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The human body continuously emits physiological and psychological information from head to toe. Wearable electronics capable of noninvasively and accurately digitizing this information without compromising user comfort or mobility have the potential to revolutionize telemedicine, mobile health, and both human-machine or human-metaverse interactions. However, state-of-the-art wearable electronics face limitations regarding wearability and functionality due to the mechanical incompatibility between conventional rigid, planar electronics and soft, curvy human skin surfaces. E-Tattoos, a unique type of wearable electronics, are defined by their ultrathin and skin-soft characteristics, which enable noninvasive and comfortable lamination on human skin surfaces without causing obstruction or even mechanical perception. This review article offers an exhaustive exploration of e-tattoos, accounting for their materials, structures, manufacturing processes, properties, functionalities, applications, and remaining challenges. We begin by summarizing the properties of human skin and their effects on signal transmission across the e-tattoo-skin interface. Following this is a discussion of the materials, structural designs, manufacturing, and skin attachment processes of e-tattoos. We classify e-tattoo functionalities into electrical, mechanical, optical, thermal, and chemical sensing, as well as wound healing and other treatments. After discussing energy harvesting and storage capabilities, we outline strategies for the system integration of wireless e-tattoos. In the end, we offer personal perspectives on the remaining challenges and future opportunities in the field.
Assuntos
Tatuagem , Dispositivos Eletrônicos Vestíveis , Humanos , EletrônicaRESUMO
One new canthinone glycoside (1), together with six known compounds (2-7) including three lignans (2-4), two coumarins (5-6) and one phenol (7) was isolated from the root barks of Ailanthus altissima. The structure of new compound 1 was established by the interpretation of UV, IR, MS and NMR data, while its absolute configuration was determined by acid hydrolysis and GIAO NMR calculations with DP4+ probability analysis. The inhibitory effects of all compounds on Nitric oxide (NO) production were investigated in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Results showed that compounds 2 and 5 displayed NO production inhibitory activity with IC50 values of 30.1 and 15.3 µM, respectively.
Assuntos
Ailanthus , Glicosídeos , Lipopolissacarídeos , Óxido Nítrico , Casca de Planta , Raízes de Plantas , Ailanthus/química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Camundongos , Estrutura Molecular , Animais , Casca de Planta/química , Raízes de Plantas/química , Células RAW 264.7 , Glicosídeos/farmacologia , Glicosídeos/química , Glicosídeos/isolamento & purificação , Lipopolissacarídeos/farmacologia , Lignanas/farmacologia , Lignanas/química , Lignanas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/isolamento & purificação , Ressonância Magnética Nuclear BiomolecularRESUMO
PURPOSE OF REVIEW: The hypolipidemic and antiobesogenic effects of tea intake have been associated with bioactive compounds that regulate peroxisome proliferator-activated receptors (PPARs). This review describes the recent research on two of these compounds, (-)-epigallocatechin gallate (EGCG) and linalool. RECENT FINDINGS: Catechins (specifically EGCG) are key bioactive compounds found in tea, and a recent study has shown that linalool may also be an active tea compound. These compounds act on lipid metabolism by regulating PPAR subtypes. EGCG inhibits the key adipogenic transcription factor PPARγ while activating PPARα, whereas linalool is a PPARα agonist activating hepatic fatty acid uptake and subsequent oxidation to reduce plasma triglyceride levels. SUMMARY: The collective activities of EGCG and linalool in tea may exert hypolipidemic and antiobesogenic effects by regulating PPARs. The research summarized in this review expands our understanding of the biological and physiological mechanisms of the bioactive compounds found in tea.
Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Chá/química , Monoterpenos Acíclicos , Animais , Catequina/análogos & derivados , Catequina/farmacologia , Catequina/uso terapêutico , Humanos , Monoterpenos/farmacologia , Monoterpenos/uso terapêuticoRESUMO
This study investigated the molecular mechanism of saponarin, a flavone glucoside, in the regulation of insulin sensitivity. Saponarin suppressed the rate of gluconeogenesis and increased cellular glucose uptake in HepG2 and TE671 cells by regulating AMPK. Using an in vitro kinase assay, we showed that saponarin did not directly interact with the AMPK protein. Instead, saponarin increased intracellular calcium levels and induced AMPK phosphorylation, which was diminished by co-stimulation with STO-609, an inhibitor of CAMKKß. Transcription of hepatic gluconeogenesis genes was upregulated by nuclear translocation of CRTC2 and HDAC5, coactivators of CREB and FoxO1 transcription factors, respectively. This nuclear translocation was inhibited by increased phosphorylation of CRTC2 and HDAC5 by saponarin-induced AMPK in HepG2 cells and suppression of CREB and FoxO1 transactivation activities in cells stimulated by saponarin. The results from a chromatin immunoprecipitation assay confirmed the reduced binding of CRTC2 on the PEPCK and G6Pase promoters. In TE671 cells, AMPK phosphorylated HDAC5, which suppressed nuclear penetration and upregulated GLUT4 transcription, leading to enhanced glucose uptake. Collectively, these results suggest that saponarin activates AMPK in a calcium-dependent manner, thus regulating gluconeogenesis and glucose uptake.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apigenina/farmacologia , Ativadores de Enzimas/farmacologia , Glucose/metabolismo , Glucosídeos/farmacologia , Benzimidazóis/farmacologia , Compostos de Bifenilo , Cálcio/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/metabolismo , Gluconeogênese , Transportador de Glucose Tipo 4/metabolismo , Células Hep G2 , Histona Desacetilases/metabolismo , Humanos , Resistência à Insulina , Metformina/farmacologia , Naftalimidas/farmacologia , Fosforilação , Pironas/farmacologia , Tiofenos/farmacologia , Fatores de Transcrição/metabolismoRESUMO
We investigated the hypotriglyceridemic mechanism of action of linalool, an aromatic monoterpene present in teas and fragrant herbs. Reporter gene and time-resolved fluorescence resonance energy transfer assays demonstrated that linalool is a direct ligand of PPARα. Linalool stimulation reduced cellular lipid accumulation regulating PPARα-responsive genes and significantly induced FA oxidation, and its effects were markedly attenuated by silencing PPARα expression. In mice, the oral administration of linalool for 3 weeks reduced plasma TG concentrations in Western-diet-fed C57BL/6J mice (31%, P < 0.05) and human apo E2 mice (50%, P < 0.05) and regulated hepatic PPARα target genes. However, no such effects were seen in PPARα-deficient mice. Transcriptome profiling revealed that linalool stimulation rewired global gene expression in lipid-loaded hepatocytes and that the effects of 1 mM linalool were comparable to those of 0.1 mM fenofibrate. Metabolomic analysis of the mouse plasma revealed that the global metabolite profiles were significantly distinguishable between linalool-fed mice and controls. Notably, the concentrations of saturated FAs were significantly reduced in linalool-fed mice. These findings suggest that the appropriate intake of a natural aromatic compound could exert beneficial metabolic effects by regulating a cellular nutrient sensor.
Assuntos
Fígado/metabolismo , Metaboloma/efeitos dos fármacos , Monoterpenos/farmacologia , PPAR alfa/biossíntese , Transcriptoma/efeitos dos fármacos , Triglicerídeos/sangue , Monoterpenos Acíclicos , Animais , Hepatócitos/metabolismo , Masculino , Camundongos , Camundongos Mutantes , PPAR alfa/agonistas , PPAR alfa/genética , Triglicerídeos/genéticaRESUMO
To investigate the underlying mechanism of targets of cyanidin, a flavonoid, which exhibits potent anti-atherogenic activities in vitro and in vivo, a natural chemical library that identified potent agonistic activity between cyanidin and peroxisome proliferator-activated receptors (PPAR) was performed. Cyanidin induced transactivation activity in all three PPAR subtypes in a reporter gene assay and time-resolved fluorescence energy transfer analyses. Cyanidin also bound directly to all three subtypes, as assessed by surface plasmon resonance experiments, and showed the greatest affinity to PPARα. These effects were confirmed by measuring the expression of unique genes of each PPAR subtype. Cyanidin significantly reduced cellular lipid concentrations in lipid-loaded steatotic hepatocytes. In addition, transcriptome profiling in lipid-loaded primary hepatocytes revealed that the net effects of stimulation with cyanidin on lipid metabolic pathways were similar to those elicited by hypolipidemic drugs. Cyanidin likely acts as a physiological PPARα agonist and potentially for PPARß/δ and γ, and reduces hepatic lipid concentrations by rewiring the expression of genes involved in lipid metabolic pathways.
Assuntos
Antocianinas/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , PPAR alfa/agonistas , Animais , Células CHO , Células Cultivadas , Cricetinae , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR gama/agonistas , PPAR beta/agonistasRESUMO
Dipeptides digested from dietary proteins can be directly absorbed by the intestine and delivered to the circulatory system. However, the dipeptides' metabolic roles and biological activities are largely unknown. Lipid-loaded HII4E cells stimulated with H-Trp-Glu-OH (WE) exhibited reduced lipid accumulation, of which the effect was abolished by peroxisome proliferator-activated receptor (PPAR) α gene knock down. A luciferase assay showed that the WE dipeptide induced PPARα transactivation in a dose-dependent manner. Surface plasmon resonance and time-resolved fluorescence resonance energy transfer analyses demonstrated that WE interacts directly with the PPARα ligand binding domain (KD, 120 µM; EC50, 83 µM). Cells stimulated with WE induced PPARα and its responsive genes and increased cellular fatty acid uptake. In conclusion, WE reduces hepatic lipid accumulation in lipid-loaded hepatocytes via the activation of PPARα by a direct interaction.
Assuntos
Dipeptídeos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/antagonistas & inibidores , Fígado/efeitos dos fármacos , PPAR alfa/agonistas , Linhagem Celular , Dipeptídeos/química , Relação Dose-Resposta a Droga , Humanos , Lipídeos/administração & dosagem , Fígado/metabolismo , Estrutura Molecular , PPAR alfa/genética , Relação Estrutura-AtividadeRESUMO
Intake of dietary aroma compounds may regulate cellular lipid metabolism. We demonstrated that trans-caryophyllene, a flavor compound in plant foods and teas, activates peroxisome proliferator-activated receptor (PPAR)-α through direct interaction with the ligand-binding domain of PPAR-α. The agonistic activity of trans-caryophyllene was investigated by the luciferase reporter assay, surface plasmon resonance, and time-resolved fluorescence resonance energy transfer assay. Following the stimulation of cells with trans-caryophyllene, intracellular triglyceride concentrations were significantly reduced by 17%, and hepatic fatty acid uptake was significantly increased by 31%. The rate of fatty acid oxidation was also significantly increased. The expressions of PPAR-α and its target genes and proteins in fatty acid uptake and oxidation were significantly up-regulated as well. In HepG2 cells transfected with small interfering RNA of PPAR-α, the effects of trans-caryophyllene on PPAR-α responsive gene expressions, intracellular triglyceride, fatty acid uptake and oxidation were disappeared. These results indicate that the aroma compound, trans-caryophyllene, is PPAR-α agonist thus regulates cellular lipid metabolism in PPAR-α dependent manners.
Assuntos
PPAR alfa/agonistas , Sesquiterpenos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Sesquiterpenos Policíclicos , Sesquiterpenos/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Meju, a naturally fermented soy block used to produce soy paste and soy sauce in Korea, is suggested to exhibit hypolipidemic and antiinflammatory activities; however, its mechanisms of action are elusive. Here, we report that the water-soluble fibers but not the amino acids and peptides from meju exhibited hypolipidemic activity in vivo. Feeding of fermented soybean fibers (FSF) from meju reduced plasma cholesterol, triglyceride, adipocyte size, and hepatic lipid accumulation in C57BL/6 J mice. FSF treatment reduced HMG-CoA reductase expression, whereas the expression of genes in the fatty acid uptake and subsequent beta-oxidation were significantly induced in the livers. Hepatic lipogenic genes, including Srebp1c and Lxrα, were unaltered. Feeding with the fermented soybean peptides and amino acids (FSPA) induced the expression of lipogenic genes, which may have canceled the induction of low-density lipoprotein receptor and Cyp7a1 gene expressions in FSPA livers. The plasma concentrations of C-reactive protein, TNF-α, and interlukin-6 were significantly reduced in the FSF, FSPA, and meju groups compared with the control groups, suggesting that both of the fibers and peptides/amino acids from meju may be beneficial. These findings suggest that soluble fibers from meju are critical hypolipidemic components that regulate hepatic gene expressions and reduce proinflammatory cytokines in vivo.
Assuntos
Anti-Inflamatórios/farmacologia , Fibras na Dieta/farmacologia , Fermentação , Glycine max/química , Hipolipemiantes/farmacologia , Animais , Citocinas/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Proteínas de Soja/farmacologiaRESUMO
This paper introduces a wirelessly powered scattered neural recording wearable system that can facilitate continuous, untethered, and long-term electroencephalogram (EEG) recording. The proposed system, including 32 standalone EEG recording devices and a central controller, is incorporated in a wearable form factor. The standalone devices are sparsely distributed on the scalp, allowing for flexible placement and varying quantities to provide extensive spatial coverage and scalability. Each standalone device featuring a low-power EEG recording application-specific integrated circuit (ASIC) wirelessly receives power through a 60 MHz inductive link. The low-power ASIC design (84.6 µW) ensures sufficient wireless power reception through a small receiver (Rx) coil. The 60 MHz inductive link also serves as the data carrier for wireless communication between standalone devices and the central controller, eliminating the need for additional data antennas. All these efforts contribute to the miniaturization of standalone devices with dimensions of 12 × 12 × 5 mm3, enhancing device wearability. The central controller applies the pulse width modulation (PWM) scheme on the 60 MHz carrier, transmitting user commands at 4 Mbps to EEG recording ASICs. The ASIC employs a novel synchronized PWM demodulator to extract user commands, operating signal digitization and data transmission. The analog frontend (AFE) amplifies the EEG signal with a gain of 45 dB and applies band-pass filtering from 0.03 Hz to 400 Hz, with an input-referred noise (IRN) of 3.62 µVRMS. The amplified EEG signal is then digitized by a 10-bit successive approximation register (SAR) analog-to-digital converter (ADC) with a peak signal-to-noise and distortion ratio (SNDR) of 55.4 dB. The resulting EEG data is transmitted to an external software-defined radio (SDR) Rx through load-shift-keying (LSK) backscatter at 3.75 Mbps. The system's functionality is fully evaluated in human experiments.
Assuntos
Eletroencefalografia , Desenho de Equipamento , Dispositivos Eletrônicos Vestíveis , Tecnologia sem Fio , Eletroencefalografia/instrumentação , Tecnologia sem Fio/instrumentação , Humanos , Processamento de Sinais Assistido por Computador/instrumentação , Fontes de Energia ElétricaRESUMO
Utilizing injectable devices for monitoring animal health offers several advantages over traditional wearable devices, including improved signal-to-noise ratio (SNR) and enhanced immunity to motion artifacts. We present a wireless application-specific integrated circuit (ASIC) for injectable devices. The ASIC has multiple physiological sensing modalities including body temperature monitoring, electrocardiography (ECG), and photoplethysmography (PPG). The ASIC fabricated using the CMOS 180 nm process is sized to fit into an injectable microchip implant. The ASIC features a low-power design, drawing an average DC power of 155.3 µW, enabling the ASIC to be wirelessly powered through an inductive link. To capture the ECG signal, we designed the ECG analog frontend (AFE) with 0.3 Hz low cut-off frequency and 45-79 dB adjustable midband gain. To measure PPG, we employ an energy-efficient and safe switched-capacitor-based (SC) light emitting diode (LED) driver to illuminate an LED with milliampere-level current pulses. A SC integrator-based AFE converts the current of photodiode with a programmable transimpedance gain. A resistor-based Wheatstone Bridge (WhB) temperature sensor followed by an instrumentation amplifier (IA) provides 27-47 °C sensing range with 0.02 °C inaccuracy. Recorded physiological signals are sequentially sampled and quantized by a 10-bit analog-to-digital converter (ADC) with the successive approximation register (SAR) architecture. The SAR ADC features an energy-efficient switching scheme and achieves a 57.5 dB signal-to-noise-and-distortion ratio (SNDR) within 1 kHz bandwidth. Then, a back data telemetry transmits the baseband data via a backscatter scheme with intermediate-frequency assistance. The ASIC's overall functionality and performance has been evaluated through an in vivo experiment.
RESUMO
We demonstrated that ombuin-3-O-ß-D-glucopyranoside (ombuine), a flavonoid from Gynostemma pentaphyllum, is a dual agonist for peroxisome proliferator-activated receptors (PPARs) α and δ/ß. Using surface plasmon resonance (SPR), time-resolved fluorescence resonance energy transfer (FRET) analyses, and reporter gene assays, we showed that ombuine bound directly to PPARα and δ/ß but not to PPARγ or liver X receptors (LXRs). Cultured HepG2 hepatocytes stimulated with ombuine significantly reduced intracellular concentrations of triglyceride and cholesterol and downregulated the expression of lipogenic genes, including sterol regulatory element binding protein-1c (SREBP1c) and stearoyl-CoA desaturase-1 (SCD-1), with activation of PPARα and δ/ß. Activation of LXRs by ombuine was confirmed by reporter gene assays, however, SPR and cell-based FRET assays showed no direct binding of ombuine to either of the LXRs suggesting LXR activation by ombuine may be operated via PPARα stimulation. Ombuine-stimulated macrophages showed significantly induced transcription of ATP binding cassette cholesterol transporter A1 (ABCA1) and G1 (ABCG1), the key genes in reverse cholesterol transport, which led to reduced cellular cholesterol concentrations. These results suggest that ombuine is a dual PPAR ligand for PPARα and δ/ß with the ability to decrease lipid concentrations by reducing lipogenic gene expression in hepatocytes and inducing genes involved in cholesterol efflux in macrophages.
Assuntos
Flavonas/farmacologia , Flavonoides/farmacologia , Glucosídeos/farmacologia , Gynostemma/química , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR beta/agonistas , Animais , Linhagem Celular , Ácidos Graxos/metabolismo , Flavonas/química , Flavonas/isolamento & purificação , Flavonoides/química , Flavonoides/isolamento & purificação , Expressão Gênica/efeitos dos fármacos , Glucosídeos/química , Glucosídeos/isolamento & purificação , Células Hep G2 , Humanos , Ligantes , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , PPAR alfa/química , PPAR delta/química , PPAR beta/químicaRESUMO
Cyanidin, a natural flavonoid abundant in fruits and vegetables, is known to regulate cellular lipid metabolism; however, its underlying mechanism of action and protein targets remain unknown. Here, the ligand binding activity of cyanidin on liver X receptors (LXRs) was investigated utilizing surface plasmon resonance and time-resolved fluorescence energy transfer (TR-FRET) analyses. LXRs are nuclear receptors which function as critical transcription factors in the regulation of cellular lipid and glucose metabolism. This includes the stimulation of high-density-lipoprotein synthesis and activation of reverse cholesterol transport. The present findings show that cyanidin induces the transactivation of LXRs and binds directly to the ligand-binding domain of both LXRα and LXRß with dissociation constants of 2.2 and 73.2µM, respectively. Cell-free FRET analysis demonstrated that cyanidin induces the recruitment of co-activator peptide for LXRα and LXRß with EC50 of 3.5µM and 125.2µM, respectively. In addition, intracellular cholesterol and triglyceride (TG) concentrations were reduced in macrophages following cyanidin stimulation. In cultured hepatocytes, cyanidin mildly induced SREBP1c gene expression but marginally affected cellular TG concentrations as well as reduced cellular cholesterol accumulations which activated the expression of genes for reverse cholesterol transport. Two cyanidin metabolites, procatechic acid and phloroglucinaldehyde, did not directly bind or activate LXRs. These results demonstrate that cyanidin is a direct ligand for both LXRα and LXRß, suggesting that cyanidin may operate, at least in part, through modulation of cellular LXR activity.
Assuntos
Antocianinas/química , Colesterol/metabolismo , Flavonoides/química , Receptores Nucleares Órfãos/agonistas , Triglicerídeos/metabolismo , Antocianinas/metabolismo , Antocianinas/farmacologia , Linhagem Celular , Flavonoides/metabolismo , Flavonoides/farmacologia , Transferência Ressonante de Energia de Fluorescência , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Ligantes , Receptores X do Fígado , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Ligação Proteica , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismoRESUMO
We investigated the effect of cineole on the expression of genes related to reverse cholesterol transport and hepatic fatty acid metabolism. Cineole, a small aroma compound in teas and herbs, significantly stimulated the transactivation of liver X receptor modulator (LXR)-α and LXR-ß. The mRNA and protein expression of LXRs and their target genes, including ABCA1 and ABCG1, was significantly increased in macrophages stimulated with cineole. This led to the subsequent removal of cholesterol from the cells. Interestingly, cineole showed tissue-selective LXR induction: hepatocytes stimulated with cineole showed significantly reduced expression of LXR-α and LXR-α-responsive genes, including FAS and SCD-1 (P <0.05). Accordingly, hepatocytes treated with cineole displayed reduced cellular lipid accumulation compared with control cells, as assessed by Oil Red O lipid staining and cholesterol quantification. These results suggest that cineole is a selective LXR modulator that regulates the expression of key genes in reverse cholesterol transport in macrophages without inducing lipogenesis in hepatocytes. This selective LXR modulator may have practical implications for the development of hypocholesterolemic or anti-atherosclerotic agents and also suggests.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Cicloexanóis/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Monoterpenos/farmacologia , Receptores Nucleares Órfãos/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Anti-Infecciosos/farmacologia , Eucaliptol , Hepatócitos/efeitos dos fármacos , Receptores X do Fígado , Receptores Nucleares Órfãos/genéticaRESUMO
Three new monomeric (1-3) and two newdimeric guaianolides (4 and 5), along with three known analogues (6-8) were isolated from the aerial part of Achillea alpina L. Compounds 1-3 were three novel 1,10-seco-guaianolides, while 4 and 5 were two novel 1,10-seco-guaianolides involved heterodimeric [4 + 2] adducts. The new structures were elucidated by analysis of spectroscopic data and quantum chemical calculations. All isolates were evaluated for their hypoglycemic activity with a glucose consumption model in palmitic acid (PA)-induced HepG2-insulin resistance (IR) cells, and compound 1 showed the most promising activity. A mechanistic study revealed that compound 1 appeared to mediate hypoglycemic activity via inhibition of the ROS/TXNIP/NLRP3/caspase-1 pathway.
Assuntos
Achillea , Sesquiterpenos , Achillea/química , Estrutura Molecular , Hipoglicemiantes/farmacologia , Extratos Vegetais/química , Sesquiterpenos/farmacologia , Sesquiterpenos/químicaRESUMO
Nonalcoholic fatty liver disease (NAFLD) is prevalent in the majority of individuals with obesity, but in a subset of these individuals, it progresses to nonalcoholic steatohepatitis (0NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of patients with NAFLD remain unclear. Here, we report that NAD(P)H oxidase 4 (NOX4) and nuclear factor erythroid 2-related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH and fibrosis. Mitochondria-derived ROS activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 antioxidant defense response. The deletion or inhibition of NOX4 in hepatocytes decreased ROS and attenuated antioxidant defense to promote mitochondrial oxidative stress, damage proteins and lipids, diminish insulin signaling, and promote cell death upon oxidant challenge. Hepatocyte NOX4 deletion in high-fat diet-fed obese mice, which otherwise develop steatosis, but not NASH, resulted in hepatic oxidative damage, inflammation, and T cell recruitment to drive NASH and fibrosis, whereas NOX4 overexpression tempered the development of NASH and fibrosis in mice fed a NASH-promoting diet. Thus, mitochondria- and NOX4-derived ROS function in concert to drive a NFE2L2 antioxidant defense response to attenuate oxidative liver damage and progression to NASH and fibrosis in obesity.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Antioxidantes , Dieta Hiperlipídica/efeitos adversos , Hepatócitos/metabolismo , Peróxido de Hidrogênio/metabolismo , Fígado/metabolismo , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Mitocôndrias/metabolismo , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Peroxisome proliferator-activated receptor-alpha (PPARα) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPARα agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPARα agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPARα. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P<0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPARα via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.
Assuntos
Glucosídeos/farmacologia , Hepatócitos/efeitos dos fármacos , Hipertrigliceridemia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR alfa/agonistas , Ácidos Graxos/metabolismo , Transferência Ressonante de Energia de Fluorescência , Genes Reporter/efeitos dos fármacos , Glucosídeos/química , Células Hep G2 , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Ligantes , Lipídeos/análiseRESUMO
We investigated the hypolipidemic effects of Melissa officinalis essential oil (MOEO) in human APOE2 transgenic mice and lipid-loaded HepG2 cells. Plasma TG concentrations were significantly less in APOE2 mice orally administered MOEO (12.5 µg/d) for 2 wk than in the vehicle-treated group. Cellular TG and cholesterol concentrations were also significantly decreased in a dose- (400 and 800 mg/L) and time- (12 and 24 h) dependent manner in HepG2 cells stimulated with MOEO compared with controls. Mouse hepatic transcriptome analysis suggested MOEO feeding altered several lipid metabolic pathways, including bile acid and cholesterol synthesis and fatty acid metabolism. In HepG2 cells, the rate of fatty acid oxidation, as assessed using [1-(14)C]palmitate, was unaltered; however, the rate of fatty acid synthesis quantified with [1-(14)C]acetate was significantly reduced by treatment with 400 and 800 mg/L MOEO compared with untreated controls. This reduction was due to the decreased expression of SREBP-1c and its responsive genes in fatty acid synthesis, including FAS, SCD1, and ACC1. Subsequent chromatin immunoprecipitation analysis further demonstrated that the binding of p300/CBP-associated factor, a coactivator of SREBP-1c, and histone H3 lysine 14 acetylation at the FAS, SCD1, and ACC1 promoters were significantly reduced in the livers of APOE2 mice and HepG2 cells treated with MOEO compared with their controls. Additionally, MOEO stimulation in HepG2 cells induced bile acid synthesis and reduced the nuclear form of SREBP-2, a key transcription factor in hepatic cholesterol synthesis. These findings suggest that the intake of phytochemicals with pleasant scent could have beneficial metabolic effects.
Assuntos
Apolipoproteína E2/genética , Hipolipemiantes/administração & dosagem , Melissa , Óleos de Plantas/administração & dosagem , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Triglicerídeos/sangue , Animais , Colesterol/sangue , Ácidos Graxos/biossíntese , Células Hep G2 , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Melissa/química , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Fitoterapia , Óleos de Plantas/química , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Transcriptoma/efeitos dos fármacosRESUMO
The present study reports a novel liver X receptor (LXR) activator, ethyl 2,4,6-trihydroxybenzoate (ETB), isolated from Celtis biondii. Using a reporter gene assay, time-resolved fluorescence resonance energy transfer (TR-FRET), and surface plasmon resonance (SPR) analysis, we showed that ETB directly bound to and stimulated the transcriptional activity of LXR-α and LXR-ß. In macrophages, hepatocytes, and intestinal cells, ETB suppressed cellular cholesterol accumulation in a dose-dependent manner and induced the transcriptional activation of LXR-α/-ß-responsive genes. Notably, ETB did not induce lipogenic gene expression or cellular triglyceride accumulation in hepatocytes. These results suggest that ETB is a dual-LXR modulator that regulates the expression of key genes in cholesterol homeostasis in multiple cells without inducing lipid accumulation in HepG2 cells.
Assuntos
Colesterol/metabolismo , Ácido Gálico/análogos & derivados , Hepatócitos/metabolismo , Macrófagos/metabolismo , Receptores Nucleares Órfãos/agonistas , Animais , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Transferência Ressonante de Energia de Fluorescência , Ácido Gálico/isolamento & purificação , Ácido Gálico/farmacologia , Genes Reporter , Hepatócitos/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores X do Fígado , Macrófagos/efeitos dos fármacos , Camundongos , Especificidade de Órgãos , Receptores Nucleares Órfãos/genética , Ressonância de Plasmônio de Superfície , Ativação Transcricional/efeitos dos fármacos , Ulmaceae/químicaRESUMO
We investigated the acute metabolic effects of isoflavones from Pueraria lobata (Willd.) Ohwi (IPL) in ovariectomized (OVX) mice. After 4 weeks of IPL feeding at 500 mg/day/kg body weight (OVX500), plasma 17ß-estradiol concentrations were significantly higher (+25%, p < 0.05), whereas plasma triglyceride levels were significantly lower in OVX mice (-15%, p < 0.05) compared with controls. Abdominal adipose tissue weight was marginally reduced in IPL-fed groups compared with OVX controls and the plasma levels of liver enzymes were unchanged. In addition, IPL significantly inhibited the reduction of bone mineral density in the femurs of OVX mice (OVX200, +22%; OVX500, +26%; p < 0.05) compared with controls after 4 weeks of IPL feeding. In quantitative polymerase chain reaction analysis the expression of aromatase was significantly suppressed and SULT1E1 was increased by IPL feeding, showing that IPL feeding may not alter the risk for breast cancer in mice. Our results suggest that IPL could ameliorate menopausal symptoms in mice. Further studies will confirm the effects of IPL in humans.