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Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.
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Peptídeo Natriurético Tipo C , Neovascularização Patológica , Microambiente Tumoral , Animais , Neovascularização Patológica/tratamento farmacológico , Peptídeo Natriurético Tipo C/farmacologia , Peptídeo Natriurético Tipo C/uso terapêutico , Camundongos , Humanos , Microambiente Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/irrigação sanguínea , Imunidade/efeitos dos fármacosRESUMO
Melanoma, a cancer arising from melanocytes, requires a novel treatment strategy because of the ineffectiveness of conventional therapies in certain patients. Fustin is a flavanonol found in young fustic (Cotinus coggygria). However, little is known about its antimelanoma effects. Our study demonstrates that fustin suppresses the growth of B16 melanoma cells. Phalloidin staining of cytoskeletal actin revealed that fustin induced a conformational change in the actin structure of melanoma cells, accompanied by suppressed phosphorylation of myosin regulatory light chain 2 (MLC2), a regulator of actin structure. Furthermore, the protein kinase A (cAMP-dependent protein kinase) inhibitor H89 completely attenuated fustin-induced downregulation of phosphorylated myosin phosphatase targeting subunit 1, which is involved in dephosphorylation of MLC2. In a mouse model, administration of fustin suppressed tumor growth in B16 melanoma cells without adverse effects. In conclusion, our findings suggest that fustin effectively suppresses melanoma cell growth both in vitro and in vivo.
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Proliferação de Células , Proteínas Quinases Dependentes de AMP Cíclico , AMP Cíclico , Melanoma Experimental , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proliferação de Células/efeitos dos fármacos , AMP Cíclico/metabolismo , Melanoma Experimental/patologia , Melanoma Experimental/metabolismo , Melanoma Experimental/tratamento farmacológico , Linhagem Celular Tumoral , Camundongos , Fosforilação/efeitos dos fármacos , Cadeias Leves de Miosina/metabolismo , Miosinas Cardíacas/metabolismo , Flavonoides/farmacologia , Isoquinolinas/farmacologia , Actinas/metabolismo , Sulfonamidas/farmacologia , Humanos , Melanoma/patologia , Melanoma/metabolismo , Melanoma/tratamento farmacológico , Camundongos Endogâmicos C57BLRESUMO
Cirrhosis is becoming one of the most common diseases worldwide. Abnormal upregulation of transforming growth factor ß (TGF-ß) signaling plays a pivotal role in the excess activation of hepatic stellate cells. However, an efficient countermeasure against abnormal hepatic stellate cell activation is yet to be established because TGF-ß signaling is involved in several biological processes. Herein, we demonstrated the antifibrotic effect of miR-12135, a microRNA with unknown function upregulated by isoflavone. Comprehensive transcriptome assay demonstrated that miR-12135 suppressed Integrin Subunit Alpha 11 (ITGA11) and that ITGA11 expression is correlated with alpha smooth muscle actin expression in patients with cirrhosis. miR-12135 suppressed the expression level of ITGA11 and liver fibrosis. Importantly, ITGA11 is overexpressed in activated hepatic stellate cells, whereas ITGA11 knockout mice are viable and fertile. In conclusions, the miR-12135/ITGA11 axis can be an ideal therapeutic target to suppress fibrosis by precisely targeting abnormally upregulated TGF-ß signaling in hepatic stellate cells.
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There are few studies on the connection between food components and circular RNA (circRNA), a type of noncoding RNA that is significant for living organisms. (-)-Epigallocatechin-3-O-gallate (EGCG) has been reported to have various biological effects, and elucidation of the molecular mechanism is important for clarifying the functionality of EGCG. In the current study, we looked at how EGCG regulates the expression of circRNA in the liver, which expresses a lot of circRNAs. Mice were given EGCG (10 mg/kg b.w.) orally for one week before circRNA microarray testing was done on their livers. The microarray analysis revealed that mice treated with EGCG had altered expression of 35 circRNAs in their livers. To clarify the function of mmu_circRNA_011775, one of the circRNAs upregulated by EGCG, mouse liver cells after the mmu_circRNA_011775 expression vector was transfected into NMuLi cells, next-generation sequencing (NGS) was used to analyze the gene expression. NGS analysis shows that the expression of the genes responsible for liver fibrosis and inflammation. Gene ontology (GO) analysis showed that mmu_circRNA_011775 changed the meaning of GO terms associated with the cardiovascular system. In the microarray, EGCG altered 35 genes expression. Among them, pre-ribosomal RNA-derived circRNA mmu_circRNA_011775 regulated the expression of various genes related to liver fibrosis and cardiovascular system.
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Catequina/análogos & derivados , MicroRNAs , RNA Circular , Animais , Camundongos , RNA Circular/genética , RNA Circular/metabolismo , RNA/genética , RNA/metabolismo , MicroRNAs/genética , Cirrose Hepática , Perfilação da Expressão GênicaRESUMO
Recently, the number of patients diagnosed with dementia has increased. The World Health Organization (WHO) estimates that 50 million patients suffer from dementia. Although several therapeutic strategies have been proposed, currently, there is no curative approach for treating dementia. Neurodegeneration is an irreversible process. As this disease gradually progresses over 15-20 years, a low-cost and sustainable method for preventing these diseases is desired. Cacao nib is consumed in many countries, and a recent clinical study indicated that cocoa intake upregulates brain-derived neurotrophic factor (BDNF), which plays a significant role in memory formation and neuronal cell survival. In the present study, neural cells were treated with cacao nib extract or the 17 characteristic components of cacao nib. Treatment with Cacao nib extract upregulates BDNF mRNA expression. In addition, cacao nib extract elicits the phosphorylation of cAMP-response-element-binding protein (CREB), which regulates the transcription of BDNF. Among the 17 species screened, isovaleraldehyde (IVA), also known as an aroma component of cacao nibs extract, improved BDNF mRNA expression without SH-SY5Y cell toxicity. IVA also promoted CREB phosphorylation through a cAMP-dependent protein kinase (PKA)-dependent mechanism. In conclusion, IVA could be responsible for the BDNF upregulation effect of cacao nib, and IVA upregulated BDNF expression via the PKA-CREB axis.
Assuntos
Aldeídos , Fator Neurotrófico Derivado do Encéfalo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Fármacos Neuroprotetores , Regulação para Cima , Fármacos Neuroprotetores/farmacologia , Aldeídos/farmacologia , Regulação para Cima/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Humanos , Linhagem Celular Tumoral , Cacau/química , Extratos Vegetais/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismoRESUMO
(-)-Epigallocatechin-3-O-gallate (EGCG) is one of the major components of green tea polyphenol. Previous studies have shown that EGCG induces cancer-specific cell death in vitro and in vivo without causing severe side effects. However, the anti-cancer effect of EGCG alone is limited. 5,7-dimethoxyflavone (5,7-DMF), one of the principal functional components of black ginger (Kaempferia parviflora), also exerts anti-cancer effects. Here, we show that 5,7-DMF synergistically enhances the anti-cancer effect of EGCG in multiple myeloma cells by potentiating EGCG-induced intracellular cyclic guanosine monophosphate (cGMP) production. Moreover, the combination of EGCG and 5,7-DMF induces apoptotic cell death in multiple myeloma cells, and this is accompanied by activation of the cGMP/acid sphingomyelinase (ASM)/cleaved caspase-3 pathway. In conclusion, we have shown that 5,7-DMF enhances the anti-cancer effect of EGCG by upregulating cGMP in multiple myeloma cells.
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Catequina , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Linhagem Celular Tumoral , Apoptose , Catequina/farmacologiaRESUMO
BACKGROUND: Oolonghomobisflavans are unique polyphenols found in oolong teas. Oolonghomobisflavan B (OHBFB), a dimer of (-)-epigallocatechin-3-O-gallate (EGCG), is an active compound found in green tea. PURPOSE: OHBFB has been reported to exert an inhibitory effect on lipase enzyme activity. However, little is known regarding its intercellular signaling induction effect. Further, there are no reports describing the anti-cancer effects of OHBFB. METHODS: The effect of OFBFB on B16 melanoma cells was evaluated by cell counting, and its mechanisms were determined by western blot analysis with or without protein phosphatase 2A (PP2A) inhibitor treatment. Intracellular cyclic adenosine monophosphate (cAMP) levels were evaluated by time-resolved fluorescence resonance energy transfer analysis. Quartz crystal microbalance (QCM) analysis was performed to assess the binding of OHBFB to 67LR. RESULTS: Cell growth assay and western blot analyses showed that OHBFB inhibited melanoma cell growth, followed by myosin phosphatase target subunit 1 (MYPT1) and myosin regulatory light chain (MRLC) dephosphorylation via protein phosphatase 2A (PP2A)-dependent mechanisms. These effects are mediated by intracellular cAMP- and protein kinase A (PKA) A-dependent mechanisms. QCM analysis identified the 67-kDa laminin receptor (67LR) as an OHBFB receptor with a Kd of 3.7 µM. We also demonstrated for the first time that OHBFB intake suppresses tumor growth in vivo. CONCLUSIONS: Taken together, these results indicate that the cAMP/PKA/PP2A/MYPT1/MRLC pathway is a key mediator of melanoma cell growth inhibition following OHBFB binding to 67LR and that OHBFB suppresses tumor growth in vivo.
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Catequina , Melanoma Experimental , Animais , Humanos , Proteína Fosfatase 2/metabolismo , Polifenóis/farmacologia , Catequina/farmacologia , Ciclo Celular , Melanoma Experimental/tratamento farmacológico , Receptores de Laminina/química , Receptores de Laminina/metabolismoRESUMO
(-)-Epigallocatechin gallate (EGCG), a key component of green tea, exerts therapeutic anticancer and antiallergic properties through its binding to the 67 kDa laminin receptor. The functionalization of EGCG is a promising strategy for creating new drug candidates and chemical probes. In our study, we developed a method for effectively modifying the A ring of EGCG through an electrophilic aromatic substitution with amidomethyl 2-alkynylbenzoates initiated with a gold complex. The 2-alkynylbenzoates treated with (Ph3P)AuOTf under neutral conditions yielded N-acylimines. A further electrophilic aromatic substitution resulted in a mixture of EGCG substituted with acylaminomethyl groups at the 6 and 8 positions with a significant amount noted at the 6 position. We then explored the synthesis of 18F-labeled EGCG with a neopentyl labeling group, an effective labeling group for radiohalogens of not only fluorine-18 but also of astatine-211. To achieve this, we prepared precursors that possessed acid-sensitive protecting groups and base-unstable leaving groups using our established method. Substitution of EGCG with a neopentyl labeling group at either the C6 or C8 position did not affect its anticancer efficacy in U266 cells. Finally, we investigated the preparation of 18F-labeled EGCG. The 18F-fluorination of a mixture of 6- and 8-substituted precursors yielded the corresponding 18F-labeled compounds in 4.5% and 3.0% radiochemical yields (RCYs), respectively. Under acidic conditions, the 18F-labeled 8-substituted compound produced 18F-labeled EGCG in 37% RCY, which heralds the potential of our functionalization approach.
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Catequina , Polifenóis , Polifenóis/farmacologia , Radioisótopos de Flúor , Catequina/farmacologia , Catequina/metabolismo , Chá/química , HalogenaçãoRESUMO
INTRODUCTION: Epidemiological studies indicated that inflammatory bowel disease (IBD), with Crohn's disease and ulcerative colitis as its two main types, is associated with dementia. However, little is known about how adolescents with IBD will affect their cognitive ability as adults. The hippocampus, which is crucial for memory and adult neurogenesis, is closely associated with modulation of cognitive processes. Using a low kDa dextran sulfate sodium (DSS, 5 kDa)-induced chronic colitis (mild chronic colitis) mice model in adolescent mice, we investigated the effects of mild chronic colitis on cognitive functions and hippocampal neurogenesis from adolescent mice to adult mice. METHODS: We induced DSS-induced mild chronic colitis in C57BL/6J male mice by multiple-cycle administration of 1%-2% DSS in autoclaved drinking water. Mice were subjected to novel-object recognition and Y-maze tests. Neurogenesis markers and neuroinflammation-related proteins in the hippocampus of mice were measured. Tight junction proteins in the colon of mice were measured. RESULTS: Mild chronic colitis induced cognitive impairment and decreased adult neurogenesis. Notably, we found a positive correlation with the protein levels between tight junction protein, ZO-1, in the colon and mature neuron marker, NeuN, in the hippocampus. Moreover, mild chronic colitis leads to hippocampal neuroinflammation in adolescent mice. CONCLUSION: Our findings provide new evidence of the association between IBD and dementia risk.
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Disfunção Cognitiva , Colite , Demência , Doenças Inflamatórias Intestinais , Masculino , Animais , Camundongos , Sulfato de Dextrana , Doenças Neuroinflamatórias , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/complicações , Colite/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Colo/metabolismo , Modelos Animais de Doenças , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , NeurogêneseRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer with a high mortality rate. Current treatments for PDACs often have side effects, and drug resistance in cancer stem cells (CSCs) would be also a problem. Cyclic guanosine monophosphate (cGMP) suppresses the mitochondrial function of PDACs and inhibits their CSC properties. Metabolic regulation plays a crucial role in the maintenance of CSC phenotype, and we hypothesized that cGMP induction suppresses cancer stem cell properties in the cancer cell through energy-related signaling pathways. We demonstrated that induction of cGMP upregulated the PPARα/PDK4 pathway and suppressed CSC properties in PDAC, and patients with pancreatic cancer with high PDK4 gene expression had a better prognosis than those with low gene expression. Therefore, these mechanisms may provide new therapeutic targets for the eradication of pancreatic CSCs.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Pâncreas/metabolismo , Células-Tronco Neoplásicas/patologia , Linhagem Celular Tumoral , Neoplasias PancreáticasRESUMO
As pulmonary fibrosis (PF), a severe interstitial pulmonary disease, has such a poor prognosis, the development of prevention and treatment methods is imperative. (-)-Epigallocatechin-3-O-gallate (EGCG), one of the major catechins in green tea, exerts an antifibrotic effect, although its mechanism remains unclear. Recently, it has been reported that microRNAs (miRNAs or miRs) transported by extracellular vesicles (EVs) from vascular endothelial cells (VECs) are involved in PF. In the present study, the effects of EGCG on the expression of miRNAs in EVs derived from human umbilical vein endothelial cells (HUVECs) were assessed and miRNAs with antifibrotic activity were identified. miRNA microarray analysis revealed that EGCG modulated the expression levels of 31 miRNAs (a total of 27 miRNAs were upregulated, and 4 miRNAs were downregulated.) in EVs from HUVECs. Furthermore, TargetScan analysis indicated that miR-6757-3p in particular, which exhibited the highest degree of change, may target transforming growth factor-ß (TGF-ß) receptor 1 (TGFBR1). To evaluate the effects of miR-6757-3p on TGFBR1 expression, human fetal lung fibroblasts (HFL-1) were transfected with an miR-6757-3p mimic. The results demonstrated that the miR-6757-3p mimic downregulated the expression of TGFBR1 as well the expression levels of fibrosis-related genes including fibronectin and α-smooth muscle actin in TGF-ß-treated HFL-1 cells. In summary, EGCG upregulated the expression levels of miR-6757-3p, which may target TGFBR1 and downregulate fibrosis-related genes, in EVs derived from VECs.
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Lung fibrosis, including idiopathic pulmonary fibrosis, is an intractable disease accompanied by an irreversible dysfunction in the respiratory system. Its pathogenesis involves the transforming growth factorß (TGFß)-induced overproduction of the extracellular matrix from fibroblasts; however, limited countermeasures have been established. In this study, we identified osa-miR172d-5p, a plant-derived microRNA (miR), as a potent anti-fibrotic miR. In silico analysis followed by an in vitro assay based on human lung fibroblasts demonstrated that osa-miR172d-5p suppressed the gene expression of TGF-ß activated kinase 1 (MAP3K7) binding protein 1 (Tab1). It also suppressed the TGFß-induced fibrotic gene expression in human lung fibroblasts. To assess the anti-fibrotic effect of osa-miR172d-5p, we established bleomycin-induced lung fibrosis models to demonstrate that osa-miR172d-5p ameliorated lung fibrosis. Moreover, it suppressed Tab1 expression in the lung tissues of bleomycin-treated mice. In conclusion, osa-miR172d-5p could be a potent candidate for the treatment of lung fibrosis, including idiopathic pulmonary fibrosis.
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Fibrose Pulmonar Idiopática , MicroRNAs , Humanos , Camundongos , Animais , MicroRNAs/metabolismo , Pulmão/patologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Fibrose , Bleomicina/toxicidade , Bleomicina/metabolismo , Fibroblastos/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
Quercetin, a flavonol present in many vegetables and fruits, has been identified as a chemoprevention agent in several cancer models. However, the molecular mechanism of quercetin's anticancer activity is not entirely understood. MicroRNAs (miRNAs), small noncoding RNAs, have been reported to play key roles in various biological processes by regulating their target genes. We hypothesized that quercetin can exert an anticancer effect through the regulation of miRNAs. To test this hypothesis, we investigated the effects of quercetin on the expression of tumor-suppressive miRNAs in cervical cancer. Quercetin up-regulated the in vivo and in vitro expression of tumor-suppressive miRNAs miR-26b, miR-126, and miR-320a. Quercetin suppressed the level of ß-catenin, encoded by catenin beta 1 (CTNNB1), by up-regulating miR-320a in HeLa cells. Moreover, quercetin increased the expression of mir-26b, mir-126, and mir-320a precursors in HeLa cells. The results from this study show that quercetin has the potential to prevent cervical cancer by regulating the expression of tumor-suppressive miRNAs.
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Many patients with allergies have anxiety about taking anti-allergic medicines due to their side effects and increased medical expenses. Thus, developing functional foods/agricultural products for allergy prevention is strongly desired. In this study, we revealed that a Citrus flavanone, hesperetin, amplified IgE/antigen-mediated degranulation-inhibitory potency of anti-allergic catechin, (-)-epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3''Me), in the rat basophilic/mast cell line RBL-2H3. Hesperetin also significantly elevated the activation of acid sphingomyelinase (ASM), essential for eliciting anti-allergic effect of EGCG3''Me through the cell surficial protein, 67-kDa laminin receptor (67LR). Furthermore, oral administration of the highly absorbent hesperidin, α-glucosyl hesperidin, also enhanced the inhibitory potency of EGCG3''Me-rich 'Benifuuki' green tea (Camellia sinensis L.) on passive cutaneous anaphylaxis (PCA) reaction evoked by IgE/antigen in BALB/c mice. These observations indicate that hesperetin amplifies the ability of EGCG3''Me to inhibit the IgE/antigen-mediated degranulation through activating ASM signaling.
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Antialérgicos , Catequina , Flavanonas , Hesperidina , Ratos , Camundongos , Animais , Antialérgicos/farmacologia , Imunoglobulina E , Anafilaxia Cutânea PassivaRESUMO
Epigallocatechin 3-O-gallate (EGCG) is a predominant component in green tea with various health benefits. The 67 kDa laminin receptor (67LR) is a nonintegrin cell surface receptor that is overexpressed in various types of cancer; 67LR was identified a cell surface EGCG target that plays a pivotal role in tumor growth, metastasis, and resistance to chemotherapy. However, the plasma concentration of EGCG is limited, and its molecular mechanisms remain unelucidated in colon cancer. In this study, we found that the phosphodiesterase 5 (PDE5) inhibitor, vardenafil (VDN), potentiates EGCG-induced apoptotic cell death in colon cancer cells. The combination of EGCG and VDN induced apoptosis via activation of the endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein kinase Cδ signaling pathway. In conclusion, the PDE5 inhibitor, VDN, may reduce the intracellular PDE5 enzyme activity that potentiates EGCG-induced apoptotic cell death in Caco-2 cells. These results suggest that PDE5 inhibitors can be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death. Therefore, EGCG may be employed as a therapeutic candidate for colon cancer.
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BACKGROUND: Polyphenols, including flavonoids, have been the focus of numerous studies that have revealed diverse health benefits. MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that function as posttranscriptional regulators of gene expression. miRNAs can be detected in the blood and these so-called circulating miRNAs are potential biomarkers of various diseases. This study aimed to explore circulating miRNAs in plasma as a means to predict the biological effects of functional food ingredients. METHODS AND RESULTS: We used miRNA microarray analysis to compare plasma miRNA levels in mice orally administered three flavonoids (daidzein, quercetin, and delphinidin). Several miRNAs were differentially expressed in plasma from mice in each treatment group compared with the vehicle-treated group. The plasma levels of miR-25-5p, miR-146b-5p, and miR-501-3p were increased in the flavonoid-treated and the plasma levels of miR-148b-3p, miR-669e-5p, and miR-3962 were decreased. CONCLUSIONS: Our findings suggested that flavonoids alter miRNA expression in plasma and identified promising plasma miRNAs for assessing the functionality of flavonoids.
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MicroRNA Circulante , MicroRNAs , Camundongos , Animais , Flavonoides/farmacologia , MicroRNAs/metabolismo , Biomarcadores , Análise em Microsséries , Perfilação da Expressão GênicaRESUMO
Anticancer agents can cause various side effects, including tissue damages/inflammatory reactions. Drug-responsive biomarkers are essential for evaluating drug toxicity in disease processes. S100 calcium-binding proteins A8/A9 (S100A8/A9) are highly expressed in neutrophils and monocytes/macrophages accumulated at inflammatory sites and are known to be related to tissue damage/inflammation; however, their response to drug toxicity has not been reported. Herein, we investigated the effects of anticancer agents (doxorubicin, cisplatin, and docetaxel) on S100A8/A9 gene expression profiles in four representative tissues (heart, kidney, liver, and lung) in normal C57BL/6J mice. Both S100A8/A9 expression was transiently or time-dependently elevated in four tissues within 48 h after dosing of the three anticancer agents under toxicity-inducing conditions. S100A8/A9 patterns differed among agents and tissues. This result suggests that S100A8/A9 is useful for evaluating anticancer agent-induced tissue damage. Metabolomic analysis revealed that some metabolites showed temporal patterns similar to that of S100A8/A9 expression. The amounts of fumarate (doxorubicin-treated heart), tyrosine (cisplatin-treated kidney), acetylcarnosine (doxorubicin-treated liver), and 2-phosphoglycerate (docetaxel-treated lung) showed similar patterns to that of S100A8/A9 expression. Although these metabolites showed different behaviors between tissues and serum, they may be useful marker candidates for evaluating anticancer agent-induced tissue damage at an earlier stage after dosing.
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Antineoplásicos , Biomarcadores Farmacológicos , Calgranulina A , Calgranulina B , Inflamação , Animais , Camundongos , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Biomarcadores Farmacológicos/metabolismo , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Cisplatino/administração & dosagem , Cisplatino/toxicidade , Docetaxel/administração & dosagem , Docetaxel/toxicidade , Doxorrubicina/administração & dosagem , Doxorrubicina/toxicidade , Fumaratos/análise , Inflamação/induzido quimicamente , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Tirosina/análiseRESUMO
The body is equipped with a "food factor-sensing system" that senses food factors, such as polyphenols, sulfur-containing compounds, and vitamins, taken into the body, and plays an essential role in manifesting their physiological effects. For example, (-)-epigallocatechin-3-O-gallate (EGCG), the representative catechin in green tea (Camellia sinensi L.), exerts various effects, including anti-cancer, anti-inflammatory, and anti-allergic effects, when sensed by the cell surficial protein 67-kDa laminin receptor (67LR). Here, we focus on three representative effects of EGCG and provide their specific signaling mechanisms, the 67LR-mediated EGCG-sensing systems. Various components present in foods, such as eriodictyol, hesperetin, sulfide, vitamin A, and fatty acids, have been found to act on the food factor-sensing system and affect the functionality of other foods/food factors, such as green tea extract, EGCG, or its O-methylated derivative at different experimental levels, i.e., in vitro, animal models, and/or clinical trials. These phenomena are observed by increasing or decreasing the activity or expression of EGCG-sensing-related molecules. Such functional interaction between food factors is called "functional food pairing". In this review, we introduce examples of functional food pairings using EGCG.
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Catequina , Animais , Catequina/análogos & derivados , Alimento Funcional , Polifenóis/farmacologia , Receptores de Laminina/metabolismo , Proteínas Ribossômicas , CháRESUMO
It is generally recognized that the main function of α-tocopherol (αToc), which is the most active form of vitamin E, is its antioxidant effect, while non-antioxidant effects have also been reported. We previously found that αToc ameliorates diabetic nephropathy via diacylglycerol kinase alpha (DGKα) activation in vivo, and the activation was not related to the antioxidant effect. However, the underlying mechanism of how αToc activates DGKα have been enigmatic. We report that the membrane-bound 67 kDa laminin receptor (67LR), which has previously been shown to serve as a receptor for epigallocatechin gallate (EGCG), also contains a novel binding site for vitamin E, and its association with Vitamin E mediates DGKα activation by αToc. We employed hydrogen-deuterium exchange mass spectrometry (HDX/MS) and molecular dynamics (MD) simulations to identify the specific binding site of αToc on the 67LR and discovered the conformation of the specific hydrophobic pocket that accommodates αToc. Also, HDX/MS and MD simulations demonstrated the detailed binding of EGCG to a water-exposed hydrophilic site on 67LR, while in contrast αToc binds to a distinct hydrophobic site. We demonstrated that 67LR triggers an important signaling pathway mediating non-antioxidant effects of αToc, such as DGKα activation. This is the first evidence demonstrating a membrane receptor for αToc and one of the underlying mechanisms of a non-antioxidant function for αToc.
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Catequina , Diacilglicerol Quinase , Diacilglicerol Quinase/metabolismo , Vitamina E/farmacologia , Receptores de Laminina/metabolismo , Catequina/farmacologia , alfa-Tocoferol , Antioxidantes/farmacologia , Sítios de LigaçãoRESUMO
INTRODUCTION: Considering that neurodegeneration is an irreversible process, an efficient, low-burden approach to prevent dementia is strongly needed. Here, we show that the daily intake of myricetin normalised cognitive dysfunction in senescence-accelerated mouse prone 8 (SAMP8) mice. METHODS: SAMP8 mice were fed a diet supplemented with myricetin and novel object recognition tests and Y-maze tests were performed. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brains of SAMP8 mice were measured. The phosphorylation level of cAMP-response-element-binding protein (CREB) level in brains of SAMP8 mice were evaluated. Also, SH-SY5Y cells were treated with myricetin and cAMP levels were measured. RESULTS: In SAMP8 mice, neurotrophins, including BDNF and NGF, were downregulated relative to levels in their normal counterparts. In addition, myricetin intake upregulated the phosphorylation of CREB, the major transcription factor for BDNF and NGF. Also, myricetin induced cAMP upregulation, and CREB phosphorylation via a cAMP-dependent protein kinase-dependent manner in SH-SY5Y cells. CONCLUSION: Taken together, myricetin improves cognitive function in SAMP8 mice and upregulates BDNF and NGF.