4/TLR2/NF-κB/STAT3 forming a negative feedback loop to regulate TNF-α levels. In addition, miR-2909, which depends on NF-κB, targeted Krueppel-like factor (KLF) 4 to regulate the levels of pro-inflammatory cytokines, IL-6, IL-1ß, and TNF-α. We conclude that miR-223-3p and miR-2909 form a complex regulatory network with pro-inflammatory factors and signaling pathways in adipose stem cells stimulated by LPS. These findings will inform the development of therapies against autoimmune and inflammatory diseases.


Assuntos
Lipopolissacarídeos/farmacologia , MicroRNAs/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tecido Adiposo/citologia , Antagomirs/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
17.
Genes Genomics ; 41(5): 557-566, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30796706

RESUMO

BACKGROUND: Inflammation in the central nervous system is closely associated with pathological neurodegenerative diseases as well as psychiatric disorders. Prolonged activation of microglia can produce many inflammatory mediators, which may result in pathological neurotoxic side effects. Interleukin (IL)-6 serves as a hallmark of the injured brain. OBJECTIVE: Whole grains are known to contain many bioactive components. However, little information is available about anti-neuroinflammatory effects of grains in the CNS. This study aims to investigate the effect of Hordeum vulgare ethanol extract (HVE) on the suppression of IL-6 expression in BV2 microglia. METHODS: Inhibitory effects of HVE on IL-6 expression were analyzed by immunoblot anaysis, immunofluoresce microscopic analysis, reverse transcription-polymerase chain reaction, and luciferase promoter reporter assay. RESULTS: HVE inhibited TNFα-induced phosphorylation of IKKα/ß, IκB, and p65/RelA NF-κB. TNFα-induced IL-6 mRNA expression and promoter activity were reduced by HVE. Point mutation of NF-κB-binding site within the IL-6 gene promoter abolished TNFα-induced reporter activity, whereas exogenous expression of p65 NF-κB enhanced IL-6 promoter activity. CONCLUSION: NF-κB-binding site within the IL-6 promoter region is a HVE target element involved in the inhibition of TNFα-induced IL-6 gene transcription. HVE inhibits TNFα-induced IL-6 expression via suppression of NF-κB signaling in BV2 microglial cells.


Assuntos
Hordeum/metabolismo , Interleucina-6/antagonistas & inibidores , Microglia/efeitos dos fármacos , Animais , Sítios de Ligação/genética , Linhagem Celular , Grão Comestível/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hordeum/fisiologia , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Regiões Promotoras Genéticas/genética , Ratos , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/fisiologia
19.
Mod Rheumatol ; 29(2): 275-286, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30686091

RESUMO

Juvenile idiopathic arthritis (JIA) is a chronic childhood arthritis. Its pathogenesis is very complicated, with the involvement of not only immune cells but various types of parenchymal cells, and is affected by both genetic and environmental predispositions. The clinical spectrum from inflammation to related conditions is largely mediated by cytokines including interleukin (IL)-6. Fluctuations in IL-6 and its related molecules can modulate the pathogenesis and the clinical presentation positively or negatively. The recent clinical impact of IL-6 blockade on JIA has begun a therapeutic paradigm shift. This review describes the characteristics of JIA, mainly focused on IL-6 with the current therapeutic perspective.


Assuntos
Artrite Juvenil/imunologia , Interleucina-6/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/imunologia , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/etiologia , Humanos , Interleucina-6/antagonistas & inibidores
20.
Biomed Pharmacother ; 110: 554-560, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30530291

RESUMO

Oxyresveratrol, an active ingredient of Artocarpus lakoocha, is known to possess anti-inflammatory and immunomodulatory properties. Current study investigates the immunomodulatory effect of oxyresveratrol in mouse model of ethanol-induced ulcer. Anti-ulcer effect was determined using histopathological evaluation (H&E staining) and different tests like, gastric ulcer scoring, ulcer index, total acid secretion, and gastric pH. The mRNA expression levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), nuclear factor-kappaB (NF-ĸB), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and trefoil factor 2 (TFF-2) were evaluated using reverse transcription polymerase chain reaction (RT-PCR). The data showed marked percentage inhibition of erosion, hemorrhage, fibrinoid necrosis, inflammatory infiltrate, and ulcer in low (30 mg/kg b.w.) and high dose (50 mg/kg b.w.) groups of oxyresveratrol. Treatment with oxyresveratrol inhibited ulcer score and ulcer index as compared with disease control group. Oxyresveratrol significantly increased gastric pH (P < 0.001) and attenuated total acid (P < 0.001) secretion. RT-PCR analysis showed significant suppression in the mRNA expression levels of IL-6 (P < 0.001), TNF-α (P < 0.01), NF-ĸB (P < 0.001), and COX-2 (P < 0.05) in oxyresveratrol treated groups, while COX-1 expression levels were found unaltered. Treatment with oxyresveratrol significantly elevated (P < 0.01) the expression levels of cytoprotective TFF-2 levels. Similar Immunomodulatory and anti-ulcer effects were found with ranitidine treatment, which was used as a reference drug. In conclusion, oxyresveratrol possess significant anti-ulcer property which might be attributed to attenuated expression levels of IL-6, TNF-α, NF-ĸB, and COX-2 and elevated expression levels of TFF-2.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/uso terapêutico , Estilbenos/uso terapêutico , Úlcera Gástrica/metabolismo , Fator Trefoil-2/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , Animais , Antiulcerosos/farmacologia , Antiulcerosos/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Etanol/toxicidade , Interleucina-6/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Moraceae , NF-kappa B/antagonistas & inibidores , Extratos Vegetais/farmacologia , Estilbenos/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Fator Trefoil-2/agonistas , Fator de Necrose Tumoral alfa/antagonistas & inibidores
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