RESUMO
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
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
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
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
Arrhythmogenic cardiomyopathy (ACM) is a cardiomyopathy that is predominantly inherited and characterized by cardiac arrhythmias and structural abnormalities. TMEM43 (transmembrane protein 43) is one of the well-known genetic culprits behind ACM. In this study, we successfully generated an induced pluripotent stem cell (iPSC) line, YCMi010-A, derived from a male patient diagnosed with ACM. Although these iPSCs harbored a heterozygous intronic splice variant, TMEM43 c.443-2A > G, they still displayed normal cellular morphology and were confirmed to express pluripotency markers. YCMi010-A iPSC line is a promising model for investigating the pathomechanisms associated with ACM and exploring potential therapeutic strategies.
Assuntos
Displasia Arritmogênica Ventricular Direita , Células-Tronco Pluripotentes Induzidas , Proteínas de Membrana , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/patologia , Displasia Arritmogênica Ventricular Direita/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Linhagem Celular , Adulto , Sítios de Splice de RNA/genética , Diferenciação CelularRESUMO
BACKGROUND: Doxorubicin (DOX) is an effective anticancer agent. However, the clinical outcomes of DOX-based therapies are severely hampered by their significant cardiotoxicity. PURPOSE: We investigated the beneficial effects of an ethanol extract of Cirsium setidens (CSE) on DOX-induced cardiomyotoxicity (DICT). METHODS: UPLC-TQ/MS analysis was used to identify CSE metabolite profiles. H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells were used to evaluate the effects of CSE on DICT-induced cell death. To elucidate the mechanism underlying it, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma co-activator l-alpha (PGC1-α), nuclear respiratory factor 1 (NRF1), NRF2, superoxide dismutase (SOD1), and SOD2 expression was detected using western blot analysis. The oxygen consumption rate (OCR), cellular ROS, and mitochondrial membrane potential were measured. Finally, we confirmed the cardioprotective effect of CSE against DICT in both C57BL/6 mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) by observing various parameters, such as electrophysiological changes, cardiac fibrosis, and cardiac cell death. RESULTS: Chlorogenic acid and nicotiflorin were the major compounds in CSE. Our data demonstrated that CSE blocked DOX-induced cell death of H9c2 cells without hindrance of its apoptotic effects on MDA-MB-231 cells. DOX-induced defects of OCR and mitochondrial membrane potential were recovered in a CSE through upregulation of the AMPK-PGC1-α-NRF1 signaling pathway. CSE accelerated NRF1 translocation to the nucleus, increased SOD activity, and consequently blocked apoptosis in H9c2 cells. In mice treated with 400 mg/kg CSE for 4 weeks, electrocardiogram data, creatine kinase and lactate dehydrogenase levels in the serum, and cardiac fibrosis, were improved. Moreover, various electrophysiological features indicative of cardiac function were significantly enhanced following the CSE treatment of hiPSCCMs. CONCLUSION: Our findings demonstrate CSE that ameliorates DICT by protecting mitochondrial dysfunction via the AMP- PGC1α-NRF1 axis, underscoring the therapeutic potential of CSE and its underlying molecular pathways, setting the stage for future investigations into its clinical applications.
Assuntos
Proteínas Quinases Ativadas por AMP , Cardiotoxicidade , Cirsium , Doxorrubicina , Miócitos Cardíacos , Extratos Vegetais , Animais , Humanos , Masculino , Camundongos , Ratos , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Cardiotoxicidade/tratamento farmacológico , Linhagem Celular Tumoral , Cirsium/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
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.
Assuntos
Apoptose , Cardiotoxicidade , Doxorrubicina , Miócitos Cardíacos , Via de Sinalização Wnt , beta Catenina , Doxorrubicina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/enzimologia , Via de Sinalização Wnt/efeitos dos fármacos , Humanos , Animais , Apoptose/efeitos dos fármacos , beta Catenina/metabolismo , beta Catenina/genética , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/induzido quimicamente , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/enzimologia , Cardiomiopatia Dilatada/fisiopatologia , Masculino , Transducina/metabolismo , Transducina/genética , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/enzimologia , Células-Tronco Pluripotentes Induzidas/patologia , Feminino , Estudos de Casos e Controles , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/toxicidadeRESUMO
Diabetes is characterized by persistently high blood glucose levels and severe complications and affects millions of people worldwide. In this study, we explored the epigenetic landscape of diabetes using data from the Korean Genome and Epidemiology Study (KoGES), specifically the Ansung-Ansan (AS-AS) cohort. Using epigenome-wide association studies, we investigated DNA methylation patterns in patients with type 2 diabetes mellitus (T2DM) and those with normal glucose regulation. Differential methylation analysis revealed 106 differentially methylated probes (DMPs), with the 10 top DMPs prominently associated with TXNIP, PDK4, NBPF20, ARRDC4, UFM1, PFKFB2, C7orf50, and ABCG1, indicating significant changes in methylation. Correlation analysis highlighted the association between the leading DMPs (e.g., cg19693031 and cg26974062 for TXNIP and cg26823705 for NBPF20) and key glycemic markers (fasting plasma glucose and hemoglobin A1c), confirming their relevance in T2DM. Moreover, we identified 62 significantly differentially methylated regions (DMRs) spanning 61 genes. A DMR associated with PDE1C showed hypermethylation, whereas DMRs associated with DIP2C, FLJ90757, PRSS50, and TDRD9 showed hypomethylation. PDE1C and TDRD9 showed a strong positive correlation between the CpG sites included in each DMR, which have previously been implicated in T2DM-related processes. This study contributes to the understanding of epigenetic modifications in T2DM. These valuable insights can be utilized in identifying potential biomarkers and therapeutic targets for effective management and prevention of diabetes.