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This study aims to elucidate the cellular mechanisms behind the secretion of complement factor B (CFB), known for its dual roles as an early biomarker for pancreatic ductal adenocarcinoma (PDAC) and as the initial substrate for the alternative complement pathway (ACP). Using parallel reaction monitoring analysis, we confirmed a consistent â¼2-fold increase in CFB expression in PDAC patients compared with that in both healthy donors (HD) and chronic pancreatitis (CP) patients. Elevated ACP activity was observed in CP and other benign conditions compared with that in HD and PDAC patients, suggesting a functional link between ACP and PDAC. Protein-protein interaction analyses involving key complement proteins and their regulatory factors were conducted using blood samples from PDAC patients and cultured cell lines. Our findings revealed a complex control system governing the ACP and its regulatory factors, including Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, adrenomedullin (AM), and complement factor H (CFH). Particularly, AM emerged as a crucial player in CFB secretion, activating CFH and promoting its predominant binding to C3b over CFB. Mechanistically, our data suggest that the KRAS mutation stimulates AM expression, enhancing CFH activity in the fluid phase through binding. This heightened AM-CFH interaction conferred greater affinity for C3b over CFB, potentially suppressing the ACP cascade. This sequence of events likely culminated in the preferential release of ductal CFB into plasma during the early stages of PDAC. (Data set ID PXD047043.).
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Factor B del Complemento/genética , Factor B del Complemento/metabolismo , Vía Alternativa del Complemento , Proteínas Proto-Oncogénicas p21(ras) , Detección Precoz del Cáncer , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genéticaRESUMEN
BACKGROUND AND AIMS: The estimated glucose disposal rate (eGDR) is an easily accessible clinical parameter for assessing insulin resistance in patients with diabetes mellitus. In this study, we aimed to investigate the link between eGDR and subclinical coronary atherosclerosis in an asymptomatic middle-aged Korean population. METHODS AND RESULTS: This study involved 4004 subjects who underwent routine health checkups with coronary multidetector computed tomography (MDCT) at Asan Medical Center from 2007 to 2011, among whom 913 had a follow-up analysis through 2014. The eGDR was calculated using: 21.16 - (0.09 ∗ waist circumference [cm]) - (3.41 ∗ hypertension) - (0.55 ∗ glycated hemoglobin [%]). Patients were categorized into three groups according to the tertiles of eGDR. Subclinical coronary atherosclerosis was defined by significant coronary stenosis (≥50%), presence of plaques, coronary artery calcification (CAC) score, and its progression. As a result, a lower eGDR level was associated with higher prevalence of significant coronary stenosis, plaques, moderate to severe CAC, and CAC progression. Compared to other markers or risk scores, eGDR was superior to other biomarkers of insulin resistance but did not provide additional information beyond classic cardiovascular risk models like the Framingham Risk Score and Pooled Cohort Equations. CONCLUSION: Decreased eGDR values were significantly associated with higher subclinical coronary atherosclerosis burdens in an asymptomatic middle-aged Korean population. However, its clinical implications remain uncertain due to its weaker performance compared to established cardiovascular risk models.
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PURPOSE: To determine whether various inflammatory-, angiogenic/anti-angiogenic-, and extracellular matrix remodeling-associated proteins in plasma, alone or in combination with conventional blood-based markers, can predict intra-amniotic inflammation and/or microbial invasion of the amniotic cavity (IAI/MIAC) in women with spontaneous preterm labor (PTL). METHODS: A total of 193 singleton pregnant women with PTL (23-33 weeks) were included in this retrospective cohort study. Plasma samples were obtained at the time of amniocentesis. Amniotic fluid (AF) was cultured for microorganism detection and consequent MIAC diagnosis. IL-6 levels were determined in AF and used to identify IAI (AF IL-6 ≥ 2.6 ng/mL). Endostatin, haptoglobin, IGFBP-2/3, LBP, M-CSF, MMP-2/8, pentraxin 3, PlGF, S100A8/A9, and VEGFR-1 levels were assayed in plasma samples by ELISA. CRP levels and neutrophil-to-lymphocyte ratio (NLR) were measured. RESULTS: Plasma LBP, MMP-8, and S100A8/A9 levels, CRP levels, and NLR were significantly higher, and plasma IGFBP-2 and MMP-2 levels were significantly lower in women with IAI/MIAC than in those without this condition, whereas no baseline variables differed significantly between the two groups. Using a stepwise regression analysis, a noninvasive prediction model for IAI/MIAC was developed, which included plasma LBP, MMP-2, and MMP-8 levels (area under the curve [AUC], 0.785). The AUC for this prediction model was significantly or borderline greater than that of any single factor included in the model. CONCLUSIONS: IGFBP-2, LBP, MMP-2, MMP-8, and S100A8/A9 may represent valuable plasma biomarkers for predicting IAI/MIAC in women with PTL. Combination of LBP, MMP-2, and MMP-8 expression data can significantly improve the predictive potential for IAI/MIAC.
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Líquido Amniótico , Biomarcadores , Proteína C-Reactiva , Corioamnionitis , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 8 de la Matriz , Trabajo de Parto Prematuro , Humanos , Femenino , Embarazo , Estudios Retrospectivos , Adulto , Trabajo de Parto Prematuro/microbiología , Trabajo de Parto Prematuro/sangre , Líquido Amniótico/microbiología , Líquido Amniótico/metabolismo , Metaloproteinasa 8 de la Matriz/sangre , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Biomarcadores/sangre , Corioamnionitis/microbiología , Corioamnionitis/sangre , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Metaloproteinasa 2 de la Matriz/sangre , Calgranulina A/sangre , Endostatinas/sangre , Proteínas de Fase Aguda/análisis , Interleucina-6/sangre , Amniocentesis , Componente Amiloide P Sérico/análisis , Componente Amiloide P Sérico/metabolismo , Haptoglobinas/análisis , Haptoglobinas/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Valor Predictivo de las Pruebas , Matriz Extracelular/metabolismo , Angiogénesis , Calgranulina BRESUMEN
Objectives: This study aimed to analyze the educational needs of interns and residents in Korean medicine as the first step in developing an education program to improve their research competencies. Methods: A mixed-method design, incorporating both quantitative and qualitative data collection methods, was used to investigate the educational needs for research competencies among interns and residents working in Korean medicine hospitals nationwide. Data were collected through online surveys and online focus group discussions (FGDs), and processed using descriptive statistical analysis and thematic analysis. The study results were derived by integrating survey data and FGD outcomes. Results: In total, 209 interns and residents participated in the survey, and 11 individuals participated in two rounds of FGDs. The majority of participants felt a lack of systematic education in research and academic writing in postgraduate medical education and highlighted the need for nationally accessible education due to significant disparities in the educational environment across hospitals and specialties. The primary barrier to learning research and academic writing identified by learners was the lack of knowledge, leading to time constraints. Improving learners' research competencies, relationship building, autonomy, and motivation through a support system was deemed crucial. The study also identified diverse learner types and preferred educational topics, indicating a demand for learner-centered education and coaching. Conclusion: This study provides foundational data for designing and developing a program on education on research competencies for interns and residents in Korean medicine and suggests the need for initiatives to strengthen these competencies.
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An unprecedented silver-mediated intramolecular oxy-argentation of 3-amidoaryne precursors that quickly generates a heteroarylsilver species is developed. AgF acts as both a stoichiometric fluoride source and a reagent for the formation of a benzoxazolylsilver intermediate via aryne generation. Pd-catalyzed coupling reactions of (hetero)aryl iodides with a silver species, generated in situ, allow for the synthesis of various C7-arylated benzoxazoles. As a result, an aryl group is selectively introduced into the meta-position of 3-amidobenzyne precursors. Mechanistic studies have indicated the presence of a benzoxazolylsilver intermediate and revealed that the reaction proceeds via an intramolecular oxy-argentation process, which is initiated by a direct fluoride attack on the silyl group.
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PROBLEM: To determine whether altered concentrations of various inflammation/immune-, acute phase-, extracellular matrix-, adhesion-, and serine protease-related proteins in the amniotic fluid (AF) are independently associated with microbial invasion of the amniotic cavity and/or intra-amniotic inflammation (MIAC/IAI), imminent spontaneous preterm delivery (SPTD; ≤7 days), and major neonatal morbidity/mortality (NMM) in women with early preterm prelabor rupture of membranes (PPROM). METHOD OF STUDY: This was a retrospective cohort study involving 111 singleton pregnant women with PPROM (24-31 weeks) undergoing amniocentesis to diagnose MIAC/IAI. The following proteins were measured in stored AF samples by enzyme-linked immunosorbent assay (ELISA): APRIL, DKK-3, Gal-3BP, IGFBP-2, IL-8, VDBP, lumican, MMP-2, MMP-8, SPARC, TGFBI, TGF-ß1, E-selectin, ICAM-5, P-selectin, haptoglobin, hepcidin, SAA1, kallistatin, and uPA. RESULTS: Multivariate logistic regression analyses revealed that (i) elevated APRIL, IL-8, MMP-8, and TGFBI levels in the AF, reduced lumican and SPARC levels in the AF, and high percentages of samples above the lower limit of quantification for AF TGF-ß1 and uPA were significantly associated with MIAC/IAI; (ii) elevated AF levels of IL-8 and MMP-8 were significantly associated with SPTD within 7 days; and (iii) elevated AF IL-6 levels were significantly associated with increased risk for major NMM, when adjusted for baseline covariates. CONCLUSION: ECM (lumican, SPRAC, TGFBI, and TGF-ß1)- and serine protease (uPA)-associated proteins in the AF are involved in the regulation of the host response to infection/inflammation in the amniotic cavity, whereas AF inflammation (IL-8, MMP-8, and IL-6)-associated mediators are implicated in the development of preterm parturition and major NMM in early PPROM.
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Líquido Amniótico , Rotura Prematura de Membranas Fetales , Humanos , Femenino , Embarazo , Líquido Amniótico/metabolismo , Líquido Amniótico/inmunología , Rotura Prematura de Membranas Fetales/metabolismo , Adulto , Estudios Retrospectivos , Inflamación/metabolismo , Recién Nacido , Serina Proteasas/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de Fase Aguda/metabolismo , Nacimiento Prematuro , Estudios de Cohortes , Corioamnionitis/metabolismo , Corioamnionitis/inmunologíaRESUMEN
The evolutionary conserved molecular chaperone heat shock protein 90 (HSP90) plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although the functionality of HSP90 is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis in certain malignancies. While various strategies targeting heat shock proteins (HSPs) involved in carcinogenesis have been explored, only inhibition of HSP90 has consistently and effectively resulted in proteasomal degradation of its client proteins. To date, a total of 22 HSP90 inhibitors (HSP90i) have been tested in 186 cancer clinical trials, as reported by clinicaltrials.gov. Among these trials, 60 % have been completed, 10 % are currently active, and 30 % have been suspended, terminated, or withdrawn. HSP90 inhibitors (HSP90i) have been used as single agents or in combination with other drugs for the treatment of various cancer types in clinical trials. Notably, improved clinical outcomes have been observed when HSP90i are used in combination therapies, as they exhibit a synergistic antitumor effect. However, as single agents, HSP90i have shown limited clinical activity due to drug-related toxicity or therapy resistance. Recently, active trials conducted in Japan evaluating TAS-116 (pimitespib) have demonstrated promising results with low toxicity as monotherapy and in combination with the immune checkpoint inhibitor nivolumab. Exploratory biomarker analyses performed in various trials have demonstrated target engagement that suggests the potential for identifying patient populations that may respond favorably to the therapy. In this review, we discuss the advances made in the past 5 years regarding HSP90i and their implications in anticancer therapeutics. Our focus lies in evaluating drug efficacy, prognosis forecast, pharmacodynamic biomarkers, and clinical outcomes reported in published trials. Through this comprehensive review, we aim to shed light on the progress and potential of HSP90i as promising therapeutic agents in cancer treatment.
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Antineoplásicos , Proteínas HSP90 de Choque Térmico , Neoplasias , Humanos , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Neoplasias/tratamiento farmacológicoRESUMEN
PROBLEM: To assess the potential of five inflammatory and six angiogenic/antiangiogenic plasma proteins for predicting imminent spontaneous preterm delivery (SPTD; ≤14 days of sampling), microbial invasion of the amniotic cavity and/or intraamniotic inflammation (MIAC/IAI), and composite neonatal morbidity and mortality (CNMM) in women with early preterm premature rupture of membranes (PPROM). METHODS OF STUDY: This retrospective cohort study included 76 singleton pregnant women with early PPROM (23-30 weeks). Amniotic fluid obtained via amniocentesis was cultured for microorganism detection and assayed for interleukin-6 to define IAI (≥2.6 ng/mL). Plasma C4a, endoglin, endostatin, IGFBP-1, IGFBP-2, MMP-9, PlGF, S100A8, S100A9, S100 A8/A9, and VEGFR-1 levels were determined using ELISA. RESULTS: Multivariate logistic regression analyses revealed significant associations between (i) high levels of plasma S100A8/A9, SPTD ≤14 days after sampling, and shorter sampling-to-delivery intervals; (ii) elevated plasma MMP-9, S100A9, and S100A8/A9 levels and MIAC/IAI, and (iii) decreased plasma endoglin levels and increased CNMM risk, while adjusting for gestational age at sampling (or delivery) and tocolytic use. The area under the curves of the aforementioned proteins ranged from 0.655 to 0.731 for each outcome. Notably, the SPTD risk increased significantly with increasing plasma S100A8/A9 levels (P for trend < .05). CONCLUSIONS: Plasma S100A8/A9, MMP-9, S100A9, and endoglin may represent valuable biomarkers associated with SPTD, MIAC/IAI, and CNMM in women with early PPROM. Owing to their less invasive nature, repeatability, and fair-to-moderate diagnostic accuracy, these biomarkers may contribute to risk stratification of PPROM-related complications in the clinical setting.
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Corioamnionitis , Rotura Prematura de Membranas Fetales , Nacimiento Prematuro , Recién Nacido , Femenino , Embarazo , Humanos , Nacimiento Prematuro/epidemiología , Nacimiento Prematuro/metabolismo , Corioamnionitis/diagnóstico , Metaloproteinasa 9 de la Matriz/metabolismo , Estudios Retrospectivos , Endoglina/metabolismo , Rotura Prematura de Membranas Fetales/metabolismo , Líquido Amniótico/metabolismo , Inflamación/metabolismo , Edad Gestacional , Morbilidad , Biomarcadores/metabolismoRESUMEN
PROBLEM: To explore the clinical utility of nine inflammatory immune-, adhesion-, and extracellular matrix-related mediators in the plasma for predicting intraamniotic inflammation and/or microbial invasion of the amniotic cavity (IAI/MIAC) and composite neonatal morbidity and/or mortality (CNMM) in women with preterm premature rupture of membranes (PPROM) when used alone or in combination with conventional blood-, ultrasound-, and clinical-based factors. METHODS OF STUDY: This retrospective cohort comprised 173 singleton pregnant women with PPROM (24 + 0 - 33 + 6 weeks), who underwent amniocentesis. Amniotic fluid was cultured for microorganisms and assayed for IL-6 levels. Plasma levels of AFP, CXCL14, E-selectin, Gal-3BP, kallistatin, progranulin, P-selectin, TGFBI, and VDBP were determined by ELISA. Ultrasonographic cervical length (CL) and neutrophil-to-lymphocyte ratio (NLR) were measured. RESULTS: Multivariate logistic regression analyses revealed significant associations between (i) decreased plasma kallistatin levels and IAI/MIAC and (ii) decreased plasma progranulin levels and increased CNMM risk after adjusting for baseline variables (e.g., gestational age at sampling [or delivery] and parity). Using stepwise regression analysis, noninvasive prediction models for IAI/MIAC and CNMM risks were developed, which included plasma progranulin levels, NLR, CL, and gestational age at sampling, and provided a good prediction of the corresponding endpoints (area under the curve: 0.79 and 0.87, respectively). CONCLUSIONS: Kallistatin and progranulin are potentially valuable plasma biomarkers for predicting IAI/MIAC and CNMM in women with PPROM. Particularly, the combination of these plasma biomarkers with conventional blood-, ultrasound-, and clinical-based factors can significantly support the diagnosis of IAI/MIAC and CNMM.
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Biomarcadores , Rotura Prematura de Membranas Fetales , Progranulinas , Serpinas , Humanos , Femenino , Embarazo , Progranulinas/sangre , Biomarcadores/sangre , Adulto , Serpinas/sangre , Estudios Retrospectivos , Rotura Prematura de Membranas Fetales/sangre , Recién Nacido , Líquido Amniótico/microbiología , Líquido Amniótico/metabolismo , Corioamnionitis/sangre , Corioamnionitis/inmunología , Péptidos y Proteínas de Señalización Intercelular/sangre , Inflamación/sangreRESUMEN
Velufenacin (DA-8010) is a new muscarinic receptor antagonist under development for the treatment of overactive bladder. This study aimed to evaluate the effect of food on the pharmacokinetics (PK) and safety of velufenacin in healthy subjects. A randomized, open-label, single-dose, 4-sequence, 4-treatment, 4-period crossover study was conducted. Subjects received a single oral dose of velufenacin 2.5 or 5 mg in a fasted or fed (high-fat meal) state in each period with a 7-day washout. PK parameters including maximum plasma concentration (Cmax ) and area under the concentration-time curve from time 0 to the last measurable point were compared between the fed and fasted states. Twenty-seven subjects completed the study. The mean area under the concentration-time curve from time 0 to the last measurable point of the velufenacin 2.5 and 5 mg doses under the fed condition showed a 1.5- and 1.3-fold increase, respectively, compared to the fasted condition. The corresponding values for Cmax were a 2.3- and 2.0-fold increase, respectively. The time to reach Cmax was comparable regardless of the dose or food intake, showing median values of 4.5-5.0 hours. These results suggest a modest increase of velufenacin absorption by food intake. Velufenacin was generally safe and well tolerated at the 2.5 and 5 mg doses regardless of food.
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Comidas , Antagonistas Muscarínicos , Humanos , Voluntarios Sanos , Estudios Cruzados , Administración Oral , Antagonistas Muscarínicos/efectos adversos , Receptores MuscarínicosRESUMEN
This study aimed to identify plasma proteins that could serve as potential biomarkers for microbial invasion of the amniotic cavity (MIAC) or intra-amniotic inflammation (IAI) in women with preterm labor (PTL). A retrospective cohort comprised singleton pregnant women with PTL (24-34 weeks) who underwent amniocentesis. Pooled plasma samples were analyzed by label-free liquid chromatography-tandem mass spectrometry for proteome profiling in a nested case-control study (concomitant MIAC/IAI cases vs. non-MIAC/IAI controls [n = 10 per group]). Eight target proteins associated with MIAC/IAI were further verified by immunoassays in a large cohort (n = 230). Shotgun proteomic analysis revealed 133 differentially expressed proteins (fold change > 1.5, P < 0.05) in the plasma of MIAC/IAI cases. Further quantification confirmed that the levels of AFP were higher and those of kallistatin and TGFBI were lower in the plasma of women with MIAC and that the levels of kallistatin and TGFBI were lower in the plasma of women with IAI than in those without these conditions. The area under the curves of plasma AFP, kallistatin, and TGFBI ranged within 0.67-0.81 with respect to each endpoint. In summary, plasma AFP, kallistatin, and TGFBI may represent valuable non-invasive biomarkers for predicting MIAC or IAI in women with PTL.
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Biomarcadores , Proteínas Sanguíneas , Trabajo de Parto Prematuro , Proteómica , Humanos , Femenino , Embarazo , Trabajo de Parto Prematuro/sangre , Adulto , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/metabolismo , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios Retrospectivos , Proteómica/métodos , Corioamnionitis/sangre , Corioamnionitis/microbiología , Inflamación/sangre , Amniocentesis , Proteoma/análisisRESUMEN
BACKGROUND: In 2023, the concept of metabolic dysfunction-associated steatotic liver disease (MASLD) was introduced as an alternative to non-alcoholic fatty liver disease (NAFLD). We aimed to assess the quantity and quality of skeletal muscle using each of these diagnostic classifications. METHODS: This cross-sectional study included 18 154 participants (11 551 [63.6%] men and 6603 [36.4%] women, mean age 53.0 ± 8.8). The participants were classified into four categories: neither steatotic liver disease (SLD), NAFLD only, MASLD only or both SLDs. An appendicular skeletal muscle mass adjusted for body mass index of <0.789 for men and <0.512 for women was defined as sarcopenia. The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area and intermuscular/intramuscular adipose tissue. Myosteatosis was defined by a T-score < -1.0 of the NAMA/TAMA index, which was calculated by dividing the NAMA by the TAMA and multiplying by 100. RESULTS: Using subjects with neither SLD as a reference, the multivariable-adjusted odds ratios (ORs) for sarcopenia were significantly increased in those with MASLD, with adjusted ORs (95% confidence interval [CI]) of 2.62 (1.94-3.54) in the MASLD-only group and 2.33 (1.92-2.82) in the both SLDs group, while the association was insignificant in those with NAFLD only (adjusted OR [95% CI]: 2.16 [0.67-6.94]). The OR for myosteatosis was also elevated in the MASLD groups, with an OR (95% CI) of 1.75 (1.52-2.02) in subjects with MASLD only and 1.70 (1.57-1.84) in those with both SLDs, while it was slightly decreased in subjects with NAFLD only (0.52 [0.29-0.95]). CONCLUSIONS: Employing the MASLD concept rather than that of the NAFLD proved to be more effective in distinguishing individuals with reduced muscle mass and compromised muscle quality.
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PURPOSE: This study aimed to identify challenges and potential improvements in Korea's medical education accreditation process according to the Accreditation Standards of the Korean Institute of Medical Education and Evaluation 2019 (ASK2019). Meta-evaluation was conducted to survey the experiences and perceptions of stakeholders, including self-assessment committee members, site visit committee members, administrative staff, and medical school professors. METHODS: A cross-sectional study was conducted using surveys sent to 40 medical schools. The 332 participants included self-assessment committee members, site visit team members, administrative staff, and medical school professors. The t-test, one-way analysis of variance and the chi-square test were used to analyze and compare opinions on medical education accreditation between the categories of participants. RESULTS: Site visit committee members placed greater importance on the necessity of accreditation than faculty members. A shared positive view on accreditation's role in improving educational quality was seen among self-evaluation committee members and professors. Administrative staff highly regarded the Korean Institute of Medical Education and Evaluation's reliability and objectivity, unlike the self-evaluation committee members. Site visit committee members positively perceived the clarity of accreditation standards, differing from self-assessment committee members. Administrative staff were most optimistic about implementing standards. However, the accreditation process encountered challenges, especially in duplicating content and preparing self-evaluation reports. Finally, perceptions regarding the accuracy of final site visit reports varied significantly between the self-evaluation committee members and the site visit committee members. CONCLUSION: This study revealed diverse views on medical education accreditation, highlighting the need for improved communication, expectation alignment, and stakeholder collaboration to refine the accreditation process and quality.
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Educación Médica , Humanos , Estudios Transversales , Reproducibilidad de los Resultados , Acreditación , República de CoreaRESUMEN
Background: Myosteatosis, ectopic fat accumulation in skeletal muscle, is a crucial component of sarcopenia, linked to various cardiometabolic diseases. This study aimed to analyze the association between dyslipidemia and myosteatosis using abdominal computed tomography (CT) in a large population. Methods: This study included 11,823 patients not taking lipid-lowering medications with abdominal CT taken between 2012 and 2013. Total abdominal muscle area (TAMA), measured at the L3 level, was segmented into skeletal muscle area (SMA) and intramuscular adipose tissue. SMA was further classified into normal attenuation muscle area (NAMA: good quality muscle) and low attenuation muscle area (poor quality muscle). NAMA divided by TAMA (NAMA/TAMA) represents good quality muscle. Atherosclerotic dyslipidemia was defined as high-density lipoprotein cholesterol (HDL-C) less than 40 mg/dL in men and 50 mg/dL in women, low-density lipoprotein cholesterol (LDL-C) greater than 160 mg/dL, triglycerides (TG) greater than 150 mg/dL, small dense LDL-C (sdLDL-C) greater than 50.0 mg/dL, or apolipoprotein B/A1 (apoB/A1) greater than 0.08. Results: The adjusted odds ratios (ORs) of dyslipidemia according to the HDL-C and sdLDL definitions were greater in both sexes in the lower quartiles (Q1~3) of NAMA/TAMA compared with Q4. As per other definitions, the ORs were significantly increased in only women for LDL-C and only men for TG and ApoB/A1. In men, all lipid parameters were significantly associated with NAMA/TAMA, while TG and ApoB/A1 did not show significant association in women. Conclusion: Myosteatosis measured in abdominal CT was significantly associated with a higher risk of dyslipidemia. Myosteatosis may be an important risk factor for dyslipidemia and ensuing cardiometabolic diseases.
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Aterosclerosis , Dislipidemias , Músculo Esquelético , Humanos , Masculino , Femenino , Dislipidemias/metabolismo , Persona de Mediana Edad , Anciano , Músculo Esquelético/metabolismo , Músculo Esquelético/diagnóstico por imagen , Aterosclerosis/metabolismo , Tomografía Computarizada por Rayos X , Sarcopenia/metabolismo , Sarcopenia/patología , Sarcopenia/diagnóstico por imagen , Adulto , LDL-Colesterol/sangre , LDL-Colesterol/metabolismo , Triglicéridos/sangre , Triglicéridos/metabolismo , Factores de RiesgoRESUMEN
Methylene blue (MB) has recently completed a Phase-3 clinical trial as leuco-methylthioninium (LMT) bis(hydromethanesulfonate) for treating Alzheimer's disease. Herein, we investigated the mechanism underlying the MB inhibition of tubulin-associated unit (tau) aggregation by focusing on tau monomers. We found that MB causes disulfide bond formation, resulting in strong nuclear magnetic resonance chemical shift perturbations in a large area of tau proteins. The oxidized form of MB, namely methylthioninium (MT+), specifically catalyzed the oxidation of cysteine residues in tau proteins to form disulfide bonds directly using O2. This process is independent of the MT+-to-LMT redox cycle. Moreover, MT+ preferentially oxidized C291 and C322 in the lysine-rich R2 and R3 domains. Under in vivo brain physoxia conditions, LMT may convert to MT+, possibly interfering with tau fibrillation via disulfide bond formation.
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Mollusca species shell such as oyster shell (OS) and snail shell (SS), are discarded after taking the meat, and the discarded shell causes the environmental problems. Therefore, recycling shell waste could potentially eliminate the environmental problems. This study aimed to evaluate the potential of OS and SS as natural calcium resources. The minerals, calcium, magnesium, potassium, phosphorus and sodium were analyzed in OS and SS extracts. Among them, the calcium content was the highest: 36.87 (%) and 33.42 (%) in the OS and SS extracts, respectively. Further, the content of ionized bioavailable form of calcium in OS and SS was higher than that of CaCO3 under simulated gastrointestinal digestion conditions. Additionally, OS and SS were added to kimchi, and their inhibitory effect on kimchi acidification was evaluated by assessing pH, titratable acidity and microbial analysis. As the results indicated that the addition of OS and SS had little effect on inhibiting the growth of lactic acid bacteria. However, it was confirmed that calcium neutralizes the organic acids produced during fermentation. Overall, the results of this study provide preliminary information on the re-use of OS and SS extracts as ionized natural calcium supplements and fermentation retardants.
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BACKGROUND: Hypertensive disorders of pregnancy (HDP) pose significant risks to both maternal and fetal health, contributing to global morbidity and mortality. Management of HDP is complex, particularly because of concerns regarding potential negative effects on utero-placental circulation and limited therapeutic options due to fetal safety. Our study investigates whether blood pressure monitoring through a mobile health (mHealth) application can aid in addressing the challenges of blood pressure management in pregnant individuals with HDP. Additionally, we aim to assess whether this intervention can improve short-term maternal and fetal outcomes and potentially mitigate long-term cardiovascular consequences. METHODS: This prospective, randomized, single-center trial will include 580 pregnant participants who meet the HDP criteria or who have a heightened risk of pregnancy-related hypertension due to factors such as multiple pregnancies, obesity, diabetes, or a history of HDP in prior pregnancies leading to preterm birth. Participants will be randomized to either the mHealth intervention group or the standard care group. The primary endpoint is the difference in systolic blood pressure from enrollment to 1 month after childbirth. The secondary endpoints include various blood pressure parameters, obstetric outcomes, body mass index trajectory, step counts, mood assessment, and drug adherence. CONCLUSIONS: This study emphasizes the potential of mHealth interventions, such as the Heart4U application, to improve blood pressure management in pregnant individuals with HDP. By leveraging technology to enhance engagement, communication, and monitoring, this study aims to positively impact maternal, fetal, and postpartum outcomes associated with HDP. This innovative approach demonstrates the potential of personalized technology-driven solutions for managing complex health conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05995106. Registered on 16 August 2023.
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Presión Sanguínea , Hipertensión Inducida en el Embarazo , Aplicaciones Móviles , Ensayos Clínicos Controlados Aleatorios como Asunto , Telemedicina , Humanos , Embarazo , Femenino , Estudios Prospectivos , Hipertensión Inducida en el Embarazo/terapia , Hipertensión Inducida en el Embarazo/diagnóstico , Hipertensión Inducida en el Embarazo/fisiopatología , Antihipertensivos/uso terapéutico , Monitoreo Ambulatorio de la Presión Arterial/métodos , Resultado del Tratamiento , Adulto , Factores de TiempoRESUMEN
Kimchi cabbage, the key ingredient in kimchi, is cultivated year-round to meet high production demands. This study aimed to examine the effects of seasonal harvesting (spring, summer, fall, and winter) on the microbial and metabolic profiles of kimchi during 30 days of fermentation. Lactic acid bacteria distribution is notably influenced by seasonal variations, with Latilactobacillus dominant in fall-harvested kimchi group and Weissella prevailing in spring, summer, and winter. The microbial communities of spring and fall group exhibited similar profiles before fermentation, whereas the microbial communities and metabolic profiles of spring and summer group were similar after 30 days of fermentation. Seasonal disparities in metabolite concentrations, including glutamic acid, serine, and cytosine, persist throughout fermentation. This study provides a comprehensive understanding of the substantial impact of seasonal harvesting of kimchi cabbage on the microbial and metabolic characteristics of kimchi, providing valuable insights into producing kimchi with diverse qualities.
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Brassica , Fermentación , Alimentos Fermentados , Microbiología de Alimentos , Estaciones del Año , Brassica/microbiología , Brassica/metabolismo , Alimentos Fermentados/microbiología , Alimentos Fermentados/análisis , Metaboloma , Microbiota , Weissella/metabolismoRESUMEN
This study aimed to evaluate the adverse effects of particulate matter (PM) exposure on endometrial cells and fertility and to identify possible underlying mechanisms. Thirteen women (aged 15-52 years) were included in this study. Enrolled patients underwent laparoscopic surgery at Gangnam Severance Hospital between 1 January and 31 December 2021. For in vivo experiments, 36 female and nine male C57BL/6 mice were randomly divided into control(vehicle), low-dose(10 mg/kg/d), and high-dose exposure groups(20 mg/kg/d). PM was inhaled nasally for four weeks and natural mating was performed. NIST® SRM® 1648a was used for PM exposure. qRT-PCR, western blotting and Masson's trichrome staining were performed. PM treatment in human endometrial stromal cells induced inflammation with significant upregulation of IL-1ß, p-NF-kB, and p-c-Jun compared to those of controls. Additionally, PM treatment significantly increased apoptosis in human endometrial stromal cells by downregulating p-AKT and upregulating p-p53/p53, Cas-3, BAX/Bcl-2, p-AMPK, and p-ERK. After PM treatment, the relative expression of IL-1ß, IL-6, TNF-α, p-NF-κB, p-c-Jun, and p-Nrf2/Nrf2 significantly increased in murine endometrium compared to those of the controls. Expression of apoptotic proteins p53, p27, and Cas-3, was also significantly elevated in murine endometrium of the PM exposure group compared to that of the controls. A significant increase in expression of procollagen â , and Masson's trichrome staining scores in the murine endometrium was noted after PM treatment. PM treatment significantly decreased ERα expression. After natural mating, all 3 female mice in the control group gave birth to 25 offspring (mean 8.1), whereas in the low-dose PM treatment group, two of three female mice gave birth to nine offspring (mean 4.5). No pregnant mice or offspring was present in the high-dose PM treatment group. PM exposure induces adverse effects on the endometrium through aberrant activation of inflammatory and apoptotic pathways and is associated with detrimental effects on murine fertility.
Asunto(s)
Apoptosis , Endometrio , Fertilidad , Inflamación , Ratones Endogámicos C57BL , Material Particulado , Material Particulado/toxicidad , Femenino , Animales , Humanos , Apoptosis/efectos de los fármacos , Ratones , Adulto , Endometrio/efectos de los fármacos , Masculino , Adolescente , Adulto Joven , Inflamación/inducido químicamente , Persona de Mediana Edad , Fertilidad/efectos de los fármacos , Contaminantes Atmosféricos/toxicidad , Células del Estroma/efectos de los fármacosRESUMEN
The asymmetric division of stem cells permits the maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows inspection of the role of the stem cell niche to provide specific insights into essential developmental phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with low hardness, as the size of the apical bud was decreased and preameloblasts were shifted to the apical side, resulting in amelogenesis imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis was accelerated with Wnt signal downregulation. Distal-Less Homeobox 3 (DLX3), a critical factor in tooth amelogenesis, is considered to be responsible for the development of amelogenesis imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization site (NLS) that promotes the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role for MAST4 as a critical regulator of the entire amelogenesis process through its control of Wnt signaling and DLX3 transcriptional activity.