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Proactive management of foodborne illness requires routine surveillance of foodborne pathogens, which requires developing simple, rapid, and sensitive detection methods. Here, a strategy is presented that enables the detection of multiple foodborne bacteria using a 3D nanostructure swab and deep learning-based Raman signal classification. The nanostructure swab efficiently captures foodborne pathogens, and the portable Raman instrument directly collects the Raman signals of captured bacteria. a deep learning algorithm has been demonstrated, 1D convolutional neural network with binary labeling, achieves superior performance in classifying individual bacterial species. This methodology has been extended to mixed bacterial populations, maintaining accuracy close to 100%. In addition, the gradient-weighted class activation mapping method is used to provide an investigation of the Raman bands for foodborne pathogens. For practical application, blind tests are conducted on contaminated kitchen utensils and foods. The proposed technique is validated by the successful detection of bacterial species from the contaminated surfaces. The use of a 3D nanostructure swab, portable Raman device, and deep learning-based classification provides a powerful tool for rapid identification (≈5 min) of foodborne bacterial species. The detection strategy shows significant potential for reliable food safety monitoring, making a meaningful contribution to public health and the food industry.
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Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint destruction due to synovial hypertrophy and the infiltration of inflammatory cells. Despite substantial progress in RA treatment, challenges persist, including suboptimal treatment responses and adverse effects associated with current therapies. This study investigates the anti-rheumatic capabilities of the newly identified multi-protein kinase inhibitor, KMU-11342, aiming to develop innovative agents targeting RA. In this study, we synthesized the novel multi-protein kinase inhibitor KMU-11342, based on indolin-2-one. We assessed its cardiac electrophysiological safety using the Langendorff system in rat hearts and evaluated its toxicity in zebrafish in vivo. Additionally, we examined the anti-rheumatic effects of KMU-11342 on human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), THP-1 cells, and osteoclastogenesis in RAW264.7 cells. KMU-11342 demonstrated the ability to inhibit LPS-induced chemokine inhibition and the upregulation of pro-inflammatory cytokines, cyclooxygenase-2, inducible nitric oxide synthase, p-IKKα/ß, p-NF-κB p65, and the nuclear translocation of NF-κB p65 in RA-FLS. It effectively suppressed the upregulation of NLR family pyrin domain containing 3 (NLRP3) and caspase-1 cleavage. Furthermore, KMU-11342 hindered the activation of osteoclast differentiation factors such as RANKL-induced TRAP, cathepsin K, NFATc-1, and c-Fos in RAW264.7 cells. KMU-11342 mitigates LPS-mediated inflammatory responses in THP-1 cells by inhibiting the activation of NLRP3 inflammasome. Notably, KMU-11342 exhibited minimal cytotoxicity in vivo and electrophysiological cardiotoxicity ex vivo. Consequently, KMU-11342 holds promise for development as a therapeutic agent in RA treatment.
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Antirreumáticos , Artritis Reumatoide , Sinoviocitos , Pez Cebra , Animales , Humanos , Ratones , Artritis Reumatoide/tratamiento farmacológico , Células RAW 264.7 , Sinoviocitos/efectos de los fármacos , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Ratas , Masculino , Citocinas/metabolismo , Células THP-1 , Indoles/farmacología , Indoles/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratas Sprague-DawleyRESUMEN
Hepatic steatosis is an initial manifestation of alcoholic liver disease. An imbalance of hepatic lipid processes including fatty acid uptake, esterification, oxidation, and triglyceride secretion leads to alcoholic fatty liver (AFL). However, the precise molecular mechanisms underlying the pathogenesis of AFL remain elusive. Here, we show that mice deficient in microRNAs (miRs)-141 and -200c display resistance to the development of AFL. We found that miR-200c directly targets HNF1 homeobox B (Hnf1b), a transcriptional activator for microsomal triglyceride transfer protein (Mttp), as well as apolipoprotein O (ApoO), an integral component of the mitochondrial contact site and cristae organizing system complex. We show that expression of these miRs is significantly induced by chronic ethanol exposure, which is accompanied by reduced HNF1B and APOO levels. Furthermore, miR-141/200c deficiency normalizes ethanol-mediated impairment of triglyceride secretion, which can be attributed to the restored levels of HNF1B and MTTP, as well as phosphatidylcholine abundance. Moreover, we demonstrate that miR-141/200c deficiency restores ethanol-mediated inhibition of APOO expression and mitochondrial dysfunction, improving mitochondrial antioxidant defense capacity and fatty acid oxidation. Taken together, these results suggest that miR-200c contributes to the modulation of lipid homeostasis in AFL disease by cooperatively regulating Hnf1b and ApoO functions.
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Apolipoproteínas , Hígado Graso Alcohólico , Factor Nuclear 1-alfa del Hepatocito , MicroARNs , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Apolipoproteínas/metabolismo , Etanol/metabolismo , Ácidos Grasos/genética , Ácidos Grasos/metabolismo , Hígado Graso Alcohólico/metabolismo , Genes Homeobox , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Homeostasis , Hígado/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Triglicéridos/metabolismoRESUMEN
Ionizing radiation (IR) triggers an overproduction of reactive oxygen species (ROS), disrupting the normal function of both immune and metabolic systems, leading to inflammation and metabolic disturbances. To address the pressing requirement for protection against IR, fucoxanthin (FX), a naturally occurring compound extracted from algae, was utilized as an efficient radioprotective agent in macrophages. In this study, we cultured murine RAW 264.7 macrophages and treated them with FX, along with agents influencing the activity of sirtuin 1 (SIRT1) and estrogen receptor α (ERα), to investigate their impact on IR-induced cellular responses. FX significantly attenuated IR-induced upregulation of pro-inflammatory genes (Il1b, Tnf, and Ccl2) and inhibited macrophage polarization toward the pro-inflammatory M1 phenotype. Additionally, FX regulated IR-induced metabolic genes mediating glycolysis and mitochondrial biogenesis. The ability of FX to mitigate IR-induced inflammation and glycolysis was ascribed to the expression and activity of SIRT1 and ERα in macrophages. This study not only uncovers the underlying mechanisms of FX's radioprotective properties but also highlights its potential as a protective agent against the detrimental effects of IR, thus offering new opportunities for enhancing radiation protection in the future.
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Receptor alfa de Estrógeno , Sirtuina 1 , Ratones , Animales , Sirtuina 1/metabolismo , Receptor alfa de Estrógeno/metabolismo , Macrófagos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Radiación IonizanteRESUMEN
Atherosclerosis (AS) is a chronic metabolic disorder and primary cause of cardiovascular diseases, resulting in substantial morbidity and mortality worldwide. Initiated by endothelial cell stimulation, AS is characterized by arterial inflammation, lipid deposition, foam cell formation, and plaque development. Nutrients such as carotenoids, polyphenols, and vitamins can prevent the atherosclerotic process by modulating inflammation and metabolic disorders through the regulation of gene acetylation states mediated with histone deacetylases (HDACs). Nutrients can regulate AS-related epigenetic states via sirtuins (SIRTs) activation, specifically SIRT1 and SIRT3. Nutrient-driven alterations in the redox state and gene modulation in AS progression are linked to their protein deacetylating, anti-inflammatory, and antioxidant properties. Nutrients can also inhibit advanced oxidation protein product formation, reducing arterial intima-media thickness epigenetically. Nonetheless, knowledge gaps remain when it comes to understanding effective AS prevention through epigenetic regulation by nutrients. This work reviews and confirms the underlying mechanisms by which nutrients prevent arterial inflammation and AS, focusing on the epigenetic pathways that modify histones and non-histone proteins by regulating redox and acetylation states through HDACs such as SIRTs. These findings may serve as a foundation for developing potential therapeutic agents to prevent AS and cardiovascular diseases by employing nutrients based on epigenetic regulation.
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Arteritis , Aterosclerosis , Enfermedades Cardiovasculares , Sirtuinas , Humanos , Epigénesis Genética , Enfermedades Cardiovasculares/genética , Acetilación , Grosor Intima-Media Carotídeo , Histonas/metabolismo , Sirtuinas/metabolismo , Inflamación/genética , Aterosclerosis/genética , Nutrientes , Arteritis/genéticaRESUMEN
Epigenetic regulation in macrophages plays a crucial role in the inflammatory response of cells. We investigated the role of macrophage histone deacetylase 4 (HDAC4) in diet-induced obesity and non-alcoholic steatohepatitis using macrophage-specific Hdac4 knockout mice (Hdac4MKO ). Hdac4 floxed control (Hdac4fl/fl ) and Hdac4MKO mice were fed a regular chow diet or an obesogenic high-fat/high-sucrose/high-cholesterol (HF/HS/HC) diet for 12 weeks. The loss of macrophage Hdac4, compared with Hdac4fl/fl control, aggravated the diet-induced inflammation in the liver and white adipose tissue only in male mice. Splenic monocytes isolated from male mice fed the HF/HS/HC diet showed increased lipopolysaccharide (LPS) sensitivity and decreased Ly6C-/Ly6C+ ratios in male Hdac4MKO mice, but not in females. Bone marrow-derived macrophages (BMMs) from male Hdac4MKO mice had a lesser efferocytotic capacity but higher proinflammatory gene expression upon LPS stimulation than male Hdac4fl/fl mice. However, female Hdac4MKO BMMs exhibited the opposite responses. The induction of estrogen receptor α (ERα, Esr1) expression by LPS was less in male but more in female Hdac4MKO BMMs than Hdac4fl/fl BMMs. Moreover, overexpression of human HDAC4 decreased basal expression of Esr1 and abolished its induction by LPS. Inhibition of ERα increased Hdac4 with induction of inflammatory genes, whereas activation of ERα decreased Hdac4 with reduction of inflammatory genes in male and female Hdac4fl/fl BMMs treated with LPS. However, regardless of the inhibition or activation of ERα, proinflammatory genes were induced by LPS more in male Hdac4MKO BMMs than Hdac4fl/fl cells, whereas cells in females showed opposite responses. In conclusion, this study suggests that the lack of macrophage Hdac4 aggravates hepatic and white adipose inflammation in male mice with diet-induced obesity and non-alcoholic steatohepatitis, and not in female mice. HDAC4 and ERα appear to counteract each other, but ERα may not be a major player in sex-dependent inflammatory responses in macrophages deficient in HDAC4. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Histona Desacetilasas/metabolismo , Macrófagos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Caracteres Sexuales , Tejido Adiposo/patología , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Inflamación/patología , Hígado/patología , Masculino , Ratones , Ratones NoqueadosRESUMEN
Macrophages play an essential role in alcohol-induced inflammation and oxidative stress. We investigated the effects of nicotinamide riboside (NR), a natural nicotinamide adenine dinucleotide (NAD+) precursor, on alcohol-induced inflammation and oxidative stress in macrophages. NR significantly decreased ethanol-induced inflammatory gene expression, with a concomitant decrease in nuclear translocation of nuclear factor κB p65 in RAW 264.7 macrophages and mouse bone marrow-derived macrophages (BMDMs). In macrophages incubated with ethanol or acetaldehyde, NR abolished the accumulation of cellular reactive oxygen species. Ethanol decreased sirtuin 1 (SIRT1) expression and activity, and cellular NAD+ level while inducing pro-inflammatory gene expression. However, NR markedly attenuated the changes. SIRT1 inhibition augmented ethanol-induced inflammatory gene expression, but its activation elicited opposing effects. Also, ethanol did not alter glycolysis but increased glycolytic capacity, glycolytic reserve, and non-glycolytic acidification, with concomitant increases in hypoxia-induced factor 1α expression and activity, phosphorylation of pyruvate dehydrogenase, and extracellular lactate levels. Interestingly, ethanol increased mitochondrial respiration and ATP production but decreased maximal respiration and spare respiration capacity. The latter was linked to decreases in mitochondrial copy numbers. NR abolished the ethanol-induced metabolic changes in the glycolytic and oxidative phosphorylation pathways in RAW 264.7 macrophages. In conclusion, NR exerts anti-inflammatory and antioxidant properties by abrogating the inhibitory effects of ethanol on the SIRT1 pathway by increasing Sirt1 expression and its activator, NAD+. Also, SIRT1 activation and normalization of ethanol-induced changes in NAD+/NADH ratios by NR are likely crucial to counteract the changes in energy phenotypes of macrophages exposed to ethanol.
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Inflamación/metabolismo , Macrófagos , Niacinamida/análogos & derivados , Estrés Oxidativo/efectos de los fármacos , Compuestos de Piridinio/farmacología , Sirtuina 1/metabolismo , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Etanol/efectos adversos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Niacinamida/farmacología , Células RAW 264.7RESUMEN
PURPOSE: Anti-inflammatory and antioxidant effects of fucoxanthin (FCX), a xanthophyll carotenoid, have been suggested. However, underlying mechanisms are elusive. The objective of this study was to elucidate the mechanisms by which FCX and its metabolites inhibit lipopolysaccharide (LPS)-induced inflammation and oxidative stress in macrophages. METHODS: The effects of the FCX on mRNA and protein expression of pro-inflammatory cytokines and antioxidant genes, and reactive oxygen species (ROS) accumulation were determined in RAW 264.7 macrophages. A potential role of FCX in the modulation of phosphatidylinositol 3-kinase (PI3K)/AKT/nuclear E2-related factor 2 (NRF2) axis was evaluated. RESULTS: FCX significantly decreased LPS-induced interleukin (Il)6, Il1b, and tumor necrosis factor α (Tnf) mRNA abundance and TNFα secretion. FCX attenuated LPS or tert-butyl-hydroperoxide-induced ROS accumulation with concomitant increases in the expression of antioxidant enzymes. Also, trolox equivalent antioxidant capacity assay demonstrated that FCX had a potent free radical scavenging property. FCX markedly increased nuclear translocation of NRF2 in LPS-treated macrophages, consequently inducing its target gene expression. Interestingly, the effect of FCX on NRF2 nuclear translocation was noticeably diminished by LY294002, an inhibitor of PI3K, but not by inhibitors of mitogen-activated protein kinases. Phosphorylation of AKT, a downstream element of PI3K, was also markedly increased by FCX. FCX metabolites, such as fucoxanthinol and amarouciaxanthin A, significantly attenuated LPS-induced ROS accumulation and pro-inflammatory cytokine expression. CONCLUSION: FCX exerts anti-inflammatory and antioxidant effects by the activation of NRF2 in the macrophages activated by LPS, which is mediated, at least in part, through the PI3K/AKT pathway.
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Lipopolisacáridos , Factor 2 Relacionado con NF-E2 , Humanos , Inflamación/tratamiento farmacológico , Macrófagos/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Fosfatidilinositol 3-Quinasa , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Xantófilas/farmacologíaRESUMEN
The physical properties of DNA have been suggested to play a central role in spatio-temporal organization of eukaryotic chromosomes. Experimental correlations have been established between the local nucleotide content of DNA and the frequency of inter- and intra-chromosomal contacts but the underlying physical mechanism remains unknown. Here, we combine fluorescence resonance energy transfer (FRET) measurements, precipitation assays, and molecular dynamics simulations to characterize the effect of DNA nucleotide content, sequence, and methylation on inter-DNA association and its correlation with DNA looping. First, we show that the strength of DNA condensation mediated by poly-lysine peptides as a reduced model of histone tails depends on the DNA's global nucleotide content but also on the local nucleotide sequence, which turns out to be qualitatively same as the condensation by spermine. Next, we show that the presence and spatial arrangement of C5 methyl groups determines the strength of inter-DNA attraction, partially explaining why RNA resists condensation. Interestingly, multi-color single molecule FRET measurements reveal strong anti-correlation between DNA looping and DNA-DNA association, suggesting that a common biophysical mechanism underlies them. We propose that the differential affinity between DNA regions of varying sequence pattern may drive the phase separation of chromatin into chromosomal subdomains.
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Secuencia de Bases/fisiología , Cromatina/química , Empaquetamiento del ADN/genética , ADN/química , Conformación de Ácido Nucleico , Fraccionamiento Químico/métodos , Precipitación Química , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina/genética , ADN/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Histonas/metabolismo , Simulación de Dinámica MolecularRESUMEN
The objective of this study was to evaluate whether fucoxanthin (FCX) have anti-fibrogenic properties in hepatic stellate cells (HSCs). FCX significantly decreased basal and transforming growth factor ß1 (TGFß1)-induced mRNA levels of fibrogenic genes with concomitant decreases in their protein levels in LX-2â¯cells. The phosphorylation of SMA- and MAD-related protein (SMAD3) was increased by TGFß1, which was attenuated by FCX. Importantly, when LX-2â¯cells were treated with FCX and SIS3, a SMAD3 inhibitor, there was synergistic repression of fibrogenic gene expression. The anti-fibrogenic effect of FCX was also confirmed in primary human HSCs. FCX prevented TGFß1-induced accumulation of reactive oxygen species by diminishing mRNA level of NADPH oxidase 4 (NOX4) in LX-2â¯cells. When FCX was present during the activation of quiescent mouse primary HSCs, it decreased the expression of fibrogenic genes while diminishing intracellular lipid droplets. The results suggest that FCX exerts an anti-fibrogenic effect in HSCs primarily by preventing TGFß1-induced pro-fibrogenic genes expression via inhibition of SMAD3 activation and by inhibiting the activation of quiescent HSCs.
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Células Estrelladas Hepáticas/efectos de los fármacos , Cirrosis Hepática/prevención & control , Sustancias Protectoras/farmacología , Xantófilas/farmacología , Animales , Línea Celular , Células Cultivadas , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Humanos , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Treatment of liver fibrosis is very limited as there is currently no effective anti-fibrotic therapy. Spirulina platensis (SP) is a blue-green alga that is widely supplemented in healthy foods. The objective of this study was to determine whether SP supplementation can prevent obesity-induced liver fibrosis in vivo. Male C57BL/6J mice were randomly assigned to a low-fat or a high-fat (HF)/high-sucrose/high-cholesterol diet or an HF diet supplemented with 2·5 % SP (w/w) (HF/SP) for 16 or 20 weeks. There were no significant differences in body weight, activity, energy expenditure, serum lipids or glucose tolerance between mice on HF and HF/SP diets. However, plasma alanine aminotransferase level was significantly reduced by SP at 16 weeks. Expression of fibrotic markers and trichrome stains showed no differences between HF and HF/SP. Splenocytes isolated from HF/SP fed mice had lower inflammatory gene expression and cytokine secretion compared with splenocytes from HF-fed mice. SP supplementation did not attenuate HF-induced liver fibrosis. However, the expression and secretion of inflammatory genes in splenocytes were significantly reduced by SP supplementation, demonstrating the anti-inflammatory effects of SP in vivo. Although SP did not show appreciable effect on the prevention of liver fibrosis in this mouse model, it may be beneficial for other inflammatory conditions.
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Antiinflamatorios/farmacología , Suplementos Dietéticos , Cirrosis Hepática/prevención & control , Spirulina , Bazo/citología , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Cirrosis Hepática/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/complicacionesRESUMEN
Bakanae disease (BD) has emerged as a serious threat in almost all rice cultivation regions worldwide. Nampyeong is a Korean japonica rice variety known to be resistant to BD. In this study, quantitative trait locus (QTL) mapping was performed with F2 and F3 plants derived from a cross between the Nampyeong variety and a susceptible Korean japonica line, DongjinAD. First, resequencing of Nampyeong and DongjinAD was performed, which identified 171,035 single nucleotide polymorphisms (SNPs) between the two parental varieties. Using these SNPs, 161 cleaved amplified polymorphic sequence (CAPS) markers and six derived CAPS markers were developed; then, a genetic map was constructed from the genotypes of 180 plants from the DongjinAD/Nampyeong F2 plants. The total length of the constructed genetic map was 1386 cM, with an average interval of 8.9 cM between markers. The BD mortality rates of each F3 family were measured by testing 40 F3 progenies using in vitro seedling screening method. QTL analysis based on the genetic map and mortality rate data revealed a major QTL, qFfR1, on rice chromosome 1. qFfR1 was located at 89.8 cM with a logarithm of the odds (LOD) score of 22.7. Further, there were three markers at this point: JNS01033, JNS01037, and JNS01041. A total of 15 genes were identified with annotations related to defense against plant diseases among the 179 genes in the qFfR1 interval at 95% probability, thereby providing potential candidate genes for qFfR1. qFfR1 and its closely linked markers will be useful in breeding rice varieties resistant to BD.
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Mapeo Cromosómico/métodos , Resistencia a la Enfermedad , Oryza/genética , Sitios de Carácter Cuantitativo , Cromosomas de las Plantas , Ligamiento Genético , Oryza/inmunología , Fitomejoramiento , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Enterovirus 71 (EV71) is a major causative agent of hand-foot-mouth disease (HFMD) and also causes severe neurological complications, leading to fatality in young children. However, no effective therapy is currently available for the treatment of this infection. METHODS: We identified small-molecule inhibitors of EV71 from a screen of 968 Food and Drug Administration (FDA)-approved drugs, with which clinical application for EV71-associated diseases would be more feasible, using EV71 subgenomic replicon system. Primary hits were extensively evaluated for their antiviral activities in EV71-infected cells. RESULTS: We identified micafungin, an echinocandin antifungal drug, as a novel inhibitor of EV71. Micafungin potently inhibits the proliferation of EV71 as well as the replication of EV71 replicon in cells with a low micromolar IC50 (~5 µM). The strong antiviral effect of micafungin on EV71 replicon and the result from time-of-addition experiment demonstrated a targeting of micafungin on virion-independent intracellular process(es) during EV71 infection. Moreover, an extensive analysis excluded the involvement of 2C and 3A proteins, IRES-dependent translation, and also that of polyprotein processing in the antiviral effect of micafungin. CONCLUSIONS: Our research revealed a new indication of micafungin as an effective inhibitor of EV71, which is the first case reporting antiviral activity of micafungin, an antifungal drug.
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Antivirales/farmacología , Equinocandinas/farmacología , Enterovirus Humano A/efectos de los fármacos , Lipopéptidos/farmacología , Animales , Línea Celular , Reposicionamiento de Medicamentos , Humanos , MicafunginaRESUMEN
Diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step in triacylglycerol (TG) synthesis, is a key enzyme associated with hepatic steatosis and insulin resistance. Here, using an in vitro screen of 20000 molecules, we identified a class of compounds with a substituted 1H-pyrrolo[2,3-b]pyridine core which proved to be potent and selective inhibitors of human DGAT2. Of these compounds, H2-003 and -005 exhibited a considerable reduction in TG biosynthesis in HepG2 hepatic cells and 3T3-L1 preadipose cells. These compounds exert DGAT2-specific-inhibitory activity, which was further confirmed in DGAT2- or DGAT1-overexpressing HEK293 cells. In addition, these compounds almost completely abolished lipid droplet formation in 3T3-L1 cells when co-treated with a DGAT1 inhibitor, which was not attained using either a DGAT2 or DGAT1 inhibitor alone. Collectively, we identified two DGAT2 inhibitors, H2-003 and -005. These compounds will aid in DGAT2-related lipid metabolism research as well as in therapeutic development for the treatment of metabolic diseases associated with excessive TG.
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Acetatos/química , Acetatos/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Descubrimiento de Drogas/métodos , Piridinas/química , Piridinas/farmacología , Células 3T3-L1 , Animales , Diacilglicerol O-Acetiltransferasa/metabolismo , Células HEK293 , Células Hep G2 , Humanos , RatonesRESUMEN
PURPOSE: Communities of practice (CoPs) offer a promising strategy to improve communication among various professionals committed to advancing employment outcomes for people with disabilities. CoPs also provide a tool for professionals to share knowledge and resources related to the Americans with Disabilities Act and job accommodations. METHODS: The current study conducted four focus groups with human resource (HR) professionals and vocational rehabilitation professionals to fully assess the need for this CoP. Coding and memoing were the two data analysis strategies employed in this study. RESULTS: Results indicate a strong interest in developing a CoP to assist with employment concerns for people with disabilities. CONCLUSIONS: HR professionals report a need for current, relevant information on this topic, and participants outline guidelines for developing the CoP and building useful content areas.
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Personas con Discapacidad , Empleo , Comunicación Interdisciplinaria , Administración de Personal , Rehabilitación Vocacional , Femenino , Grupos Focales , Guías como Asunto , Humanos , Internet , Masculino , Evaluación de Necesidades , Investigación Cualitativa , Red SocialRESUMEN
PURPOSE: With the recent increase in interest in patient safety, prevention of falls in hospitalized children has become important. This study aimed to identify the incidence rate of falls among hospitalized children and explore fall-related characteristics. METHODS: This retrospective descriptive study analyzed the medical information of 18,119 patients aged <18 years admitted to a general hospital in South Korea from electronic medical records and fall event reports between January 1, 2018, and September 30, 2023. The study variables included the general and clinical characteristics of the fall group and fall-related characteristics of the fall events. This study employed descriptive statistics and a chi-square test using IBM SPSS version 26.0. RESULTS: Among the patients, 82 fall events were identified. Therefore, the fall incidence rate was 4.5 falls per 1,000 patients. Furthermore, a statistically significant difference was found concerning the type of injury sustained between children >1 year old and those <1 year old, and most cases had no damage or bruises. More cases were found in which falls occurred two days after hospitalization in winter and summer than on the day or the day after hospitalization, which was a statistically significant difference. In addition, fall prevalence was higher between 8 am and 4 pm, and when no caregiver was present. CONCLUSION: Based on the results of this study, education and interventions to prevent fall events in infants and toddlers should persist throughout hospitalization, and it is necessary to guide continuous management and observation of the caregivers.
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CONTEXT: Cancer has become a chronic disease to which new therapeutic approaches are being applied and many patients are interested in the long-term consequences of these approaches. Aromatherapy is one approach that has been used as a safe and comfortable method to alleviate symptoms in patients with cancer, and its effects on various aspects of life have been reported. OBJECTIVES: A systematic review and meta-analysis were conducted to examine the effects of aromatherapy on quality of life (QoL) and pain in patients with cancer. METHODS: Using a comprehensive search strategy, 11 databases were searched from their inception to July 2023 for randomized controlled trials. In the meta-analysis, the standardized mean difference and 95% confidence interval were calculated as effect measures by applying a random effects model. RESULTS: Fifteen studies met the inclusion criteria. Aromatherapy was found to have favorable effects in improving QoL (Hedges' g = 0.62, 95% CI: 0.24-1.00), but no statistically significant effect of aromatherapy on pain was found (Hedges' g = -0.46, 95% CI: -0.99 to 0.07). CONCLUSION: The findings indicate statistically significant improvements in QoL when combining aromatherapy and massage, but it was not possible to disentangle the individual effects of each. Considering the characteristics of cancer patients, aromatherapy has beneficial effects as a non-pharmacological method. Further research is needed to investigate the effect of aromatherapy on symptom management, considering factors such as the duration of cancer development and type of cancer.
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Histone deacetylase 4 (HDAC4), a class IIa HDAC, has gained attention as a potential therapeutic target in treating inflammatory and metabolic processes based on its essential role in various biological pathways by deacetylating non-histone proteins, including transcription factors. The activity of HDAC4 is regulated at the transcriptional, post-transcriptional, and post-translational levels. The functions of HDAC4 are tissue-dependent in response to endogenous and exogenous factors and their substrates. In particular, the association of HDAC4 with non-histone targets, including transcription factors, such as myocyte enhancer factor 2, hypoxia-inducible factor, signal transducer and activator of transcription 1, and forkhead box proteins, play a crucial role in regulating inflammatory and metabolic processes. This review summarizes the regulatory modes of HDAC4 activity and its functions in inflammation, insulin signaling and glucose metabolism, and cardiac muscle development.
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Histona Desacetilasas , Inflamación , Transducción de Señal , Humanos , Histona Desacetilasas/metabolismo , Inflamación/metabolismo , Animales , Proteínas Represoras/metabolismo , Glucosa/metabolismo , Insulina/metabolismoRESUMEN
We previously demonstrated the beneficial effects of U.S.-grown sugar kelp (Saccharina latissima), a brown seaweed, on reducing serum triglycerides (TG) and total cholesterol (TC) and protecting against inflammation and fibrosis in the adipose tissue of diet-induced obesity mice. In this current study, we aimed to explore whether the dietary consumption of sugar kelp can prevent atherosclerosis using low-density lipoprotein receptor knockout (Ldlr KO) mice fed an atherogenic diet. Eight-week-old male Ldlr KO mice were fed either an atherogenic high-fat/high-cholesterol control (HF/HC) diet or a HF/HC diet supplemented with 6% (w/w) sugar kelp (HF/HC-SK) for 16 weeks. Consumption of sugar kelp significantly increased the body weight gain without altering fat mass and lean mass. Also, there were no significant differences in energy expenditure and physical activities between the groups. The two groups did not show significant differences in serum and hepatic TG and TC levels or the hepatic expression of genes involved in cholesterol and lipid metabolism. Although serum alanine aminotransferase (ALT) activity did not differ significantly between the two groups, there were significant increases in the expression of macrophage markers, including adhesion G protein-coupled receptor E1 and cluster of differentiation 68, as well as tumor necrosis factor alpha in the HF/HC-SK group compared to the HF/HC mice. The consumption of sugar kelp did not elicit a significant effect on the development of aortic lesions. Moreover, lipopolysaccharide-stimulated splenocytes isolated from HF/HC-SK-fed mice showed no significant changes in the mRNA levels of pro-inflammatory genes compared with those from the HF/HC mice. In summary, the consumption of dietary sugar kelp did not elicit anti-atherogenic and hepatoprotective effects in Ldlr KO mice.
Asunto(s)
Aterosclerosis , Ratones Noqueados , Receptores de LDL , Animales , Receptores de LDL/genética , Receptores de LDL/metabolismo , Ratones , Masculino , Aterosclerosis/prevención & control , Aterosclerosis/genética , Aterosclerosis/metabolismo , Triglicéridos/sangre , Triglicéridos/metabolismo , Kelp , Ratones Endogámicos C57BL , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Colesterol/sangre , Colesterol/metabolismo , Humanos , Metabolismo de los Lípidos , Algas Comestibles , LaminariaRESUMEN
Bioactive compounds (BCs) are known to exhibit antioxidant, anti-inflammatory, and anti-cancer properties by regulating the cellular redox balance and histone acetylation state. BCs can control chronic oxidative states caused by dietary stress, i.e., alcohol, high-fat, or high-glycemic diet, and adjust the redox balance to recover physiological conditions. Unique functions of BCs to scavenge reactive oxygen species (ROS) can resolve the redox imbalance due to the excessive generation of ROS. The ability of BCs to regulate the histone acetylation state contributes to the activation of transcription factors involved in immunity and metabolism against dietary stress. The protective properties of BCs are mainly ascribed to the roles of sirtuin 1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (NRF2). As a histone deacetylase (HDAC), SIRT1 modulates the cellular redox balance and histone acetylation state by mediating ROS generation, regulating nicotinamide adenine dinucleotide (NAD+)/NADH ratio, and activating NRF2 in metabolic progression. In this study, the unique functions of BCs against diet-induced inflammation, oxidative stress, and metabolic dysfunction have been considered by focusing on the cellular redox balance and histone acetylation state. This work may provide evidence for the development of effective therapeutic agents from BCs.