RESUMO
OBJECTIVE: Asthma is an airway inflammatory disease caused by activation of numerous immune cells including macrophages. Bakuchicin (BKC) is known to exhibit anti-inflammatory effects and type 2 T helper (Th2) regulation, but has not been investigated for airway inflammation. This study aimed to evaluate the effects of BKC on airway inflammation and demonstrate the mechanisms of macrophage polarization. METHODS: The anti-inflammatory effects were determined using lipopolysaccharide (LPS)-stimulated macrophages. The ovalbumin (OVA)-induced asthma mouse model was used to evaluate the effects of BKC on airway inflammation and Th2 responses. Moreover, the effect of BKC on macrophage polarization was confirmed in bone marrow-derived macrophages (BMDMs) differentiation. RESULTS: BKC suppressed nitric oxide production and expression of pro-inflammatory cytokines by inhibiting signaling pathway in LPS-stimulated macrophages. In an OVA-induced asthma model, BKC treatment alleviated histological changes and mast cell infiltration and reduced the levels of eosinophil peroxidase, ß-hexosaminidase, and immunoglobulin levels. In addition, BKC alleviated Th2 responses and M2 macrophage populations in bronchoalveolar fluid. In BMDMs, BKC suppressed IL-4-induced M2 macrophage polarization and the expression of M2 markers such as arginase-1 and Fizz-1 through inhibiting sirtuin 2 levels. CONCLUSION: BKC could be a drug candidate for the treatment of allergic asthma.
Assuntos
Asma , Macrófagos , Camundongos Endogâmicos BALB C , Ovalbumina , Animais , Asma/tratamento farmacológico , Asma/induzido quimicamente , Asma/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Feminino , Citocinas/metabolismo , Óxido Nítrico/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Células Th2/imunologia , Células Th2/efeitos dos fármacos , Lipopolissacarídeos , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos Endogâmicos C57BLRESUMO
Osteoporosis is characterized by the deterioration of bone structures and decreased bone mass, leading to an increased risk of fracture. Estrogen deficiency in postmenopausal women and aging are major factors of osteoporosis and are some of the reasons for reduced quality of life. In this study, we investigated the effects of n-trans-hibiscusamide (NHA) and its derivative 4-O-(E)-feruloyl-N-(E)-hibiscusamide (HAD) on receptor activator of nuclear factor kappa-Β (NF-κB) ligand (RANKL)-induced osteoclast differentiation and an ovariectomized osteoporosis mouse model. NHA and HAD significantly inhibited the differentiation of osteoclasts from bone marrow-derived macrophages (BMMs) and the expression of osteoclast differentiation-related genes. At the molecular level, NHA and HAD significantly downregulated the phosphorylation of mitogen-activated protein kinase (MAPK) signaling molecules. However, Akt and NF-κB phosphorylation was inhibited only after NHA or HAD treatment. In the ovariectomy (OVX)-induced osteoporosis model, both NHA and HAD effectively improved trabecular bone structure. C-terminal telopeptide (CTX), a bone resorption marker, and RANKL, an osteoclast stimulation factor, were significantly reduced by NHA and HAD. The tartrate-resistant acid phosphatase (TRAP)-stained area, which indicates the osteoclast area, was also decreased by these compounds. These results show the potential of NHA and HAD as therapeutic agents for osteoporosis.
Assuntos
Acrilamidas/farmacologia , Guaiacol/análogos & derivados , Osteoporose/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Guaiacol/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteoporose/etiologia , Osteoporose/metabolismo , Ovariectomia/efeitos adversos , Ligante RANK/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Asthma is characterized by airway hyperresponsiveness and allergic inflammation, detrimentally affecting the patients' quality of life. The development of new drugs for the treatment of asthma is warranted to alleviate these issues. Recent studies have demonstrated that sirtuin2 (SIRT2) aggravates asthmatic inflammation by up-regulation of T-helper type 2 responses and macrophage polarization. However, effects of SIRT2 on mast cell activation remain obscure. In this study, we investigated the effects of AGK2, an inhibitor for SIRT2, on mast cell-mediated allergic airway inflammation. Pre-treatment with AGK2 inhibited degranulation of mast cells by suppressing the FcεRI signaling pathway and intracellular calcium influx. The expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-4, IL-5, IL-6, and IL-8, was inhibited via regulation of transcription factors such as NF-κB and NRF2. These effects of AGK2 were verified in passive cutaneous anaphylaxis and acute lung injury animal models. AGK2 attenuated Evans blue pigmentation by inhibiting mast cell activation and lung barrier dysfunction by inhibiting inflammatory responses in these animal models. In the ovalbumin (OVA)-induced allergic airway inflammation murine model, AGK2 alleviated allergic asthma symptoms such as lung histological changes (immune cell and mast cell infiltration, collagen deposition, and α-smooth muscle actin expression) and serum immunoglobulins (Ig) levels (IgE, OVA-specific IgE, IgG1, and IgG2a). Moreover, AGK2 reduced the levels of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-4, IL-5, and IL-6) and inflammatory mediators (myeloperoxidase, eosinophil peroxidase, and tumor growth factor-α) in the bronchoalveolar lavage fluid and lung tissues. In addition, the anti-fibrotic effects of AGK2 were verified using lung epithelial cells and TGF-ß/Smad reporter stable cells. In conclusion, our findings suggest that SIRT2 plays a role in mast cell-mediated airway inflammatory disease. Therefore, AGK2 is a good potential candidate for treating allergic asthma and lung inflammation.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Furanos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Pulmão/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Quinolinas/farmacologia , Receptores de IgE/antagonistas & inibidores , Sirtuína 2/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo , Células A549 , Animais , Asma/enzimologia , Asma/imunologia , Asma/fisiopatologia , Degranulação Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose , Liberação de Histamina/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/enzimologia , Pulmão/imunologia , Pulmão/fisiopatologia , Masculino , Mastócitos/enzimologia , Mastócitos/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de IgE/metabolismo , Transdução de Sinais , Sirtuína 2/metabolismoRESUMO
Rosa rugosa Thunb., is as a medicinal plant known for anti-diabetic, and anti-inflammatory activities. However, the specific active compounds responsible for the individual pharmacological effects of in R. rugosa extract (95% EtOH) remain unknown. Here, we hypothesized that terpenoid structure, the most abundant constituents in R. rugosa extract, are responsible for its anti-inflammatory activity. We investigated the phytochemical substituents (compounds 1-13) and newly purified 11-methoxy polisin A, and 13-methoxy bisaborosaol F using NMR and ESI-MS and to screened their effects on NO production in LPS-induced macrophages. Rugosic acid A (RA) induced to ameliorate NO production, iNOS, and pro-inflammatory cytokines associated with the NF-κB. And, RA suppressed IL-6 secretion and IL-6-mediated STAT3 activation in LPS-mediated inflammation. In addition, RA was evaluated in LPS-mediated acute lung injury (ALI) model similar to acute pneumonia. Our results suggested that RA was suppressed to translocate nuclear NF-κB and IL-6-mediated STAT3 activation. Finally, RA led to amelioration of ALI by decreasing myeloperoxidase (MPO) and inhibiting phosphorylation of NF-κB and STAT3. Our group originally found that R. rugosa extract had new methoxy compounds and RA may be alternative natural agent for acute pneumonia similar to severe acute respiratory syndrome by coronavirus.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Interleucina-6/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Rosa , Fator de Transcrição STAT3/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Lipopolissacarídeos , Camundongos Endogâmicos BALB CRESUMO
Chronic and excessive inflammation can destroy host organs and cause inflammatory diseases such as inflammatory bowel disease, asthma, and rheumatoid arthritis. In this study, we investigated the anti-inflammatory effects of Alpinia katsumadai seed-derived 2,3,5,22,23-pentahydroxy-2,6,10,15,19,23-hexamethyl-tetracosa-6,10,14,18-tetraene (PHT) using lipopolysaccharide (LPS)-stimulated J774 cells and a formalin-induced chronic paw inflammation mouse model. The in vitro results showed that PHT exhibited no cytotoxicity and decreased LPS-induced NO secretion. Additionally, PHT inhibited LPS-induced inducible NO synthase (iNOS) and cyclooxygenase 2 (COX2) protein expression. The quantitative real-time PCR results showed that PHT downregulated the gene expression of the proinflammatory cytokines interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) but not tumor necrosis factor α (TNF-α). PHT inhibited the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB). In a mouse model, oral administration of 50 mg/kg PHT significantly alleviated both mouse paw thickness and volume. These results indicate that PHT has potential anti-inflammatory effects and should be considered a possible functional material.
Assuntos
Alpinia/química , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inflamação/tratamento farmacológico , Óxido Nítrico Sintase Tipo II/metabolismo , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular , Modelos Animais de Doenças , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Formaldeído/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Interleucina-1beta/genética , Interleucina-6/genética , Lipopolissacarídeos/efeitos adversos , Camundongos , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Triterpenos/química , Triterpenos/isolamento & purificação , Fator de Necrose Tumoral alfa/genéticaRESUMO
Many studies have reported the biological activities of retrofractamide C (RAC). However, few studies have investigated the anti-inflammatory effect of RAC. In the present study, we investigated the anti-inflammatory effect of RAC using lipopolysaccharide (LPS)-induced J774A.1 cells and a xylene-induced mouse ear edema model. Treatment with RAC decreased LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) secretion and inducible NO synthase (iNOS) and cyclooxygenase 2 (COX2) protein expression. It also downregulated the LPS-induced production of interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) but not tumor necrosis factor α (TNF-α). In the LPS-induced signaling pathway, RAC inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) but not c-Jun N-terminal kinase (JNK) or p38. In a xylene-induced mouse ear edema model, RAC treatment alleviated edema formation and inflammatory cell infiltration. In conclusion, the present study indicates that RAC has the potential to have anti-inflammatory effects and could be a prospective functional food.
Assuntos
Amidas/farmacologia , Orelha/patologia , Edema/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Piper/química , Amidas/química , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Camundongos Endogâmicos ICR , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Xilenos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Many studies have identified and described various medicinal effects of cirsiliol. Here, we investigated the signaling pathway involved in the anti-inflammatory effects of cirsiliol on IL-6-induced activity. Cirsiliol showed no cytotoxicity and inhibited pSTAT3-induced luciferase activity. At the molecular level, cirsiliol suppressed the expression of IL-6-induced inflammatory marker genes such as CRP, IL-1ß, ICAM-1 and SOCS3, IL-6-induced activation of Jak2, gp130, STAT3 and ERK and nuclear translocation of STAT3, as measured by PCR, immunofluorescence staining and western blot analysis. However, the interaction between IL-6 and its receptor was not affected by cirsiliol treatment. These results indicate that cirsiliol attenuates IL-6-induced cellular signaling by regulating Jak2 phosphorylation. Therefore, cirsiliol could be a therapeutic agent for IL-6-related inflammatory diseases.
Assuntos
Anti-Inflamatórios/uso terapêutico , Flavonas/uso terapêutico , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Anti-Inflamatórios/farmacologia , Flavonas/farmacologia , Humanos , Técnicas In VitroRESUMO
Four new aster saponins (1-4) together with five known analogues (5-9) were isolated from Aster tataricus. The chemical structures of 1-4 were elucidated based on spectrometric and spectroscopic analysis and comparison with reported data. The potential anti-inflammatory activities of aster saponins 1-9 were evaluated subsequently by measuring lipopolysaccharide (LPS)-enhanced nitric oxide (NO) formation in murine macrophages. Among these, aster saponin B (6) exhibited the most potent inhibitory activity (IC50: 1.2 µM). Additionally, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein levels were dose-dependently suppressed by 6 in LPS-activated RAW 264.7 cells. Investigation of the anti-inflammatory mechanism indicated that 6 attenuated the phosphorylation and degradation of the inhibitor of NF-κB (IκB), which led to the blocking of NF-κB p65 translocation to the nucleus.
Assuntos
Anti-Inflamatórios/isolamento & purificação , Aster/química , Sistema de Sinalização das MAP Quinases/fisiologia , NF-kappa B/fisiologia , Saponinas/isolamento & purificação , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , Ácido Oleanólico/análogos & derivados , Células RAW 264.7 , Saponinas/química , Saponinas/farmacologiaRESUMO
Three new sesquiterpenoids (compounds 4, 5, and 26), along with 23 known sesquiterpenoids (compounds 1-3 and 6-25) and two diterpenoids (compounds 27 and 28), were obtained from Curcuma phaeocaulis, and their chemical structures were determined through nuclear magnetic resonance (NMR), circular dichroism (CD), and high-resolution electrospray ionization (HRESIMS) spectroscopic data, which were compared to the data from previous studies. All isolates were tested for inhibitory activity against interleukin (IL)-6-stimulated STAT3 expression using a luciferase reporter assay, and curzerenone (21) and 8-epi-galanolactone (28) displayed promising signal transducer and activator of transcription (STAT3)-inhibitory activities with IC50 values of 4.8 and 4.1⯵M, respectively. In addition, these candidates significantly suppressed the mRNA expression levels of the proinflammatory genes IL-1ß and C-reactive protein (CRP) via blockade of the IL-6-activated Janus kinase 2 (JAK2)/STAT3 and ERK-MAPK signaling pathways. These results suggest that curzerenone (21) and 8-epi-galanolactone (28) may be potential candidates for ameliorating severe inflammatory diseases.
Assuntos
Curcuma/química , Diterpenos/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Sesquiterpenos/farmacologia , Animais , Linhagem Celular Tumoral , Diterpenos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/farmacologia , Modelos Moleculares , Compostos Fitoquímicos , Sesquiterpenos/químicaRESUMO
In this study, skin cream containing ziyuglycoside I isolated from Sanguisorba officinalis was manufactured and examined the protective effects of the skin cream against UVB-induced hairless mice. UVB-induced hairless mice were topically treated with the skin cream once a day for 5 weeks. Application of the skin cream did not exhibit side effect on body growth showing normal body weight and food efficiency in the mice. The skin cream treatment also was inhibited mRNA expression of interleukin (IL)-1ß, matrix metalloproteinase (MMP)-2, MMP-9, and MMP-2 protein expression in the mice. Furthermore, the skin cream treatment inhibits epidermal wrinkle formation, wrinkle depth, wrinkle thickness, and collagen degradation in UVB-induced hairless mice. Therefore, the skin cream was able to play a role in the attenuation of photoaging caused by UVB irradiation via downregulation of mRNA expression of inflammatory cytokine IL-1ß, MMP-2, MMP-9, and suppression of MMP-2 proteins expression.
Assuntos
Sanguisorba/química , Saponinas/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Creme para a Pele/farmacologia , Raios Ultravioleta , Animais , Peso Corporal/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Interleucina-1beta/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Pelados , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Three undescribed diarylheptanoids (3: -5: ) and six known curcuminoids (1, 2: , and 6: -9: ) were obtained from the ethyl acetate-soluble fraction of an ethanolic extract of Curcuma phaeocaulis. Their chemical structures and absolute configurations were elucidated by high-resolution electrospray ionization mass spectrometry, nuclear magnetic resonance spectroscopy, circular dichroism spectroscopy, and the modified Mosher's method. Previous studies constructed Hep3B cells stably transfected with pSTAT3-Luc plasmid containing STAT3 binding site to discover STAT3 inhibitors from natural products. The STAT3 inhibitory activities of all isolates were measured in transfected Hep3B cells after treatment with IL-6. Compound 5: ((5R)-1,7-Bis(3,4-dimethoxyphenyl)-3-methoxy-1-hepten-5-ol), demethoxycurcumin (7: ), and curcumin (8: ) exhibited significant inhibitory activity (IC50 values: 11.1, 1.9, and 1.6 µM, respectively). Furthermore, IL-6-induced phosphorylation of STAT3, and the mRNA expression levels of inflammation-related genes such as CRP, IL-1ß, ICAM-1, and SOCS3 were significantly reduced by exposure to compound 5: . These data suggested that the inhibitory activity of 5: is associated with the suppression of STAT3 phosphorylation. Thus, compound 5: may be a promising candidate for the treatment of cancer or inflammatory diseases related to the IL-6/STAT3 signaling pathway.
Assuntos
Curcuma , Diarileptanoides/farmacologia , Interleucina-6/farmacologia , Fator de Transcrição STAT3/efeitos dos fármacos , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Curcuma/química , Diarileptanoides/isolamento & purificação , Humanos , Interleucina-6/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Plantas Medicinais/química , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Oleanolic acid acetate (OAA), a major triterpenoid compound of Vigna angularis (azuki bean, V. angularis), has been shown to downregulate inflammatory responses in macrophages. Here, we show the molecular basis for the effect of OAA on Toll-like receptor (TLR) downstream signaling. OAA treatment significantly inhibited the secretion of embryonic alkaline phosphatase (SEAP) induced by polyinosinic acid (poly(I), TLR3 ligand) in a dose-dependent manner and without cytotoxicity in THP1-XBlue cells. In addition, OAA downregulated the gene expression of poly(I) induced pro-inflammatory cytokines and chemokines genes such as MCP-1, IL-1ß, IL-8, VCAM-1 and ICAM-1. Furthermore, we found that the inhibition activity of OAA was accompanied by decreased activation of not only nuclear factor-kappa B (NF-κB) signaling but also mitogen-activated protein kinase (MAPK) signaling upon stimulation with the TLR3 agonist. Interestingly, the interaction of OAA with IκB kinase α/ß (IKKα/ß) strongly attenuated the production of certain proteins and inflammatory cytokines in the TLR3 signaling pathway, such as nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkBα), extracellular regulated kinases (ERK), and p38, in an in vitro model. The action of OAA was regulated by TLR3, demonstrating that TLR3 plays a critical role in mediating the physiologically-relevant anti-inflammatory action of OAA and that the interaction with IKKα/ß is modulated through TLR3. These results reveal new insight into the understanding of the regulatory mechanisms of the downstream TLR3 signaling pathway and consequent inflammatory responses that are involved in the development and progression of inflammatory diseases.
Assuntos
Acetatos/farmacologia , Anti-Inflamatórios/farmacologia , Quinase I-kappa B/metabolismo , Inflamação/tratamento farmacológico , NF-kappa B/metabolismo , Ácido Oleanólico/farmacologia , Receptor 3 Toll-Like/metabolismo , Linhagem Celular , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Portulaca oleracea is as a medicinal plant known for its neuroprotective, hepatoprotective, antidiabetic, antioxidant, anticancer, antimicrobial, antiulcerogenic, and anti-inflammatory activities. However, the specific active compounds responsible for the individual pharmacological effects of P. oleracea extract (95% EtOH) remain unknown. Here, we hypothesized that alkaloids, the most abundant constituents in P. oleracea extract, are responsible for its anti-inflammatory activity. We investigated the phytochemical substituents (compounds 1-22) using nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI-MS) and screened their effects on NO production in lipopolysaccharide (LPS)-induced macrophages. Compound 20, 1-carbomethoxy-ß-carboline, as an alkaloid structure, ameliorated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and proinflammatory cytokines associated with the mitogen-activated protein kinase (MAPK) pathways, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Subsequently, we observed that compound 20 suppressed nuclear translocation of nuclear factor κB (NF-κB) using immunocytochemistry. Moreover, we recently reported that compound 8, trans-N-feruloyl-3', 7'-dimethoxytyramine, was originally purified from P. oleracea extracts. Our results suggest that 1-carbomethoxy-ß-carboline, the most effective anti-inflammatory agent among alkaloids in the 95% EtOH extract of P. oleracea, was suppressing the MAPK pathway and nuclear translocation of NF-κB. Therefore, P. oleracea extracts and specifically 1-carbomethoxy-ß-carboline may be novel therapeutic candidates for the treatment of inflammatory diseases associated with the activation of MAPKs and NF-κB.
Assuntos
Anti-Inflamatórios , Carbolinas , Núcleo Celular/metabolismo , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Portulaca/química , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Carbolinas/química , Carbolinas/isolamento & purificação , Carbolinas/farmacologia , Núcleo Celular/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , MAP Quinase Quinase 4/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Alkaloids 1â»10 were isolated from the aerial parts of Tetrastigma hemsleyanum (APTH) and obtained from species of the genus Tetrastigma for the first time. The chemical structures of the isolated compounds were identified by NMR, UV, and MS analyses. Their anti-inflammatory activities were investigated by measuring nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Among all the isolates, compounds 6, 7 and 10 showed potent inhibitory activity against LPS-stimulated NO production in RAW264.7 cells (IC50: 31.9, 25.2 and 6.3 µM, respectively). Furthermore, APTH and S-(−)-trolline (10) inhibited induction of inflammatory cytokines or mediators such as interleukin-1ß (IL-1ß) and inducible nitric oxide synthase (iNOS) via suppression of nuclear factor κB (NF-κB) translocation into the nucleus. In addition, 10 suppressed extracellular signal-regulated protein kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) phosphorylation in a dose-dependent manner. These results conclusively demonstrated that compound 10 displays anti-inflammatory activity via suppression of NF-κB activation and the ERK-MAPK signaling pathway in LPS-stimulated RAW264.7 cells.
Assuntos
Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Lipopolissacarídeos/efeitos adversos , Macrófagos/metabolismo , Vitaceae/química , Alcaloides/química , Animais , Anti-Inflamatórios/química , Citocinas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Fosforilação/efeitos dos fármacos , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células RAW 264.7RESUMO
Nine new sesquiterpenoid lactones and 11 known analogues were isolated from the aerial parts of Salvia plebeia R.Br. Their structures were elucidated via HRESIMS and NMR data, and their absolute configurations were defined via electronic circular dichroism data, X-ray crystallographic analysis, and the modified Mosher's ester method. Compounds 1-20 were investigated for their ability to inhibit LPS-stimulated nitric oxide production in murine macrophage cells. Of the isolates, epi-eudebeiolide C (20) showed the highest inhibitory effect (IC50 of 17.9 µM). mRNA and protein expression of inducible nitric oxide synthase (iNOS), but not that of cyclooxygenase-2 (COX-2), was dose-dependently decreased by 20 in LPS-activated RAW 264.7 cells. Based on a mechanistic study involving the nuclear factor-κB (NF-κB) signaling pathway, the anti-inflammatory effect of 20 was attributed to NF-κB activation blockade via inhibition of NF-κB (IκB) phosphorylation. Therefore, 20 might be a potential candidate for relieving inflammatory diseases.
Assuntos
Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Lactonas/isolamento & purificação , Lactonas/farmacologia , Componentes Aéreos da Planta/química , Salvia/química , Sesquiterpenos de Eudesmano/isolamento & purificação , Sesquiterpenos de Eudesmano/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Proteínas I-kappa B/metabolismo , Lactonas/química , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Ressonância Magnética Nuclear Biomolecular , República da Coreia , Sesquiterpenos de Eudesmano/química , Transdução de Sinais/efeitos dos fármacosRESUMO
The seeds of Alpinia katsumadai yielded two new acyclic triterpenoids, 2,3,6,22,23-pentahydroxy-2,6,11,15,19,23-hexamethyl-tetracosa-7,10,14,18-tetraene (3) and 2,3,6,22,23-pentahydroxy-2,10,15,19,23-hexamethyl-7-methylenetetracosa-10,14,18-triene (4), as well as two known compounds, 2,3,22,23-tertrahydroxy-2,6,10,15,19,23-hexamethyl-tetracosa-6,10,14,18-tetraene (1) and 2,3,5,22,23-pentahydroxy-2,6,10,15,19,23-hexamethyl-tetracosa-6,10,14,18-tetraene (2). The absolute configurations of 2 and 3, which were determined by means of a modified Mosher's method, are suggested as (3R; 5S; 22R) and (3R; 22R), respectively. Compounds 1-4 inhibited IL-6-induced JAK2/STAT3 activity in a dose-dependent fashion, with IC50 values of 0.67, 0.71, 2.18, and 2.99 µM. Moreover, IL-6-stimulated phosphorylation of STAT3 was significantly suppressed in U266 cells by the administration of A. katsumadai EtOH extract and Compounds 1 and 2. These results suggest that major phytochemicals, Compounds 1 and 2, obtained from A. katsumadai may be useful candidates for designing new IL-6 inhibitors as anti-inflammatory agents.
Assuntos
Alpinia/química , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Triterpenos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/químicaRESUMO
This study investigated the chemical composition changes of Salvia plebeia R.Br. cultivated under different light sources, including florescent light and sunlight. The plants were exposed to fluorescent light for four months and sunlight and then examined for the next 5-7 months. Plants were harvested monthly during the seven months, and we examined whether the difference in light source affected the phenolic and flavonoid contents and antioxidant activity. A simple and reliable HPLC method using a PAH C18 column was applied for the quantitative analysis of two triterpenoids from the S. plebeia groups. Oleanolic acid (OA) and ursolic acid (UA) showed good linearity (R² > 0.9999) within the test ranges (0.005-0.05 mg/mL), and the average percentage recoveries of the OA and UA were 95.1-104.8% and 97.2-107.1%, respectively. The intra- and inter-day relative standard deviations (RSDs) were less than 2.0%. After exposure to sunlight, the phenolic contents, including rosmarinic acid, showed a reduced tendency, whereas the flavonoid contents, including homoplantaginin and luteolin 7-glucoside, were increased. The content of the triterpenoids also showed an increased tendency under sunlight irradiation, but the variance was not larger than those of the phenolic and flavonoid contents. Among experimental groups, the group harvested at six months, having been exposed to sunlight for two months, showed the most potent antioxidant activity. Therefore, these results showed that the chemical composition and antioxidant activities of S. plebeia R.Br. was affected from environmental culture conditions, such as light source. Our studies will be useful for the development of functional materials using S. plebeia R.Br.
Assuntos
Extratos Vegetais/química , Salvia/efeitos da radiação , Luz Solar , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Cromatografia Líquida de Alta Pressão , Flavonoides/química , Humanos , Camundongos , Estrutura Molecular , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Fenóis/química , Fotossíntese , Células RAW 264.7 , Salvia/química , Salvia/crescimento & desenvolvimento , Triterpenos/química , Triterpenos/farmacologia , Ácido UrsólicoRESUMO
[Purpose] The purpose of the present study was to investigate the effects of dysphagia therapy in an old man with difficulty swallowing in the oral and pharyngeal phases. [Subjects and Methods] The subject was a 72-year-old man with no history of neurological disorders. He was admitted to local hospital because of the complaint of swallowing difficulty. The interventions performed were electrical stimulation and conventional dysphagia therapy. We assessed the tongue and lip muscle strengths. Swallowing function was evaluated by using the videofluoroscopic dysphagia and penetration-aspiration scales. [Results] After the intervention, the tongue and lip muscle strengths increased from 35 to 39 kPa and from 18 to 23 kPa, respectively. Moreover, the oral and pharyngeal phases of the videofluoroscopic dysphagia scale were improved. Furthermore, aspiration decreased from 4 to 2 points in the penetration-aspiration scale. [Conclusion] Our results suggest that electrical stimulation and conventional dysphagia therapy were effective in improving the swallowing function in an elderly individual with dysphagia.
RESUMO
Two new guaiane-type (2, 6) and one new furanogermacrane-type (11) sesquiterpenoids have been isolated along with twelve known compounds from an EtOAc-soluble extract of Curcuma phaeocaulis rhizomes. The structures of the isolated compounds were elucidated using a combination of NMR, MS, and circular dichroism (CD) spectra. The inhibitory effects of each compound on lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4) activation in THP-1-Blue cells were assessed, and compound 4 showed more potent inhibitory activity against LPS-stimulated TLR4 activation.
Assuntos
Curcuma/química , Lipopolissacarídeos/antagonistas & inibidores , Rizoma/química , Sesquiterpenos/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/farmacologia , Conformação Molecular , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Relação Estrutura-Atividade , Receptor 4 Toll-Like/metabolismoRESUMO
Two new feruloyl amides, N-cis-hibiscusamide (5) and (7'S)-N-cis-feruloylnormetanephrine (9), and eight known feruloyl amides were isolated from Portulaca oleracea L. and the geometric conversion of the ten isolated feruloyl amides by UV light was verified. The structures of the feruloyl amides were determined based on spectroscopic data and comparison with literature data. The NMR data revealed that the structures of the isolated compounds showed cis/trans-isomerization under normal laboratory light conditions. Therefore, cis and trans-isomers of feruloyl amides were evaluated for their convertibility and stability by UV light of a wavelength of 254 nm. After 96 h of UV light exposure, 23.2%-35.0% of the cis and trans-isomers were converted to trans-isomers. Long-term stability tests did not show any significant changes. Among all compounds and conversion mixtures collected, compound 6 exhibited the strongest inhibition of IL-6-induced STAT3 activation in Hep3B cells, with an IC50 value of 0.2 µM. This study is the first verification of the conversion rates and an equilibrium ratio of feruloyl amides. These results indicate that this natural material might provide useful information for the treatment of various diseases involving IL-6 and STAT3.