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BACKGROUND AND PURPOSE: Various types of cerebral small vessel diseases (CSVD) are commonly coexisting and the clinical outcome possibly is determined by their combined effect. The present study was designed to explore the possible relationship between the global burden of CSVD and clinical outcomes after recombinant tissue plasminogen activator (rt-PA) treatment of ischemic stroke. METHODS: We enrolled patients with acute ischemic stroke (AIS) after IV rt-PA treatment between August 2016 and July 2018. According to the total burden rating scale of CSVD, we calculated the total CSVD score for white matter hyperintensities, lacunar infarction, cerebral microbleeds, and perivascular spaces. All patients were assessed on the basis of the National Institutes of Health Stroke Scale (NIHSS) score and the modified Rankin Scale (mRS) score at 90 days after stroke. We used multivariate logistic regression analysis to examine the associations between global burden of CSVD and degree of neurological deficit and clinical outcomes. ROC curve analysis was used to determine cut-off values of the total CSVD score in predicting poor outcomes. RESULTS: The results showed that the total CSVD score was independently associated with moderate to severe stroke (OR 2.187, 95%CI 1.495-3.119, P < 0.001). Initial NIHSS (OR 1.23, 95%CI 1.144-1.330, P < 0.001), OTT (OR 1.007, 95%CI 1.000-1.014, P = 0.037), and CSVD score (OR 3.157, 95%CI 2.120-4.703, P < 0.001) was significantly related to poor functional outcome at 3 months. The total CVSD score cut-off value of 1.5 was determined at best to distinguish between good prognosis and poor outcome (AUC 0.7534 [95%CI 0.6883-0.8185]). CONCLUSIONS: The global burden of CSVD was independently associated with neurological deficit severity and clinical outcomes of AIS after IV rt-PA treatment. The total CVSD score is a reliable predictor for poor outcomes of AIS after IV rt-PA treatment.
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Isquemia Encefálica/diagnóstico , Isquemia Encefálica/psicología , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico , Enfermedades de los Pequeños Vasos Cerebrales/psicología , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/psicología , Activador de Tejido Plasminógeno/uso terapéutico , Anciano , Isquemia Encefálica/complicaciones , Isquemia Encefálica/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Oat protein is becoming an important ingredient in beverages and formulated foods owing to its high nutritive value and bland flavor; yet, its functionality remains largely unexplored. This study sought to enhance the surface activity of oat protein isolate (OPI) through high-intensity ultrasound (HIU; at 20 or 60 °C) combined with high pressure homogenization (HP; 30 MPa) treatments. Sonication disturbed the protein conformation and significantly improved surface hydrophobicity (19.7%) and ζ-potential (15.7%), which were further augmented by subsequent HP (P < 0.05). Confocal microscopy revealed a uniform oil droplet distribution in emulsions prepared with HIU+HP combination treated OPI, and the oil droplet size decreased up to 35.6% when compared to that of non-treated OPI emulsion (d = 1718 nm). Emulsifying activity was greater for HIU+HP than for HIU, and the viscosity followed a similar trend. Moreover, while emulsions prepared with HIU or HP treated OPI were more stable than control, the 60 °C HIU+HP combination treatment yielded the maximum stability. In corroboration, a model salad dressing prepared from HIU+HP treated OPI displayed a homogenous oil droplet distribution and an improved viscosity. Therefore, thermosonication combined with high pressure homogenization may be suitable for salad dressings and other oil-imbedded food products.
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Avena , Condimentos , Emulsiones/química , Viscosidad , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
Hemorrhagic transformation can complicate ischemic strokes after recanalization treatment within a time window that requires early intervention. To determine potential therapeutic effects of matrilin-3, rat cerebral ischemia-reperfusion was produced using transient middle cerebral artery occlusion (tMCAO); intracranial hemorrhage and infarct volumes were assayed through hemoglobin determination and 2,3,5-triphenyltetrazoliumchloride (TTC) staining, respectively. Oxygen-glucose deprivation (OGD) modeling of ischemia was performed on C8-D1A cells. Interactions between matrilin-3 and YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) were determined using RNA immunoprecipitation assay and actinomycin D treatment. Reperfusion after tMCAO modeling increased hemorrhage, hemoglobin content, and infarct volumes; these were alleviated by matrilin treatment. Matrilin-3 was expressed at low levels and YTHDF2 was expressed at high levels in ischemic brains. In OGD-induced cells, matrilin-3 was negatively regulated by YTHDF2. Matrilin-3 overexpression downregulated p-PI3K/PI3K, p-AKT/AKT, ZO-1, VE-cadherin and occludin, and upregulated p-JNK/JNK in ischemic rat brains; these effects were reversed by LY294002 (a PI3K inhibitor). YTHDF2 knockdown inactivated the PI3K/AKT pathway, inhibited inflammation and decreased blood-brain barrier-related protein levels in cells; these effects were reversed by matrilin-3 deficiency. These results indicate that YTHDF2-regulated matrilin-3 protected ischemic rats against post-reperfusion hemorrhagic transformation via the PI3K/AKT pathway and that matrilin may have therapeutic potential in ischemic stroke.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Daño por Reperfusión , Ratas , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Matrilinas/farmacología , Proteínas Matrilinas/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Ratas Sprague-Dawley , Isquemia Encefálica/metabolismo , Hemorragia , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Factores de Transcripción , Reperfusión , Hemoglobinas/farmacología , Hemoglobinas/uso terapéutico , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
Talking face generation aims at generating photorealistic video portraits of a target person driven by input audio. According to the nature of audio to lip motions mapping, the same speech content may have different appearances even for the same person at different occasions. Such one-to-many mapping problem brings ambiguity during training and thus causes inferior visual results. Although this one-to-many mapping could be alleviated in part by a two-stage framework (i.e., an audioto- expression model followed by a neural-rendering model), it is still insufficient since the prediction is produced without enough information (e.g., emotions, wrinkles, etc.). In this paper, we propose MemFace to complement the missing information with an implicit memory and an explicit memory that follow the sense of the two stages respectively. More specifically, the implicit memory is employed in the audio-to-expression model to capture high-level semantics in the audio-expression shared space, while the explicit memory is employed in the neural-rendering model to help synthesize pixel-level details. Our experimental results show that our proposed MemFace surpasses all the state-of-theart results across multiple scenarios consistently and significantly.
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Background: Previous research has yielded conflicting results on the link between epilepsy risk and lipid-lowering medications. The aim of this study is to determine whether the risk of epilepsy outcomes is causally related to lipid-lowering medications predicted by genetics. Methods: We used genetic instruments as proxies to the exposure of lipid-lowering drugs, employing variants within or near genes targeted by these drugs and associated with low-density lipoprotein cholesterol (LDL cholesterol) from a genome-wide association study. These variants served as controlling factors. Through drug target Mendelian randomization, we systematically assessed the impact of lipid-lowering medications, including HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and Niemann-Pick C1-like 1 (NPC1L1) inhibitors, on epilepsy. Results: The analysis demonstrated that a higher expression of HMGCR was associated with an elevated risk of various types of epilepsy, including all types (OR = 1.17, 95% CI:1.03 to 1.32, p = 0.01), focal epilepsy (OR = 1.24, 95% CI:1.08 to 1.43, p = 0.003), and focal epilepsy documented with lesions other than hippocampal sclerosis (OR = 1.05, 95% CI: 1.01 to 1.10, p = 0.02). The risk of juvenile absence epilepsy (JAE) was also associated with higher expression of PCSK9 (OR = 1.06, 95% CI: 1.02 to 1.09, p = 0.002). For other relationships, there was no reliable supporting data available. Conclusion: The drug target MR investigation suggests a possible link between reduced epilepsy vulnerability and HMGCR and PCSK9 inhibition.
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Disulfide bonds play an essential structural role but may hinder the molecular flexibility and functionality of proteins. The present study investigated the effect of disulfide cleavage on emulsifying activity of oat protein isolate (OPI). Four reducing agents tested (dithiothreitol, ascorbic acid, cysteine, and sodium bisulfite) except ascorbic acid disrupted inter-subunit SS bonds of OPI (up to 90 %) in a dose-dependent manner. Emulsification properties were measured specifically on cysteine-modified OPI, and the results showed increased emulsifying activity up to 37 % after subunit dissociation, which exposed hydrophobic groups and loosened the structure. In particular, emulsions formed by cysteine-treated OPI (1.7 to 6.7 mM/mg protein) displayed a superior interfacial protein coverage (0.170 m2/mg compared to 0.092 m2/mg for control) and reduced emulsion particle size (from 4722 to 2238 nm). The application of cysteine as a structure-modifying food additive can broaden the utilization of oat protein in emulsion-based food products.
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Avena , Disulfuros , Emulsiones/química , Disulfuros/química , Cisteína , Ácido Ascórbico , Emulsionantes/químicaRESUMEN
The effects of different concentrations of eugenol (EG = 0, 5, 10, 20, 50, and 100 mg/g protein) on the structural properties and gelling behavior of myofibrillar proteins (MPs) were investigated. The interaction of EG and MPs decreased free thiol and amine content, and reduced tryptophan fluorescence intensity and thermal stability, but enhanced surface hydrophobicity and aggregation of MPs. Compared with the control (EG free), the MPs' gels treated with 5 and 10 mg/g of EG had a higher storage modulus, compressive strength, and less cooking loss. A high microscopic density was observed in these EG-treated gels. However, EG at 100 mg/g was detrimental to the gelling properties of the MPs. The results indicate that an EG concentration of 20 mg/g is a turning point, i.e., below 20 mg/g, EG promoted MPs gelation, but above 20 mg/g, it impeded gelation by interfering with protein network formation. The EG modification of MPs could provide a novel ingredient strategy to improve the texture of comminuted meat products.
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Eugenol , Proteínas Musculares , Porcinos , Animales , Proteínas Musculares/química , Eugenol/farmacología , Oxidación-Reducción , Interacciones Hidrofóbicas e Hidrofílicas , Geles/química , Reología , Miofibrillas/químicaRESUMEN
The purpose of this study is to investigate the impact of varied oil body (OB) concentrations and interfacial compositions on the network topology and rheological and functional aspects of composite whey protein isolate (WPI) gels. Particle size and ζ-potential analyzes of the mixed gel solutions containing the OBs extracted at pH 6.8 (6.8-OB) and 11.0 (11.0-OB) revealed a greater aggregation in the 6.8-OB-containing mixed gel solution. 6.8-OB and 11.0-OB generated particle aggregates and oil-drop-embedded network architectures in the WPI gel, respectively. FT-IR analyses showed that OBs stabilized the protein gels' polymeric matrix by hydrogen bonding, steric hindrance, and hydrophobic interactions. Rheology and texture showed that OBs hardened gels. Low-field nuclear magnetic resonance showed that excessive inclusion of OBs (30% of 6.8-OB and 35% of 11.0-OB) compromised gel integrity and freeze-thaw stability. This study found that OBs can be active fillers in protein gels for functional meals.
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Methicillin-resistant Staphylococcus epidermidis (MRSE) is one of the most commonly found pathogens that may cause uncontrollable infections in immunocompromised and hospitalized patients. Compounds isolated from cinnamon such as cinnamaldehyde and cinnamic acid showed promising anti-oxidant, anti-tumor, and immunoregulatory effects; more importantly, these compounds also possess promising broad-spectrum antibacterial activity. In this study, the potential antibacterial activity of 2-methoxycinnamaldehyde (MCA), another compound in cinnamon, against MRSE was investigated. Combining the broth microdilution test, live/dead assay, and biofilm formation assay, we found MCA was able to inhibit the proliferation, as well as the biofilm formation of MRSE, indicating MCA could not only affect the growth of MRSE but also inhibit the pathogenic potential of this bacterium. Additionally, the results of scanning electron microscopy (SEM) and transmission electron microscopy (TEM) demonstrated that MCA caused morphological changes and the leakage of DNA, RNA, and cellular contents of MRSE. Due to the close relationship between cell wall synthesis, ROS formation, and cell metabolism, the ROS level and metabolic profile of MRSE were explored. Our study showed MCA significantly increased the ROS production in MRSE, and the following metabolomics analysis showed that the increased ROS production may partially be due to the increased metabolic flux through the TCA cycle. In addition, we noticed the metabolic flux through the pentose phosphate pathway (PPP) was upregulated accompanied by elevated ROS production. Therefore, the alterations in cell metabolism and increased ROS production could lead to the damage of the cell wall, which in turn decreased the proliferation of MRSE. In conclusion, MCA seemed to be a promising alternative antimicrobial agent to control MRSE infections.
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Understanding the relationship between ionic strength and protein solubility is essential to the utilization of salt in the formulation design of plant protein-based food and beverage products. In this study, suspensions of oat protein isolate (OPI) were treated with two kinds of common salts (sodium chloride NaCl; sodium phosphate NaP) at different ionic strengths (I). Electrical conductivity, protein solubility, particle size, and protein profile (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) were analyzed. The results showed the highest protein solubility at extremely low I (< 0.005 for NaCl; < 0.012 for NaP) and a minimum solubility at I 0.03 to 0.2 depending on the type of salt. Particle size and electrophoretic patterns supported the solubility profile. The combination effect of ionic strength and pH was also investigated. A characteristic U-shaped solubility curve observed within pH 2.0 to 8.0 at low ionic strengths (I < 0.01) was altered by increasing the salt concentration. The findings demonstrate that ionic strength and ion species play a crucial role in oat protein solubility, and the ionic effect can be modified by changing the pH. Therefore, the application of appropriate salt concentrations is vitally important to the manufacture of oat protein-based food products. PRACTICAL APPLICATION: Sodium chloride and phosphate are two of the most widely utilized salts in food processing. This study highlights the relationship between ionic strength of the two salts and oat protein solubility at different pH levels, providing useful information for selecting proper salt concentrations in the manufacture of oat protein-based food products.
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Avena/química , Manipulación de Alimentos/métodos , Proteínas de Plantas/química , Concentración de Iones de Hidrógeno , Iones , Concentración Osmolar , Tamaño de la Partícula , Fosfatos/química , Cloruro de Sodio/química , SolubilidadRESUMEN
Neuroinflammation has been intensively demonstrated to be related to various neurodegenerative diseases including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). A natural polymethoxylated flavone, nobiletin (NOB) has been reported to alleviate oxidative stress, insulin resistance, and obesity. In this study, we evaluated the protection effects of NOB on neuroinflammation and memory deficit. Three-month mice were administrated with NOB by oral gavage every day for 6 weeks (100 mg/kg/day); subsequently mice were injected intraperitoneally with lipopolysaccharide (LPS) for 7 days. Results of behavioral tests revealed that NOB dramatically ameliorated LPS-triggered memory deficit regarding synaptic dysfunctions and neuronal loss. Also, NOB suppressed the microglial activation and proinflammatory cytokine secretion, such as COX-2, IL-1ß, TNF-α, and iNOS. Similarly, upon LPS stimulation, pretreatment NOB diminished the secretion of the proinflammatory cytokines in BV-2 microglia cells by exposure to LPS via modulating MAPKs, PI3K/AKT, and NF-κB signaling pathways. In addition, NOB alleviated LPS-amplified redox imbalance, disturbance of mitochondrial membrane potential (MMP), and dampening of the expression of protein related to mitochondrial respiration. The present study provides compelling evidence that NOB decreased LPS-stimulated neuroinflammation and memory impairment through maintaining cellular oxidative balance and blocking the NF-κB transcriptional pathway, illustrating that the nutritional compound NOB may serve as a potential approach to alleviate neuroinflammation-related diseases.
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Flavonas/administración & dosificación , Inflamación/complicaciones , Trastornos de la Memoria/prevención & control , Quinasas de Proteína Quinasa Activadas por Mitógenos/inmunología , FN-kappa B/inmunología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/inmunología , Humanos , Inflamación/genética , Inflamación/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/genética , Trastornos de la Memoria/inmunología , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/inmunología , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , FN-kappa B/genética , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Intracerebral hemorrhage (ICH) is a common and severe neurological disorder, which is associated with high rates of mortality and morbidity. This study aimed to evaluate whether general control non-derepressible-2 (GCN2) stimulation ameliorated neuroinflammation after ICH. Male CD-1 mice were subjected to experimental ICH by infusion of bacterial collagenase. Post-ictus assessment included neurobehavioral tests, brain edema measurement, quantification of neutrophil infiltration and microglia activation, and measurement of TNF-α and IL-1ß expression at 24h after ICH. Furthermore, we tested the long-term neurological improvement by GCN2 at 21â¯days after ICH. Our results showed that GCN2 improved neurological function and reduced brain edema at 24 and 72â¯h following experimental ICH in CD-1 mice in contrast to the vehicle administration alone. GCN2 was also found to decrease levels of IL-1ß and TNF-α, and inhibit neutrophil infiltration activation. In addititon, GCN2 also alleviated long-term neurological impairment after ICH. However, inhibition of eIF2α or ATF4 abolished the protective effects of GCN2, indicating eIF2α/ATF4 signaling pathway as the downstream mediator of GCN2.
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Factor de Transcripción Activador 4/efectos de los fármacos , Antiinflamatorios/farmacología , Hemorragia Cerebral/complicaciones , Factor 2 Eucariótico de Iniciación/efectos de los fármacos , Inflamación/etiología , Inflamación/prevención & control , Proteínas Serina-Treonina Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Factor de Transcripción Activador 4/biosíntesis , Animales , Conducta Animal , Edema Encefálico/etiología , Edema Encefálico/prevención & control , Hemorragia Cerebral/psicología , Citocinas/biosíntesis , Factor 2 Eucariótico de Iniciación/biosíntesis , Inflamasomas/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Infiltración Neutrófila/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Circadian rhythms are intimately linked to cellular redox status homeostasis via the regulation of mitochondrial function. Tea polyphenols (TP) are nutraceuticals that possess powerful antioxidant properties, especially ameliorating oxidative stress. The objective of this study was to investigate whether circadian clock is involved in the protection effect of TP on oxidative stress cell models. TP ameliorate H2O2-triggered relatively shallow daily oscillations and phase shift of circadian clock genes transcription and protein expression. Meanwhile, TP attenuate H2O2-stimulated excessive secretions of reactive oxygen species (ROS) and restore the depletions of mitochondrial function in a Bmal1-dependent manner. Furthermore, TP treatment accelerates nuclear translocation of Nrf2 and modulates the downstream expressions of antioxidant enzymes. Intriguingly, knockdown of Bmal1 notably blocked Nrf2/ARE/HO-1 redox-sensitive transcription pathway. Our study revealed that TP, as a Bmal1-enhancing natural compound, alleviated redox imbalance via strengthening Keap1/Nrf2 antioxidant defense pathway and ameliorating mitochondrial dysfunction in a Bmal1-dependent manner.
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Factores de Transcripción ARNTL/efectos de los fármacos , Relojes Circadianos , Hepatocitos/efectos de los fármacos , Mitocondrias Hepáticas/efectos de los fármacos , Polifenoles/farmacología , Té/química , Factores de Transcripción ARNTL/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proteínas CLOCK/genética , Ritmo Circadiano , Hemo-Oxigenasa 1/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Peróxido de Hidrógeno/farmacología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias Hepáticas/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
As a major nutraceutical component of green tea (-)-epigallocatechin-3-gallate (EGCG) has attracted interest from scientists due to its well-documented antioxidant and antiobesity bioactivities. In the current study, we aimed to investigate the protective effect of EGCG on metabolic misalignment and in balancing the redox status in mice liver and HepG2 cells under insulin resistance condition. Our results indicated that EGCG accelerates the glucose uptake and evokes IRS-1/Akt/GLUT2 signaling pathway via dampening the expression of protein tyrosine phosphatase 1B (PTP1B). Consistently, ectopic expression of PTP1B by Ad-PTP1B substantially impaired EGCG-elicited IRS-1/Akt/GLUT2 signaling pathway. Moreover, EGCG co-treatment stimulated nuclear translocation of Nrf2 by provoking P13K/AKT signaling pathway and thus modulated the downstream expressions of antioxidant enzymes such as HO-1 and NQO-1 in HepG2 cells. Furthermore, knockdown Nrf2 by small interfering RNA (siRNA) notably enhanced the expression of PTP1B and blunt EGCG-stimulated glucose uptake. Consistent with these results, in vivo study revealed that EGCG supplement significantly ameliorated high-fat and high-fructose diet (HFFD)-triggered insulin resistance and oxidative stress by up-regulating the IRS-1/AKT and Keap1/Nrf2 transcriptional pathways. Administration of an appropriate chemopreventive agent, such as EGCG, could potentially serve as an additional therapeutic intervention in the arsenal against obesity.
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Transporte Activo de Núcleo Celular/efectos de los fármacos , Catequina/análogos & derivados , Resistencia a la Insulina , Factor 2 Relacionado con NF-E2/metabolismo , Obesidad/tratamiento farmacológico , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Animales , Catequina/farmacología , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Humanos , Insulina/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Obesidad/genética , Obesidad/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Many studies have shown that oxidative stress is a major cause of cellular injuries in a variety of human diseases including cognitive impairment. Tea polyphenols (TPs), natural plant flavonoids found in tea plant leaves, possess the bioactivity to affect the pathogenesis of several chronic diseases via antioxidant associated mechanisms. However, the possible antioxidant and neuroprotective properties of TPs in the brain of mice housed in constant darkness and in H2O2-stimulated SH-SY5Y cells are yet to be elucidated. In this study, pretreatment with TPs markedly attenuated H2O2-elicited cell viability loss and mitochondrial dysfunction, suppressed the induced apoptosis and reduced the elevated levels of intracellular ROS and H2O2. Additionally, TPs modulate the nuclear translocation of Nrf2 and the TrkB/CREB/BDNF signaling pathway by provoking the PI3K/AKT pathway and thus, they transcriptionally regulate the downstream expression of antioxidant enzymes including HO-1, NQO-1, and BDNF in SH-SY5Y cells. Furthermore, an in vivo study revealed that housing mice in constant darkness, simulating shift work disruption in humans, notably affects the AKT/CREB/BDNF signal pathway and the nuclear translocation of Nrf2 and its downstream phase II detoxification enzymes in brain tissue. Remarkably, TP supplementation through drinking water eliminated these changes. These results suggest that TPs possess protective effects against oxidative stress-triggered cognitive impairment, which might be a potential nutritional preventive strategy for neurodegenerative diseases implicated with oxidative stress in shift workers.
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Encéfalo/efectos de los fármacos , Proteína de Unión a CREB/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Extractos Vegetales/administración & dosificación , Polifenoles/administración & dosificación , Receptor trkB/metabolismo , Animales , Apoptosis/efectos de los fármacos , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a CREB/genética , Camellia sinensis/química , Supervivencia Celular/efectos de los fármacos , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Receptor trkB/genética , Transducción de Señal/efectos de los fármacosRESUMEN
SCOPE: Normal physiological processes require a robust biological timer called the circadian clock. Dysregulation of circadian rhythms contributes to a variety of metabolic syndrome, including obesity and insulin resistance. (-)-Epigallocatechin-3-gallate (EGCG) has been demonstrated to possess antioxidant, anti-inflammatory, and cardioprotective bioactivities. The objective of this study was to explore whether the circadian clock is involved in the protective effect of EGCG against insulin resistance. METHODS AND RESULTS: The results demonstrated that EGCG reverses the relatively shallow daily oscillations of circadian clock genes transcription and protein expression induced by glucosamine in HepG2 cells. EGCG also alleviates insulin resistance by enhancing tyrosine phosphorylated levels of IRS-1, stimulating the translocation of GLUT2, and activating PI3K/AKT as well as AMPK signaling pathways in a Bmal1-dependent manner both in HepG2 cells and primary hepatocytes. Glucosamine-stimulated excessive secretions of ROS and depletions of mitochondrial membrane potential were notably attenuated in EGCG co-treated HepG2 cells, which consistent with the recovery in expression of mitochondrial respiration complexes. CONCLUSION: The results demonstrated that EGCG possesses a Bmal1-dependent efficacy against insulin resistance conditions by strengthening the insulin signaling and eliminating oxidative stress, suggesting that EGCG may serve as a promising natural nutraceutical for the regulation of metabolic disorders relevant to circadian clocks.