RESUMO
Psoriasis is a chronic autoimmune inflammatory skin disorder that affects approximately 2-3% of the global population due to significant genetic predisposition. It is characterized by an uncontrolled growth and differentiation of keratinocytes, leading to the formation of scaly erythematous plaques. Psoriasis extends beyond dermatological manifestations to impact joints and nails and is often associated with systemic disorders. Although traditional treatments provide relief, their use is limited by potential side effects and the chronic nature of the disease. This review aims to discuss the therapeutic potential of keratinocyte-targeting natural products in psoriasis and highlight their efficacy and safety in comparison with conventional treatments. This review comprehensively examines psoriasis pathogenesis within keratinocytes and the various related signaling pathways (such as JAK-STAT and NF-κB) and cytokines. It presents molecular targets such as high-mobility group box-1 (HMGB1), dual-specificity phosphatase-1 (DUSP1), and the aryl hydrocarbon receptor (AhR) for treating psoriasis. It evaluates the ability of natural compounds such as luteolin, piperine, and glycyrrhizin to modulate psoriasis-related pathways. Finally, it offers insights into alternative and sustainable treatment options with fewer side effects.
Assuntos
Produtos Biológicos , Queratinócitos , Psoríase , Transdução de Sinais , Humanos , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Receptores de Hidrocarboneto Arílico/metabolismo , Terapia de Alvo MolecularRESUMO
Excessive lipid accumulation in adipocytes is a primary contributor to the development of metabolic disorders, including obesity. The consumption of bioactive compounds derived from natural sources has been recognized as being safe and effective in preventing and alleviating obesity. Therefore, we aimed to explore the antilipidemic effects of pennogenin 3-O-ß-chacotrioside (P3C), a steroid glycoside, on hypertrophied 3T3-L1 adipocytes. Oil Red O and Nile red staining demonstrated a P3C-induced reduction in lipid droplet accumulation. Additionally, the increased expression of adipogenic and lipogenic factors, including PPARγ and C/EBPα, during the differentiation process was significantly decreased by P3C treatment at both the protein and mRNA levels. Furthermore, P3C treatment upregulated the expression of fatty acid oxidation-related genes such as PGC1α and CPT1a. Moreover, mitochondrial respiration and ATP generation increased following P3C treatment, as determined using the Seahorse XF analyzer. P3C treatment also increased the protein expression of mitochondrial oxidative phosphorylation in hypertrophied adipocytes. Our findings suggest that P3C could serve as a natural lipid-lowering agent, reducing lipogenesis and enhancing mitochondrial oxidative capacity. Therefore, P3C may be a promising candidate as a therapeutic agent for obesity-related diseases.
Assuntos
Adipogenia , Metabolismo dos Lipídeos , Camundongos , Animais , Adipogenia/genética , Obesidade/metabolismo , Hipertrofia , Lipídeos/farmacologia , Estresse Oxidativo , Células 3T3-L1 , PPAR gama/metabolismoRESUMO
Doxorubicin (DOX), an effective chemotherapeutic drug, causes cardiotoxicity in a cumulative and dose-dependent manner. The aim of this study is to investigate the effects of hot-water extract of Capsella bursa-pastoris (CBW) on DOX-induced cardiotoxicity (DICT). We utilized H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells to evaluate the effects of CBW on DOX-induced cell death. Superoxide dismutase (SOD) levels, reactive oxygen species (ROS) production, and oxygen consumption rate were measured in H9c2 cells. C57BL/6 mice were treated with DOX and CBW to assess their impact on various cardiac parameters. Human-induced pluripotent stem-cell-derived cardiomyocytes were also used to investigate DOX-induced electrophysiological changes and the potential ameliorative effects of CBW. UPLC-TQ/MS analysis identified seven flavonoids in CBW, with luteolin-7-O-glucoside and isoorientin as the major compounds. CBW inhibited DOX-induced death of H9c2 rat cardiomyocytes but did not affect DOX-induced death of MDA-MB-231 human breast cancer cells. CBW increased SOD levels in a dose-dependent manner, reducing ROS production and increasing the oxygen consumption rate in H9c2 cells. The heart rate, RR interval, QT, and ST prolongation remarkably recovered in C57BL/6 mice treated with the combination of DOX and CBW compared to those in mice treated with DOX alone. Administration of CBW with DOX effectively alleviated collagen accumulation, cell death in mouse heart tissues, and reduced the levels of creatinine kinase (CK) and lactate dehydrogenase (LDH) in serum. Furthermore, DOX-induced pathological electrophysiological features in human-induced pluripotent stem-cell-derived cardiomyocytes were ameliorated by CBW. CBW may prevent DICT by stabilizing SOD and scavenging ROS. The presence of flavonoids, particularly luteolin-7-O-glucoside and isoorientin, in CBW may contribute to its protective effects. These results suggest the potential of CBW as a traditional therapeutic option to mitigate DOX-induced cardiotoxicity.
Assuntos
Neoplasias da Mama , Capsella , Ratos , Camundongos , Animais , Humanos , Feminino , Antioxidantes/metabolismo , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Capsella/metabolismo , Estresse Oxidativo , Camundongos Endogâmicos C57BL , Doxorrubicina/toxicidade , Doxorrubicina/metabolismo , Miócitos Cardíacos/metabolismo , Flavonoides/farmacologia , Superóxido Dismutase/metabolismo , Neoplasias da Mama/metabolismo , ApoptoseRESUMO
Doxorubicin (DOX), an anthracycline-based chemotherapeutic agent, is widely used to treat various types of cancer; however, prolonged treatment induces cardiomyotoxicity. Although studies have been performed to overcome DOX-induced cardiotoxicity (DICT), no effective method is currently available. This study investigated the effects and potential mechanisms of Poncirus trifoliata aqueous extract (PTA) in DICT. Changes in cell survival were assessed in H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells. The C57BL/6 mice were treated with DOX to induce DICT in vivo, and alterations in electrophysiological characteristics, serum biomarkers, and histological features were examined. The PTA treatment inhibited DOX-induced decrease in H9c2 cell viability but did not affect the MDA-MB-231 cell viability. Additionally, the PTA restored the abnormal heart rate, R-R interval, QT interval, and ST segment and inhibited the decrease in serum cardiac and hepatic toxicity indicators in the DICT model. Moreover, the PTA administration protected against myocardial fibrosis and apoptosis in the heart tissue of mice with DICT. PTA treatment restored DOX-induced decrease in the expression of NAD(P)H dehydrogenase quinone acceptor oxidoreductase 1 in a PTA concentration-dependent manner. In conclusion, the PTA inhibitory effect on DICT is attributable to its antioxidant properties, suggesting the potential of PTA as a phytotherapeutic agent for DICT.
Assuntos
Miócitos Cardíacos , Poncirus , Ratos , Camundongos , Humanos , Animais , NAD/metabolismo , Poncirus/metabolismo , Regulação para Cima , Estresse Oxidativo , Camundongos Endogâmicos C57BL , Doxorrubicina/toxicidade , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Oxirredutases/metabolismo , Quinonas/farmacologiaRESUMO
3,3',4',5,7-Pentahydroxyflavone-3-rhamnoglucoside (rutin) is a flavonoid with a wide range of pharmacological activities. Dietary rutin is hardly absorbed because the microflora in the large intestine metabolize rutin into a variety of compounds including quercetin and phenol derivatives such as 3,4-dihydroxyphenolacetic acid (DHPAA), 3,4-dihydroxytoluene (DHT), 3,4-hydroxyphenylacetic acid (HPAA) and homovanillic acid (HVA). We examined the potential of rutin and its metabolites as novel histone acetyltransferase (HAT) inhibitors. DHPAA, HPAA and DHT at the concentration of 25 µM significantly inhibited in vitro HAT activity with DHT having the strongest inhibitory activity. Furthermore, DHT was shown to be a highly efficient inhibitor of p300 HAT activity, which corresponded with its high degree of inhibition on intracellular lipid accumulation in HepG2 cells. Docking simulation revealed that DHT was bound to the p300 catalytic pocket, bromodomain. Drug affinity responsive target stability (DARTS) analysis further supported the possibility of direct binding between DHT and p300. In HepG2 cells, DHT concentration-dependently abrogated p300-histone binding and induced hypoacetylation of histone subunits H3K9, H3K36, H4K8 and H4K16, eventually leading to the downregulation of lipogenesis-related genes and attenuating lipid accumulation. In ob/ob mice, administration of DHT (10, 20 mg/kg, iv, every other day for 6 weeks) dose-dependently improved the NAFLD pathogenic features including body weight, liver mass, fat mass, lipid accumulation in the liver, and biochemical blood parameters, accompanied by the decreased mRNA expression of lipogenic genes in the liver. Our results demonstrate that DHT, a novel p300 histone acetyltransferase inhibitor, may be a potential preventive or therapeutic agent for NAFLD.
Assuntos
Catecóis/farmacologia , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Lipoproteínas/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Proteína p300 Associada a E1A , Células Hep G2 , Histonas/metabolismo , Humanos , Masculino , Camundongos , Rutina/metabolismo , Rutina/uso terapêutico , Triglicerídeos/metabolismoRESUMO
Programmed cell death 5 (PDCD5) has been associated with human cancers as a regulator of cell death; however, the role of PDCD5 in the endothelium has not been revealed. Thus, we investigated whether PDCD5 regulates protein kinase B (PKB/AKT)-endothelial nitric oxide synthase (eNOS)-dependent signal transduction in the endothelium and affects atherosclerosis. Endothelial-specific PDCD5 knockout mice showed significantly reduced vascular remodeling compared with wild-type (WT) mice after partial carotid ligation. WT PDCD5 competitively inhibited interaction between histone deacetylase 3 (HDAC3) and AKT, but PDCD5L6R, an HDAC3-binding-deficient mutant, did not. Knockdown of PDCD5 accelerated HDAC3-AKT interaction, AKT and eNOS phosphorylation, and nitric oxide (NO) production in human umbilical vein endothelial cells. Moreover, we found that serum PDCD5 levels reflect endothelial NO production and are correlated with diabetes mellitus, high-density lipoprotein cholesterol, and coronary calcium in human samples obtained from the cardiovascular high-risk cohort. Therefore, we conclude that PDCD5 is associated with endothelial dysfunction and may be a novel therapeutic target in atherosclerosis.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Remodelação Vascular , Animais , Proteínas Reguladoras de Apoptose/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , HDL-Colesterol/genética , HDL-Colesterol/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Endotélio Vascular/patologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/genética , Proteínas Proto-Oncogênicas c-akt/genéticaRESUMO
Until now, several studies have looked at the issue of anthocyanin and cancer, namely the preventive and inhibitory effects of anthocyanins, as well as the underlying molecular processes. However, no targeted review is available regarding the anticarcinogenic effects of delphinidin and its glycosides on various cancers and their plausible molecular mechanisms. Considerable evidence shows significant anticancer properties of delphinidin-rich preparations and delphinidin alone both in vitro and in vivo. This review covers the in vitro and preclinical implications of delphinidin-mediated cell protection and cancer prevention; thus, we strongly recommend that delphinidin-rich preparations be further investigated as potential functional food, dietary antioxidant supplements, and natural health products targeting specific chronic diseases, including cancer. In addition to in vitro investigations, future research should focus on more animal and human studies to determine the true potential of delphinidin.
Assuntos
Antocianinas/farmacologia , Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Neoplasias/prevenção & controle , Animais , Antocianinas/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Suplementos Nutricionais , Glicosídeos/química , Glicosídeos/farmacologia , Glicosilação , Humanos , Camundongos , Neoplasias/tratamento farmacológicoRESUMO
The purpose of this study was to investigate the role of piceatannol (PT) in statin (rosuvastatin and simvastatin) resistance and tolerance and its association with PCSK9 expression via its p300 inhibitory (p300i) activity. An in vitro study was performed using HepG2 cells that were exposed to statins (rosuvastatin or simvastatin) with or without PT in delipidated serum (DLPS) medium. In the statin exposed conditions, PCSK9 expression was reduced following PT treatment when compared to HepG2 cells w/o PT treatment. Furthermore, no significant difference was observed in the expression of the transcription factors SREBP2 and HNF1α, which regulate PCSK9 expression. This resulted in low density lipoprotein receptor (LDLR) stabilization and reduced cellular cholesterol levels. This indicates that PT epigenetically controls statin-induced PCSK9 expression. Interestingly, PT attenuated p300 histone acetyltransferase (HAT) activity. Moreover, simulation of PT-p300 binding suggested that PT inhibits p300 as PT could be docked in the p300 HAT domain. Furthermore, inhibition of p300 HAT activity using C-646, a selective p300 inhibitor, or through an siRNA system effectively reduced PCSK9 induction upon statin exposure in HepG2 cells. The chromatin immunoprecipitation (ChIP) assays revealed that PT blocked the recruitment of p300 to the PCSK9 promoter region. In summary, PT attenuated statin-induced PCSK9 expression by inhibiting p300 HAT activity. Finally, co-administration of simvastatin and PT for 10 weeks further reduced plasma low-density lipoprotein-cholesterol (LDL-C) levels and stabilized the hepatic LDLR protein level compared with those resulting from single treatment of simvastatin in a high-fat diet-induced hypercholesterolemia mouse model. Our findings indicate that PT is a new nutraceutical candidate to reduce the statin resistance and tolerance that occurs in patients with hypercholesterolemia.
Assuntos
Hepatócitos/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/metabolismo , Rosuvastatina Cálcica/farmacologia , Sinvastatina/farmacologia , Estilbenos/farmacologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Animais , LDL-Colesterol/sangue , Modelos Animais de Doenças , Regulação para Baixo , Resistência a Medicamentos , Células Hep G2 , Hepatócitos/enzimologia , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/enzimologia , Hipercolesterolemia/genética , Masculino , Camundongos Endogâmicos C57BL , Pró-Proteína Convertase 9/genética , Estabilidade Proteica , Receptores de LDL/metabolismo , Fatores de Transcrição de p300-CBP/genética , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
Dysregulation of Wnt signaling has been implicated in tumorigenesis. The role of Transducin ß-like proteins TBL1-TBLR1 in the promotion of Wnt/ß-catenin-mediated oncogenesis has recently been emphasized; however, the molecular basis of activation of Wnt signaling by the corepressor TBL1-TBLR1 is incompletely understood. Here, we show that both TBL1 and TBLR1 are SUMOylated in a Wnt signaling-dependent manner, and that this modification is selectively reversed by SUMO-specific protease I (SENP1). SUMOylation dismissed TBL1-TBLR1 from the nuclear hormone receptor corepressor (NCoR) complex, increased recruitment of the TBL1-TBLR1-ß-catenin complex to the promoter of Wnt target genes, and consequently led to activation of Wnt signaling. Conversely, SENP1 decreased formation of the TBL1-TBLR1-ß-catenin complex, leading to inhibition of ß-catenin-mediated transcription. Importantly, inhibition of SUMOylation significantly decreased the tumorigenicity of SW480 colon cancer cells. Thus, our data reveal a mechanism for activation of Wnt signaling via the SUMOylation-dependent disassembly of the corepressor complex.
Assuntos
Proteínas Nucleares/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Células 3T3 , Animais , Humanos , Camundongos , Proteínas Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Sumoilação , Transducina/genética , Transducina/metabolismo , Transfecção , Células Tumorais Cultivadas , Proteínas Wnt/genética , beta Catenina/genéticaRESUMO
BACKGROUND AND OBJECTIVES: The association between black-colored foods (black foods) such as black beans, known for their high antioxidant capacity, and the prevention of metabolic diseases has been explored, but not in a large population. Therefore, this study examined relationships between the consumption of black foods and metabolic syndrome in Korean adults. METHODS AND STUDY DESIGN: Data from 9,499 40-65-year old subjects (3,675 men and 5,824 women) from the 2010-2015 Korea National Health and Nutrition Examination Survey were used in the analysis. Black food consumption was estimated using 24-h dietary recall data, and analyses were performed according to black food consumer and non-consumer groups. RESULTS: The average total consumption of black foods was higher in women than men. The total black food consumer group in women had a 24% reduced risk of abdominal obesity than the non-consumer group (p=0.007). Furthermore, waist circumference decreased significantly with an increase in total black food consumption in women. High consumption of total black foods and black beans reduced the risk of abdominal obesity by 26% (p for trend=0.012) and 29% (p for trend=0.003) compared with no consumption. No risk factors for metabolic syndrome were associated with black food consumption in men. CONCLUSIONS: In conclusion, black foods, including black beans, may have beneficial effects on metabolic syndrome components, especially abdominal obesity.
Assuntos
Dieta/métodos , Inquéritos Nutricionais/estatística & dados numéricos , Obesidade Abdominal/epidemiologia , Adulto , Idoso , Cor , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Fatores de Risco , Fatores SexuaisRESUMO
Caffeic acid phenethyl ester (CAPE), a naturally occurring bioactive compound, displays anti-inflammatory, anti-carcinogenic, and anti-microbial effects. However, the effect of CAPE on skin photoaging is unknown. Herein, we investigated the inhibitory effect of CAPE against ultraviolet (UV) irradiation-mediated matrix metalloproteinase (MMP)-1 expression and its underlying molecular mechanism. CAPE treatment suppressed UV-induced MMP-1 levels in both human dermal fibroblasts (HDF) and human skin tissues. While CAPE did not display any significant effects against the upstream regulatory pathways of MMP-1, CAPE was capable of reversing UV-mediated epigenetic modifications. CAPE suppressed UV-induced acetyl-histone H3 (Lys9) as well as total lysine acetylation in HDF cells. Similarly, CAPE also attenuated UV-induced lysine acetylations in human skin tissues, suggesting that the CAPE-mediated epigenetic alterations can be recapitulated in ex vivo conditions. CAPE was found to attenuate UV-induced histone acetyltransferase (HAT) activity in HDF. Notably, CAPE was able to directly inhibit the activity of several HATs including p300, CREP-binding protein (CBP), and p300/CBP-associated factor (PCAF), further confirming that CAPE can function as an epigenetic modulator. Thus, our study suggests that CAPE maybe a promising agent for the prevention of skin photoaging via targeting HATs.
Assuntos
Ácidos Cafeicos/farmacologia , Fibroblastos/enzimologia , Histona Acetiltransferases/antagonistas & inibidores , Metaloproteinase 1 da Matriz/genética , Álcool Feniletílico/análogos & derivados , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Regulação da Expressão Gênica , Histona Acetiltransferases/metabolismo , Humanos , Álcool Feniletílico/farmacologia , Pele/efeitos dos fármacos , Pele/enzimologia , Pele/metabolismo , Pele/efeitos da radiação , Raios UltravioletaRESUMO
Deciphering the molecular basis of neuronal cell death is a central issue in the etiology of neurodegenerative diseases, such as Parkinson's and Alzheimer's. Dysregulation of p53 levels has been implicated in neuronal apoptosis. The role of histone deacetylase 3 (HDAC3) in suppressing p53-dependent apoptosis has been recently emphasized; however, the molecular basis of modulation of p53 function by HDAC3 remains unclear. Here we show that PTEN-induced putative kinase 1 (PINK1), which is linked to autosomal recessive early-onset familial Parkinson's disease, phosphorylates HDAC3 at Ser-424 to enhance its HDAC activity in a neural cell-specific manner. PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c. PINK1-mediated phosphorylation of HDAC3 enhances its direct association with p53 and causes subsequent hypoacetylation of p53. Genetic deletion of PINK1 partly impaired the suppressive role of HDAC3 in regulating p53 acetylation and transcriptional activity. However, depletion of HDAC3 fully abolished the PINK1-mediated p53 inhibitory loop. Finally, ectopic expression of phosphomometic-HDAC3(S424E) substantially overcomes the defective action of PINK1 against oxidative stress in dopaminergic neuronal cells. Together, our results uncovered a mechanism by which PINK1-HDAC3 network mediates p53 inhibitory loop in response to oxidative stress-induced damage.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Histona Desacetilases/metabolismo , Proteínas Quinases/metabolismo , Acetilação/efeitos dos fármacos , Animais , Caspase 7/metabolismo , Morte Celular/genética , Linhagem Celular , Citoplasma/metabolismo , Neurônios Dopaminérgicos/patologia , Ativação Enzimática , Histona Desacetilases/genética , Humanos , Peróxido de Hidrogênio/farmacologia , Camundongos , Especificidade de Órgãos , Fosforilação , Proteínas Quinases/genética , Proteólise , Proteína Supressora de Tumor p53/metabolismoRESUMO
Mitogen-inducible gene 6 (MIG6) is a tumor suppressor implicated in the development of human cancers; however, the regulatory mechanisms of MIG6 remain unknown. Here, using a yeast two-hybrid screen, we identified DnaJ homolog subfamily B member I (DNAJB1) as a novel MIG6-interacting protein. We found that DNAJB1 binds to and decreases MIG6 protein, but not mRNA, levels. DNAJB1 overexpression dosage-dependently decreased MIG6 protein levels. Conversely, DNAJB1 knockdown increased MIG6 protein levels. DNAJB1 destabilizes MIG6 by enhancing K48-linked ubiquitination of MIG6. However, knocking-down of DNAJB1 reduced the ubiquitination of MIG6. DNAJB1 positively regulates the epidermal growth factor receptors (EGFR) signaling pathway via destabilization of MIG6; however, DNAJB1 knockdown diminishes activation of EGFR signaling as well as elevation of MIG6. Importantly, the increased levels of MIG6 by DNAJB1 knockdown greatly enhanced the gefitinib sensitivity in A549 cells. Thus, our study provides a new molecular mechanism to regulate EGFR signaling through modulation of MIG6 by DNAJB1 as a negative regulator.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Receptores ErbB/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Transdução de Sinais/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitinação/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Receptores ErbB/genética , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico HSP40/genética , Humanos , Ligação Proteica , Proteínas Supressoras de Tumor/genéticaRESUMO
Programmed cell death 5 (PDCD5) plays a crucial role in TP53-mediated apoptosis, but the regulatory mechanism of PDCD5 itself during apoptosis remains obscure. We identified YY1-associated factor 2 (YAF2) as a novel PDCD5-interacting protein in a yeast two-hybrid screen for PDCD5-interacting proteins. We found that YY1-associated factor 2 (YAF2) binds to and increases PDCD5 stability by inhibiting the ubiquitin-dependent proteosomal degradation pathway. However, knocking-down of YAF2 diminishes the levels of PDCD5 protein but not the levels of PDCD5 mRNA. Upon genotoxic stress response, YAF2 promotes TP53 activation via association with PDCD5. Strikingly, YAF2 failed to promote TP53 activation in the deletion of PDCD5, whereas restoration of wild-type PDCD5WT efficiently reversed the ineffectiveness of YAF2 on TP53 activation. Conversely, PDCD5 efficiently overcame the knockdown effect of YAF2 on ET-induced TP53 activation. Finally, impaired apoptosis upon PDCD5 ablation was substantially rescued by restoration of PDCD5WT but not YAF2-interacting defective PDCD5E4D nor TP53-interacting defective PDCD5E16D mutant. Our findings uncovered an apoptotic signaling cascade linking YAF2, PDCD5, and TP53 during genotoxic stress responses.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Dano ao DNA , Proteínas Musculares/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Leupeptinas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Ligação Proteica , Multimerização Proteica , Estabilidade Proteica/efeitos dos fármacos , UbiquitinaçãoRESUMO
In the epithelial-mesenchymal transition (EMT), an important cellular process, epithelial cells become mesenchymal cells. This process is also critically involved in cancer metastasis. Sanguiin H6 is a compound derived from ellagitannin, which is found in berries. Sanguiin H6 shows various pharmacological properties, including anti-angiogenic activity. Because the possible role of sanguiin H6 in the EMT and the underlying molecular mechanisms are unclear, we investigated the effect of sanguiin H6 on the EMT. Transforming growth factor-beta 1 (TGF-ß1) induces the EMT and promotes lung adenocarcinoma migration and invasion through the Smad2/3 signaling pathway. Thus, to understand the inhibitory effects of sanguiin H6 on lung cancer migration and invasion, we investigated the ability of sanguiin H6 to inhibit TGF-ß1-induced EMT in the A549 cell line. We found that sanguiin H6 significantly prevented the activation of Smad2/3 signaling pathway by TGF-ß1. Additionally, sanguiin H6 increased the expression of the epithelial marker E-cadherin and repressed the expression of Snail and the mesenchymal marker N-cadherin during TGF-ß1-induced EMT. Moreover, sanguiin H6 regulated the expression of EMT-dependent genes induced by TGF-ß1. Finally, sanguiin H6 inhibited the migration and invasion of TGF-ß1-stimulated A549 cells. Taken together, our findings provide new evidence that sanguiin H6 suppresses lung cancer migration and invasion in vitro by inhibiting TGF-ß1 induction of the EMT.
Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Taninos Hidrolisáveis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Invasividade NeoplásicaRESUMO
Glyoxal, methylglyoxal, and diacetyl are toxic α-dicarbonyl compounds found in heat-processed foods, including edible oils. Dispersive liquid-liquid microextraction was combined with gas chromatography mass spectrometry to determine the glyoxal, methylglyoxal, and diacetyl contents in sesame oil. Chloroform and methanol were selected as the optimal extraction and dispersive solvents, respectively. The maximum derivatization efficiency was obtained using 500 µg of the derivatization agent, o-phenylenediamine. The derivatization of glyoxal was completed in 1 h, whereas those of methylglyoxal and diacetyl were completed immediately. The optimized method was validated, and was found to exhibit a good linearity, recovery, intraday repeatability, and interday reproducibility. The α-dicarbonyl compound concentrations in the oils were dependent on the roasting temperature. The sesame oil concentrates contained 0-175.4, 0-990.5, and 0-220.9 ng g-1 of glyoxal, methylglyoxal, and diacetyl, respectively. For the perilla oils, the respective concentrations were 0-96.4, 0-410.8, and 0-197.5 ng g-1.
RESUMO
Unlike general nutritional ranges that meet the nutritional needs essential for maintaining the life of an entire population, personalized nutrition is characterised by maintaining health through providing customized nutrition according to individuals' lifestyles or genetic characteristics. The development of technology and services for personalized nutrition is increasing, owing to the acquisition of knowledge about the differences in nutritional requirements according to the diversity of individuals and an increase in health interest. Regarding genetics, technology is being developed to distinguish the various characteristics of individuals and provide customized nutrition. Therefore, to understand the current state of personalized nutrition technology, understanding genomics is necessary to acquire information on nutrition research based on genomics. We reviewed patents related to personalized nutrition-targeting genomics and examined their mechanisms of action. Using the patent database, we searched 694 patents on nutritional genomics and extracted 561 highly relevant valid data points. Furthermore, an in-depth review was conducted by selecting core patents related to genome-based personalized nutrition technology. A marked increase was observed in personalized nutrition technologies using methods such as genetic scoring and disease-specific dietary recommendations.
RESUMO
The primary inflammatory process in atherosclerosis, a major contributor to cardiovascular disease, begins with monocyte adhering to vascular endothelial cells. Actinidia arguta (kiwiberry) is an edible fruit that contains various bioactive components. While A. arguta extract (AAE) has been recognized for its anti-inflammatory characteristics, its specific inhibitory effect on early atherogenic events has not been clarified. We used tumor necrosis factor-α (TNF-α)-stimulated human umbilical vein endothelial cells (HUVECs) for an in vitro model. AAE effectively hindered the attachment of THP-1 monocytes and reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) in HUVECs. Transcriptome analysis revealed that AAE treatment upregulated phosphatase and tensin homolog (PTEN), subsequently inhibiting phosphorylation of AKT and glycogen synthase kinase 3ß (GSK3ß) in HUVECs. AAE further hindered phosphorylation of AKT downstream of the nuclear factor kappa B (NF-κB) signaling pathway, leading to suppression of target gene expression. Oral administration of AAE suppressed TNF-α-stimulated VCAM-1 expression, monocyte-derived macrophage infiltration, and proinflammatory cytokine expression in C57BL/6 mouse aortas. Myo-inositol, identified as the major compound in AAE, played a key role in suppressing THP-1 monocyte adhesion in HUVECs. These findings suggest that AAE could serve as a nutraceutical for preventing atherosclerosis by inhibiting its initial pathogenesis.
Assuntos
Actinidia , Adesão Celular , Glicogênio Sintase Quinase 3 beta , Células Endoteliais da Veia Umbilical Humana , Inositol , Monócitos , NF-kappa B , PTEN Fosfo-Hidrolase , Extratos Vegetais , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Fator de Necrose Tumoral alfa , Molécula 1 de Adesão de Célula Vascular , Molécula 1 de Adesão de Célula Vascular/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Humanos , NF-kappa B/metabolismo , NF-kappa B/genética , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Actinidia/química , Animais , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Adesão Celular/efeitos dos fármacos , Camundongos , Inositol/farmacologia , Inositol/análogos & derivados , Camundongos Endogâmicos C57BL , Aterosclerose/metabolismo , Aterosclerose/tratamento farmacológico , MasculinoRESUMO
Metabolic abnormalities in the liver are closely associated with diverse metabolic diseases such as non-alcoholic fatty liver disease, type 2 diabetes, and obesity. The aim of this study was to evaluate the ameliorating effect of robinetin (RBN) on the significant pathogenic features of metabolic failure in the liver and to identify the underlying molecular mechanism. RBN significantly decreased triglyceride (TG) accumulation by downregulating lipogenesis-related transcription factors in AML-12 murine hepatocyte cell line. In addition, mice fed with Western diet (WD) containing 0.025% or 0.05% RBN showed reduced liver mass and lipid droplet size, as well as improved plasma insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) values. CD38 was identified as a target of RBN using the BioAssay database, and its expression was increased in OPA-treated AML-12 cells and liver tissues of WD-fed mice. Furthermore, RBN elicited these effects through its anti-histone acetyltransferase (HAT) activity. Computational simulation revealed that RBN can dock into the HAT domain pocket of p300, a histone acetyltransferase, which leads to the abrogation of its catalytic activity. Additionally, knock-down of p300 using siRNA reduced CD38 expression. The chromatin immunoprecipitation (ChIP) assay showed that p300 occupancy on the promoter region of CD38 was significantly decreased, and H3K9 acetylation levels were diminished in lipid-accumulated AML-12 cells treated with RBN. RBN improves the pathogenic features of metabolic failure by suppressing the p300-CD38 axis through its anti-HAT activity, which suggests that RBN can be used as a new phytoceutical candidate for preventing or improving this condition.
RESUMO
AIMS: Doxorubicin (DOX) is a widely used anthracycline anticancer agent; however, its irreversible effects on the heart can result in DOX-induced cardiotoxicity (DICT) after cancer treatment. Unfortunately, the pathophysiology of DICT has not yet been fully elucidated, and there are no effective strategies for its prevention or treatment. In this investigation, the novel role of transducin beta-like protein 1 (TBL1) in developing and regulating DICT was explored. METHODS AND RESULTS: We observed a reduction in TBL1 protein expression levels as well as cleavage events in the transplanted cardiac tissues of patients diagnosed with Dilated Cardiomyopathy and DICT. It was revealed that DOX selectively induces TBL1 cleavage at caspase-3 preferred sites-D125, D136, and D215. Interestingly, overexpression of the uncleaved TBL1 mutant (TBL1uclv) variant reduced apoptosis, effectively preventing DOX-induced cell death. We confirmed that cleaved TBL1 cannot form a complex with ß-catenin. As a result, Wnt reporter activity and Wnt target gene expression collectively indicate a decrease in Wnt/ß-catenin signalling, leading to DICT progression. Furthermore, the cleaved TBL1 triggered DOX-induced abnormal electrophysiological features and disrupted calcium homeostasis. However, these effects were improved in TBL1uclv-overexpressing human-induced pluripotent stem cell-derived cardiomyocytes. Finally, in a DICT mouse model, TBL1uclv overexpression inhibited the DICT-induced reduction of cardiac contractility and collagen accumulation, ultimately protecting cardiomyocytes from cell death. CONCLUSION: Our findings reveal that the inhibition of TBL1 cleavage not only mitigates apoptosis but also enhances cardiomyocyte function, even in the context of DOX administration. Consequently, this study's results suggest that inhibiting TBL1 cleavage may be a novel strategy to ameliorate DICT.