RESUMEN
The spread of prion-like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several cell surface receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remain poorly understood. Here, it is shown that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF but not the monomer of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. These results identify neuronal Lag3 as a receptor of pathologic Tau in the brainï¼and for AD and related Tauopathies, a therapeutic target.
Asunto(s)
Proteína del Gen 3 de Activación de Linfocitos , Neuronas , Tauopatías , Proteínas tau , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Antígenos CD/metabolismo , Antígenos CD/genética , Modelos Animales de Enfermedad , Neuronas/metabolismo , Proteínas tau/metabolismo , Proteínas tau/genética , Tauopatías/metabolismo , Tauopatías/genética , Tauopatías/patologíaRESUMEN
HYPOTHESIS: The dip coating of suspensions made of monodisperse non-Brownian spherical particles dispersed in a Newtonian fluid leads to different coating regimes depending on the ratio of the particle diameter to the thickness of the film entrained on the substrate. In particular, dilute particles dispersed in the liquid are entrained only above a threshold value of film thickness. In the case of anisotropic particles, in particular fibers, the smallest characteristic dimension will control the entrainment of the particle. Furthermore, it is possible to control the orientation of the anisotropic particles depending on the substrate geometry. In the thick film regime, the Landau-Levich-Derjaguin model remains valid if one account for the change in viscosity. EXPERIMENT: To test the hypotheses, we performed dip-coating experiments with dilute suspensions of non-Brownian fibers with different length-to-diameter aspect ratios. We characterize the number of fibers entrained on the surface of the substrate as a function of the withdrawal velocity, allowing us to estimate a threshold capillary number below which all the particles remain in the liquid bath. Besides, we measure the angular distribution of the entrained fibers for two different substrate geometries: flat plates and cylindrical rods. We then measure the film thickness for more concentrated fiber suspensions. FINDINGS: The entrainment of the fibers on a flat plate and a cylindrical rod is primarily controlled by the smaller characteristic length of the fibers: their diameter. At first order, the entrainment threshold scales similarly to that of spherical particles. The length of the fibers only appears to have a minor influence on the entrainment threshold. No preferential alignment is observed for non-Brownian fibers on a flat plate, except for very thin films, whereas the fibers tend to align themselves along the axis of a cylindrical rod for a large enough ratio of the fiber length to the radius of the cylindrical rod. The Landau-Levich-Derjaguin law is recovered for more concentrated suspension by introducing an effective capillary number accounting for the change in viscosity.
RESUMEN
The spread of prion-like protein aggregates is believed to be a common driver of pathogenesis in many neurodegenerative diseases. Accumulated tangles of filamentous Tau protein are considered pathogenic lesions of Alzheimer's disease (AD) and related Tauopathies, including progressive supranuclear palsy, and corticobasal degeneration. Tau pathologies in these illnesses exhibits a clear progressive and hierarchical spreading pattern that correlates with disease severity1,2. Clinical observation combined with complementary experimental studies3,4 have shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remains poorly understood. Here, we show that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF, but not monomer, of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. Our results identify neuronal Lag3 as a receptor of pathologic Tau in the brain, and for AD and related Tauopathies a therapeutic target.
RESUMEN
BACKGROUND: The purpose of this study was to analyze G test results according to the Three-Factor Eating Questionnaire (TFEQ), body composition, and physical fitness of fourth-grade air force cadets. This was done to identify the relationship between the TFEQ, body composition, and G resistance, in order to provide basic data for pilots and air force cadets to strengthen G tolerance.METHODS: From the Republic of Korea Air Force Academy (ROKAFA), 138 fourth-year cadets were assessed using the TFEQ and for body composition and physical fitness. Based on these measurement results, a G test result analysis and a correlation analysis were conducted.RESULT: The TFEQ showed statistically significant differences in several areas when comparing the G test pass group (GP group) to the G test fail group (GF group). Three-km running time was significantly faster in the GP group than in the GF group. Physical activity levels were higher in the GP group compared to the GF group.CONCLUSION: The TFEQ demonstrated utility in predicting whether cadets will pass or fail G-LOC testing. G test success for any cadet will require improvement in continuous eating behavior and physical fitness management. If variables affecting the G test are analyzed and applied to physical education and training through continuous research over the next two to three years, it is expected to have a greater effect on the success of the G test for every cadet.Sung J-Y, Kim I-K, Jeong D-H. Gravitational acceleration test results by lifestyle and physical fitness of air force cadets. Aerosp Med Hum Perform. 2023; 94(5):384-388.
Asunto(s)
Personal Militar , Aptitud Física , Humanos , Prueba de Esfuerzo , Ejercicio Físico , Composición Corporal , Estilo de VidaRESUMEN
The Licania genus has been used in the treatment of dysentery, diabetes, inflammation, and diarrhea in South America. Of these plants, the strong anti-inflammatory activity of Licania macrocarpa Cuatrec (Chrysobalanaceae) has been reported previously. However, the beneficial activities of this plant on skin health have remained unclear. This study explores the protective activity of a methanol extract (50-100 µg/mL) in the aerial parts of L. macrocarpa Cuatrec (Lm-ME) and its mechanism, in terms of its moisturizing/hydration factors, skin wrinkles, UV radiation-induced cell damage, and radical generation (using RT/real-time PCR, carbazole assays, flowcytometry, DPPH/ABTS, and immunoblotting analysis). The anti-pigmentation role of Lm-ME was also tested by measuring levels of melanin, melanogenesis-related genes, and pigmentation-regulatory proteins. Lm-ME decreased UVB-irradiated death in HaCaT cells by suppressing apoptosis and inhibited matrix metalloproteinases 1/2 (MMP1/2) expression by enhancing the activity of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. It was confirmed that Lm-ME displayed strong antioxidative activity. Lm-ME upregulated the expression of hyaluronan synthases-2/3 (HAS-2/3) and transglutaminase-1 (TGM-1), as well as secreted levels of hyaluronic acid (HA) via p38 and JNK activation. This extract also significantly inhibited the production of hyaluronidase (Hyal)-1, -2, and -4. Lm-ME reduced the melanin expression of microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein-1/2 (TYRP-1/2) in α-melanocyte-stimulating hormone (α-MSH)-treated B16F10 cells via the reduction of cAMP response element-binding protein (CREB) and p38 activation. These results suggest that Lm-ME plays a role in skin protection through antioxidative, moisturizing, cytoprotective, and skin-lightening properties, and may become a new and promising cosmetic product beneficial for the skin.
RESUMEN
A total 42.68 g/L monosaccharide with 0.10 g/L HMF was obtained from 10% (w/v) Kappaphycus alvarezii with thermal acid hydrolysis using 350 mM HNO3 at 121 °C for 60 min and enzymatic saccharification with a 1:1 mixture of Viscozyme L and Celluclast 1.5 L for 72 h. To enhance the galactose utilization rate, fermentation was performed with overexpression of GAL1 (galactokinase), GAL7 (galactose-1-phosphate uridyltransferase), GAL10 (UDP-glucose-4-epimerase), and PGM2 (phosphoglucomutase 2) in Saccharomyces cerevisiae CEN.PK2 using CCW12 as a strong promoter. Among the strains, the overexpression of PGM2 showed twofold high galactose utilization rate (URgal) and produced ethanol 1.4-fold more than that of the control. Transcriptional analysis revealed the increase of PGM2 transcription level leading to enhance glucose-6-phosphate and fructose-6-phosphate and plays a key role in ensuring a higher glycolytic flux in the PGM2 strain. This finding shows particular importance in biofuel production from seaweed because galactose is one of the major monosaccharides in seaweeds such as K. alvarezii.
Asunto(s)
Galactosa/metabolismo , Regulación Fúngica de la Expresión Génica , Extractos Vegetales/química , Rhodophyta/química , Proteínas de Saccharomyces cerevisiae/biosíntesis , Saccharomyces cerevisiae/metabolismo , Galactosa/químicaRESUMEN
Background: Inflammation, a vital immune response to infection and injury, is mediated by macrophage activation. While spleen tyrosine kinase (Syk) and myeloid differentiation primary response 88 (MyD88) are reportedly involved in inflammatory responses in macrophages, their roles and underlying mechanisms are largely unknown. Methods: Here, the role of the MyD88-Syk axis and the mechanism by which Syk and MyD88 cooperate during macrophage-mediated inflammatory responses are explored using knockout conditions of these proteins and mutation strategy as well as flowcytometric and immunoblotting analyses. Results: Syk rapidly activates the nuclear factor-kappa B (NF-κB) signaling pathway in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and the activation of the NF-κB signaling pathway is abolished in Syk-/- RAW264.7 cells. MyD88 activates Syk and Syk-induced activation of NF-κB signaling pathway in LPS-stimulated RAW264.7 cells but Syk-induced inflammatory responses are significantly inhibited in MyD88-/- RAW264.7 cells. MyD88 interacts with Syk through the tyrosine 58 residue (Y58) in the hemi-immunoreceptor tyrosine-based activation motif (ITAM) of MyD88, leading to Syk activation and Syk-induced activation of the NF-κB signaling pathway. Src activates MyD88 by phosphorylation at Y58 via the Src kinase domain. In addition, Ras-related C3 botulinum toxin substrate 1 (Rac1) activation and Rac1-induced formation of filamentous actin (F actin) activate Src in LPS-stimulated RAW264.7 cells. Conclusions: These results suggest that the MyD88-Syk axis is a critical player in macrophage-mediated inflammatory responses, and its function is promoted by an upstream Src kinase activated by Rac1-generated filamentous actin (F-actin).
Asunto(s)
Inflamación/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Factor 88 de Diferenciación Mieloide/inmunología , Quinasa Syk/inmunología , Animales , Células HEK293 , Humanos , Inflamación/genética , Inflamación/metabolismo , Activación de Macrófagos/genética , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/genética , FN-kappa B/inmunología , FN-kappa B/metabolismo , Fosforilación , Unión Proteica , Células RAW 264.7 , Transducción de Señal/inmunología , Quinasa Syk/genética , Quinasa Syk/metabolismo , Tirosina/genética , Tirosina/inmunología , Tirosina/metabolismoRESUMEN
This study was aimed at enhancing galactose consumption from the red seaweed Kappaphycus alvarezii. The optimal pretreatment condition of thermal acid hydrolysis was treated with 350 mM HNO3 for 60 min at 121 °C. The enzymatic saccharification with a 1:1 mixture of Celluclast 1.5 L and Viscozyme L showed the maximum yield of glucose; 42-g/L monosaccharide concentration was obtained with the highest yield of pretreatment and enzymatic saccharification (EPS) and the lowest inhibitory compound concentration. The deletion of the GAL80, MIG1, CYC8, or TUP1 gene was performed to improve the galactose consumption rate. The strains with the deletion of the MIG1 gene (mig1Δ) showed higher galactose consumption rate and ethanol yield than other strains. High transcription levels of regulatory genes revealed that the mig1Δ relieved glucose repression. These results show that the mig1Δ enhances galactose consumption rate from K. alvarezii.
Asunto(s)
Galactosa , Eliminación de Gen , Rhodophyta/química , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Galactosa/química , Galactosa/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
Linusorbs (LOs) are natural peptides found in flaxseed oil that exert various biological activities. Of LOs, LOB3 ([1-9-NαC]-linusorb B3) was reported to have antioxidative and anti-inflammatory activities; however, its anti-cancer activity has been poorly understood. Therefore, this study investigated the anti-cancer effect of LOB3 and its underlying mechanism in glioblastoma cells. LOB3 induced apoptosis and suppressed the proliferation of C6 cells by inhibiting the expression of anti-apoptotic genes, B cell lymphoma 2 (Bcl-2) and p53, as well as promoting the activation of pro-apoptotic caspases, caspase-3 and -9. LOB3 also retarded the migration of C6 cells, which was achieved by suppressing the formation of the actin cytoskeleton critical for the progression, invasion, and metastasis of cancer. Moreover, LOB3 inhibited the activation of the proto-oncogene, Src, and the downstream effector, signal transducer and activator of transcription 3 (STAT3), in C6 cells. Taken together, these results suggest that LOB3 plays an anti-cancer role by inducing apoptosis and inhibiting the migration of C6 cells through the regulation of apoptosis-related molecules, actin polymerization, and proto-oncogenes.
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Actinas/metabolismo , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Aceite de Linaza/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Caspasas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Activación Enzimática/efectos de los fármacos , Humanos , Proteína Oncogénica pp60(v-src)/antagonistas & inhibidores , Proteína Oncogénica pp60(v-src)/genética , Polimerizacion/efectos de los fármacos , Proto-Oncogenes Mas , Factor de Transcripción STAT3/antagonistas & inhibidoresRESUMEN
Olea europaea is a beneficial edible plant with a number of biological activities like anti-inflammatory, anti-oxidant, antithrombic, antihyperglycemic, and anti-ischemic activities. The mechanisms behind the antiphotoaging and anti-inflammatory effects of Olea europaea are not fully understood. To investigate how an ethanol extract of Olea europaea (Oe-EE) exerts these effects, we explored its activities in human keratinocytes and dermal fibroblasts. We assessed the anti-oxidant effects of Oe-EE via 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2[Formula: see text]-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) assays and measured the expression levels of matrix metalloproteinases (MMPs), cyclooxygenase-2, interleukin (IL)-6, tumor necrosis factor (TNF)-[Formula: see text], and moisturizing factors. Antiphotoaging and anti-inflammatory mechanisms of Oe-EE were explored by assessing signaling molecule activation via immunoblotting. Oe-EE treatment decreased the mRNA expression level of MMPs, cyclooxygenase-2, IL-6, and TNF-[Formula: see text] and restored type I collagen, filaggrin, and sirtuin 1 expression in UVB-irradiated cells. Furthermore, Oe-EE inhibited the activities of several activator protein 1 regulatory enzymes, including extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), and inhibited nuclear factor (NF)-[Formula: see text]B pathway signaling proteins. Therefore, our results indicate that Oe-EE has photoaging-protective and anti-inflammatory effects.
Asunto(s)
Antiinflamatorios , FN-kappa B/metabolismo , Olea/química , Extractos Vegetales/farmacología , Protectores contra Radiación , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factor de Transcripción AP-1/metabolismo , Antioxidantes , Dermis/citología , Fibroblastos/metabolismo , Proteínas Filagrina , Células HaCaT , Humanos , Queratinocitos/metabolismo , Extractos Vegetales/aislamiento & purificación , Rayos Ultravioleta/efectos adversosRESUMEN
[This corrects the article DOI: 10.1155/2019/6879346.].
RESUMEN
Patrinia villosa (Thunb.) Juss is a traditional herb commonly used in East Asia including Korea, Japan, and China. It has been administered to reduce and treat inflammation in Donguibogam, Korea. The mechanism for its anti-inflammatory effects has already been reported. In this study, we confirmed the efficacy of Patrinia villosa (Thunb.) Juss ethanol extract (Pv-EE) for inducing autophagy and investigate its anti-melanogenic properties. Melanin secretion and content were investigated using cells from the melanoma cell line B16F10. Pv-EE inhibited melanin in melanogenesis induced by α-melanocyte-stimulating hormone (α-MSH). The mechanism of inhibition of Pv-EE was confirmed by suppressing the mRNA of microphthalmia-associated transcription factor (MITF), decreasing the phosphorylation level of CREB, and increasing the phosphorylation of ERK. Finally, it was confirmed that Pv-EE induces autophagy through the autophagy markers LC3B and p62, and that the anti-melanogenic effect of Pv-EE is inhibited by the autophagy inhibitor 3-methyl adenine (3-MA). These results suggest that Pv-EE may be used as a skin protectant due to its anti-melanin properties including autophagy.
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Autofagia/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melaninas/metabolismo , Patrinia/química , Extractos Vegetales/farmacología , Hojas de la Planta/química , Raíces de Plantas/química , Animales , Etanol/química , Regulación de la Expresión Génica/efectos de los fármacos , Melanoma Experimental/patología , Ratones , Factor de Transcripción Asociado a Microftalmía/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo , Modelos Biológicos , ARN Mensajero/genética , ARN Mensajero/metabolismo , alfa-MSH/farmacologíaRESUMEN
3-Deazadenosine (3-DA) is a general methylation inhibitor that depletes S-adenosylmethionine, a methyl donor, by blocking S-adenosylhomocysteine hydrolase (SAHH). In this study, we investigated the inhibitory activity and molecular mechanisms of 3-DA in inflammatory responses. 3-DA suppressed the secretion of inflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide-treated RAW264.7 cells and phorbol 12-myristate 13-acetate (PMA)-differentiated U937 cells. It also reduced mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, interleukin-1ß (IL-1 ß), and IL-6, indicating that 3-DA has anti-inflammatory properties in murine and human macrophages. Moreover, 3-DA strongly blocked AP-1 and NF-κB luciferase activity under PMA-, MyD88-, and TRIF-stimulated conditions and decreased the translocation of c-Jun, c-Fos, p65, and p50 into the nucleus. In addition, the p-ERK level in AP-1 signaling and the p-IκBα level in NF-kB signaling were diminished by 3-DA treatment. Interestingly, 3-DA did not alter the phosphorylation of MEK1/2, an ERK modulator, or IKKα/ß, an IκBα regulator. Instead, 3-DA prevented MEK1/2 and IKKα/ß from combining with ERK and IκBα, respectively, and directly suppressed MEK1/2 and IKKα/ß kinase activity. These results indicate that MEK1/2 and IKKα/ß are direct targets of 3-DA. In addition, suppression of SAHH by siRNA or treatment with adenosine dialdehyde, another SAHH inhibitor, showed inhibitory patterns against p-ERK and IκBα similar to those of 3-DA. Taken together, this study demonstrates that 3-DA inhibits AP-1 and NF-κB signaling by directly blocking MEK1/2 and IKKα/ß or indirectly mediating SAHH, resulting in anti-inflammatory activity.
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Adenosilhomocisteinasa/antagonistas & inhibidores , Mediadores de Inflamación/antagonistas & inhibidores , Lipopolisacáridos/toxicidad , FN-kappa B/antagonistas & inhibidores , Factor de Transcripción AP-1/antagonistas & inhibidores , Tubercidina/farmacología , Adenosilhomocisteinasa/metabolismo , Animales , Antiinflamatorios/farmacología , Células HEK293 , Humanos , Mediadores de Inflamación/metabolismo , Ratones , FN-kappa B/metabolismo , Células RAW 264.7 , Factor de Transcripción AP-1/metabolismo , Células U937RESUMEN
Human skin acts as a barrier to protect our bodies from UV rays and external pathogens and to prevent water loss. Phenotypes of aging, or natural aging due to chronic damage, include wrinkles and the reduction of skin thickness that occur because of a loss of skin cell function. The dysregulation of autophagy, a lysosome-related degradation pathway, can lead to cell senescence, cancer, and various human diseases due to abnormal cellular homeostasis. Here, we discuss the roles and molecular mechanisms of autophagy involved in the anti-aging effects of autophagy and the relationship between autophagy and aging in skin cells.
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Autofagia/fisiología , Envejecimiento de la Piel/fisiología , Enfermedades de la Piel/fisiopatología , Piel/citología , Células Madre Adultas/fisiología , Células Madre Adultas/efectos de la radiación , Senescencia Celular/fisiología , Senescencia Celular/efectos de la radiación , Fibroblastos/fisiología , Fibroblastos/efectos de la radiación , Humanos , Queratinocitos/fisiología , Queratinocitos/efectos de la radiación , Melanocitos/fisiología , Melanocitos/efectos de la radiación , Piel/efectos de la radiación , Envejecimiento de la Piel/efectos de la radiación , Enfermedades de la Piel/etiología , Rayos Ultravioleta/efectos adversos , Pérdida Insensible de Agua/fisiología , Pérdida Insensible de Agua/efectos de la radiaciónRESUMEN
Although flax (Linum usitatissimum L.) has long been used as Ayurvedic medicine, its anti-inflammatory role is still unclear. Therefore, we aimed to investigate the anti-inflammatory role of a linusorb mixture (LOMIX) recovered from flaxseed oil. Effects of LOMIX on inflammation and its mechanism of action were examined using several in vitro assays (i.e., NO production, real-time PCR analysis, luciferase-reporter assay, Western blot analysis, and kinase assay) and in vivo analysis with animal inflammation models as well as acute toxicity test. Results: LOMIX inhibited NO production, cell shape change, and inflammatory gene expression in stimulated RAW264.7 cells through direct targeting of Src and Syk in the NF-κB pathway. In vivo study further showed that LOMIX alleviated symptoms of gastritis, colitis, and hepatitis in murine model systems. In accordance with in vitro results, the in vivo anti-inflammatory effects were mediated by inhibition of Src and Syk. LOMIX was neither cytotoxic nor did it cause acute toxicity in mice. In addition, it was found that LOB3, LOB2, and LOA2 are active components included in LOMIX, as assessed by NO assay. These in vitro and in vivo results suggest that LOMIX exerts an anti-inflammatory effect by inhibiting the inflammatory responses of macrophages and ameliorating symptoms of inflammatory diseases without acute toxicity and is a promising anti-inflammatory medication for inflammatory diseases.
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Antiinflamatorios/farmacología , Inhibidores Enzimáticos/farmacología , Lino/química , Extractos Vegetales/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Células RAW 264.7 , Quinasa Syk/antagonistas & inhibidores , Quinasa Syk/metabolismo , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
Loratadine is an antihistamine drug that shows promise as an anti-inflammatory drug, but supportive studies are lacking. We elucidated the effects and mechanisms by which loratadine inhibits inflammatory responses. Molecular components were evaluated in macrophages by nitric oxide assay, polymerase chain reaction, luciferase assay, immunoblotting, overexpression strategies and cellular thermal shift assay. At the molecular level, loratadine reduced the levels of nitric oxide, iNOS, IL-1ß, TNF-α, IL-6, and COX-2 in RAW264.7 cells treated with lipopolysaccharide. Loratadine also specifically inhibited the NF-kB pathway, targeting the Syk and Src proteins. Furthermore, loratadine bound Src in the bridge between SH2 and SH3, and bound Syk in the protein tyrosine kinase domain. The NF-kB signaling pathway was assessed along with putative binding sites through a docking approach. The anti-inflammatory effect of loratadine was tested using mouse models of gastritis, hepatitis, colitis, and peritonitis. Stomach tissue histopathology, liver morphology, and colon length in the loratadine group were improved over the group without loratadine treatment. Taken together, loratadine inhibited the inflammatory response through the NF-kB pathway by binding with the Syk and Src proteins.
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Antiinflamatorios/farmacología , Loratadina/farmacología , Macrófagos/efectos de los fármacos , FN-kappa B/metabolismo , Animales , Gastritis/metabolismo , Gastritis/prevención & control , Expresión Génica/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Quinasa Syk/antagonistas & inhibidores , Quinasa Syk/metabolismo , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
UVB irradiation can induce generation of reactive oxygen species (ROS) that cause skin aging or pigmentation. Lactobacillus acidophilus is a well-known probiotic strain that regulates skin health through antimicrobial peptides and organic products produced by metabolism and through immune responses. In this study, we investigated the antioxidative, antiwrinkle, and antimelanogenesis effects of tyndallized Lactobacillus acidophilus KCCM12625P (AL). To analyze the effects of AL on UV irradiation-induced skin wrinkle formation in vitro, human keratinocytes and human dermal fibroblasts were exposed to UVB. Subsequent treatment with AL induced antiwrinkle effects by regulating wrinkle-related genes such as matrix metalloproteinases (MMPs), SIRT-1, and type 1 procollagen (COL1AL). In addition, Western blotting assays confirmed that regulation of MMPs by AL in keratinocytes was due to regulation of the AP-1 signaling pathway. Furthermore, we confirmed the ability of AL to regulate melanogenesis in B16F10 murine melanoma cells treated with α-melanocyte-stimulating hormone (α-MSH). In particular, AL reduced the mRNA expression of melanogenesis-related genes such as tyrosinase, TYRP-1, and TYRP-2. Finally, we used Western blotting assays to confirm that the antimelanogenesis role of AL was due to its regulation of the cyclic adenosine monophosphate (cAMP) signaling pathway. Collectively, these results indicate that AL has an antiwrinkle activity in damaged skin and can inhibit melanogenesis. Thus, AL should be considered an important substance for potential use in anti-aging drugs or cosmetics.
Asunto(s)
Fibroblastos/efectos de la radiación , Queratinocitos/efectos de la radiación , Lactobacillus acidophilus , Probióticos , Rayos Ultravioleta , Animales , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , AMP Cíclico/metabolismo , Fibroblastos/enzimología , Fibroblastos/metabolismo , Humanos , Oxidorreductasas Intramoleculares/metabolismo , Queratinocitos/enzimología , Queratinocitos/metabolismo , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Glicoproteínas de Membrana/metabolismo , Ratones , Monofenol Monooxigenasa/metabolismo , Oxidorreductasas/metabolismo , Procolágeno/genética , Procolágeno/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Sirtuina 1/genética , Sirtuina 1/metabolismo , Piel/enzimología , Piel/efectos de la radiación , Factor de Transcripción AP-1/metabolismo , Rayos Ultravioleta/efectos adversos , alfa-MSH/farmacologíaRESUMEN
Cytokines and chemokines are transcriptionally regulated by inflammatory transcription factors such as nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and interferon regulatory factor (IRF)-3. A daidzein derivative compound, 8-hydroxydaidzein (8-HD), isolated from soy products, has recently gained attention due to various pharmacological benefits, including anti-inflammatory activities. However, regulation of the inflammatory signaling mechanism for 8-HD is still poorly understood, particularly with respect to the IRF-3 signaling pathway. In this study, we explored the molecular mechanism of 8-HD in regulating inflammatory processes, with a focus on the IRF-3 signaling pathway using a lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid [Poly (I:C)] stimulated murine macrophage cell line (RAW264.7). The 8-HD downregulated the mRNA expression level of IRF-3-dependent genes by inhibiting phosphorylation of the IRF-3 transcription factor. The inhibitory mechanism of 8-HD in the IRF-3 signaling pathway was shown to inhibit the kinase activity of IKKε to phosphorylate IRF-3. This compound can also interfere with the TRIF-mediated complex formation composed of TRAF3, TANK, and IKKε leading to downregulation of AKT phosphorylation and reduction of IRF-3 activation, resulted in inhibition of IRF-3-dependent expression of genes including IFN-ß, C-X-C motif chemokine 10 (CXCL10), and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1). Therefore, these results strongly suggest that 8-HD can act as a promising compound with the regulatory function of IRF-3-mediated inflammatory responses.
Asunto(s)
Antiinflamatorios/farmacología , Regulación hacia Abajo/efectos de los fármacos , Factor 3 Regulador del Interferón/genética , Isoflavonas/farmacología , Macrófagos/efectos de los fármacos , Animales , Factor 3 Regulador del Interferón/inmunología , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Células RAW 264.7RESUMEN
Linusorbs (flaxseed orbitides) are a family of naturally-occurring cyclic peptides. Previously, we reported that their anticancer effects were associated with their structures. In this study, we investigated the anti-inflammatory activities of 2 different linusorbs ([1-9-NαC]-linusorb B2 and [1-9-NαC]-linusorb B3) in lipopolysaccharide (LPS)-induced THP-1 macrophage activation as well as the underlying mechanism of this inflammatory response. Both molecules suppressed pro-inflammatory mediators (TNF-α, IL-1ß, IL-6, NO and COX-2) and were involved in downregulating the NF-κB signaling pathway. The suppressive effects on pro-inflammatory mediators were comparable and the concentration range of action was similar (1-4 µM). However, the concentration of compound that induced downregulation of the NF-κB pathway was different for each compound. While [1-9-NαC]-linusorb B3 could inhibit the activation of the NF-κB pathway at concentrations of 1 and 2 µM, [1-9-NαC]-linusorb B2 induced a comparable inhibitory effect at a concentration of 4 µM.
RESUMEN
A total monosaccharide concentration of 47.0 g/L from 12% (w/v) Gracilaria verrucosa was obtained by hyper thermal acid hydrolysis with 0.2 M HCl at 140°C for 15 min and enzymatic saccharification with CTec2. To improve galactose utilization, we overexpressed two genes, SNR84 and PGM2, in a Saccharomyces cerevisiae CEN-PK2 using CRISPR/Cas-9. The overexpression of both SNR84 and PGM2 improved galactose utilization and ethanol production compared to the overexpression of each gene alone. The overexpression of both SNR84 and PGM2 and of PGM2 and SNR84 singly in S. cerevisiae CEN-PK2 Cas9 produced 20.0, 18.5, and 16.5 g/L ethanol with ethanol yield (YEtOH) values of 0.43, 0.39, and 0.35, respectively. However, S. cerevisiae CEN-PK2 adapted to high concentration of galactose consumed galactose completely and produced 22.0 g/L ethanol at a YEtOH value of 0.47. The overexpression of both SNR84 and PGM2 increased the transcriptional levels of GAL and regulatory genes; however, the transcriptional levels of these genes were lower than those in S. cerevisiae adapted to high galactose concentrations.