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BACKGROUND: We investigated the impacts of tocolytic agents on maternal and neonatal blood glucose levels in women with gestational diabetes mellitus (GDM) who used tocolytics for preterm labor. METHODS: This multi-center, retrospective cohort study included women with GDM who were admitted for preterm labor from twelve hospitals in South Korea. We excluded women with multiple pregnancies, anomalies, overt DM diagnosed before pregnancy or 23 weeks of gestation, and women who received multiple tocolytics. The patients were divided according to the types of tocolytics; atosiban, ritodrine, and nifedipine group. We collected baseline maternal characteristics, pregnancy outcomes, maternal glucose levels during hospitalization, and neonatal glucose levels. We compared the frequency of maternal hyperglycemia and neonatal hypoglycemia among three groups. A multivariate logistic regression analysis was performed to evaluate the contributing factors to the occurrence of maternal hyperglycemia and neonatal hypoglycemia. RESULTS: A total of 128 women were included: 44 (34.4%), 51 (39.8%), and 33 (25.8%) women received atosiban, ritodrine, and nifedipine, respectively. Mean fasting blood glucose (FBG) (112.3, 109.6, and 89.5 mg/dL, P < 0.001) and 2-hour postprandial glucose (PPG2) levels (145.4, 148.3, and 116.5 mg/dL, P = 0.004) were significantly higher in atosiban and ritodrine group than those in nifedipine group. Even after adjusting for covariates including antenatal steroid use, gestational age at admission, and pre-pregnancy body mass index, there was an increased risk of high maternal mean FBG (≥ 95 mg/dL) and PPG2 (≥ 120 mg/dL) levels in the atosiban and ritodrine group than in nifedipine group. The atosiban and ritodrine groups are also at increased risk of neonatal hypoglycemia (< 47 mg/dL) compared to the nifedipine group with the odds ratio of 4.58 and 4.67, respectively (P < 0.05). CONCLUSION: There is an increased risk of maternal hyperglycemia and neonatal hypoglycemia in women with GDM using atosiban and ritodrine tocolytics for preterm labor compared to those using nifedipine.
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Glucemia , Diabetes Gestacional , Hipoglucemia , Nifedipino , Ritodrina , Tocolíticos , Vasotocina , Humanos , Femenino , Embarazo , Diabetes Gestacional/tratamiento farmacológico , Tocolíticos/uso terapéutico , Tocolíticos/efectos adversos , Glucemia/análisis , Estudios Retrospectivos , Adulto , Nifedipino/uso terapéutico , Nifedipino/efectos adversos , Recién Nacido , Ritodrina/uso terapéutico , Ritodrina/efectos adversos , Vasotocina/análogos & derivados , Vasotocina/uso terapéutico , Vasotocina/efectos adversos , Modelos Logísticos , Hiperglucemia/tratamiento farmacológico , Oportunidad Relativa , Trabajo de Parto Prematuro/tratamiento farmacológico , Resultado del Embarazo , República de CoreaRESUMEN
BACKGROUND: Currently, diverse minipigs have acquired a common dwarfism phenotype through independent artificial selections. Characterizing the population and genetic diversity in minipigs is important to unveil genetic mechanisms regulating their body sizes and effects of independent artificial selections on those genetic mechanisms. However, full understanding for the genetic mechanisms and phenotypic consequences in minipigs still lag behind. RESULTS: Here, using whole genome sequencing data of 41 pig breeds, including eight minipigs, we identified a large genomic diversity in a minipig population compared to other pig populations in terms of population structure, demographic signatures, and selective signatures. Selective signatures reveal diverse biological mechanisms related to body size in minipigs. We also found evidence for neural development mechanism as a minipig-specific body size regulator. Interestingly, selection signatures within those mechanisms containing neural development are also highly different among minipig breeds. Despite those large genetic variances, PLAG1, CHM, and ESR1 are candidate key genes regulating body size which experience different differentiation directions in different pig populations. CONCLUSIONS: These findings present large variances of genetic structures, demographic signatures, and selective signatures in the minipig population. They also highlight how different artificial selections with large genomic diversity have shaped the convergent dwarfism.
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Enanismo , Porcinos Enanos , Animales , Porcinos Enanos/genética , Porcinos , Enanismo/genética , Enanismo/veterinaria , Tamaño Corporal/genética , Fenotipo , Selección Genética , Variación Genética , Genómica , Secuenciación Completa del GenomaRESUMEN
Microglia are primarily involved in inflammatory reactions and oxidative stress in the brain; as such reducing microglial activation has been proposed as a potential therapeutic strategy for neurodegenerative disorders. Herein, we investigated the anti-inflammatory and antioxidant activities of coniferaldehyde (CFA), a naturally occurring cinnamaldehyde derivative, on activated microglia to evaluate its therapeutic potential. CFA inhibited the production of nitric oxide (NO) and proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. CFA also inhibited intracellular reactive oxygen species levels and oxidative stress markers such as 4-HNE and 8-OHdG. Detailed mechanistic studies showed that CFA exerted anti-inflammatory effects by inhibiting TAK1-mediated MAP kinase/NF-κB activation and upregulating AMPK signaling pathways. In addition, CFA exerted antioxidant effects by inhibiting the NADPH oxidase subunits and by increasing the expression of antioxidant enzymes such as HO-1, NQO1, and catalase by upregulating Nrf2 signaling. Finally, we confirmed the effects of CFA on the brains of the LPS-injected mice. CFA inhibited microglial activation and the expression of proinflammatory markers and increased Nrf2-driven antioxidant enzymes. Furthermore, CFA inhibited the production of 4-HNE and 8-OHdG in the brains of LPS-injected mice. As a result, CFA's significant anti-inflammatory and antioxidant properties may have therapeutic applications in neuroinflammatory disorders related with oxidative stress and microglial activation.
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Proteínas Quinasas Activadas por AMP , Antiinflamatorios , Antioxidantes , Lipopolisacáridos , Quinasas Quinasa Quinasa PAM , Microglía , Factor 2 Relacionado con NF-E2 , FN-kappa B , Transducción de Señal , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Antioxidantes/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , FN-kappa B/metabolismo , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Masculino , Quinasas Quinasa Quinasa PAM/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Transducción de Señal/efectos de los fármacos , Línea Celular , Estrés Oxidativo/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Acroleína/análogos & derivados , Acroleína/farmacología , Citocinas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
INTRODUCTION: Hair loss is driven by multiple factors, including genetics. Androgenetic alopecia (AGA) is a condition in which treatments necessitate prolonged compliance with prescribed medications. We have developed IVL3001, a long-acting injectable (LAI) formulation of finasteride encapsulated within poly lactic-co-glycolic acid microspheres, to enhance the efficacy of the finasteride and to achieve consistent positive outcomes in adults. An open-label, sequential, single-dose phase I clinical trial was designed to evaluate the safety, pharmacokinetic (PK), and pharmacodynamic (PD) of IVL3001. METHODS: A total of 40 non-smoking, healthy adult males were divided into three cohorts where the IVL3001 group received a single subcutaneous injection of 12-36 mg IVL3001 and 1 mg finasteride (Propecia®) once daily for 28 days. The plasma concentrations of finasteride, dihydrotestosterone (DHT), and testosterone were measured using liquid chromatography-tandem mass spectrometry. The tolerability of the injections was assessed, and compartment models were developed to predict the effective dose and assess PK/PD profiles. RESULTS: IVL3001 and finasteride 1 mg tablets were well tolerated. IVL3001 showed consistent plasma concentrations without bursts or fluctuations. Consistent with its mechanism of action, IVL3001 reduced DHT levels. Simulation data showed that the administration of 12-36 mg of IVL3001 every 4 weeks achieved plasma concentrations similar to finasteride, with comparable DHT reduction. CONCLUSION: The present study represents the first clinical trial to evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD), and tolerability of finasteride long-acting injectables (LAI) in adults. The rapid onset of action sustained effective drug concentration and the prolonged half-life of IVL3001 suggest that it offers multiple benefits over conventional oral formulations in terms of therapeutic response and compliance. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04945226.
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Inhibidores de 5-alfa-Reductasa , Alopecia , Finasterida , Humanos , Finasterida/farmacocinética , Finasterida/administración & dosificación , Finasterida/efectos adversos , Alopecia/tratamiento farmacológico , Masculino , Adulto , Inhibidores de 5-alfa-Reductasa/farmacocinética , Inhibidores de 5-alfa-Reductasa/administración & dosificación , Inhibidores de 5-alfa-Reductasa/efectos adversos , Inhibidores de 5-alfa-Reductasa/farmacología , Dihidrotestosterona/farmacocinética , Dihidrotestosterona/administración & dosificación , Dihidrotestosterona/sangre , Persona de Mediana Edad , Preparaciones de Acción Retardada , Testosterona/farmacocinética , Testosterona/sangre , Inyecciones Subcutáneas , Adulto Joven , MicroesferasRESUMEN
PURPOSE: The aim of this study was to investigate the mediating effects of health literacy on the relationship between frailty and health-related quality of life (HRQOL) among community-dwelling older adults. METHODS: This study used the Korean Frailty and Aging Cohort Database (KFACD) for secondary data analysis. We selected data from 1,631 people without missing main variable values for analysis. Frailty was determined based on the modified Fried's phenotype [MFP], and HRQOL was measured using the Korean version of the 5-level EuroQol questionnaire (EQ-5D-5L). Health literacy was assessed using the questions on the Behavioral Risk Factor Surveillance System (BRFSS) used by the U.S. Center for Disease Control and Prevention. To examine the mediating role of health literacy in the relationship between frailty and HRQOL, Baron & Kenny's three-step mediating effect verification method was utilized. RESULTS: The participants had a mean frailty score of 1.37±1.02, health literacy score of 8.56±2.59, and HRQOL score of 0.84±0.10. Frailty was negatively correlated with health literacy (r = -0.27, p < .001) and HRQOL (r = -0.32, p < .001), while health literacy was positively correlated with HRQOL (r = 0.34, p < .001). We observed that health literacy played a partial mediating role in the relationship between frailty and HRQOL. CONCLUSION: To increase older adults' HRQOL, measures that directly prevent and manage frailty as well as interventions that target the enhancement of health literacy are needed.
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Fragilidad , Alfabetización en Salud , Vida Independiente , Calidad de Vida , Humanos , Anciano , Masculino , Femenino , Vida Independiente/psicología , Fragilidad/psicología , Anciano de 80 o más Años , República de Corea , Anciano Frágil/psicología , Encuestas y CuestionariosRESUMEN
PURPOSE: Dental implants have been successfully implemented as a treatment for tooth loss. However, peri-implantitis, an inflammatory reaction owing to microbial deposition around the implant, can lead to implant failure. So, it is necessary to treat peri-implantitis. Therefore, this numerical study is aimed at investigating conditions for treating peri-implantitis. METHODS: Photothermal therapy, a laser treatment method, utilizes photothermal effect, in which light is converted to heat. This technique has advantage of selectively curing inflamed tissues by increasing their temperature. Accordingly, herein, photothermal effect on peri-implantitis is studied through numerical analysis with using Arrhenius damage integral and Arrhenius thermal damage ratio. RESULTS: Through numerical analysis on peri-implantitis treatment, we explored temperature changes under varied laser settings (laser power, radius, irradiation time). We obtained the temperature distribution on interface of artificial tooth root and inflammation and determined whether temperature exceeds or does not exceed 47â to know which laser power affects alveolar bone indirectly. We defined the Arrhenius thermal damage ratio as a variable and determined that the maximum laser power that does not exceed 47â at the AA' line is 1.0 W. Additionally, we found that the value of the Arrhenius thermal damage ratio is 0.26 for a laser irradiation time of 100 s and 0.50 for 500 s. CONCLUSION: The result of this numerical study indicates that the Arrhenius thermal damage ratio can be used as a standard for determining the treatment conditions to help assisted laser treatment for peri-implantitis in each numerical analysis scenario.
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Periimplantitis , Terapia Fototérmica , Periimplantitis/terapia , Periimplantitis/radioterapia , Humanos , Terapia Fototérmica/métodos , Temperatura , Implantes Dentales/efectos adversos , Rayos LáserRESUMEN
The epithelial-mesenchymal transition (EMT) and fibroblast activation are major events in idiopathic pulmonary fibrosis pathogenesis. Here, we investigated whether growth arrest-specific protein 6 (Gas6) plays a protective role in lung fibrosis via suppression of the EMT and fibroblast activation. rGas6 administration inhibited the EMT in isolated mouse ATII cells 14 days post-BLM treatment based on morphologic cellular alterations, changes in mRNA and protein expression profiles of EMT markers, and induction of EMT-activating transcription factors. BLM-induced increases in gene expression of fibroblast activation-related markers and the invasive capacity of primary lung fibroblasts in primary lung fibroblasts were reversed by rGas6 administration. Furthermore, the hydroxyproline content and collagen accumulation in interstitial areas with damaged alveolar structures in lung tissue were reduced by rGas6 administration. Targeting Gas6/Axl signaling events with specific inhibitors of Axl (BGB324), COX-2 (NS-398), EP1/EP2 receptor (AH-6809), or PGD2 DP2 receptor (BAY-u3405) reversed the inhibitory effects of rGas6 on EMT and fibroblast activation. Finally, we confirmed the antifibrotic effects of Gas6 using Gas6-/- mice. Therefore, Gas6/Axl signaling events play a potential role in inhibition of EMT process and fibroblast activation via COX-2-derived PGE2 and PGD2 production, ultimately preventing the development of pulmonary fibrosis.
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Transición Epitelial-Mesenquimal , Fibroblastos , Péptidos y Proteínas de Señalización Intercelular , Animales , Ratones , Ciclooxigenasa 2/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibrosis Pulmonar Idiopática/metabolismo , Péptidos y Proteínas de Señalización Intercelular/farmacología , Pulmón/metabolismoRESUMEN
BACKGROUND: Many studies have been performed to identify various genomic loci and genes associated with the meat quality in pigs. However, the full genetic architecture of the trait still remains unclear in part because of the lack of accurate identification of related structural variations (SVs) which resulted from the shortage of target breeds, the limitations of sequencing data, and the incompleteness of genome assemblies. The recent generation of a new pig breed with superior meat quality, called Nanchukmacdon, and its chromosome-level genome assembly (the NCMD assembly) has provided new opportunities. RESULTS: By applying assembly-based SV calling approaches to various genome assemblies of pigs including Nanchukmacdon, the impact of SVs on meat quality was investigated. Especially, by checking the commonality of SVs with other pig breeds, a total of 13,819 Nanchukmacdon-specific SVs (NSVs) were identified, which have a potential effect on the unique meat quality of Nanchukmacdon. The regulatory potentials of NSVs for the expression of nearby genes were further examined using transcriptome- and epigenome-based analyses in different tissues. CONCLUSIONS: Whole-genome comparisons based on chromosome-level genome assemblies have led to the discovery of SVs affecting meat quality in pigs, and their regulatory potentials were analyzed. The identified NSVs will provide new insights regarding genetic architectures underlying the meat quality in pigs. Finally, this study confirms the utility of chromosome-level genome assemblies and multi-omics analysis to enhance the understanding of unique phenotypes.
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Genoma , Genómica , Porcinos/genética , Animales , Carne/análisis , Fenotipo , CromosomasRESUMEN
BACKGROUND/AIMS: To determine whether metformin, which is considered a host-directed therapy for tuberculosis (TB), is effective in improving the prognosis of patients with TB and diabetes mellitus (DM), who have higher mortality than those without DM. METHODS: This cohort study included patients who were registered as having TB in the National Tuberculosis Surveillance System. The medical and death records of matched patients were obtained from the National Health Information Database and Statistics Korea, respectively, and data from 2011 to 2017 were collected retrospectively. We classified patients according to metformin use among participants who used diabetes drugs for more than 28 days. The primary outcome was all-cause mortality during TB treatment. Double propensity score adjustment was applied to reduce the effects of confounding and multivariable Cox proportional hazard models were used to estimate adjusted hazard ratio (aHR) with 95% confidence interval (CI). RESULTS: The all-cause mortality rate during TB treatment was lower (9.5% vs. 12.4%, p < 0.01) in the metformin user group. The hazard of death due to all causes after double propensity score adjustment was also lower in the metformin user group (aHR 0.76, 95% CI 0.67-0.86, p < 0.01). There was no significant difference in mortality between metformin users and non-users for TB-related deaths (p = 0.22); however, there was a significant difference in the non-TB-related deaths (p < 0.01). CONCLUSION: Metformin use in patients with TB-DM co-prevalence is associated with reduced all-cause mortality, suggesting the potential for metformin adjuvant therapy in these patients.
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Diabetes Mellitus Tipo 2 , Metformina , Tuberculosis , Humanos , Metformina/efectos adversos , Estudios de Cohortes , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estudios Retrospectivos , Tuberculosis/tratamiento farmacológico , Hipoglucemiantes/efectos adversosRESUMEN
Parkinson's disease (PD) is an incurable neurological disorder that causes typical motor deficits. In this study, we investigated the effects of creatine supplementation and exercise in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We found that 2% creatine supplementation and/or exercise intervention for 4 weeks elicited neurobehavioral recovery and neuroprotective effects regarding dopaminergic cell loss in MPTP-treated mice; this effect implies functional preservation of dopaminergic cells in the substantia nigra, as reflected by tyrosine hydroxylase expression recovery. Creatine and exercise reduced necroptotic activity in dopaminergic cells by lowering mixed lineage kinase domain-like protein (MLKL) modification to active phenotypes (phosphorylation at Ser345 and oligomerization) and phosphorylated receptor-interacting protein kinase 1 (RIPK1) (Ser166-p) and RIPK3 (Ser232-p) levels. In addition, creatine and exercise reduced the MPTP-induced increase in pathogenic α-synuclein forms, such as Ser129 phosphorylation and oligomerization. Furthermore, creatine and exercise had anti-inflammatory and antioxidative effects in MPTP mice, as evidenced by a decrease in microglia activation, NF-κB-dependent pro-inflammatory molecule expression, and increase in antioxidant enzyme expression. These phenotypic changes were associated with the exercise/creatine-induced AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) and sirtuin 3 (SIRT3)/forkhead box O3 (FoxO3a) signaling pathways. In all experiments, combining creatine with exercise resulted in considerable improvement over either treatment alone. Consequently, these findings suggest that creatine supplementation with exercise has anti-inflammatory, antioxidative, and anti-α-synucleinopathy effects, thereby reducing necroptotic cell death in a PD mouse model.
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Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Animales , Enfermedad de Parkinson/tratamiento farmacológico , alfa-Sinucleína/metabolismo , Creatina/farmacología , Creatina/uso terapéutico , Necroptosis , Neuronas Dopaminérgicas/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Antiinflamatorios/farmacología , Suplementos Dietéticos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/metabolismoRESUMEN
The implantation of good-quality embryos to the receptive endometrium is essential for successful live birth through in vitro fertilization (IVF). The higher the quality of embryos, the higher the live birth rate per cycle, and so efforts have been made to obtain as many high-quality embryos as possible after fertilization. In addition to an effective controlled ovarian stimulation process to obtain high-quality embryos, the composition of the embryo culture medium in direct contact with embryos in vitro is also important. During embryonic development, under the control of female sex hormones, the fallopian tubes and endometrium create a microenvironment that supplies the nutrients and substances necessary for embryos at each stage. During this process, the development of the embryo is finely regulated by signaling molecules, such as growth factors and cytokines secreted from the epithelial cells of the fallopian tube and uterine endometrium. The development of embryo culture media has continued since the first successful human birth through IVF in 1978. However, there are still limitations to mimicking a microenvironment similar to the reproductive organs of women suitable for embryo development in vitro. Efforts have been made to overcome the harsh in vitro culture environment and obtain high-quality embryos by adding various supplements, such as antioxidants and growth factors, to the embryo culture medium. Recently, there has been an increase in the number of studies on the effect of supplementation in different clinical situations such as old age, recurrent implantation failure (RIF), and unexplained infertility; in addition, anticipation of the potential benefits from individuation is rising. This article reviews the effects of representative supplements in culture media on embryo development.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos , Melatonina , Femenino , Humanos , Embarazo , Medios de Cultivo/química , Medios de Cultivo/farmacología , Citocinas , Factor I del Crecimiento Similar a la Insulina , Melatonina/farmacologíaRESUMEN
Despite its significant impact on mortality, tuberculosis (TB)-diabetes mellitus (DM) co-prevalence has not been well-elucidated for the cause of death. We investigated the impact of DM on TB-related and non-TB-related deaths in patients with TB. This retrospective nationwide cohort study included patients diagnosed with TB between 2011 and 2017 in South Korea. We performed Fine and Gray regression model analyses to assess the mortality risk of DM classified by cause of death. Of 239,848 patients, 62,435 (26.0%) had DM, and 20,203 died during anti-TB treatment. Of all deaths, 47.9% (9,668) were caused by TB, and the remaining 52.1% (10,535) was attributed to various non-TB-related causes. The mortality rate was higher in the DM than in the non-DM groups in both men and women. DM was associated with a higher risk of TB-related (adjusted hazard ratio [aHR] 1.07, 95% confidence interval [CI] 1.01-1.13) and non-TB-related (aHR 1.21, 95% CI 1.15-1.27) deaths in men; however, only a higher risk of non-TB-related deaths (aHR 1.29, 95% CI 1.20-1.38) in women. Our findings indicate that DM is independently associated with a greater risk of death during anti-TB treatment among patients with TB for both TB-related and non-TB-related deaths.
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Diabetes Mellitus , Tuberculosis , Masculino , Humanos , Femenino , Estudios de Cohortes , Estudios Retrospectivos , Causas de Muerte , Tuberculosis/diagnóstico , Factores de RiesgoRESUMEN
This study aims to investigate the neuroprotective effects of nootkatone (NKT), a sesquiterpenoid compound isolated from grapefruit, in an MPTP-induced Parkinson's disease (PD) mouse model. NKT restored MPTP-induced motor impairment and dopaminergic neuronal loss and increased the expression of neurotrophic factors like BDNF, GDNF, and PGC-1α. In addition, NKT inhibited microglial and astrocyte activation and the expression of pro-inflammatory markers like iNOS, TNF-α, and IL-1ß and oxidative stress markers like 4-HNE and 8-OHdG. NKT increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2)-driven antioxidant enzymes like HO-1 and NQO-1 in astrocytes, but not in neurons or microglia in MPTP-treated mice. To investigate whether Nrf2 mediates the anti-inflammatory, antioxidant, or neuroprotective effects of NKT, mice were pretreated with Nrf2-specific inhibitor brusatol (BT) prior to NKT treatment. BT attenuated the NKT-mediated inhibition of 4-HNE and 8-OHdG and the number of Nrf2+/HO-1+/NQO1+ cells co-localized with GFAP+ astrocytes in the substantia nigra of MPTP-treated mice. In addition, BT reversed the effects of NKT on dopaminergic neuronal cell death, neurotrophic factors, and pro-/anti-inflammatory cytokines in MPTP-treated mice. Collectively, these data suggest that astrocytic Nrf2 and its downstream antioxidant molecules play pivotal roles in mediating the neuroprotective and anti-inflammatory effects of NKT in an MPTP-induced PD mouse model.
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FMRP is a multifunctional protein encoded by the Fragile X Messenger Ribonucleoprotein 1 gene (FMR1). The inactivation of the FMR1 gene results in fragile X syndrome (FXS), a serious neurodevelopmental disorder. FMRP deficiency causes abnormal neurite outgrowth, which is likely to lead to abnormal learning and memory capabilities. However, the mechanism of FMRP in modulating neuronal development remains unknown. We found that FMRP enhances the translation of 4EBP2, a neuron-specific form of 4EBPs that inactivates eIF4E by inhibiting the interaction between eIF4E and eIF4G. Depletion of 4EBP2 results in abnormal neurite outgrowth. Moreover, the impairment of neurite outgrowth upon FMRP depletion was overcome by the ectopic expression of 4EBP2. These results suggest that FMRP controls neuronal development by enhancing 4EBP2 expression at the translational level. In addition, treatment with 4EGI-1, a chemical that blocks eIF4E activity, restored neurite length in FMRP-depleted and 4EBP2-depleted cells. In conclusion, we discovered that 4EBP2 functions as a key downstream regulator of FMRP activity in neuronal development and that FMRP represses eIF4E activity by enhancing 4EBP2 translation.
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Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil , Humanos , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor 4E Eucariótico de Iniciación/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Neuronas/metabolismo , Síndrome del Cromosoma X Frágil/genética , Diferenciación Celular/genéticaRESUMEN
PURPOSE: We aimed to develop the Korean Hospital Frailty Risk Score (K-HFRS) by applying the International Classification of Diseases-10 codes to community-dwelling older adults' medical data. METHODS: We selected data from 2,761 people with no missing main variable values from the Korean Frailty and Aging Cohort Data (KFACD) and National Health Insurance Database (NHID) for analysis. Frailty was determined based on modified Fried's phenotype [MFP] and Korean Frailty Index for Primary Care [KFI-PC] in the KFACD. A previously established method calculated the K-HFRS, verified by the area under the receiver operating characteristic (ROC) curve. The calculated cutoff value predicted the medical use. RESULTS: The respective K-HFRSs of the frailty group using the MFP and KFI-PC criteria ranged from 3.64 (±3.03) to 8.15 (±5.72) and 4.07 (±3.42) to 9.10 (±6.28), with 7.67 (±5.40) and 8.59 (±6.03) when four diagnoses were included. The K-HFRS of the frailty group using the KFI-PC criteria was higher than that using the MFP criteria. With four diagnoses included using the MFP criteria, the adjusted odds ratio (OR) for medical expenditures in the frailty group compared to the non-frailty group was 3.01 (95% confidence interval [CI] 2.52-3.60, p < .001); for the number of emergency room (ER) visits was 2.19 (95% CI 1.77-2.70, p < .001); for inpatient days was 2.48 (95% CI 2.08-2.96, p < .001). With four diagnoses included using the KFI-PC criteria, the adjusted OR value for medical expenditures was 2.77 (95% CI 2.35-3.27, p < .001); for the number of ER visits was 1.87 (95% CI 1.51-2.32, p < .001); for inpatient days was 2.07 (95% CI 1.75-2.45, p < .001). CONCLUSION: This study substantiated that the K-HFRS can measure frailty efficiently at a lower cost. Follow-up studies are needed for additional validity.
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Fragilidad , Humanos , Anciano , Fragilidad/diagnóstico , Fragilidad/epidemiología , Vida Independiente , Anciano Frágil , Registros de Hospitales , Factores de Riesgo , HospitalesRESUMEN
As plentiful high-quality genome assemblies have been accumulated, reference-guided genome assembly can be a good approach to reconstruct a high-quality assembly. Here, we present a chromosome-level genome assembly of the Korean crossbred pig called Nanchukmacdon (the NCMD assembly) using the reference-guided assembly approach with short and long reads. The NCMD assembly contains 20 chromosome-level scaffolds with a total size of 2.38 Gbp (N50: 138.77 Mbp). Its BUSCO score is 93.1%, which is comparable to the pig reference assembly, and a total of 20,588 protein-coding genes, 8,651 non-coding genes, and 996.14 Mbp of repetitive elements are annotated. The NCMD assembly was also used to close many gaps in the pig reference assembly. This NCMD assembly and annotation provide foundational resources for the genomic analyses of pig and related species.
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Cromosomas , Genoma , Sus scrofa , Porcinos , Animales , Cromosomas/genética , Genómica , Anotación de Secuencia Molecular , República de Corea , Sus scrofa/genética , Porcinos/genéticaRESUMEN
Background: This study evaluated the risk factors of long-term mortality in patients with multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in South Korea who were lost to follow-up (LTFU). Methods: This was a retrospective longitudinal follow-up study using an integrated database constructed by data linkage of the three national databases, which included 7226 cases of MDR/RR-TB notified between 2011 and 2017 in South Korea. Post-treatment outcomes of patients who were LTFU were compared with those of patients who achieved treatment success. Results: Of the 7226 MDR/RR-TB cases, 730 (10.1%) were LTFU. During a median follow-up period of 4.2â years, 101 (13.8%) of the LTFU patients died: 25 deaths (3.4%) were TB related and 76 (10.4%) were non-TB related. In the LTFU group, the adjusted hazard ratio (aHR) of all-cause mortality (aHR 2.50, 95% CI 1.99-3.15, p<0.001), TB-related mortality (aHR 5.38, 95% CI 3.19-9.09, p<0.001) and non-TB-related mortality (HR 2.21, 95% CI 1.70-2.87, p<0.001) was significantly higher than that in the treatment success group. Independent risk factors for all-cause mortality in the LTFU group were age >55â years, fluoroquinolone resistance, cancer and no retreatment. In the LTFU patients who did not receive retreatment, the risk of non-TB-related mortality (aHR 5.00, 95% CI 1.53-16.37, p=0.008) and consequent all-cause mortality (aHR 2.18, 95% CI 1.08-4.40, p=0.030) was significantly higher than that of patients who received retreatment. Conclusion: Non-TB-related mortality was the main cause of death and might be reduced by retreatment in LTFU patients with MDR/RR-TB.
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Background: In this study, the geniatric status of OECD (Organisation for Economic Co-operation and Development) countries was measured, and the effects of aging status on disease patterns in each country were quantitatively assessed. A theoretical model explaining the effects was suggested, and the implications were discussed. Methods: Data used in this study were the OECD Health Statistics data and WHO Global Burden of Disease data. The values for each country were paired with disability-adjusted life years (DALYs) presented by the WHO and Institute for Health Metrics and Evaluation (IHME). A cross-country panel analysis was conducted to analyze the effects of senility on the burden of disease in OECD countries. Results: Geniatric status had effects on the burden of disease (P = .048). Total health expenditure significantly reduced the burden of disease (P = .001). In the panel model with YLL (Year of Life Lost) as the outcome variable, geniatric status had twice greater effects on the burden of disease than that in the model with DALY (P = .003). Conclusions: In medical insurance-related policies, the characteristics of the disease should be considered. In particular, chronic diseases have not received much attention compared to their risk. However, the disease that actually affects the burden of disease is a disease that becomes chronic and requires long-term treatment rather than a disease with a high fatality rate. And, as a result of this study, the higher the level of resource consumption for treatment in OECD countries, where aging is progressing, the burden of disease was rather reduced. Therefore, if there is institutional support to receive appropriate treatment, it will be possible to reduce the national burden of disease.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastation to human society through its high virulence, infectivity, and genomic mutations, which reduced the efficacy of vaccines. Here, we report the development of aptamers that effectively interfere with SARS-CoV-2 infection by targeting its spike protein, which plays a pivotal role in host cell entry of the virus through interaction with the viral receptor angiotensin-converting enzyme 2 (ACE2). To develop highly effective aptamers and to understand their mechanism in inhibiting viral infection, we determined the three-dimensional (3D) structures of aptamer/receptor-binding domain (RBD) complexes using cryogenic electron microscopy (cryo-EM). Moreover, we developed bivalent aptamers targeting two distinct regions of the RBD in the spike protein that directly interact with ACE2. One aptamer interferes with the binding of ACE2 by blocking the ACE2-binding site in RBD, and the other aptamer allosterically inhibits ACE2 by binding to a distinct face of RBD. Using the 3D structures of aptamer-RBD complexes, we minimized and optimized these aptamers. By combining the optimized aptamers, we developed a bivalent aptamer that showed a stronger inhibitory effect on virus infection than the component aptamers. This study confirms that the structure-based aptamer-design approach has a high potential in developing antiviral drugs against SARS-CoV-2 and other viruses.
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COVID-19 , Humanos , SARS-CoV-2/metabolismo , Enzima Convertidora de Angiotensina 2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Sitios de Unión , Unión ProteicaRESUMEN
BACKGROUND: Korea's aging population has raised several challenges, especially concerning healthcare costs. Consequently, this study evaluated the association of frailty transitions with healthcare utilization and costs for older adults aged 70 to 84. METHODS: This study linked the frailty status data of the Korean Frailty and Aging Cohort Study to the National Health Insurance Database. We included 2,291 participants who had frailty measured by Fried Frailty phenotype at baseline in 2016-2017 and follow-up in 2018-2019. We conducted a multivariate regression analysis to determine the association between their healthcare utilization and costs by frailty transition groups. RESULTS: After 2 years, changes from "pre-frail" to "frail" (Group 6) and "frail" to "pre-frail" (Group 8) were significantly associated with increased inpatient days (P < 0.001), inpatient frequency (P < 0.001), inpatient cost (P < 0.001 and P < 0.01, respectively), and total healthcare cost (P < 0.001) than "robust" to "robust" (Group 1) older adults. A transition to frailty from "pre-frail" to "frail" (Group 6) resulted in a $2,339 total healthcare cost increase, and from "frail" to "pre-frail" (Group 8), a $1,605, compared to "robust" to "robust" older adults. CONCLUSION: Frailty among community-dwelling older adults is economically relevant. Therefore, it is crucial to study the burden of medical expenses and countermeasures for older adults to not only provide appropriate medical services but also to prevent the decline in their living standards due to medical expenses.