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Sarcopenia is a condition marked by a significant reduction in muscle mass and strength, primarily due to the aging process, which critically impacts muscle protein dynamics, metabolic functions, and overall physical functionality. This condition leads to increased body fat and reduced daily activity, contributing to severe health issues and a lower quality of life among the elderly. Recognized in the ICD-10-CM only in 2016, sarcopenia lacks definitive treatment options despite its growing prevalence and substantial social and economic implications. Given the aging global population, addressing sarcopenia has become increasingly relevant and necessary. The primary causes include aging, cachexia, diabetes, and nutritional deficiencies, leading to imbalances in protein synthesis and degradation, mitochondrial dysfunction, and hormonal changes. Exercise remains the most effective intervention, but it is often impractical for individuals with limited mobility, and pharmacological options such as anabolic steroids and myostatin inhibitors are not FDA-approved and are still under investigation. This review is crucial as it examines the potential of natural products as a novel treatment strategy for sarcopenia, targeting multiple mechanisms involved in its pathogenesis. By exploring natural products' multi-targeted effects, this study aims to provide innovative and practical solutions for sarcopenia management. Therefore, this review indicates significant improvements in muscle mass and function with the use of specific natural compounds, suggesting promising alternatives for those unable to engage in regular physical activity.
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Alterations in the intestinal microbial flora are known to cause various diseases, and many people routinely consume probiotics or prebiotics to balance intestinal microorganisms and the growth of beneficial bacteria. In this study, we selected a peptide from fish (tilapia) skin that induces significant changes in the intestinal microflora of mice and reduces the Firmicutes/Bacteroidetes ratio, which is linked to obesity. We attempted to verify the anti-obesity effect of selected fish collagen peptides in a high-fat-diet-based obese mouse model. As anticipated, the collagen peptide co-administered with a high-fat diet significantly inhibited the increase in the Firmicutes/Bacteroidetes ratio. It increased specific bacterial taxa, including Clostridium_sensu_stricto_1, Faecalibaculum, Bacteroides, and Streptococcus, known for their anti-obesity effects. Consequently, alterations in the gut microbiota resulted in the activation of metabolic pathways, such as polysaccharide degradation and essential amino acid synthesis, which are associated with obesity inhibition. In addition, collagen peptide also effectively reduced all obesity signs caused by a high-fat diet, such as abdominal fat accumulation, high blood glucose levels, and weight gain. Ingestion of collagen peptides derived from fish skin induced significant changes in the intestinal microflora and is a potential auxiliary therapeutic agent to suppress the onset of obesity.
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Bacteroidetes , Firmicutes , Animales , Ratones , Obesidad/metabolismo , Aumento de Peso , Bacterias , Dieta Alta en Grasa , Péptidos/farmacología , Ratones Endogámicos C57BLRESUMEN
Intimate partner violence (IPV) is often studied as a problem that predominantly affects younger women. However, studies show that older women are also frequently victims of abuse even though the physical effects of abuse are harder to detect. In this study, we mined the electronic health records (EHR) available through IBM Explorys to identify health correlates of IPV that are specific to older women. Our analyses suggested that diagnostic terms that are co-morbid with IPV in older women are dominated by substance abuse and associated toxicities. When we considered differential co-morbidity, i.e., terms that are significantly more associated with IPV in older women compared to younger women, we identified terms spanning mental health issues, musculoskeletal issues, neoplasms, and disorders of various organ systems including skin, ears, nose and throat. Our findings provide pointers for further investigation in understanding the health effects of IPV among older women, as well as potential markers that can be used for screening IPV.
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Violencia de Pareja , Trastornos Relacionados con Sustancias , Humanos , Femenino , Anciano , Registros Electrónicos de Salud , Violencia de Pareja/psicología , Trastornos Relacionados con Sustancias/epidemiología , Comorbilidad , Factores de Riesgo , PrevalenciaRESUMEN
BACKGROUND/AIM: Metformin is an antidiabetic drug that has been reported to have antitumor activity in many cancer types. This study investigated the molecular mechanisms underlying the antitumor effect of metformin. MATERIALS AND METHODS: We investigated the molecular mechanism of the antitumor effect of metformin alone and in combination with AKT serine/threonine kinase (AKT) inhibition via cell viability and western blot analyses. RESULTS: Notably, metformin increased the phosphorylation of AKT at serine 473 using protein array screening. Metformin-induced AKT activation was markedly suppressed by siRNA targeting activating transcription factor 4 (ATF4) but not AMP-activated protein kinase α. These results indicate that AKT activation by metformin was induced in an ATF4-dependent and AMPKα-independent manner. Treatment using metformin combined with MK-2206, an AKT inhibitor, or a siRNA for AKT markedly reduced the viability of cells compared with those cells treated with these agents alone. In addition, MK-2206 increased cell sensitivity to the combination of metformin with ionizing radiation or cisplatin. CONCLUSION: Inhibition of AKT can enhance the antitumor effect of metformin and would be a promising strategy to sensitize non-small-cell lung cancer to a combination of metformin with radiation or cisplatin.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Metformina/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Hipoglucemiantes/farmacología , Neoplasias Pulmonares/metabolismoRESUMEN
BACKGROUND: Although the major anticancer effect of metformin involves AMPK-dependent or AMPK-independent mTORC1 inhibition, the mechanisms of action are still not fully understood. METHODS: To investigate the molecular mechanisms underlying the effect of metformin on the mTORC1 inhibition, MTT assay, RT-PCR, and western blot analysis were performed. RESULTS: Metformin induced the expression of ATF4, REDD1, and Sestrin2 concomitant with its inhibition of mTORC1 activity. Treatment with REDD1 or Sestrin2 siRNA reversed the mTORC1 inhibition induced by metformin, indicating that REDD1 and Sestrin2 are important for the inhibition of mTORC1 triggered by metformin treatment. Moreover, REDD1- and Sestrin2-mediated mTORC1 inhibition in response to metformin was independent of AMPK activation. Additionally, lapatinib enhances cell sensitivity to metformin, and knockdown of REDD1 and Sestrin2 decreased cell sensitivity to metformin and lapatinib. CONCLUSIONS: ATF4-induced REDD1 and Sestrin2 expression in response to metformin plays an important role in mTORC1 inhibition independent of AMPK activation, and this signalling pathway could have therapeutic value.
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Factor de Transcripción Activador 4/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Metformina/farmacología , Metformina/uso terapéutico , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Humanos , TransfecciónRESUMEN
Mechanistic target of rapamycincomplex 1 (mTORC1) integrates various environmental signals to regulate cell growth and metabolism. mTORC1 activity is sensitive to changes in amino acid levels. Here, we investigated the effect of lysine on mTORC1 activity in non-small cell lung cancer (NSCLC) cells. Lysine deprivation suppressed mTORC1 activity and lysine replenishment restored the decreased mTORC1 activity in lysine-deprived cells. Supplementing growth factors, such as insulin growth factor-1 or insulin restored the decreased mTORC1 activity in serum-deprived cells. However, in serum/lysine-deprived cells, supplementing growth factors was not sufficient to restore mTORC1 activity, suggesting thatgrowth factors could not activate mTORC1 efficiently in the absence of lysine. General control nonderepressible 2 and AMP-activated protein kinase were involved in lysine deprivation-mediated inhibition of mTORC1. Taken together, these results suggest that lysine might play role in the regulation of mTORC1 activation in NSCLC cells.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Lisina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Células A549 , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Línea Celular Tumoral , Medio de Cultivo Libre de Suero , Técnicas de Silenciamiento del Gen , Humanos , Insulina/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Lisina/administración & dosificación , Lisina/deficiencia , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Interferente Pequeño/genéticaRESUMEN
O-linked ß-N-acetylglucosamine (O-GlcNAc) modification regulates the activity of hundreds of nucleocytoplasmic proteins involved in a wide variety of cellular processes, such as gene expression, signaling, and cell growth; however, the mechanism underlying the regulation of B cell development and function by O-GlcNAcylation remains largely unknown. Here, we demonstrate that changes in cellular O-GlcNAc levels significantly affected the growth of pre-B cells, which rapidly proliferate to allow expansion of functional clones that express successfully rearranged heavy chains at the pro-B stage during early B cell development. In our study, the overall O-GlcNAc levels in these proliferative pre-B cells, which are linked to the glucose uptake rate, were highly induced when compared with those in pro-B cells. Thus, pharmacologically, genetically, or nutritionally, inhibition of O-GlcNAcylation in pre-B cells markedly downregulated c-Myc expression, resulting in cell cycle arrest via blockade of cyclin expression. Importantly, the population of B cells after the pro-B cell stage in mouse bone marrow was severely impaired by the administration of an O-GlcNAc inhibitor. These results strongly suggest that O-GlcNAcylation-dependent expression of c-Myc represents a new regulatory component of pre-B cell proliferation, as well as a potential therapeutic target for the treatment of pre-B cell-derived leukemia.
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Acetilglucosamina/química , Proliferación Celular , Células Precursoras de Linfocitos B/citología , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Ciclo Celular , Femenino , Glicosilación , Ratones , Ratones Endogámicos BALB C , Células Precursoras de Linfocitos B/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de SeñalRESUMEN
Here, we report a sustainable approach for the synthesis of starch-based microparticles with well-defined shape and size through molecular self-assembly of short-chain glucan (SCG) obtained enzymatically from waxy maize starch. We employed chitosan as a steric stabilizer to modulate the nucleation process, which significantly reduced undesirable aggregations during the nucleation and growth phases, resulting in the production of highly monodisperse microparticles. The size of chitosan-assisted starch microparticles (CS-SMPs) was effectively controlled by the concentration of debranching enzyme as well as by debranching time, of which the factors influencing the final size were investigated. By modulating the rate and time of debranching reaction in combination with the steric stabilizing effect of chitosan, we were able to prepare highly monodisperse CS-SMPs from 200 nm to 5 µm with a production yield of over 70% from natural starch. Furthermore, the potential of CS-SMPs as a carrier system for oral delivery of bioactive compounds were demonstrated using model guest molecules.
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Starch microparticles (SMPs) of well-defined size and morphology were synthesized through pullulanase-mediated debranching of waxy maize starch followed by spontaneous re-assembly of the resulting short-chain glucan molecules in aqueous solution. Enzymatic debranching of amylopectins from native starch generated two major fractions corresponding to a smaller glucan and partially digested larger amylopectin molecules. The ratio of short-chain glucan (SCG) over partially digested amylopectin (PDAp) turned out to be the deterministic factors for the size and crystallinity of SMPs, of which the ratio could be controlled by the concentration of debranching enzyme. The PDAp fraction was closely associated with the creation of nuclei, determining the growth kinetics of SMPs which led to the formation of SMPs with a diameter ranging from 0.52.5 µm. In addition, we demonstrated that iron oxide nanoparticles (IONPs) were successfully incorporated into the starch microstructure by introducing them during the self-assembly reaction, conferring desired functionality onto the final SMPs. The incorporated IONPs rendered the SMPs an excellent magnetic sensitivity, which were successfully applied for the separation and concentration of target bacteria upon conjugation of specific antibody on the surface of SMPs. The simple processes and biocompatible nature of starch would make this approach attractive for many applications in the area of food, medicine and other related materials sciences.
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Glucanos/química , Microesferas , Almidón/química , Zea mays/química , Glicósido Hidrolasas/metabolismo , Cinética , Magnetismo , Almidón/síntesis química , Temperatura , Difracción de Rayos XRESUMEN
Herein, we report a fairly simple and environmentally friendly approach for the fabrication of starch-based magnetic polymer beads (SMPBs) with uniform shape and size through spontaneous rearrangement of short-chain glucan (SCG) produced by enzymatic debranching of waxy maize starch. The paramagnetic materials, dextran-coated iron oxide nanoparticles (Dex@IONPs), were readily incorporated into the starch microstructure and rendered a superparamagnetic property to the SMPBs. The morphology and size of resulting SMPBs turned out to be modulated by Dex@IONPs in a concentration-dependent manner, of which Dex@IONPs was assumed to be acting as a seed inducing the epitaxial crystallization of SCG and further transforming it into homogeneous microparticles. The surface of SMPBs was readily functionalized with an antibody through a one-step reaction using a linker protein. The immuno-SMPBs showed great capture efficiency (>90%) for target bacteria. The colloidal stability and favorable surface environment for biomolecules are believed to be responsible for the high capture efficiency and specificity of the SMPBs. Furthermore, the captured bacteria along with antibody and linker protein were effectively eluted from the surface of SMPBs by adding free maltose, making this new material suitable for various chromatographic applications.
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Glucanos/química , Extractos Vegetales/química , Almidón/química , Zea mays/química , Bacterias/química , Cristalización , Magnetismo , Nanopartículas/química , Tamaño de la Partícula , Polímeros/química , Difracción de Rayos XRESUMEN
In order to understand the effect of Pb-CuI co-doping on the thermoelectric performance of Bi2Te3, n-type Bi2Te3 co-doped with x at % CuI and 1/2x at % Pb (x = 0, 0.01, 0.03, 0.05, 0.07, and 0.10) were prepared via high temperature solid state reaction and consolidated using spark plasma sintering. Electron and thermal transport properties, i.e., electrical conductivity, carrier concentration, Hall mobility, Seebeck coefficient, and thermal conductivity, of CuI-Pb co-doped Bi2Te3 were measured in the temperature range from 300 K to 523 K, and compared to corresponding x% of CuI-doped Bi2Te3 and undoped Bi2Te3. The addition of a small amount of Pb significantly decreased the carrier concentration, which could be attributed to the holes from Pb atoms, thus the CuI-Pb co-doped samples show a lower electrical conductivity and a higher Seebeck coefficient when compared to CuI-doped samples with similar x values. The incorporation of Pb into CuI-doped Bi2Te3 rarely changed the power factor because of the trade-off relationship between the electrical conductivity and the Seebeck coefficient. The total thermal conductivity(κtot) of co-doped samples (κtot ~ 1.4 W/mâK at 300 K) is slightly lower than that of 1% CuI-doped Bi2Te3 (κtot ~ 1.5 W/mâK at 300 K) and undoped Bi2Te3 (κtot ~ 1.6 W/mâK at 300 K) due to the alloy scattering. The 1% CuI-Pb co-doped Bi2Te3 sample shows the highest ZT value of 0.96 at 370 K. All data on electrical and thermal transport properties suggest that the thermoelectric properties of Bi2Te3 and its operating temperature can be controlled by co-doping.
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The aim of this study was to evaluate clinical manifestations, age distribution and risk factors of adverse drug reactions (ADRs) of statins. Korean Adverse Event Reporting System (KAERS) database records (July 2009-June 2014) on statin-treated adults were used. ADRs classified as 'certain', 'probable' and 'possible' based on the WHO-Uppsala Monitoring Centre criteria were analysed. The frequency of ADRs was compared between adults (18-64 years) and older people (age ≥65 years) groups. In total, 2161 ADRs from 1690 patients (579, 34.3% older people) were included for analysis. Mean patient age and ADRs per patient were 60.46 ± 12.72 years and 1.28, respectively. ADRs were reported with atorvastatin (48.4%), rosuvastatin (23.0%), pitavastatin (10.4%) and simvastatin (9.1%). The frequent ADRs were gastrointestinal (421 events, 19.5%), musculoskeletal (331, 15.3%), skin (312, 14.4%) and hepatobiliary disorders (286, 13.2%). Skin disorders were significantly more frequent in adults compared to those in older patients (16.3% versus 12.4%, p = 0.021). Common clinical symptoms were myalgia (263 events, 12.2%), dyspepsia (133, 6.2%) and pruritus (103, 4.8%). Myalgia was more frequently reported in adults (12.7% versus 9.5%, p = 0.039) and dizziness was more frequent in older people (3.4% versus 5.8%, p = 0.015). According to KAERS data, leading statin ADRs were gastrointestinal and musculoskeletal disorders. Myalgia and dyspepsia were the common clinical symptoms.
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Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Farmacovigilancia , Adolescente , Adulto , Distribución por Edad , Anciano , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , República de Corea , Factores de Riesgo , Adulto JovenRESUMEN
Amylose microparticles can be produced by self-assembly of amylose molecules through an amylosucrase-mediated synthesis. Here we investigated the role of short-chain fatty acids in the formation of amylose microparticles and the fate of these fatty acids at the end of the reaction. The rate of self-assembly and production yields of amylose microparticles were significantly enhanced in the presence of fatty acids. The effect was dependent on the length of the fatty acid carbon tail; butanoic acid (C4) was the most effective, followed by hexanoic acid (C6) and octanoic acid (C8). The amylose microparticles were investigated by carrying out SEM, XRD, Raman, NMR, FT-IR and DSC analysis. The size, morphology and crystal structure of the resulting amylose microparticles were comparable with those of amylose microparticles produced without fatty acids. The results indicated the carboxyl group of the fatty acid to be responsible for promoting the self-assembly of amylose chains to form microparticles. The fatty acids were eventually removed from the microstructure through the tight association of amylose double helices to form the amylose microparticles.
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Amilosa/química , Ácidos Grasos Volátiles/química , Glucosiltransferasas/metabolismo , Microesferas , Deinococcus/enzimología , Modelos Moleculares , Conformación MolecularRESUMEN
This paper presents the successful fabrication of a transparent electrode comprising a sandwich structure of silicone/Ag nanowires (AgNWs)/silicone equipped with Diels-Alder (DA) adducts as crosslinkers to realise highly stable stretchability. Because of the reversible DA reaction, the crosslinked silicone successfully bonds with the silicone overcoat, which should completely seal the electrode. Thus, any surrounding liquid cannot leak through the interfaces among the constituents. Furthermore, the nanowires are protected by the silicone cover when they are stressed by mechanical loads such as bending, folding, and stretching. After delicate optimisation of the layered silicone/AgNW/silicone sandwich structure, a stretchable transparent electrode which can withstand 1000 cycles of 50% stretching-releasing with an exceptionally high stability and reversibility was fabricated. This structure can be used as a transparent strain sensor; it possesses a strong piezoresistivity with a gauge factor greater than 11.
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Flavonoid myricetin has been shown to exhibit anti-inflammatory and anti-oxidant effects. Nevertheless, the effect of myricetin on the TNF-α-stimulated production of inflammatory mediators in keratinocytes has not been studied. Using human keratinocytes, we examined the effect of myricetin on the TNF-α-stimulated production of inflammatory mediators in relation to the Akt, mTOR and NF-κB pathways, which regulate the transcription genes involved in immune and inflammatory responses. TNF-α stimulated production of the inflammatory mediators and reactive oxygen species in keratinocytes, and activation of the Akt, mTOR and NF-κB pathways in HaCaT cells and primary keratinocytes. Myricetin, Akt inhibitor, Bay 11-7085 (an inhibitor of NF-κB activation), rapamycin (mTOR inhibitor) and N-acetylcysteine attenuated TNF-α-induced activation of Akt, mTOR and NF-κB. Myricetin and N-acetylcysteine attenuated the TNF-α-stimulated production of cytokines and chemokines, and production of reactive oxygen species in keratinocytes. The results show that myricetin may reduce TNF-α-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of the Akt, mTOR and NF-κB pathways. The effect of myricetin appears to be associated with inhibition of the production of reactive oxygen species. Further, myricetin appears to attenuate the proinflammatory mediator-induced inflammatory skin diseases.
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Flavonoides/farmacología , Mediadores de Inflamación/metabolismo , Queratinocitos/efectos de los fármacos , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
A mechanically robust, transparent, and healable electrode was successfully developed by embedding Ag nanowires (AgNWs) on the surface of polydimethylsiloxane-based polyurethane (PDMS-CPU) cross-linked by Diels-Alder (DA) adducts. The reversibility of the DA reaction enabled the heated dimethylformamide (DMF) vapor to induce de-cross-linking of the PDMS-CPU preformed as a substrate. A combination of the retro-DA reaction and the plasticizer effect softened the polymer surface, embedding the coated AgNWs on the surface of the polymer. With this simple postprocessing, the surface roughness and mechanical stability of the electrode were largely enhanced. Even with a 55 µm bending radius, which corresponds to a strain of 90%, the resistance of the electrode after 10 min of vapor treatment increased by 2.1% for inward bending and 5.3% for outward bending. This result shows a great potential of the proposed method, as it can also be used to fabricate various mechanically deformable transparent electrode. Furthermore, swelling of the PDMS-CPU film owing to the DMF vapor facilitated the healing properties of the scratched electrodes.
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Dysfunction of the proteasome system has been suggested to be implicated in neuronal degeneration. Modulation of KATP channels appears to affect the viability of neuronal cells exposed to toxic insults. However, the effect of KATP channel blockers on the neuronal cell death mediated by proteasome inhibition has not been studied. The present study investigated the effect of KATP channel blockers on proteasome inhibitor-induced apoptosis in differentiated PC12 cells and SH-SY5Y cells. 5-Hydroxydecanoate (a selective KATP channel blocker) and glibenclamide (a cell surface and mitochondrial KATP channel inhibitor) reduced the proteasome inhibitor-induced apoptosis. Addition of the KATP channel blockers attenuated the proteasome inhibitor-induced changes in the levels of apoptosis-related proteins, the loss of the mitochondrial transmembrane potential, the increase in the formation of reactive oxygen species and the depletion of glutathione in both cell lines. The results show that KATP channel blockers may attenuate proteasome inhibitor-induced apoptosis in PC12 cells by suppressing activation of the mitochondrial pathway and of the caspase-8- and Bid-dependent pathways. The preventive effect appears to be associated with the inhibition of the formation of reactive oxygen species and the depletion of glutathione. KATP channel blockade appears to prevent proteasome inhibition-induced neuronal cell death.
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Apoptosis/efectos de los fármacos , Ácidos Decanoicos/farmacología , Gliburida/farmacología , Hidroxiácidos/farmacología , Canales KATP/antagonistas & inhibidores , Leupeptinas/farmacología , Neurogénesis , Neuronas/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Inhibidores de Proteasoma/farmacología , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Glutatión/metabolismo , Humanos , Canales KATP/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Degeneración Nerviosa , Neuronas/enzimología , Neuronas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Complejo de la Endopetidasa Proteasomal/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Cholesterol oxidation products are suggested to be involved in neuronal degeneration. Apocynin has demonstrated to have anti-inflammatory and anti-oxidant effects. We assessed the effect of apocynin on the cholesterol oxidation product-induced programmed cell death in neuronal cells using differentiated PC12 cells in relation to NF-κB-mediated cell death process. 7-Ketocholesterol and 25-hydroxycholesterol decreased the levels of Bid and Bcl-2, increased the levels of Bax and p53, and induced loss of the mitochondrial transmembrane potential, release of cytochrome c and activation of caspases (-8, -9 and -3). 7-Ketocholesterol caused an increase in the levels of cytosolic and nuclear NF-κB p65, cytosolic NF-κB p50 and cytosolic phospho-IκB-α, which was inhibited by the addition of 0.5 µM Bay11-7085 (an inhibitor of NF-κB activation). Apocynin attenuated the cholesterol oxidation product-induced changes in the programmed cell death-related protein levels, NF-κB activation, production of reactive oxygen species, and depletion of GSH. The results show that apocynin appears to attenuate the cholesterol oxidation product-induced programmed cell death in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways that are mediated by NF-κB activation. The preventive effect appears to be associated with the inhibitory effect on the production of reactive oxygen species and depletion of GSH.
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Acetofenonas/farmacología , Antioxidantes/farmacología , Diferenciación Celular/efectos de los fármacos , Hidroxicolesteroles/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Diferenciación Celular/fisiología , Citocromos c/antagonistas & inhibidores , Citocromos c/metabolismo , Hidroxicolesteroles/metabolismo , FN-kappa B/metabolismo , Oxidación-Reducción/efectos de los fármacos , Células PC12 , Ratas , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Caffeoyl derivatives exhibit antiinflammatory and antioxidant effects. However, the effect of 3,4,5-tricaffeoylquinic acid on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in keratinocytes that may be involved in skin diseases has not been studied. In this respect, we investigated the effect of 3,4,5-tricaffeoylquinic acid on TRAIL-induced apoptosis in human keratinocytes. 3,4,5-Tricaffeoylquinic acid and oxidant scavengers attenuated the decrease in the cytosolic levels of Bid, Bcl-2, and survivin proteins; the increase in the levels of cytosolic Bax, p53, and phosphorylated p53; the increase in the levels of phosphorylated p38; the increase in the mitochondrial levels of the voltage-dependent anion channel; loss of the mitochondrial transmembrane potential; the release of cytochrome c; activation of caspases (8, 9, and 3); cleavage of poly [ADP-ribose] polymerase-1; production of reactive oxygen species; the depletion of glutathione (GSH); nuclear damage; and cell death in keratinocytes treated with TRAIL. These results suggest that 3,4,5-tricaffeoylquinic acid may reduce TRAIL-induced apoptosis in human keratinocytes by suppressing the activation of the caspase-8 and Bid pathways and the mitochondria-mediated cell death pathway. The effect appears to be associated with the inhibitory effect on the production of reactive oxygen species and depletion of GSH. 3,4,5-Tricaffeoylquinic acid appears to be effective in the prevention of TRAIL-induced apoptosis-mediated skin diseases.