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1.
Eur J Med Chem ; 193: 112217, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32182488

RESUMO

Because of the complex etiology in neuroinflammatory process, the design of multifunctional agents is a potent strategy to cure neuroinflammatory diseases including AD and PD. Herein, based on the combination principles, 23 of N-salicyloyl tryptamine derivatives as multifunctional agents were designed and their new application for anti-neuroinflammation was disclosed. In cyclooxygenase assay, two compounds 3 and 16 displayed extremely preferable COX-2 inhibition than N-salicyloyl tryptamine. In LPS-induced C6 and BV2 cell models, some compounds decreased the production of proinflammatory mediators NO, PGE2, TNF-α, iNOS, COX-2 and ROS, while increased the production of IL-10. Among them, compound 3 and 16 showed approximately six-fold better inhibition on nitric oxide production than N-salicyloyl tryptamine in C6. Besides, compounds 3, 13 and 16 attenuated the activation of BV2 and C6 cells. More importantly, in vivo, compounds 3 and 16 reduced GFAP and Iba-1 levels in the hippocampus, and displayed neuroprotection in Nissl staining. Besides, both compounds 3 and 16 had high safety (LD50 > 1000 mg/kg). Longer plasma half-life of compounds 3 and 16 than melatonin supported combination strategy. All these results demonstrated that N-salicyloyl tryptamine derivatives are potential anti-neuroinflammation agents for the treatment of neurodegenerative disorder.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Triptaminas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/química
2.
Biochim Biophys Acta Biomembr ; 1862(8): 183273, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171739

RESUMO

Antimicrobial peptides (AMPs) play an important role in the host defense against various microbes. One of the most efficient human AMPs is the human beta defensin-3 (hBD-3) which is produced by, e.g. keratinocytes and lung epithelial cells. However, the structure-function relationship for AMPs and in particular for defensins with their typical three disulfide bonds is still poorly understood. In this study the importance of the three disulfide bonds for the activity of the AMPs is investigated with biological assays and with biophysical experiments utilizing different membrane reconstitution systems. The activities of natural hBD-3, hBD-3-c (cyclic variant with one disulfide bond), and hBD-3-l (linear variant without disulfide bonds) and fragments thereof were tested against specific Gram-negative bacteria. Furthermore, hemolytic and cytotoxic activities were analyzed as well as the potency to neutralize immune cell stimulation of lipopolysaccharide (LPS). Experiments using reconstituted lipid matrices composed of phospholipids or LPS purified from the respective Gram-negative bacteria, showed that the membrane activity of all three hBD-3 peptides is decisive for their capability to kill bacteria and to neutralize LPS. In most of the test systems the linear hBD-3-l showed the highest activity. It was also the only peptide significantly active against polymyxin B-resistant Proteus mirabilis R45. However, the stability of hBD-3 against protease activity decreases with decreasing number of disulfide bonds. This study demonstrates that the refining of AMP structures can generate more active compounds against certain strains.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Infecções Bacterianas/tratamento farmacológico , Bactérias Gram-Negativas/efeitos dos fármacos , beta-Defensinas/química , Sequência de Aminoácidos/genética , Peptídeos Catiônicos Antimicrobianos/farmacologia , Infecções Bacterianas/microbiologia , Dissulfetos/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/microbiologia , Bactérias Gram-Negativas/genética , Bactérias Gram-Negativas/patogenicidade , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/microbiologia , Lipopolissacarídeos/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Polimixina B/efeitos adversos , Polimixina B/farmacologia , Domínios Proteicos/efeitos dos fármacos , Proteus mirabilis/efeitos dos fármacos , Proteus mirabilis/patogenicidade , Relação Estrutura-Atividade , beta-Defensinas/farmacologia
3.
J Nutr ; 150(5): 1303-1312, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32040591

RESUMO

BACKGROUND: Metabolic endotoxemia is considered a cause for high-fat diet (HFD)-induced inflammation. However, convincing experimental evidence in humans is scant. OBJECTIVE: We determined whether a HFD or moderately HFD increases LPS and LPS-mediated cytokine production in the postprandial blood (PPB). METHODS: Ninety-eight volunteers (age: 37.3 ± 1.5 y) from the cross-sectional phenotyping study (PS) and 62 volunteers (age: 26.8 ± 1.2 y) from the intervention study (IS) consumed a breakfast containing 60% kcal fat (HF) and 36% kcal fat (moderately HF), respectively. For the IS, only the results from the placebo group are presented. Blood samples were probed for LPS-mediated cytokine production by incubating them with LPS inhibitor polymyxin B (PMB) for 24 h at 37°C besides the Limulus amebocyte lysate (LAL) assay. Repeated-measures ANOVA was used to compare the temporal changes of metabolic profiles and treatment outcomes. RESULTS: At least 87.5% of the plasma LPS measurements in 32 PS volunteers from each time point were below the LAL assay sensitivity (0.002 EU/mL). PMB suppressed IL-1ß (P = 0.035) and IL-6 (P = 0.0487) production in the 3 h PPB of the PS after 24 h incubation at 37°C compared to the vehicle control, suggesting the presence of LPS. However, the amount of LPS did not increase the cytokine concentrations in the 3 h PPB above the fasting concentrations. Such suppression was not detected in the PPB of the IS. Treating whole blood with lipoprotein lipase (LPL) significantly (P < 0.05) increased FFA and cytokine (IL-1ß, IL-6, TNF-α) concentrations in both studies. CONCLUSION: LPS may not be the major cause of postprandial inflammation in healthy adults consuming a moderately HF meal (36% kcal fat, similar to the typical American diet) or a HF meal (60% kcal fat). Plasma FFAs may modulate postprandial inflammation. The prevailing concept of HFD-induced metabolic endotoxemia requires careful re-evaluation. The PS was registered at clinicaltrials.gov as NCT02367287 and the IS as NCT02472171.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Inflamação/sangue , Inflamação/etiologia , Lipopolissacarídeos/sangue , Período Pós-Prandial/fisiologia , Adulto , Desjejum , Estudos Transversais , Citocinas/sangue , Método Duplo-Cego , Ácidos Graxos não Esterificados/sangue , Feminino , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipase Lipoproteica/metabolismo , Masculino , Placebos , Polimixina B/farmacologia
4.
Org Lett ; 22(4): 1336-1339, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32037840

RESUMO

Aspermeroterpene A (1) with an unprecedented and highly congested 5/3/6/6/6/5 hexacyclic skeleton, together with two precursors aspermeroterpenes B (2) and C (3), were isolated from the marine-derived fungus Aspergillus terreus GZU-31-1. Their structures were elucidated by quantum chemical calculations, X-ray diffraction, and spectroscopic methods. The biogenetic pathway for 1-3 is proposed. Aspermeroterpenes A-C (1-3) showed significant inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 cells compared to positive control.


Assuntos
Aspergillus/química , Terpenos/farmacologia , Animais , Cristalografia por Raios X , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Terpenos/química , Terpenos/isolamento & purificação
6.
J Infect Chemother ; 26(5): 520-522, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32001173

RESUMO

Previously, we generated and screened a panel of monoclonal antibodies (mAbs) against methicillin-resistant Staphylococcus aureus (MRSA) to identify protective mAbs in mouse infection models. One of these mAbs, ZBIA3H, bound to lipoteichoic acid (LTA) and exerted protective effects in a mouse sepsis model. To reinforce the ability of the mAb to protect against infection, combination therapies with the mAb and antibiotics need to be examined. Therefore, herein, we studied the efficacy of ZBIA3H (in combination or alone) in a mouse sepsis model. ZBIA3H improved the survival rate in the mouse models of sepsis induced by highly virulent or refractory S. aureus (community-acquired MRSA strain MW2, vancomycin-intermediate S. aureus strain Mu3, or vancomycin-resistant S. aureus strain VRS1). Furthermore, ZBIA3H remarkably improved the survival rate in combination with antimicrobial agents (vancomycin, daptomycin, or linezolid) in mouse sepsis models. From these results we conclude that anti-LTA mAb ZBIA3H or its humanized form is a promising mAb individually, or in combination with antibiotics, against clinical refractory infection of S. aureus.


Assuntos
Anticorpos Monoclonais/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Sepse/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Ácidos Teicoicos/antagonistas & inibidores , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anticorpos Antibacterianos , Anticorpos Monoclonais/uso terapêutico , Daptomicina/farmacologia , Daptomicina/uso terapêutico , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Linezolida/farmacologia , Linezolida/uso terapêutico , Lipopolissacarídeos/metabolismo , Camundongos , Staphylococcus aureus/efeitos dos fármacos , Ácidos Teicoicos/metabolismo , Vancomicina/farmacologia , Vancomicina/uso terapêutico
7.
Dalton Trans ; 49(7): 2323-2330, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32022053

RESUMO

A superoxide dismutase mimic (Mn1) was functionalized with three positively charged-peptides: RRRRRRRRR (Mn1-R9), RRWWWRRWRR (Mn1-RW9) or Fx-r-Fx-K (Mn1-MPP). Characterization of the physico-chemical properties of the complexes show that they share similar binding affinity for Mn2+, apparent reduction potential and intrinsic superoxide dismutase activity. However, their accumulation in cells is different (Mn1-R9 < Mn1-MPP < Mn1-RW9 < Mn1), as well as their subcellular distribution. In addition, the three functionalized-complexes display a better anti-inflammatory activity than Mn1 when assayed at 10 µM. This improvement is due to a combination of an anti-inflammatory effect of the peptidyl moiety itself, and of the SOD mimic for Mn1-RW9 and Mn1-MPP. In contrast, the enhanced anti-inflammatory activity of Mn1-R9 is solely due to the SOD mimic.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Peptídeos Penetradores de Células/farmacologia , Superóxido Dismutase/metabolismo , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/metabolismo , Células HT29 , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Superóxido Dismutase/química , Termodinâmica
8.
PLoS One ; 15(2): e0228806, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084157

RESUMO

INTRODUCTION: Periodontitis is associated with increased serum lipopolysaccharide (LPS) activity, which may be one mechanism linking periodontitis with the risk of cardiovascular diseases. As LPS-carrying proteins including lipoproteins modify LPS-activity, we investigated the determinants of serum LPS-neutralizing capacity (LPS-NC) in ischemic stroke. The association of LPS-NC and Aggregatibacter actinomycetemcomitans, a major microbial biomarker in periodontitis, was also investigated. MATERIALS AND METHODS: The assay to measure LPS-NC was set up by spiking serum samples with E. coli LPS. The LPS-NC, LPS-binding protein (LBP), soluble CD14 (sCD14), lipoprotein profiles, apo(lipoprotein) A-I, apoB, and phospholipid transfer protein (PLTP) activity, were determined in 98 ischemic stroke patients and 100 age- and sex-matched controls. Serum and saliva immune response to A. actinomycetemcomitans, its concentration in saliva, and serotype-distribution were examined. RESULTS: LPS-NC values ranged between 51-83% in the whole population. Although several of the LPS-NC determinants differed significantly between cases and controls (PLTP, sCD14, apoA-I, HDL-cholesterol), the levels did not (p = 0.056). The main determinants of LPS-NC were i) triglycerides (ß = -0.68, p<0.001), and ii) HDL cholesterol (0.260, <0.001), LDL cholesterol (-0.265, <0.001), PLTP (-0.196, 0.011), and IgG against A. actinomycetemcomitans (0.174, 0.011). Saliva A. actinomycetemcomitans concentration was higher [log mean (95% CI), 4.39 (2.35-8.19) vs. 10.7 (5.45-21) genomes/ml, p = 0.023) and serotype D more frequent (4 vs. 0%, p = 0.043) in cases than controls. Serotypeablity or serotypes did not, however, relate to the LPS-NC. CONCLUSION: Serum LPS-NC comprised low PLTP-activity, triglyceride and LDL cholesterol concentrations, as well as high HDL cholesterol and IgG against A. actinomycetemcomitans. The present findings let us to conclude that LPS-NC did not associate with stroke.


Assuntos
Isquemia Encefálica/complicações , Lipopolissacarídeos/antagonistas & inibidores , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Idoso , Feminino , Humanos , Masculino
9.
Biochim Biophys Acta Gen Subj ; 1864(4): 129532, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31953126

RESUMO

BACKGROUND: Hybridization is a useful strategy to bond the advantages of different peptides into novel constructions. We designed a series of AMPs based on the structures of a synthetic AMP KFA3 and a naturally-occurred host defense peptide substance P (SP) to obtain peptides retaining the high antibacterial activity of KFA3 and the immunomodulatory activity and low cytotoxicity of SP. METHODS: Two repeats of KFA and different C terminal fragments of SP were hybridized, generating a series of novel AMPs (KFSP1-8). The antibacterial activities, host cell toxicity and immunomodulation were measured. The antibacterial mechanisms were investigated. RESULTS: Hybrid peptides KFSP1-4 exerted substantial antibacterial activities against Gram-negative bacteria of standard strains and clinical drug-resistant isolates including E.coli, A.baumannii and P.aeruginosa, while showing little toxicity towards host cells. Compared with KFA3, moderate reduction in α-helix content and the interruption in α-helix continuality were indicated in CD spectra analysis and secondary-structure simulation in these peptides. Membrane permeabilization combined with time-kill studies and FITC-labeled imaging, indicated a selective membrane interaction of KFSP1 with bacteria cell membranes. By specially activating NK1 receptor, the hybrid peptides kept the ability of SP to induce intracellular calcium release and ERK1/2 phosphorylation, but unable to stimulate NF-κB phosphorylation. KFSP1 facilitated the survival of mouse macrophage RAW264.7, directly interacting with LPS and inhibiting the LPS-induced NF-κB phosphorylation and TNF-α expression. CONCLUSION: Hybridization is a useful strategy to bond the advantages of different peptides. KFSP1 and its analogs are worth of advanced efforts to explore their potential applications as novel antimicrobial agents.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Oligopeptídeos/farmacologia , Substância P/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Bactérias Gram-Negativas/química , Células Hep G2 , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Lipopolissacarídeos/antagonistas & inibidores , Camundongos , Oligopeptídeos/síntese química , Oligopeptídeos/química , Células RAW 264.7 , Relação Estrutura-Atividade , Substância P/síntese química , Substância P/química
10.
Phytochemistry ; 171: 112247, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31927201

RESUMO

Four previously undescribed acylated iridoid glucosides, linaburiosides A‒D, one undescribed iridoid, 7-deoxyiridolactonic acid, and one known acylated iridoid glucoside, iridolinarin C, were isolated from the aerial parts of a Mongolian traditional herbal medicine, Linaria buriatica. Linaburiosides A‒D had an acyl moiety corresponding to 7-deoxyiridolactonic acid. Detailed spectroscopic analyses of linaburiosides A‒D and 7-deoxyiridolactonic acid led to the assignment of their structures. The absolute configuration of 7-deoxyiridolactonic acid was elucidated by application of the PGME method; those of linaburiosides A‒D were assigned on the basis of chemical conversions, as well as application of the modified Mosher's method. The absolute configuration of iridolinarin C was also elucidated in this study. Anti-inflammatory and antiproliferative activities of isolated compounds and their derivatives were evaluated.


Assuntos
Anti-Inflamatórios/farmacologia , Glucosídeos/farmacologia , Iridoides/farmacologia , Linaria/química , Compostos Fitoquímicos/farmacologia , Células A549 , Acilação , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Glucosídeos/química , Glucosídeos/isolamento & purificação , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/biossíntese , Iridoides/química , Iridoides/isolamento & purificação , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Células MCF-7 , Microglia/efeitos dos fármacos , Microglia/metabolismo , Conformação Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Células Tumorais Cultivadas
11.
Carbohydr Polym ; 232: 115811, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952610

RESUMO

In mice, porphyran extracted from Pyropia yezoensis exerts anti-inflammatory effects and suppresses lipopolysaccharide (LPS)-induced immune activation and sepsis. Here, we investigated inhibition of LPS-induced activation of human immune cells by porphyran and the underlying mechanisms. We demonstrated that porphyran may inhibit LPS-induced proinflammatory cytokine production in peripheral blood mononuclear cells, monocyte-derived dendritic cells, and peripheral blood dendritic cells. We also observed that porphyran-mediated LPS-induced activation of DC suppressed syngeneic T cell proliferation, resulting in reduced production of interferon-γ. The mechanism of LPS-induced immune cell activation requires the activation of toll like receptor 4 following binding of LPS to myeloid differentiation factor 2 (MD2). Additionally, we show that porphyran competes with LPS for binding to MD2 and thereby suppresses immune cell activation. Porphyran may, therefore, be a promising therapeutic candidate for the treatment of endotoxin-mediated septic shock and inflammation in humans.


Assuntos
Células Dendríticas/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/antagonistas & inibidores , Sefarose/análogos & derivados , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Células Dendríticas/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos/farmacologia , Sefarose/farmacologia
12.
Phytochemistry ; 171: 112233, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31911267

RESUMO

Eight previously undescribed and 15 known components, including six neolignans, two monolignan, three sesquineolignans, three dineolignans, eight phenylpropanoids, and one steroid were identified from the seed testa of Vernicia fordii. Their structures were established based on the comprehensive analysis of NMR and ECD data. The anti-neuroinflammatory effects of the isolates were evaluated through nitrite assays in LPS-induced BV2 cells. As a result, isodiverniciasin A, diverniciasin B, diverniciasin C, isoprincepin, princepin, 3, 3'-bisdemethylpinoresinol, (+)-7-epi-sesamin-dicatechol, isoamericanin A, americanin B, 7S, 8R-americanin D, 4-hydroxyl cinnamic aldehyde, 3-hydroxyl-4-methoxyl cinnamic aldehyde and 24R-6ß-hydroxy-24- ethylcholest-4-en-3-one exhibited significant inhibitory effects on nitric oxide (NO) production and isoprincepin, princepin, americanin B, and 4-hydroxyl cinnamic aldehyde suppressed the overexpression of inflammatory cytokines TNF-α, IL-1ß, and IL-6 in over-activated microglia. The results suggested that bioactive ingredients from the seed testa of V. fordii can serve as potential therapeutic agents for neurodegenerative diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Euphorbiaceae/química , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Compostos Fitoquímicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Conformação Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Nitritos/análise , Nitritos/antagonistas & inibidores , Nitritos/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação
13.
Acta Pharmacol Sin ; 41(1): 119-128, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31534201

RESUMO

Inefficient diabetic ulcer healing and scar formation remain a challenge worldwide, owing to a series of disordered and dynamic biological events that occur during the process of healing. A functional wound dressing that is capable of promoting ordered diabetic wound recovery is eagerly anticipated. In this study, we designed a silicone elastomer with embedded 20(S)-protopanaxadiol-loaded nanostructured lipid carriers (PPD-NS) to achieve ordered recovery in scarless diabetic ulcer healing. The nanostructured lipid carriers were prepared through an emulsion evaporation-solidification method and then incorporated into a network of silicone elastomer to form a unique nanostructured lipid carrier-enriched gel formulation. Interestingly, the PPD-NS showed excellent in vitro anti-inflammatory and proangiogenic activity. Moreover, in diabetic mice with full-thickness skin excision wound, treatment with PPD-NS significantly promoted in vivo scarless wound healing through suppressing inflammatory infiltration in the inflammatory phase, promoting angiogenesis during the proliferation phase, and regulating collagen deposition in the remodeling phase. Hence, this study demonstrates that the developed PPD-NS could facilitate ordered diabetic wound recovery via multifunctional improvement during different wound-healing phases. This novel approach could be promising for scarless diabetic wound healing.


Assuntos
Inibidores da Angiogênese/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Pé Diabético/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Sapogeninas/farmacologia , Elastômeros de Silicone/química , Inibidores da Angiogênese/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Pé Diabético/patologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Géis/administração & dosagem , Géis/química , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Lipídeos/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Nanoestruturas/química , Neovascularização Patológica/patologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Tamanho da Partícula , Células RAW 264.7 , Sapogeninas/administração & dosagem , Sapogeninas/química , Elastômeros de Silicone/administração & dosagem , Propriedades de Superfície , Cicatrização/efeitos dos fármacos
14.
Acta Pharmacol Sin ; 41(1): 10-21, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31213669

RESUMO

Neuroinflammation is one of the critical events in neurodegenerative diseases, whereas microglia play an important role in the pathogenesis of neuroinflammation. In this study, we investigated the effects of a natural sesquiterpene lactone, 6-O-angeloylplenolin (6-OAP), isolated from the traditional Chinese medicine Centipeda minima (L.) A.Br., on neuroinflammation and the underlying mechanisms. We showed that treatment with lipopolysaccharide (LPS) caused activation of BV2 and primary microglial cells and development of neuroinflammation in vitro, evidenced by increased production of inflammatory cytokines TNF-α and IL-1ß, the phosphorylation and nuclear translocation of NF-κB, and the transcriptional upregulation of COX-2 and iNOS, leading to increased production of proinflammatory factors NO and PGE2. Moreover, LPS treatment induced oxidative stress through increasing the expression levels of NOX2 and NOX4. Pretreatment with 6-OAP (0.5-4 µM) dose-dependently attenuated LPS-induced NF-κB activation and oxidative stress, thus suppressed neuroinflammation in the cells. In a mouse model of LPS-induced neuroinflammation, 6-OAP (5-20 mg·kg-1·d-1, ip, for 7 days before LPS injection) dose-dependently inhibited the production of inflammatory cytokines, the activation of the NF-κB signaling pathway, and the expression of inflammatory enzymes in brain tissues. 6-OAP pretreatment significantly ameliorated the activation of microglia and astrocytes in the brains. 6-OAP at a high dose caused a much stronger antineuroinflammatory effect than dexamethansone (DEX). Furthermore, we demonstrated that 6-OAP pretreatment could inhibit LPS-induced neurite and synaptic loss in vitro and in vivo. In conclusion, our results demonstrate that 6-OAP exerts antineuroinflammatory effects and can be considered a novel drug candidate for the treatment of neuroinflammatory diseases.


Assuntos
Inflamação/tratamento farmacológico , Lactonas/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Sesquiterpenos/farmacologia , Animais , Asteraceae/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lactonas/química , Lactonas/isolamento & purificação , Lipopolissacarídeos/farmacologia , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Oxirredução , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação
15.
Arch Physiol Biochem ; 126(1): 74-81, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30320514

RESUMO

This study evaluated the anti-inflammatory potential of a 40% prethanol extract of Trifolium pratense leaves (40% PeTP) using in vitro (RAW264.7 cells) and in vivo (carrageenan-induced inflammation model) experiments. Pretreatment with 40% PeTP significantly inhibited the LPS-induced expression of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and inflammatory cytokines, including tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in RAW264.7 cells, without inducing cytotoxicity. The inhibitory effects of 40% PeTP are mediated through suppression of the nuclear translocation of nuclear factor (NF)-κB and the phosphorylation of mitogen-activated protein kinases (MAPKs). Oral administration of 40% PeTP at 50, 100, and 200 mg/kg of body weight suppressed carrageenan-induced oedema in a dose-dependent manner. Collectively, our results suggested that 40% PeTP exerts potential anti-inflammatory effects by suppressing the activation of the NF-κB and MAPK pathways in vitro, and by reducing carrageenan-induced paw oedema in vivo.


Assuntos
Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/genética , NF-kappa B/genética , Extratos Vegetais/farmacologia , Trifolium/química , Administração Oral , Animais , Carragenina/administração & dosagem , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Modelos Animais de Doenças , Esquema de Medicação , Edema/induzido quimicamente , Edema/genética , Edema/patologia , Regulação da Expressão Gênica , Inflamação , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Folhas de Planta/química , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
16.
Chem Biodivers ; 17(1): e1900479, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31667925

RESUMO

Chroogomphus rutilus is a rare fungal species that grows under pine trees and is now widely used as a functional food and pharmaceutical product. However, the chemical constituents and biological activities of Chroogomphus rutilus have been relatively limited. The present study aimed at determining the total polyphenols and flavonoids contents, biological activities and main phenolic compounds of Chroogomphus rutilus from different geographical origins at the stipe and pileus. The results suggested that Chroogomphus rutilus polyphenol extracts revealed a higher antioxidant, anti-inflammatory, and cytotoxic activities, and there were significant differences between samples from different locations and regions. Correlation analysis showed that the contents of total polyphenols and flavonoids were significantly correlated with antioxidant and anti-inflammatory activities. However, only the content of total flavonoids was significantly correlated with cytotoxicity, which means that the cytotoxicity of Chroogomphus rutilus polyphenol extracts may be regulated by flavonoids or other compounds. HPLC-DAD analysis revealed that the main phenolic compound was protocatechuic acid, followed by baicalin, p-hydroxyphenylacetic acid and p-hydroxybenzoic acid, but comparing with the pileus extracts, the stipe extracts can be considered as a higher concentration of phenolic compounds. Therefore, antioxidant, anti-inflammatory and cytotoxic activities of Chroogomphus rutilus polyphenol extracts could be due to the identified compounds. This study investigated a deep knowledge about the constituents and activities of Chroogomphus rutilus and provided the reference for its application in food and pharmaceutical.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Basidiomycota/química , Polifenóis/isolamento & purificação , Polifenóis/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Polifenóis/química , Células RAW 264.7
17.
J Enzyme Inhib Med Chem ; 35(1): 85-95, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31707866

RESUMO

To develop novel anti-inflammatory agents, a series of 5-alkyl-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide derivatives were designed, synthesised, and evaluated for anti-inflammatory effects using RAW264.7 cells. Structures of the synthesised compounds were determined using 1H NMR, 13 C NMR, and HRMS. All the compounds were screened for anti-inflammatory activity based on their inhibitory effects against LPS-induced NO release. Among them, 5-(3,4,5-trimethoxybenzyl)-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide (6p) showed the highest anti-inflammatory activity and inhibited NO release more potently than the lead compound D1. Further studies revealed that compound 6p reduced the levels of NO, TNF-α, and IL-6, and that its anti-inflammatory activity involves the inhibition of COX-2 and iNOS and downregulation of the mitogen-activated protein kinases (MAPK) signal pathway. Notably, compound 6p displayed more prominent anti-inflammatory activity than D1 and the positive control ibuprofen in the in vivo acute inflammatory model. Overall, these findings indicate that compound 6p is a therapeutic candidate for the treatment of inflammation.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Descoberta de Drogas , Quinoxalinas/farmacologia , Úlcera Gástrica/tratamento farmacológico , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Quinoxalinas/síntese química , Quinoxalinas/química , Células RAW 264.7 , Ratos , Úlcera Gástrica/metabolismo , Relação Estrutura-Atividade
18.
Future Med Chem ; 12(1): 5-17, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710253

RESUMO

Aim: Over the years, indole has proved to be a versatile scaffold for the design of molecules acting as anti-inflammatory agents. Materials & Methods: A small library of 3-amino-alkylated indoles has been obtained by an optimized Mannich green approach. The anti-inflammatory activity of the new 3-amino-alkylated indoles, GLYC 0-10, was evaluated in RAW 264.7 macrophages. Results: The anti-inflammatory activity of the new 3-amino-alkylated indoles, GLYC 0-10, was evaluatedn and, among them, GLYC 4, 5 and 9 displayed the greatest inhibitory effects on nitric oxide production, with IC50 values of 5.41, 4.22 and 6.3 µM, respectively. Conclusion: Our outcomes, overall, highlight the importance of the indole substitution in the anti-inflammatory activity of these compounds, exerted by acting on the interlinked NF-κB/ERK1/2 pathways.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Indóis/farmacologia , Alquilação , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
19.
Chem Biodivers ; 17(1): e1900683, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31797569
20.
Appl Microbiol Biotechnol ; 104(1): 351-363, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31768613

RESUMO

The first step in the development of Helicobacter pylori pathogenicity is receptor-mediated adhesion to gastric epithelium. Adhesins of H. pylori not only enable colonisation of the epithelium, with BabA interacting with Lewisb, but also interaction of lipopolysaccharide (LPS) with galectin-3 contributes to attachment of H. pylori to the host cells. Anti-adhesive compounds against H. pylori have been described, but specific analytical assays for pinpointing the interaction with BabA are limited. LPS-galectin-3 inhibitors have not been described until now. A sandwich ELISA with recombinant BabA547-6K was developed to investigate the interaction of BabA with Lewisb-HSA. Isothermal titration calorimetry gave thermodynamic information on the interaction between BabA, Lewisb-HSA and anti-adhesive compounds. A highly esterified rhamnogalacturonan from Abelmoschus esculentus inhibited the adhesion of H. pylori to adherent gastric adenocarcinoma (AGS) cells (IC50 550 µg/mL) and interacted with BabA (IC50 17 µg/mL). Pectins with similar rhamnogalacturonan structure showed weak anti-adhesive activity. Highly branched rhamnogalacturonans with low uronic acid content and high degree of esterification are potent BabA inhibitors. BabA represents a promising target for the development of anti-adhesive drugs against H. pylori. The rhamnogalacturonan influenced also the binding affinity of H. pylori to recombinant galectin-3 in a concentration-dependent manner with an IC50 of 222 µg/mL. Similar effects were obtained with pectin from apple fruits, while pectins from other sources were inactive.


Assuntos
Adesinas Bacterianas/metabolismo , Aderência Bacteriana/efeitos dos fármacos , Helicobacter pylori/efeitos dos fármacos , Pectinas/farmacologia , Abelmoschus/química , Adenocarcinoma/microbiologia , Linhagem Celular Tumoral , Frutas/química , Humanos , Concentração Inibidora 50 , Antígenos do Grupo Sanguíneo de Lewis/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Malus/química , Pectinas/química , Extratos Vegetais/farmacologia , Neoplasias Gástricas/microbiologia
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