RESUMO
BACKGROUND: Cruciferous vegetable sprout has been highlighted as a promising functional material rich in bioactive compounds called isothiocyanates (ITCs) and it can be grown in very short periods in controlled indoor farms. However, because ITCs content depends on multiple factors such as cultivar, germination time and myrosinase activity, those variables need to be controlled during germination or extraction to produce functional materials enriched in ITCs. Sulforaphene (SFEN), an ITC found primarily in radishes (Raphanus sativus L.), exerts beneficial effects on obesity. However, the optimal germination and extraction conditions for radish sprout (RSP) to increase SFEN content remain unascertained, and the extract's anti-obesity effect has yet to be evaluated. RESULTS: The present study found that the SFEN content was highest in purple radish sprout (PRSP) among the six cultivars investigated. Optimal SFEN content occurred after 2 days of PRSP germination (2 days PRSP). To maximize the dry matter yield, total ITCs and SFEN contents in RSP extract, we found the optimal conditions for extracting PRSP [27.5 °C, 60 min, 1:75.52 solute/solvent (w/v), no ascorbic acid] using response surface methodology. Consistent with high SFEN content, 2 days PRSP extract significantly outperformed 3 days or 4 days PRSP extract in inhibiting lipid accumulation in 3T3-L1 cells. Moreover, 2 days PRSP extract suppressed adipogenesis and lipogenesis-related protein expression. CONCLUSION: Regarding the cultivar, germination time and extraction conditions, optimally produced PRSP extract contains high SFEN content and exerts anti-obesity effects. Thus, we suggest PRSP extract as a potent functional material for obesity prevention. © 2024 Society of Chemical Industry.
Assuntos
Germinação , Isotiocianatos , Extratos Vegetais , Raphanus , Raphanus/química , Raphanus/crescimento & desenvolvimento , Raphanus/metabolismo , Germinação/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Isotiocianatos/farmacologia , Isotiocianatos/isolamento & purificação , Isotiocianatos/química , Isotiocianatos/análise , Camundongos , Animais , Células 3T3-L1 , SulfóxidosRESUMO
The transient receptor potential vanilloid 1 (TRPV1) protein is a pain receptor that elicits a hot sensation when an organism eats the capsaicin of red chili peppers. This calcium (Ca2+)-permeable cation channel is mostly expressed in the peripheral nervous system sensory neurons but also in the central nervous system (e.g. hippocampus and cortex). Preclinical studies found that TRPV1 mediates behaviors associated with anxiety and depression. Loss of TRPV1 functionality increases expression of genes related to synaptic plasticity and neurogenesis. Thus, we hypothesized that TRPV1 deficiency may modulate Alzheimer's disease (AD). We generated a triple-transgenic AD mouse model (3xTg-AD+/+) with wild-type (TRPV1+/+), hetero (TRPV1+/-) and knockout (TRPV1-/-) TRPV1 to investigate the role of TRPV1 in AD pathogenesis. We analyzed the animals' memory function, hippocampal Ca2+ levels and amyloid-ß (Aß) and tau pathologies when they were 12 months old. We found that compared with 3xTg-AD-/-/TRPV1+/+ mice, 3xTg-AD+/+/TRPV1+/+ mice had memory impairment and increased levels of hippocampal Ca2+, Aß and total and phosphorylated tau. However, 3xTg-AD+/+/TRPV1-/- mice had better memory function and lower levels of hippocampal Ca2+, Aß, tau and p-tau, compared with 3xTg-AD+/+/TRPV1+/+ mice. Examination of 3xTg-AD-derived primary neuronal cultures revealed that the intracellular Ca2+ chelator BAPTA/AM and the TRPV1 antagonist capsazepine decreased the production of Aß, tau and p-tau. Taken together, these results suggested that TRPV1 deficiency had anti-AD effects and promoted resilience to memory loss. These findings suggest that drugs or food components that modulate TRPV1 could be exploited as therapeutics to prevent or treat AD.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Cálcio/metabolismo , Transtornos da Memória/metabolismo , Canais de Cátion TRPV/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Canais de Cálcio/metabolismo , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Quelantes/farmacologia , Modelos Animais de Doenças , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Hipocampo/metabolismo , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/genética , Camundongos , Camundongos Knockout , Nociceptores/metabolismo , Nociceptores/patologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Proteínas tau/genéticaRESUMO
Atopic dermatitis is a skin disease characterized by chronic inflammatory lesions, and new therapies are needed to address its rising prevalence. Soy isoflavone has been highlighted as a potential new cosmeceutical material that may have applications in atopic dermatitis care. We have developed a technique to attach an additional -OH group to the ortho position of -OH in the phenol ring using a special enzyme. By adding the -OH group to daidzein, 7,3',4'-trihydroxyisoflavone can be generated for possible use as a cosmeceutical and functional food material. In this study, we sought to examine the anti-atopic effects of 7,3',4'-trihydroxyisoflavone, an analog of daidzein. Topical application of 7,3',4'-trihydroxyisoflavone reduced Dermatophagoides farina extract-induced atopic dermatitis symptoms in NC/Nga mice. Histological analysis demonstrated that 7,3',4'-trihydroxyisoflavone suppressed D. farina extract-induced infiltration of eosinophils and mast cells into skin lesions. We also found that 7,3',4'-trihydroxyisoflavone significantly reduces the D. farina extract-induced increases in serum IgE and macrophage-derived chemokine (CCL22) levels. We observed that 7,3',4'-trihydroxyisoflavone suppresses atopic markers including macrophage-derived chemokine (CCL22) and thymus and activation-regulated chemokine (CCL17) in HaCaT cells. 7,3',4'-Trihydroxyisoflavone also reduced TNF-α/IFN-γ-induced phosphorylation of ERK1/2 and JNK1/2. These results highlight several desirable properties of 7,3',4'-trihydroxyisoflavone, which support its use as a cosmeceutical ingredient for the treatment of atopic dermatitis.
Assuntos
Dermatite Atópica , Animais , Imunoglobulina E , Isoflavonas , Mastócitos , Camundongos , Extratos Vegetais , PeleRESUMO
Several metabolomics of polymeric flavan-3-ols have reported that proanthocyanidins are extensively metabolized by gut microbiota. 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (DHPV) has been reported to be the major microbial metabolite of proanthocyanidins. We demonstrated that DHPV has stronger prevention effect on tumor necrosis factor (TNF)-α-stimulated adhesion of THP-1 human monocytic cells to human umbilical vein endothelial cells compared to its potential precursors such as procyanidin A1, A2, B1 and B2, (+)catechin, (-)epicatechin and its microbial metabolites such as 3-(3,4-dihydroxyphenyl)propionic acid and 2-(3,4-dihydroxyphenyl)acetic acid. Mechanism study showed that DHPV prevents THP-1 monocyte-endothelial cell adhesion by downregulating TNF-α-stimulated expressions of the two biomarkers of atherosclerosis such as vascular cell adhesion molecule-1 and monocyte chemotactic protein-1, activation of nuclear factor kappa B transcription and phosphorylation of I kappa-B kinase and IκBα. We suggested that DHPV has higher potentiality in prevention of atherosclerosis among the proanthocyanidin metabolites.
Assuntos
Adesão Celular/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Monócitos/metabolismo , Proantocianidinas/farmacologia , Linhagem Celular , Células Endoteliais/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas , Monócitos/imunologia , NF-kappa B/genética , NF-kappa B/metabolismo , Fosforilação , Proantocianidinas/metabolismo , Regiões Promotoras Genéticas , Substâncias Protetoras , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Soybean-derived isoflavones have been investigated for their preventative effects against UV-induced symptoms of skin damage including wrinkle formation and inflammation. Haematococcus pluvialis is a freshwater species of Chlorophyta that contains high concentrations of the natural carotenoid pigment astaxanthin. Astaxanthin is known to be involved in retinoic acid receptor (RAR) signaling and previously been associated with the inhibition of activator protein (AP)-1 dependent transcription. Based on previous studies, we hypothesized that a combination of soy extract (SE) and Haematococcus extract (HE) may prevent UVB-induced photoaging through specific signaling pathways, as measured by UVB-induced wrinkling on hairless mice skin and expression changes in human dermal fibroblasts (HDFs). The 1:2 ratio of SE and HE mixture (SHM) showed the optimal benefit in vivo. SHM was found to inhibit wrinkle formation via the downregulation of matrix metalloproteinase (MMP)-1 mRNA and protein expression. SHM also inhibited mitogen-activated protein kinase (MAPK) phosphorylation and the transactivation of AP-1 which plays an important role in regulating MMP expression. These results highlight the potential for SHM to be developed as a therapeutic agent to prevent UVB-induced skin wrinkling.
Assuntos
Clorófitas/química , Glycine max/química , Extratos Vegetais/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Administração Oral , Animais , Senescência Celular/efeitos dos fármacos , Senescência Celular/efeitos da radiação , Colágeno/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Epiderme/patologia , Epiderme/efeitos da radiação , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Camundongos , Camundongos Nus , Extratos Vegetais/administração & dosagem , Proteólise , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Fatores de Tempo , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
Licorice extracts containing glycyrrhizin exhibit anti-carcinogenic properties. Because glycyrrhizin induces severe hypokalemia and hypertension, we prepared a hexane/ethanol extract of Glycyrrhiza uralensis (HEGU) that lacks glycyrrhizin, and showed that HEGU induces apoptosis and G1 cell cycle arrest and inhibits migration of DU145 human prostate cancer cells. Our previous in vitro studies identified two active components in HEGU: isoangustone A, which induces apoptosis and G1 cycle arrest, and licoricidin, which inhibits metastasis. This study examined whether HEGU and licoricidin inhibit metastasis using the 4T1 mammary cancer model. Both HEGU and licoricidin treatment reduced pulmonary metastasis and the expression of CD45, CD31, HIF-1α, iNOS, COX-2, and VEGF-A in tumor tissues. Additionally, a decrease in protein expression of VEGF-R2, VEGF-C, VEGF-R3, and LYVE-1 was noted in tumor tissues of licoricidin-treated mice. Furthermore, the blood concentrations of MMP-9, ICAM-1, VCAM-1, and VEGF-A were decreased in HEGU-treated mice. In vitro 4T1 cell culture results showed that both HEGU and licoricidin inhibited cell migration, MMP-9 secretion, and VCAM expression. The present study demonstrates that the licoricidin in HEGU inhibits lung metastasis of 4T1 mammary carcinoma cells, which may be mediated via inhibition of cancer cell migration, tumor angiogenesis, and lymphangiogenesis.
Assuntos
Antineoplásicos/uso terapêutico , Benzopiranos/farmacologia , Carcinoma/tratamento farmacológico , Glycyrrhiza/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzopiranos/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma/patologia , Ciclo-Oxigenase 2/sangue , Feminino , Humanos , Neoplasias Pulmonares/secundário , Células MCF-7 , Neoplasias Mamárias Experimentais/patologia , Metaloproteinase 9 da Matriz/sangue , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/farmacologia , Molécula 1 de Adesão de Célula Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Benzyl isothiocyanate (BITC) is a hydrolysis product of glucotropaeolin, a compound found in cruciferous vegetables, and has been shown to have anti-tumor properties. In the present study, we investigated whether BITC inhibits the development of prostate cancer in the transgenic adenocarcinoma mouse prostate (TRAMP) mice. Five-week old, male TRAMP mice and their nontransgenic littermates were gavage-fed with 0, 5, or 10 mg/kg of BITC every day for 19 weeks. The weight of the genitourinary tract increased markedly in TRAMP mice and this increase was suppressed significantly by BITC feeding. H and E staining of the dorsolateral lobes of the prostate demonstrated that well-differentiated carcinoma (WDC) was a predominant feature in the TRAMP mice. The number of lobes with WDC was reduced by BITC feeding while that of lobes with prostatic intraepithelial neoplasia was increased. BITC feeding reduced the number of cells expressing Ki67 (a proliferation marker), cyclin A, cyclin D1, and cyclin-dependent kinase (CDK)2 in the prostatic tissue. In vitro cell culture results revealed that BITC decreased DNA synthesis, as well as CDK2 and CDK4 activity in TRAMP-C2 mouse prostate cancer cells. These results indicate that inhibition of cell cycle progression contributes to the inhibition of prostate cancer development in TRAMP mice treated with BITC.
Assuntos
Antineoplásicos/administração & dosagem , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Isotiocianatos/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isotiocianatos/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Tamanho do Órgão/efeitos dos fármacos , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We reported previously that high-fat diet (HFD) feeding stimulated solid tumor growth and lymph node (LN) metastasis in C57BL/6N mice injected with B16F10 melanoma cells. ß-caryophyllene (BCP) is a natural bicyclic sesquiterpene found in many essential oils and has been shown to exert anti-inflammatory activities. To examine whether BCP inhibits HFD-induced melanoma progression, 4-weeks old, male C57BL/6N mice were fed a control diet (CD, 10 kcal% fat) or HFD (60 kcal% fat + 0, 0.15 or 0.3% BCP) for the entire experimental period. After 16 weeks of feeding, B16F10s were subcutaneously injected into mice. Three weeks later, tumors were resected, and mice were killed 2 weeks post-resection. Although HFD feeding increased body weight gain, fasting blood glucose levels, solid tumor growth, LN metastasis, tumor cell proliferation, angiogenesis and lymphangiogenesis, it decreased apoptotic cells, all of which were suppressed by dietary BCP. HFD feeding increased the number of lipid vacuoles and F4/80+ macrophage (MΦ) and macrophage mannose receptor (MMR)+ M2-MΦs in tumor tissues and adipose tissues surrounding the LN, which was suppressed by BCP. HFD feeding increased the levels of CCL19 and CCL21 in the LN and the expression of CCR7 in the tumor; these changes were blocked by dietary BCP. In vitro culture results revealed that BCP inhibited lipid accumulation in 3T3-L1 preadipocytes; monocyte migration and monocyte chemoattractant protein-1 secretion by B16F10s, adipocytes and M2-MΦs; angiogenesis and lymphangiogenesis. The suppression of adipocyte and M2-cell accumulation and the inhibition of CCL19/21-CCR7 axis may be a part of mechanisms for the BCP suppression of HFD-stimulated melanoma progression.
Assuntos
Antineoplásicos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Melanoma Experimental/tratamento farmacológico , Sesquiterpenos/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Células 3T3 , Adipócitos/metabolismo , Animais , Peso Corporal , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL19/antagonistas & inibidores , Quimiocina CCL19/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL21/antagonistas & inibidores , Quimiocina CCL21/metabolismo , Gorduras na Dieta , Lectinas Tipo C/metabolismo , Linfonodos/patologia , Metástase Linfática , Macrófagos/citologia , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Obesidade/patologia , Sesquiterpenos Policíclicos , Distribuição Aleatória , Receptores CCR7/antagonistas & inibidores , Receptores CCR7/biossíntese , Receptores de Superfície Celular/metabolismo , Neoplasias Cutâneas/patologia , Gordura Subcutânea/citologia , Gordura Subcutânea/patologia , Vacúolos/patologia , Aumento de Peso/efeitos dos fármacosRESUMO
To examine the effects of high-fat diet (HFD) on melanoma progression, HFD-fed C57BL/6N mice were subcutaneously injected with syngeneic B16F10 melanoma cells. At 3 weeks post-injection, the tumors were resected; the mice were then sacrificed at 2 weeks post-resection. HFD stimulated melanoma growth and lymph node (LN) metastasis as well as tumor and LN lymphangiogenesis. Lipid vacuoles in the tumor and M2-macrophage (MΦ)s in the adipose and tumor tissues were increased in HFD-fed mice. CCL19 and CCL21 contents were higher in LNs than in tumors. HFD increased both CCL19 and CCL21 levels in LNs and CCR7 in tumors. Adipose tissue-conditioned media (CM) from HFD-fed mice enhanced lymphangiogenesis, and mature adipocyte (MA)/M2-MΦ co-culture CM markedly stimulated the tube formation of lymphatic endothelial cell (LEC)s and B16F10 migration. Monocyte migration was moderately stimulated by B16F10 or MA CM, but tremendously stimulated by B16F10/M2-MΦ co-culture CM, which was enhanced by MA/B16F10/M2-MΦ co-culture CM. The co-culture results revealed that MAs increased CCL2, M-CSF and CCR7 mRNAs in B16F10s; vascular endothelial growth factor (VEGF)-D mRNA in M2-MΦs; and CCL19, CCL21 and VEGF receptor (VEGFR)3 mRNA in LECs. M2-MΦs increased CCL2, M-CSF and VEGF-A mRNAs in B16F10s, whereas B16F10s increased VEGF-C mRNAs in M2-MΦs and VEGFR3 mRNA in LECs. These results indicate that in HFD-fed mice, MA-induced CCL2 and M-CSF in tumor cells increase M2-MΦs in tumor; the crosstalk between tumor cells and M2-MΦs further increases cytokines and angiogenic and lymphangiogenic factors. Additionally, MA-stimulated CCL19, CCL21/CCR7 axis contributes to increased LN metastasis in HFD-fed mice.
Assuntos
Adipócitos/patologia , Dieta Hiperlipídica/efeitos adversos , Linfangiogênese , Macrófagos/patologia , Melanoma Experimental/patologia , Obesidade/etiologia , Adipócitos/metabolismo , Aloenxertos , Animais , Apoptose , Western Blotting , Proliferação de Células , Quimiocinas/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Leptina/fisiologia , Metástase Linfática , Macrófagos/metabolismo , Masculino , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica , Obesidade/fisiopatologia , Análise Serial de Proteínas , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 4 de Melanocortina/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Microambiente TumoralRESUMO
We previously reported that a high-fat diet (HFD) and M2-macrophages induce changes in tumor microenvironments and stimulate tumor growth and metastasis of 4T1 mammary cancer cells in BALB/c mice. In this study, we attempted to determine whether benzyl isothiocyanate (BITC) inhibits HFD-induced changes in tumor progression and in tumor microenvironments. Four groups of female BALB/c mice (4-week-old) were fed on a control diet (CD, 10 kcal% fat) and HFD (60 kcal% fat) containing BITC (0, 25, or 100 mg/kg diet) for 20 weeks. Following 16 weeks of feeding, 4T1 cells (5×10(4) cells) were injected into the mammary fat pads, and animals were killed 30 d after the injection. HFD feeding increased solid tumor growth and the number of tumor nodules in the lung and liver, as compared to the CD group, and these increases were inhibited by BITC supplementation. The number of lipid vacuoles, CD45+ leukocytes and CD206+ M2-macrophages, expression of Ki67, levels of cytokines/chemokines, including macrophage-colony stimulating factor (M-CSF) and monocyte chemoattractant protein-1, and mRNA levels of F4/80, CD86, Ym1, CD163, CCR2, and M-CSF receptor were increased in the tumor tissues of HFD-fed mice, and these increases were inhibited by BITC supplementation. In vitro culture results demonstrated that BITC inhibited macrophage migration as well as lipid droplet accumulation in 3T3-L1 cells. These results suggest that suppression of lipid accumulation and macrophage infiltration in tumor tissues may be one of the mechanisms by which BITC suppresses tumor progression in HFD-fed mice.
Assuntos
Gorduras na Dieta/efeitos adversos , Isotiocianatos/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Microambiente Tumoral/efeitos dos fármacos , Células 3T3-L1 , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Isotiocianatos/farmacologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Obesidade/metabolismoRESUMO
BACKGROUND: Eotaxin proteins are a potential therapeutic target in treating the peribronchial eosinophilia associated with allergic airway diseases. Since inflammation is often associated with an increased generation of reactive oxygen species (ROS), oxidative stress is a mechanistically imperative factor in asthma. Astragalin (kaempferol-3-O-glucoside) is a flavonoid with anti-inflammatory activity and newly found in persimmon leaves and green tea seeds. This study elucidated that astragalin inhibited endotoxin-induced oxidative stress leading to eosinophilia and epithelial apoptosis in airways. METHODS: Airway epithelial BEAS-2B cells were exposed to lipopolysaccharide (LPS) in the absence and presence of 1-20 µM astragalin. Western blot and immunocytochemical analyses were conducted to determine induction of target proteins. Cell and nuclear staining was also performed for ROS production and epithelial apoptosis. RESULTS: When airway epithelial cells were exposed to 2 µg/ml LPS, astragalin nontoxic at ≤ 20 µM suppressed cellular induction of Toll-like receptor 4 (TLR4) and ROS production enhanced by LPS. Both LPS and H2O2 induced epithelial eotaxin-1 expression, which was blocked by astragalin. LPS activated and induced PLCγ1, PKCß2, and NADPH oxidase subunits of p22phox and p47phox in epithelial cells and such activation and induction were demoted by astragalin or TLR4 inhibition antagonizing eotaxin-1 induction. H2O2-upregulated phosphorylation of JNK and p38 MAPK was dampened by adding astragalin to epithelial cells, while this compound enhanced epithelial activation of Akt and ERK. H2O2 and LPS promoted epithelial apoptosis concomitant with nuclear condensation or caspase-3 activation, which was blunted by astragalin. CONCLUSIONS: Astragalin ameliorated oxidative stress-associated epithelial eosinophilia and apoptosis through disturbing TLR4-PKCß2-NADPH oxidase-responsive signaling. Therefore, astragalin may be a potent agent antagonizing endotoxin-induced oxidative stress leading to airway dysfunction and inflammation.
Assuntos
Apoptose/efeitos dos fármacos , Quimiocina CCL11/antagonistas & inibidores , Quempferóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Preparações de Plantas/farmacologia , Brônquios , Caspase 3/metabolismo , Células Cultivadas , Diospyros , Ativação Enzimática/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Células Epiteliais , Humanos , Peróxido de Hidrogênio/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NADPH Oxidases/metabolismo , Oxidantes/farmacologia , Fosfolipase C gama/metabolismo , Fosforilação/efeitos dos fármacos , Folhas de Planta , Proteína Quinase C beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Skeletal muscle inflammation and atrophy are closely associated with metabolic impairment such as insulin resistance. Quercetin, a natural polyphenol flavonoid, is known to elicit anti-inflammatory and antioxidant activities. In this study, we investigated its effect on obesity-induced skeletal muscle inflammation and atrophy in mice. Male C57BL/6 mice were fed a regular diet, a high-fat diet (HFD), and an HFD supplemented with quercetin for nine weeks. Quercetin reduced levels of inflammatory cytokines and macrophage accumulation in the skeletal muscle of the HFD-fed obese mice. It also reduced transcript and protein levels of the specific atrophic factors, Atrogin-1 and MuRF1, in the skeletal muscle of the HFD-fed obese mice, and protected against the reduction of muscle mass and muscle fiber size. In vitro, quercetin markedly diminished transcript levels of inflammatory receptors and activation of their signaling molecules (ERK, p38 MAPK, and NF-κB) in cocultured myotubes/macrophages, and this was accompanied by reduced expression of the atrophic factors. Together, these findings suggest that quercetin reduces obesity-induced skeletal muscle atrophy by inhibiting inflammatory receptors and their signaling pathway. Quercetin may be useful for preventing obesity-induced muscle inflammation and sarcopenia.
Assuntos
Antioxidantes/química , Atrofia/patologia , Inflamação/patologia , Músculo Esquelético/patologia , Obesidade/complicações , Quercetina/química , Animais , Sequência de Bases , Linhagem Celular , Citocinas/metabolismo , Inflamação/metabolismo , Resistência à Insulina , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Sarcopenia/metabolismo , Transdução de Sinais , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Berteroin (5-methylthiopentyl isothiocyanate) is a sulforaphane analog present in cruciferous vegetables, including Chinese cabbage, rucola salad leaves, and mustard oil. We examined whether berteroin exerts anti-inflammatory activities using lipopolysaccharide (LPS)-stimulated Raw 264.7 macrophages and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin inflammation models. Berteroin decreased LPS-induced release of inflammatory mediators and pro-inflammatory cytokines in Raw 264.7 macrophages. Berteroin inhibited LPS-induced degradation of inhibitor of κBα (IκBα) and nuclear factor-κB p65 translocation to the nucleus and DNA binding activity. Furthermore, berteroin suppressed degradation of IL-1 receptor-associated kinase and phosphorylation of transforming growth factor ß activated kinase-1. Berteroin also inhibited LPS-induced phosphorylation of p38 MAPK, ERK1/2, and AKT. In the mouse ear, berteroin effectively suppressed TPA-induced edema formation and down-regulated iNOS and COX-2 expression as well as phosphorylation of AKT and ERK1/2. These results demonstrate that berteroin exhibits potent anti-inflammatory properties and suggest that berteroin can be developed as a skin anti-inflammatory agent.
Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Isotiocianatos/farmacologia , Macrófagos/efeitos dos fármacos , Pele/efeitos dos fármacos , Verduras/química , Animais , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/imunologia , Citocinas/imunologia , Feminino , Proteínas I-kappa B/imunologia , Inflamação/induzido quimicamente , Inflamação/imunologia , Isotiocianatos/química , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Camundongos , Inibidor de NF-kappaB alfa , Óxido Nítrico/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Pele/imunologia , Acetato de Tetradecanoilforbol/análogos & derivadosRESUMO
We previously noted that kaempferol, a flavonol present in vegetables and fruits, reduced cell cycle progression of HT-29 cells. To examine whether kaempferol induces apoptosis of HT-29 cells and to explore the underlying molecular mechanisms, cells were treated with various concentrations (0-60 µmol/L) of kaempferol and analyzed by Hoechst staining, Annexin V staining, JC-1 labeling of the mitochondria, immunoprecipitation, in vitro kinase assays, Western blot analyses, and caspase-8 assays. Kaempferol increased chromatin condensation, DNA fragmentation and the number of early apoptotic cells in HT-29 cells in a dose-dependent manner. In addition, kaempferol increased the levels of cleaved caspase-9, caspase-3 and caspase-7 as well as those of cleaved poly (ADP-ribose) polymerase. Moreover, it increased mitochondrial membrane permeability and cytosolic cytochrome c concentrations. Further, kaempferol decreased the levels of Bcl-xL proteins, but increased those of Bik. It also induced a reduction in Akt activation and Akt activity and an increase in mitochondrial Bad. Additionally, kaempferol increased the levels of membrane-bound FAS ligand, decreased those of uncleaved caspase-8 and intact Bid and increased caspase-8 activity. These results indicate that kaempferol induces the apoptosis of HT-29 cells via events associated with the activation of cell surface death receptors and the mitochondrial pathway.
Assuntos
Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Quempferóis/toxicidade , Clorometilcetonas de Aminoácidos/farmacologia , Caspase 3/química , Caspase 3/metabolismo , Caspase 7/química , Caspase 7/metabolismo , Caspase 8/química , Caspase 8/metabolismo , Caspase 9/química , Caspase 9/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Citocromos c/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Células HT29 , Humanos , Mitocôndrias/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína bcl-X/metabolismoRESUMO
Carnosic acid is a natural benzenediol abietane diterpene found in rosemary and exhibits anti-inflammatory, antioxidant, and anti-carcinogenic activities. In this study, we evaluated the effects of carnosic acid on the metastatic characteristics of B16F10 melanoma cells. When B16F10 cells were cultured in an in vitro Transwell system, carnosic acid inhibited cell migration in a dose-dependent manner. Carnosic acid suppressed the adhesion of B16F10 cells, as well as the secretion of matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1, urokinase plasminogen activator (uPA), and vascular cell adhesion molecule (VCAM)-1. Interestingly, secretion of TIMP-2 increased significantly in B16F10 cells treated with 10 µmol/L carnosic acid. Additionally, carnosic acid suppressed the mesenchymal markers snail, slug, vimentin, and N-cadherin and induced epithelial marker E-cadherin. Furthermore, carnosic acid suppressed phosphorylation of Src, FAK, and AKT. These results indicate that inhibition of the epithelial-mesenchymal transition may be important for the carnosic acid-induced inhibition of B16F10 cell migration.
Assuntos
Abietanos/farmacologia , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Melanoma/metabolismo , Extratos Vegetais/farmacologia , Animais , Linhagem Celular Tumoral , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Fatores de Transcrição da Família Snail , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/genética , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Vimentina/genética , Vimentina/metabolismoRESUMO
Capsosiphon fulvescens (CF) is a green alga widely consumed in East Asian countries, particularly in Korea. It has a rich composition of vitamins, minerals, dietary fibers, and bioactive compounds, which contribute to its multiple therapeutic properties. Its application ranges from acting as an antioxidant and anti-inflammatory agent to supporting the skin system. Despite these benefits of CF, the effects and mechanisms of action related to photoaging of the skin have not yet been elucidated. To investigate the photoprotective effects of CF against photoaging, both animal (SKH-1 mouse) and cell models (HaCaT cell line) were used in this study. As a result, administering the CF extract over a period of 10 weeks, which included times of Ultraviolet B (UVB) exposure, significantly reduced erythema and various UVB-induced skin changes, such as wrinkle formation, and the thickening of the epidermis and dermis, as well as alterations in the length and depth of wrinkles. Furthermore, our investigation into CF extract's antiwrinkle properties revealed its efficacy in enhancing skin hydration and collagen content, counteracting the collagen depletion and moisture loss induced by UVB radiation. Also, the fact that the levels of p-ERK, p-p38, and p-JNK proteins went down shows that the CF extract might have a controlling effect on the MAPK signaling pathways. Our findings suggest that CF holds significant potential for preventing photoaging, providing a foundation for the development of functional foods or botanical drugs targeting skin aging and related skin disorders. PRACTICAL APPLICATION: This research proved that Capsosiphon fulvescen, a green alga widely consumed in East Asian countries, provides photoprotective activities against UV-induced skin aging. Therefore, Capsosiphon fulvescen can be utilized as functional foods or botanical drugs targeting skin aging and related skin disorders.
Assuntos
Queratinócitos , Extratos Vegetais , Envelhecimento da Pele , Raios Ultravioleta , Animais , Raios Ultravioleta/efeitos adversos , Camundongos , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Extratos Vegetais/farmacologia , Humanos , Clorófitas/química , Camundongos Pelados , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Células HaCaT , Feminino , Colágeno/metabolismo , Algas ComestíveisRESUMO
This review investigates the therapeutic effects of Ulmus species extracts, traditionally used as tea ingredients in East Asia, on bone health and inflammatory conditions. Through the analysis of 9757 studies, narrowing down to 56 pertinent ones, we evaluated the safety and efficacy of Ulmus extracts. The focus was on catechin glycosides (CG) and flavonoid glycosides (FG), key compounds identified for their potential benefits. The research highlights the extracts' role in enhancing bone mineral density (BMD) by stimulating osteoblast activity and suppressing osteoclast differentiation, suggesting a protective effect against osteoporosis. Furthermore, the extracts demonstrated significant anti-inflammatory properties by modulating inflammatory markers and pathways. The findings confirm the historical use of Ulmus extracts in East Asia for health benefits and recommend further exploration into functional foods and nutraceuticals. The review calls for more rigorous research, including clinical trials, to establish optimal use and integration into modern health solutions. It underscores the potential of Ulmus extracts in promoting bone health and managing inflammation, advocating for a bridge between traditional practices and contemporary scientific validation. In conclusion, Ulmus extracts, a material long consumed as tea ingredients in East Asia, exhibit significant potential for improving bone health and reducing inflammation. This review calls for additional research to explore their full therapeutic capabilities, emphasizing the need for optimized extraction methods and clinical trials. It reinforces the importance of bridging traditional knowledge with contemporary scientific approaches to health and dietary solutions, promoting overall wellness.
RESUMO
Obesity instigates various health problems such as atherosclerosis, diabetes, and cancer. Resistin, an adipose tissue-specific secretory adipokine, operates endocrine functions through increasing insulin resistance. Vascular smooth muscle cells (SMC) migrate into the subendothelial space and proliferate, thereby contributing to neointimal formation in atherosclerosis and restenosis. The aim of this study was to elucidate whether celastrol obtained from Tripterygium wilfordii Hook, inhibited human aortic SMC migration. Celastrol capable of antagonizing inflammatory responses attenuated the resistin secretion from THP-1-derived macrophages. The macrophage-conditioned media promoted SMC proliferation and MMP-2 production, which was dampened by 10-100 nM celastrol. Celastrol encumbered the SMC migration in response to 50 ng/ml resistin, concomitant with the inhibition of induction of connective tissue growth factor and collagen I/IV. In addition, celastrol disabled human aortic SMC exposed to resistin from migrating. The resistin-induced shedding of integrin ß2/ß3 expression was demoted by celastrol, thereby contributing to the inhibition of collagen matrix-SMC interaction. Next, resistin-induced Toll-like receptor-4 (TLR-4) expression was abrogated by celastrol, indicating that TLR-4 was the resistin signaling receptor that was blocked by celastrol. Collectively, these results demonstrate that anti-inflammatory celastrol blunted the macrophage secretion of the adipokine resistin, and suppressed the SMC migration by disturbing the interaction between SMC and intimal collagen matrix. Therefore, celastrol may inhibit atherogenic migration of vascular SMC upon resistin loading by intimal macrophages within atherosclerotic lesions.
Assuntos
Aterosclerose/metabolismo , Resistência à Insulina , Músculo Liso Vascular , Resistina/metabolismo , Triterpenos/administração & dosagem , Aorta/citologia , Aorta/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Colágeno Tipo IV/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Resistência à Insulina/genética , Macrófagos/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Triterpenos Pentacíclicos , Receptor 4 Toll-Like/metabolismo , TripterygiumRESUMO
Licorice extract which is used as a natural sweetener has been shown to possess inhibitory effects against prostate cancer, but the mechanisms responsible are poorly understood. Here, we report a compound, isoangustone A (IAA) in licorice that potently suppresses the growth of aggressive prostate cancer and sought to clarify its mechanism of action. We analyzed its inhibitory effects on the growth of PTEN-deleted human prostate cancer cells, in vitro and in vivo. Administration of IAA significantly attenuated the growth of prostate cancer cell cultures and xenograft tumors. These effects were found to be attributable to inhibition of the G1/S phase cell cycle transition and the accumulation of p27(kip1). The elevated p27(kip1) expression levels were concurrent with the decrease of its phosphorylation at threonine 187 through suppression of CDK2 kinase activity and the reduced phosphorylation of Akt at Serine 473 by diminishing the kinase activity of the mammalian target of rapamycin (mTOR). Further analysis using recombinant proteins and immunoprecipitated cell lysates determined that IAA exerts suppressive effects against CDK2 and mTOR kinase activity by direct binding with both proteins. These findings suggested that the licorice compound IAA is a potent molecular inhibitor of CDK2 and mTOR, with strong implications for the treatment of prostate cancer. Thus, licorice-derived extracts with high IAA content warrant further clinical investigation for nutritional sources for prostate cancer patients.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Quinase 2 Dependente de Ciclina/efeitos dos fármacos , Isoflavonas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Serina-Treonina Quinases TOR/efeitos dos fármacos , Animais , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Ativação Enzimática/efeitos dos fármacos , Imunofluorescência , Ácido Glicirrízico/farmacologia , Humanos , Imuno-Histoquímica , Imunoprecipitação , Indicadores e Reagentes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Resveratrol is a phytoalexin abundantly found in red grape skin and is effective in antitumor and antiinflammation associated with immune responses. This study investigated whether resveratrol suppressed immunoglobulin (Ig)E-mediated allergic responses and passive cutaneous anaphylaxis (PCA) in rat RBL-2H3 mast cells and in BALB/c mice. The release of ß-hexosaminidase and histamine was enhanced in mast cells sensitized with anti-dinitrophenyl (DNP)-IgE and subsequently stimulated by DNP-human serum albumin (HSA), indicative of mast cell degranulation. When mast cells were pretreated with nontoxic resveratrol at 1-25 µmol/L, such induction was dose dependently diminished. Spleen tyrosine kinase (Syk) and phospholipase Cγ (PLCγ) of sensitized mast cells were activated by stimulation with DNP-HSA antigen, which was dampened by ≥5 µmol/L resveratrol. The phosphorylation of protein kinase C (PKC)µ and PKCθ was attenuated by administering resveratrol to DNP-HSA-exposed mast cells, whereas quiescent PKCζ/λ in sensitized cells was dose-dependently activated by resveratrol. Male BALB/c mice were sensitized for 24 h with DNP-IgE and orally administered with resveratrol 1 h before the DNP-HSA challenge. The histamine concentration was enhanced in sensitized mice challenged to DNP-HSA, which was reversed by administration of 10 mg/kg resveratrol. Additionally, it encumbered the tissue activation of Syk, PLCγ, and PKCµ in antigen-exposed mice. Resveratrol decreased IgE-mediated PCA and alleviated allergic edema of mouse ear and dorsal skin. Mast cell degranulation and allergic inflammation, accompanying the induction of monocyte chemotactic protein-1 and macrophage inflammatory protein-2, were inhibited by supplementing resveratrol to antigen-challenged mice. Resveratrol inhibited mast cell-derived, immediate-type allergic reactions, and these responses of resveratrol suggest possible therapeutic strategies in preventing allergic inflammatory diseases.