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Ribes fasciculatum has been consumed as a food and as a traditional medicine for treating autoimmune diseases and aging in diverse countries. A previous study showed that a mixture of Ribes fasciculatum and Cornus officinalis prohibited adipocyte differentiation and lipid accumulation in preadipocytes and suppressed diet-induced obesity. Nevertheless, the mechanism of R. fasciculatum to regulate energy homeostasis solely through thermogenic signaling remains unclear. Thus, we investigated its effects on energy homeostasis using R. fasciculatum fed to C57BL/6 mice with a 45% high-fat diet. Chronic consumption of R. fasciculatum decreased the body weight of obese mice with increasing food intakes and improved metabolic-syndrome-related phenotypes. Therefore, we further tested its thermogenic effects. Cold chamber experiments and qPCR studies indicated that R. fasciculatum elevated thermogenic signaling pathways, demonstrated by increased body temperature and uncoupling protein 1 (UCP1) signaling in the white and brown adipose tissues. Afzelin is one major known compound derived from R. fasciculatum. Hence, the isolated compound afzelin was treated with preadipocytes and brown adipocytes for cell viability and luciferase assay, respectively, to further examine its thermogenic effect. The studies showed that the response of afzelin was responsible for cell viability and the increased UCP1. In conclusion, our data indicated that R. fasciculatum elevated peripheral thermogenic signaling through increased UCP1 via afzelin activation and ameliorated diet-induced obesity.
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Dieta Alta en GrasaAsunto(s)
Sistemas CRISPR-Cas , Inmunidad Innata , Oryza , Proteínas de Plantas , Factores de Transcripción , Oryza/genética , Oryza/inmunología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Inmunidad Innata/genética , Mutagénesis , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/inmunología , Genes de Plantas , Inmunidad de la Planta/genéticaRESUMEN
Tyrosinase is a key enzyme that catalyses the initial rate-limiting steps of melanin synthesis. Due to its critical role in melanogenesis, various attempts were made to find potent tyrosinase inhibitors although many were not safe and effective in vivo. We evaluated tyrosinase inhibitory activity of six compounds. Among them, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-thioxothiazolidin-4-one (5-HMT) had the greatest inhibitory effect and potency as the IC50 value of 5-HMT was lower than that of kojic acid, widely-known tyrosinase inhibitor. Based on in silico docking simulation, 5-HMT had a greater binding affinity than kojic acid with a different binding conformation in the tyrosinase catalytic site. Furthermore, its skin depigmentation effect was confirmed in vivo as 5-HMT topical treatment significantly reduced UVB-induced melanogenesis in HRM2 hairless mice. In conclusion, our study demonstrated that 5-HMT has a greater binding affinity and inhibitory effect on tyrosinase and may be a potential candidate for a therapeutic agent for preventing melanogenesis.
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Inhibidores Enzimáticos/farmacología , Melaninas/química , Melanocitos/citología , Monofenol Monooxigenasa/antagonistas & inhibidores , Animales , Diseño de Fármacos , Concentración 50 Inhibidora , Ratones , Simulación del Acoplamiento Molecular , Pironas/farmacología , Pigmentación de la Piel , Tiazolidinas/farmacología , Rayos UltravioletaRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is frequently observed in obese and aged individuals. Peroxisome proliferator-activated receptors (PPARs) play a role in regulating hepatic lipid accumulation, a hallmark of NAFLD development. A PPAR pan agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) has been shown to prevent fatty liver formation and insulin resistance in obese mice (db/db) model. However, the beneficial effects of MHY2013 in aged model remain unknown. In this study, we investigated whether MHY2013 alleviates hepatic lipid accumulation in aged Sprague-Dawley (SD) rats. We confirmed that MHY2013 increased the activities of three PPAR subtypes in HepG2 cells using luciferase assay. When administered orally in aged SD rats, MHY2013 markedly decreased the hepatic triglyceride levels without changes in body weight. Regarding underlying mechanisms, MHY2013 increased the mRNA levels of lipid oxidation-related genes, including carnitine palmitoyltransferase 1 (CPT1) and peroxisomal acyl-CoA oxidase 1 (ACOX1), without apparent change in the mRNA expression of lipogenesis-related genes. Furthermore, MHY2013 significantly increased systemic fibroblast growth factor 21 (FGF21) and adiponectin levels and suppressed inflammatory mRNA expression in the liver. In conclusion, MHY2013 alleviated age-related hepatic lipid accumulation, in part by upregulating ß-oxidation signaling and suppressing inflammation in the liver. Therefore, MHY2013 is a potential pharmaceutical agent for treating age-related hepatic lipid accumulation.
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Envejecimiento/metabolismo , Benzotiazoles/farmacología , Citocinas/genética , Ácidos Grasos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Receptores Activados del Proliferador del Peroxisoma/agonistas , Propionatos/farmacología , Triglicéridos/metabolismo , Administración Oral , Animales , Modelos Animales de Enfermedad , Factores de Crecimiento de Fibroblastos/sangre , Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Inflamación , Lipogénesis/efectos de los fármacos , Lipogénesis/genética , Masculino , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Oxidación-Reducción , Ratas Sprague-Dawley , Triglicéridos/sangreRESUMEN
As part of continued efforts for the development of new tyrosinase inhibitors, (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-one derivatives (1a - 1l) were rationally synthesized and evaluated for their inhibitory potential in vitro. These compounds were designed and synthesized based on the structural attributes of a ß-phenyl-α,ß-unsaturated carbonyl scaffold template. Among these compounds, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin-4-one (1e, MHY773) exhibited the greatest tyrosinase inhibition (IC50 = 2.87 µM and 8.06 µM for monophenolase and diphenolase), and outperformed the positive control, kojic acid (IC50 = 15.59 and 31.61 µM). The kinetic and docking studies demonstrated that MHY773 interacted with active site of tyrosinase. Moreover, a melanin quantification assay demonstrated that MHY773 attenuates α-melanocyte-stimulating hormone (α-MSH) and 3-isobutyl-1-methylxanthine (IBMX)-induced melanin contents in B16F10 melanoma cells. Taken together, these data suggest that MHY773 suppressed the melanin production via the inhibition of tyrosinase activity. MHY773 is a promising for the development of effective pharmacological and cosmetic agents for skin-whitening.
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Ultraviolet (UV) radiation exposure is the primary cause of extrinsic skin aging, which results in skin hyperpigmentation and wrinkling. In this study, we investigated the whitening effect of (2E,5E)-2,5-bis(3-hydroxy-4-methoxybenzylidene)cyclopentanone (BHCP) on B16F10 melanoma and its anti-wrinkle activity on Hs27 fibroblasts cells. BHCP was found to potently inhibit tyrosinase, with 50% inhibition concentration (IC50) values of 1.10 µM and 8.18 µM for monophenolase (l-tyrosine) and diphenolase (l-DOPA), and the enzyme kinetics study revealed that BHCP is a competitive-type tyrosinase inhibitor. Furthermore, BHCP significantly inhibited melanin content and cellular tyrosinase activity, and downregulated the levels of microphthalmia-associated transcription factor (MITF), phosphorylated levels of cAMP response element-binding (CREB) protein, and tyrosinase in α-melanocyte stimulating hormone (α-MSH)-induced B16F10 melanoma cells. Moreover, BHCP inhibited the phosphorylation of p65 and expression of matrix metalloproteinases (MMP-1, MMP-9, MMP-12, and MMP-13) in Hs27 fibroblasts stimulated with UV radiation. Therefore, our results demonstrate that BHCP may be a good candidate for the development of therapeutic agents for diseases associated with hyperpigmentation and wrinkling.
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Ciclopentanos/farmacología , Melaninas/antagonistas & inhibidores , Melanoma Experimental/patología , Envejecimiento de la Piel/efectos de los fármacos , Animales , Regulación hacia Abajo , Fibroblastos/efectos de los fármacos , Melaninas/metabolismo , Ratones , Fosforilación , Rayos UltravioletaRESUMEN
Late-onset hypogonadism (LOH) is an age-related disease in men characterized by decreased testosterone levels with symptoms such as decreased libido, erectile dysfunction, and depression. Thymus quinquecostatus Celakovski (TQC) is a plant used as a volatile oil in traditional medicine, and its bioactive compounds have anti-inflammatory potential. Based on this knowledge, the present study aimed to investigate the effects of TQC extract (TE) on LOH in TM3 Leydig cells and in an in vivo aging mouse model. The aqueous extract of T. quinquecostatus Celakovski (12.5, 25, and 50⯵g/mL concentrations) was used to measure parameters such as cell viability, testosterone level, body weight, and gene expression, via in vivo studies. Interestingly, TE increased testosterone levels in TM3 cells in a dose-dependent manner without affecting cell viability. Furthermore, TE significantly increased the expression of genes involved in the cytochrome P450 family (Cyp11a1, Cyp17a1, Cyp19a1, and Srd5a2), which regulate testosterone biosynthesis. In aging mouse models, TE increased testosterone levels without affecting body weight and testicular tissue weight tissue of an aging animal group. In addition, the high-dose TE-treated group (50â¯mg/kg) showed significantly increased expression of the cytochrome p450 enzymes, similar to the in vitro results. Furthermore, HPLC-MS analysis confirmed the presence of caffeic acid and rosmarinic acid as bioactive compounds in TE. Thus, the results obtained in the present study confirmed that TQC and its bioactive compounds can be used for LOH treatment to enhance testosterone production.
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Envejecimiento , Extractos Vegetales , Testículo , Testosterona , Thymus (Planta) , Animales , Testosterona/sangre , Masculino , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Ratones , Extractos Vegetales/farmacología , Testículo/efectos de los fármacos , Testículo/metabolismo , Thymus (Planta)/química , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Supervivencia Celular/efectos de los fármacos , Línea Celular , Hipogonadismo/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: The effect of pomegranate vinegar (PV) on adiposity was investigated in high-fat diet (HF)-induced obese rats. METHODS: The rats were divided into 5 groups and treated with HF with PV or acetic acid (0, 6.5 or 13% w/w) for 16 weeks. Statistical analyses were performed by the Statistical Analysis Systems package, version 9.2. RESULTS: Compared to control, PV supplementation increased phosphorylation of AMP-activated protein kinase (AMPK), leading to changes in mRNA expressions: increases for hormone sensitive lipase and mitochondrial uncoupling protein 2 and decreases for sterol regulatory element binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptorγ (PPARγ) in adipose tissue; increases for PPARα and carnitinepalmitoyltransferase-1a (CPT-1a) and decrease for SREBP-1c in the liver. Concomitantly, PV reduced increases of body weight (p = 0.048), fat mass (p = 0.033), hepatic triglycerides (p = 0.005), and plasma triglycerides (p = 0.001). CONCLUSIONS: These results suggest that PV attenuates adiposity through the coordinated control of AMPK, which leads to promotion of lipolysis in adipose tissue and stimulation of fatty acid oxidation in the liver.
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Ácido Acético/administración & dosificación , Tejido Adiposo/efectos de los fármacos , Adiposidad/efectos de los fármacos , Hígado/efectos de los fármacos , Lythraceae/química , Obesidad/dietoterapia , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Tejido Adiposo/metabolismo , Animales , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Dieta Alta en Grasa , Grasas de la Dieta/efectos adversos , Ácidos Grasos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Canales Iónicos/genética , Canales Iónicos/metabolismo , Lipólisis/efectos de los fármacos , Hígado/metabolismo , Masculino , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Obesidad/etiología , Obesidad/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Ratas , Ratas Sprague-Dawley , Esterol Esterasa/genética , Esterol Esterasa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/sangre , Proteína Desacopladora 2RESUMEN
Flavonoid C-glucosides, which are found in several plant families, are characterized by several biological properties, including antioxidant, anticancer, anti-inflammatory, neuroprotective, hepatoprotective, cardioprotective, antibacterial, antihyperalgesic, antiviral, and antinociceptive activities. The biosynthetic pathway of flavonoid C-glucosides in plants has been elucidated. In the present study, a pathway was introduced to Escherichia coli to synthesize four flavonoid C-glucosides, namely, isovitexin, vitexin, kaempferol 6-C-glucoside, and kaempferol 8-C-glucoside. A five- or six-step metabolic pathway for synthesizing flavonoid aglycones from tyrosine was constructed and two regioselective flavonoid C-glycosyltransferases from Wasabia japonica (WjGT1) and Trollius chinensis (TcCGT) were used. Additionally, the best shikimate gene module construct was selected to maximize the titer of each C-glucoside flavonoid. Isovitexin (30.2 mg/L), vitexin (93.9 mg/L), kaempferol 6-C-glucoside (14.4 mg/L), and kaempferol 8-C-glucoside (38.6 mg/L) were synthesized using these approaches. The flavonoid C-glucosides synthesized in this study provide a basis for investigating and unraveling their novel biological properties.
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Flavonoides , Glucósidos , Flavonoides/metabolismo , Glucósidos/metabolismo , Quempferoles/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismoRESUMEN
Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.
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Enfermedad de Alzheimer , Células Madre Pluripotentes Inducidas , Humanos , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Astrocitos/metabolismo , Fosforilación Oxidativa , Células Cultivadas , Células Madre Pluripotentes Inducidas/metabolismo , Apolipoproteína E3/metabolismo , Colesterol/metabolismo , Enfermedad de Alzheimer/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismoRESUMEN
Chronic inflammation and oxidative stress cause microglia to be abnormally activated in the brain, resulting in neurodegenerative diseases such as Alzheimer's disease (AD). Menthae Herba (MH) has been widely used as a medicinal plant with antimicrobial, anti-inflammatory, and antioxidant properties. In this study, we sought to evaluate the effects of MH on the inflammatory response and possible molecular mechanisms in microglia stimulated with lipopolysaccharide (LPS). Transcriptional and translational expression levels of the proinflammatory factors were measured using ELISA, RT-qPCR, and Western blot analysis. MH extract inhibited the production of proinflammatory enzymes and mediators nitric oxide (NO), NO synthase, cyclooxygenase-2, tumor necrosis factor-α, and interleukin-6 in LPS-stimulated cells. Our molecular mechanism study showed that MH inhibited the production of reactive oxygen species (ROS) and the phosphorylation of mitogen-activated protein kinase and nuclear factor (NF)-κB. In contrast, MH activated HO-1 and its transcriptional factors, cAMP response element-binding protein (CREB), and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. Thus, MH reduces ROS and NF-κB-mediated inflammatory signaling and induces CREB/Nrf2/HO-1-related antioxidant signaling in microglia. Together, these results may provide specific prospects for the therapeutic use of MH in the context of neuroinflammatory diseases, including AD.
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BACKGROUND: Samhwangsasim-tang (SST) is a traditional medicine used to treat hypertension and arteriosclerosis. Additionally, due to the effects of its constituent herbs, SST is considered effective for memory-related disorders. PURPOSE: We investigated the effects of SST on neuronal survival and memory in glutamate-induced hippocampal cells and in a mouse model of scopolamine-induced memory impairment. METHODS: SST components were identified using 3D-ultra performance liquid chromatography (3D-UPLC). In vitro, we induced glutamate-induced excitotoxicity in HT22 cells after SST pretreatment. We used a cell counting kit-8 and cell cytotoxicity assay, flow cytometry, and western blotting to test the protective effects of SST on neuronal death. In vivo, C57BL/6J mice were administered with 150 and 300 mg/kg SST once daily for 7 days and then intraperitoneally injected with 1 mg/kg scopolamine for 7 days to induce cognitive impairment. We then measured cognitive behavior using a novel object recognition test (NORT) and passive avoidance test (PAT) and analyzed the histological and protein changes. RESULTS: Our results showed that treatment with 50 and 100 µg/ml SST provided significant protection against glutamate-induced cell death. Flow cytometry and western blotting results suggested that 100 µg/ml SST treatment reduced oxidative stress and mitochondrial dysfunction. SST treatment also increased brain-derived neurotrophic factor (BDNF), its receptor, TrkB receptor, and cAMP-response element binding protein (CREB) activation while reducing the P75NTR and JNK signaling activation. Our in vivo results showed that SST administration improved cognitive impairment, similar to donepezil treatment (as a positive control), in NORT and PAT. SST and donepezil decreased neuronal cell death and apoptosis, and acetylcholine levels were increased in the scopolamine-treated hippocampus. Additionally, SST promoted CREB phosphorylation and BDNF maturation while reducing JNK and P75NTR activation; in contrast, donepezil did not alter levels of these proteins in the scopolamine-treated mouse hippocampus. CONCLUSION: Our results suggest that SST has neuroprotective effects to attenuate neuronal cell death and oxidative stress through CREB/JNK signaling via BDNF activation. SST may regulate endogenous survival factors in the hippocampus, which may be a safe and potential clinical treatment for cognitive impairment in AD.
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The WRKY family of transcription factors plays a pivotal role in plant responses to biotic and abiotic stress. The WRKY Group III transcription factor OsWRKY114 is a positive regulator of innate immunity against Xanthomonas oryzae pv. oryzae; however, its role in abiotic stress responses is largely unknown. In this study, we showed that the abundant OsWRKY114 transcripts present in transgenic rice plants are reduced under drought conditions. The overexpression of OsWRKY114 significantly increased drought sensitivity in rice, which resulted in a lower survival rate after drought stress. Moreover, we showed that stomatal closure, which is a strategy to save water under drought, is restricted in OsWRKY114-overexpressing plants compared with wild-type plants. The expression levels of PYR/PYL/RCAR genes, such as OsPYL2 and OsPYL10 that confer drought tolerance through stomatal closure, were also markedly lower in the OsWRKY114-overexpressing plants. Taken together, these results suggest that OsWRKY114 negatively regulates plant tolerance to drought stress via inhibition of stomatal closure, which would otherwise prevent water loss in rice.
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Since ancient times, Banhasasim-tang (BHS) has been used to treat functional dyspepsia in East Asia. Here, we aimed to determine the protective action of BHS on hippocampal neurons against oxidative stress. We investigated the functional effect of BHS on a scopolamine-induced mouse model, and molecular analysis was performed in glutamate-induced HT22 cells. We observed that BHS administration ameliorated memory dysfunction in scopolamine-treated mice. BHS administration also increased neuronal survival and acetylcholine activity and phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus of mice. In hippocampal cells, BHS treatment rescued glutamate-induced cytotoxicity, apoptosis, and oxidative stress. We observed an increase of HO-1 and a decrease of Nrf2 protein expression in glutamate-induced oxidative stress; however, the expression level of these proteins was significantly rescued by BHS treatment. BHS treatment also regulated phosphorylation of p38, p53, ERK, and CREB. Therefore, our data indicated that BHS may reduce oxidative stress through regulation of ERK-CREB and p38-p53 signaling in the hippocampus, resulting in decreased neuronal damage and improved memory in rodent models of neurodegenerative disease.
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Medicamentos Herbarios Chinos/farmacología , Transducción de Señal/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ácido Glutámico/farmacología , Hipocampo/citología , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Escopolamina/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Immune checkpoints such as programmed death-1 (PD-1) have been proven as antitumor targets by enhancing cytotoxic T cell activity. All immune checkpoint blockades are antibody therapeutics that have large size and high affinity, as well as known immune-related side effects and low responses. To overcome the limitation of antibody therapeutics, we have explored PD-1/PD-L1 (programmed death-ligand 1) blockades in traditional oriental medicine, which has a long history but has not yet studied PD-1/PD-L1 blockades. Sanguisorbae Radix extract (SRE) blocked PD-1 and PD-L1 binding in competitive ELISA. SRE effectively inhibited the PD-1/PD-L1 interaction, thereby improving T cell receptor (TCR) signaling and the NFAT-mediated luciferase activity of T cells. SRE treatment reduced tumor growth in the humanized PD-L1 MC38 cell allograft humanized PD-1 mouse model. Additionally, the combination of SRE and pembrolizumab (anti-PD-1 antibody) suppressed tumor growth and increased infiltrated cytotoxic T cells to a greater extent did either agent alone. This study showed that SRE alone has anticancer effects via PD-1/PD-L1 blockade and that the combination therapy of SRE and pembrolizumab has enhanced immuno-oncologic effects.
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Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Linfocitos T CD8-positivos/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/farmacología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Extractos Vegetales/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Sanguisorba , Adenocarcinoma/inmunología , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Células CHO , Técnicas de Cocultivo , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Cricetulus , Humanos , Células Jurkat , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Extractos Vegetales/aislamiento & purificación , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Sanguisorba/química , Transducción de Señal , Carga TumoralRESUMEN
Sargassum serratifolium (C. Agardh) C.Agardh, a marine brown alga, has been consumed as a food and traditional medicine in Asia. A previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of S. serratifolium (MES) induced adipose tissue browning and suppressed diet-induced obesity and metabolic syndrome when orally supplemented. Sargahydroquinoic acid (SHQA) is a major component of MES. However, it is unclear whether SHQA regulates energy homeostasis through the central nervous system. To examine this, SHQA was administrated through the third ventricle in the hypothalamus in high-fat diet-fed C57BL/6 mice and investigated its effects on energy homeostasis. Chronic administration of SHQA into the brain reduced body weight without a change in food intake and improved metabolic syndrome-related phenotypes. Cold experiments and biochemical analyses indicated that SHQA elevated thermogenic signaling pathways, as evidenced by an increase in body temperature and UCP1 signaling in white and brown adipose tissues. Peripheral denervation experiments using 6-OHDA indicated that the SHQA-induced anti-obesity effect is mediated by the activation of the sympathetic nervous system, possibly by regulating genes associated with sympathetic outflow and GABA signaling pathways. In conclusion, hypothalamic injection of SHQA elevates peripheral thermogenic signaling and ameliorates diet-induced obesity.
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Alquenos/farmacología , Benzoquinonas/farmacología , Dieta Alta en Grasa/efectos adversos , Termogénesis/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Alquenos/administración & dosificación , Animales , Benzoquinonas/administración & dosificación , Hipotálamo , Masculino , Síndrome Metabólico , Ratones Endogámicos C57BL , Obesidad/inducido químicamente , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Protease-activated receptor 2 (PAR2) is a member of G protein-coupled receptors. There are two types of PAR2 signaling pathways: Canonical G-protein signaling and ß-arrestin signaling. Although PAR2 signaling has been reported to aggravate hepatic steatosis, the exact mechanism is still unclear, and the role of PAR2 in autophagy remains unknown. In this study, we investigated the regulatory role of PAR2 in autophagy during high-fat diet (HFD)-induced hepatic steatosis in mice. Increased protein levels of PAR2 and ß-arrestin-2 and their interactions were detected after four months of HFD. To further investigate the role of PAR2, male and female wild-type (WT) and PAR2-knockout (PAR2 KO) mice were fed HFD. PAR2 deficiency protected HFD-induced hepatic steatosis in male mice, but not in female mice. Interestingly, PAR2-deficient liver showed increased AMP-activated protein kinase (AMPK) activation with decreased interaction between Ca2+/calmodulin-dependent protein kinase kinase ß (CAMKKß) and ß-arrestin-2. In addition, PAR2 deficiency up-regulated autophagy in the liver. To elucidate whether PAR2 plays a role in the regulation of autophagy and lipid accumulation in vitro, PAR2 was overexpressed in HepG2 cells. Overexpression of PAR2 decreased AMPK activation with increased interaction of CAMKKß with ß-arrestin-2 and significantly inhibited autophagic responses in HepG2 cells. Inhibition of autophagy by PAR2 overexpression further exacerbated palmitate-induced lipid accumulation in HepG2 cells. Collectively, these findings suggest that the increase in the PAR2-ß-arrestin-2-CAMKKß complex by HFD inhibits AMPK-mediated autophagy, leading to the alleviation of hepatic steatosis.
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Adenilato Quinasa/metabolismo , Autofagia/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Receptor PAR-2/metabolismo , Adenilato Quinasa/genética , Animales , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/efectos adversos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptor PAR-2/genética , Regulación hacia Arriba , Arrestina beta 2/genética , Arrestina beta 2/metabolismoRESUMEN
Protease-activated receptor 2 (PAR2) is a member of G-protein-coupled receptors and affects ligand-modulated calcium signaling. Although PAR2 signaling promotes obesity and adipose tissue inflammation in high fat- (HF-) fed conditions, its role in adipocyte differentiation under nonobesogenic conditions needs to be elucidated. Here, we used several tissues and primary-cultured adipocytes of mice lacking PAR2 to study its role in the development of adipose tissues. C57BL/6J mice with PAR2 deficiency exhibited a mild lipodystrophy-like phenotype in a chow diet-fed condition. When adipocyte differentiation was examined using primary-cultured preadipocytes, PAR2 deficiency led to a notable decrease in adipocyte differentiation and related protein expression, and PAR2 agonist treatment elevated adipocyte differentiation. Regarding the mechanism, PAR2-deficient preadipocytes exhibited impaired mitochondrial energy consumption. Further studies indicated that calcium-related signaling pathways for mitochondrial biogenesis are disrupted in the adipose tissues of PAR2-deficient mice and PAR2-deficient preadipocytes. Also, a PAR2 antagonist elevated mitochondrial reactive oxygen species and reduced the MitoTracker fluorescent signal in preadipocytes. Our studies revealed that PAR2 is important for the development of adipose tissue under basal conditions through the regulation of mitochondrial biogenesis and adipocyte differentiation.
Asunto(s)
Adipocitos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor PAR-2/deficiencia , Animales , Diferenciación Celular , Masculino , Ratones , MitocondriasRESUMEN
Three undescribed bicyclo[3.2.1]octanoid neolignan glucosides, along with a known neolignan, were isolated from the leaves of Piper crocatum Ruiz & Pav. Their chemical structures were elucidated using extensive spectroscopic analyses including 1D and 2D NMR experiments and HR-ESI-MS analysis, as well as through comparison with previously reported data. Two compounds were assessed for their inhibitory effect against pyruvate dehydrogenase E1α S300 phosphorylation. The fluorescent image suggested that both compounds (60 µM) revealed a stronger inhibition effect than the positive control (dichloroacetate, DCA 5 mM), with IC50 values of 99.82 µM and 80.25 µM, respectively.
RESUMEN
Lactobacillus gasseri BNR17 is a strain isolated from human breast milk. The objective of this randomized, double-blind, placebo-controlled, and preliminary dose-finding trial was to find the effective dose and evaluate the effect of Lb. gasseri BNR17 on irritable bowel syndrome (IBS) symptoms. A total of 55 volunteers aged over 20 years with body mass index over 23 kg/m2 were randomized to intake a placebo, low-dose (BNR-L, 2 × 108 CFU/day), intermediate-dose (BNR-M, 2 × 109 CFU/day), or high-dose BNR (BNR-H, 2 × 5 × 109 CFU/day) for four weeks. Questionnaire for IBS symptoms scores and Lb. gasseri BNR17 in feces were assessed at the beginning and end of the trial. Among IBS symptoms scores, abdominal pain score was significantly reduced in BNR-H group. Lb. gasseri BNR17 was detected in all intake groups except placebo. In the preliminary study, Lb. gasseri BNR17 was confirmed to have probiotic properties.