Publications by authors named "Hyun Yang"

424 Publications

Ethanolic extract of Pyrrosia lingua (Thunb.) Farw. ameliorates OVX-induced bone loss and RANKL-induced osteoclastogenesis.

Biomed Pharmacother 2022 Jan 13;147:112640. Epub 2022 Jan 13.

KM Convergence Research Division, Korea Institute of Oriental Medicine, Yuseong-daero 1672, Yuseong-gu, Daejeon 34054, Republic of Korea. Electronic address:

Pyrrosia lingua (Thunb.) Farw is a common plant that has been widely used as a traditional herbal medicine in China and Korea to treat patients suffering from pain, vaginal bleeding and urolithiasis. However, the pharmacological effects of P. lingua on bone remain unknown. We investigated the anti-osteoporotic effects of an ethanolic extract of P. lingua (EEPL). We found that EEPL suppressed osteoclast differentiation by directly acting on osteoclast precursor cells. EEPL suppressed the expression of receptor activator of nuclear factor-κB ligand (RANKL)-induced nuclear factor of activated T cells 1, a major transcription factor for osteoclastogenesis, by inhibiting RANKL-induced expression of aryl hydrocarbon receptor/c-Fos, and activation of nuclear factor-κB and mitogen-activated protein kinases. Moreover, administration of EEPL inhibited trabecular bone loss and weight gain in ovariectomized mice. Furthermore, we identified phytochemicals in EEPL that are known to exert anti-osteoclastogenic or anti-osteoporotic effects using ultra-high-performance liquid chromatography-tandem mass-spectrometry analysis. Overall, the results of this study suggest that EEPL is effective therapeutic candidate that can be used to prevent or treat postmenopausal osteoporosis.
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http://dx.doi.org/10.1016/j.biopha.2022.112640DOI Listing
January 2022

Prevalence trends of non-alcoholic fatty liver disease among young men in Korea: A Korean military population-based cross-sectional study.

Clin Mol Hepatol 2022 Jan 13. Epub 2022 Jan 13.

The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Background: Non-alcoholic fatty liver disease (NAFLD) has become a major concern in Korea since its emergence as a dominant cause of chronic liver disease. However, no study has explored its prevalence in adults under 30 years of age. Therefore, we performed a cross-sectional study to investigate the prevalence of NAFLD in Korean men in their early twenties.

Methods: We collected data on 596,359 Korean soldiers who participated in a health examination between January 2015 and July 2021. A total of 571,872 individuals were analyzed after excluding those with missing data and hepatitis B antigen positivity. Hepatic steatosis was determined using the hepatic steatosis index (HSI). Participants with an HSI >36 were considered to have NAFLD.

Results: All participants were men, and the mean age was 20.9 ± 1.3 years. Of the 571,872 participants screened, 77,020 (13.47%) were classified as having NAFLD. The prevalence of NAFLD consistently increased from 2015 to 2021 (10.66% vs. 16.44%, P<0.001). Increases from 2015 to 2021 were also noted in the prevalence of hypercholesterolemia, hyperglycemia, and hypertension (P<0.001 for all). The mean body mass index also increased from 23.3 ± 3.0 kg/m2 to 23.9 ± 3.1 kg/m2 between 2015 and 2021 (P<0.001).

Conclusions: The prevalence of NAFLD and of other metabolic dysfunctions in Korean men in their early twenties increased from 2015 to 2021.
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http://dx.doi.org/10.3350/cmh.2021.0371DOI Listing
January 2022

Water Extract of Bulbus Inhibits RANKL-Mediated Osteoclastogenesis and Ovariectomy-Induced Trabecular Bone Loss.

Molecules 2021 Dec 28;27(1). Epub 2021 Dec 28.

Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Yuseong-daero 1672, Daejeon 34054, Korea.

bulbus has been widely used to treat symptoms of coughs and airway congestion in the chest due to pathological colds and damp phlegm in traditional Chinese medicine. Despite its long history of traditional use, its pharmacological activities on osteoclastogenesis and osteoporosis have not been evaluated. This study investigated the effects of the water extract of bulbus (WEFT) on osteoclast differentiation in bone marrow-derived macrophage cells and on ovariectomy (OVX)-induced osteoporosis in mice. We found that WEFT significantly inhibited osteoclastogenesis by downregulating the receptor activator of the NF-κB ligand (RANKL) signaling-induced nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) expression. In an OVX-induced osteoporosis model, WEFT significantly prevented the OVX-induced trabecular loss of femurs, accompanied by a reduction in fat accumulation in the bone marrow and liver. In addition, WEFT significantly prevented weight gain and gonadal fat gain without recovering uterine atrophy. Using ultrahigh-performance liquid chromatography-tandem mass spectrometry, seven alkaloids (peimisine glucoside, yibeissine, peiminoside, sipeimine-glucoside, peimisine, peimine, and peiminine) were identified in WEFT. The results of this study suggest that WEFT can be a potential pharmacological candidate to reduce menopausal osteoporosis and menopause-related symptoms, such as fat accumulation.
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http://dx.doi.org/10.3390/molecules27010169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8746409PMC
December 2021

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation.

Int J Mol Sci 2022 Jan 4;23(1). Epub 2022 Jan 4.

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced β-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from β-oxidation to glycolysis, may induce cardiac structural remodeling.
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http://dx.doi.org/10.3390/ijms23010547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745349PMC
January 2022

Data-Driven Analysis for Safe Ship Operation in Ports Using Quantile Regression Based on Generalized Additive Models and Deep Neural Network.

Sensors (Basel) 2021 Dec 10;21(24). Epub 2021 Dec 10.

Division of Navigation Convergence Studies, Korea Maritime and Ocean University, Busan 49112, Korea.

Marine accidents in ports can cause loss of human life and property and have negative material and environmental impacts. In South Korea, due to a pier collision accident of a large container ship in Busan New Port of South Korea, the need for safe ship operation guidelines in ports emerged. Therefore, to support quantitative safe ship operation guidelines, ship trajectory data based on automatic information system information have been used. However, because this trajectory information is variable and uncertain due to various situations arising during a ship's navigation, there is a limit to deriving results through traditional regression analysis. Considering the characteristics of these data, we analyzed ship trajectories through quantile regression using two models based on generalized additive models and neural networks corresponding to deep learning. Among the automatic information system information, the speed over ground, course over ground, and ship's position were analyzed, and the model was evaluated based on quantile loss. Based on this study, it is possible to suggest safe operation guidelines for the position, speed, and course of the ship. In addition, the results of this work can be further developed as a manual for the in-port-autonomous operation of ships in the future.
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http://dx.doi.org/10.3390/s21248254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708069PMC
December 2021

Gram-negative bacteria and their lipopolysaccharides in Alzheimer's disease: pathologic roles and therapeutic implications.

Transl Neurodegener 2021 12 7;10(1):49. Epub 2021 Dec 7.

Department of Biochemistry, College of Medicine, Konyang University, Daejeon, 35365, Republic of Korea.

Alzheimer's disease (AD) is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline. Failures in the development of therapeutics targeting amyloid-β (Aβ) and tau, principal proteins inducing pathology in AD, suggest a paradigm shift towards the development of new therapeutic targets. The gram-negative bacteria and lipopolysaccharides (LPS) are attractive new targets for AD treatment. Surprisingly, an altered distribution of gram-negative bacteria and their LPS has been reported in AD patients. Moreover, gram-negative bacteria and their LPS have been shown to affect a variety of AD-related pathologies, such as Aβ homeostasis, tau pathology, neuroinflammation, and neurodegeneration. Moreover, therapeutic approaches targeting gram-negative bacteria or gram-negative bacterial molecules have significantly alleviated AD-related pathology and cognitive dysfunction. Despite multiple evidence showing that the gram-negative bacteria and their LPS play a crucial role in AD pathogenesis, the pathogenic mechanisms of gram-negative bacteria and their LPS have not been clarified. Here, we summarize the roles and pathomechanisms of gram-negative bacteria and LPS in AD. Furthermore, we discuss the possibility of using gram-negative bacteria and gram-negative bacterial molecules as novel therapeutic targets and new pathological characteristics for AD.
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http://dx.doi.org/10.1186/s40035-021-00273-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650380PMC
December 2021

Serum and aqueous humor adiponectin levels correlate with diabetic retinopathy development and progression.

PLoS One 2021 15;16(11):e0259683. Epub 2021 Nov 15.

Department of Ophthalmology, Veterans Health Service Medical Center, Seoul, South Korea.

Purpose: To compare adiponectin (APN) levels in the serum and aqueous humor (AH) and evaluate their association with the development/progression of diabetic retinopathy (DR).

Methods: Diabetic patients with (group 3; n = 59) and without (group 2; n = 39) DR and age- and sex-matched normal subjects (group 1; n = 35) were compared. Duration of diabetes, body mass index, serum HbA1c, vascular endothelial growth factor (VEGF), APN, pentraxin 3 (PTX3), platelet derived growth factor (PDGF), intercellular adhesion molecule-1 (ICAM-1), and APN were measured and analyzed.

Results: One hundred and thirty-three participants were included. Compared to patients without diabetes, diabetic patients with DR had significantly elevated average serum APN levels (5.99±3.89 μg/ml versus 3.51±1.44 μg/ml, P = 0.002) and average AH APN levels (10.94±11.74 ng/ml versus 3.65±3.33 ng/ml, P<0.001). Serum APN was significantly correlated with AH APN (R = 0.512, P<0.001) and AH VEGF (R = 0.202, P = 0.020). The log serum APN was significantly correlated with intraocular cytokines, including log APN, log VEGF, log ICAM, log leptin, log PTX3, log PDGF, angiopoietin, C-reactive protein, and interleukins (IL)-5 and IL-10 (P<0.001, P = 0.020, P<0.001, P<0.001, P = 0.001, P<0.001, P = 0.008, P = 0.009, P<0.001, and P = 0.046, respectively). Log serum VEGF showed a significant correlation only with log AH VEGF (P = 0.001). Multivariate logistic analysis was performed to evaluate the association of DR progression and cytokine concentrations; log Serum APN and log AH APN showed good correlation with the DR progression in each model.

Conclusions: AH APN levels correlated well with DR development and progression. Serum APN could be a better marker for estimating intraocular cytokines, including both intraocular APN and VEGF concentrations in clinical field, than serum VEGF in DR patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0259683PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592425PMC
December 2021

A mathematical model to evaluate the role of memory B and T cells in heterologous secondary dengue infection.

J Theor Biol 2022 Feb 11;534:110961. Epub 2021 Nov 11.

Institute of Mathematics, Statistics and Scientific Computing - University of Campinas, Campinas, SP, Brazil.

We propose a mathematical model to investigate the antibody-dependent enhancement (ADE) phenomenon during secondary dengue infection. The model consists of an ODE system that describes the interaction of the dengue virus with macrophages and memory B and T cell role during the infection. The qualitative model analysis is done in terms of memory B and T cell cloning parameters and the basic reproduction number R. In the absence of memory B and T cell cloning, if R<1 the dengue virus population extinguishes, while for R>1, it tends asymptotically to a positive equilibrium. However, when we consider the memory B cell cloning, it is possible to occur dengue infection even when R<1. Memory T cells have an essential role in eliminating the possibility of ADE occurrence when R<1.
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http://dx.doi.org/10.1016/j.jtbi.2021.110961DOI Listing
February 2022

Antinociceptive and Anti-Inflammatory Effects of Recombinant Crotamine in Mouse Models of Pain.

Toxins (Basel) 2021 Oct 6;13(10). Epub 2021 Oct 6.

Department of Physiology, Biomedical Institute of Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

Crotamine, a toxin found in the venom of the South American rattlesnake , has been reported to have antinociceptive effects. We purified recombinant crotamine expressed in and investigated its antinociceptive and anti-inflammatory effects using the hot-plate test, acetic-acid-induced writhing method, and formalin test in mice. Recombinant crotamine was administered intraperitoneally (0.04-1.2 mg kg) or intraplantarly (0.9-7.5 μg 10 μL) before the tests. The paw volume was measured with a plethysmometer. To evaluate the antagonistic and anti-inflammatory effects of naloxone, subcutaneous naloxone (4 mg kg) or intraplantar naloxone (5 μg 10 μL) was administered before recombinant crotamine. For tumor necrosis factor (TNF)-α assays, blood was drawn 3 h after formalin injection and measured using enzyme-linked immunosorbent assay. Intraperitoneal and intraplantar recombinant crotamine had antinociceptive and anti-inflammatory effects, neither of which were affected by pre-treatment with naloxone. The mean serum TNF-α levels were significantly lower in the intraperitoneal recombinant crotamine (0.4 and 1.2 mg kg) or intraplantar (2.5 and 7.5 μg 10 μL) recombinant crotamine groups than in the saline group and were not affected by naloxone pre-treatment. In conclusion, recombinant crotamine possesses significant antinociceptive and anti-inflammatory effects that do not appear to be related to the opioid receptor. The antinociceptive and anti-inflammatory effects of intraperitoneal or intraplantar recombinant crotamine are related to TNF-α.
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http://dx.doi.org/10.3390/toxins13100707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538437PMC
October 2021

Identification and pharmacokinetics of bioavailable anti-resorptive phytochemicals after oral administration of Psoralea corylifolia L.

Biomed Pharmacother 2021 Dec 12;144:112300. Epub 2021 Oct 12.

Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea; University of Science & Technology (UST), Korean Convergence Medicine Major KIOM, Daejeon 34054, Republic of Korea. Electronic address:

Osteoporosis and resulting bone fractures are the major health issues associated with morbidity in the aging population; however, there is no effective treatment that does not cause severe side effects. In East Asia, dried seeds of Psoralea corylifolia L. (PC) have traditionally been used as an herbal medicine to manage urinary tract, cutaneous, and gastrointestinal disorders, as well as bone health. However, the mechanism of action and active biocomponents of PC are unclear. Here, we adopted a pharmacokinetic (PK) study aiming to identify the bioavailable phytochemicals in aqueous and ethanolic extracts of PC (APC) and (EPC), respectively. In addition, we aimed to determine anti-resorptive constituents of PC, which accounted for its beneficial effects on bone health. To this end, we used ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A rapid, sensitive, and reliable UPLC-MS/MS method was developed and determined the 17 PC ingredients. In the PK study, nine components (two chalcones, two coumarins, one coumestan, two flavonoids, and two isoflavonoids) were observed between 36 and 48 h after oral administration of APC or EPC. Among the bioavailable ingredients, four PC constituents (psoralidin, isobavachin, corylifol A, and neobavaisoflavone) inhibited M-CSF-and RANKL-induced osteoclast differentiation in bone marrow-derived macrophages. In addition, two chalcones and two isoflavonoids markedly inhibited cathepsin K activity, and their binding modes to cathepsin K were determined by molecular docking. In summary, our data suggest that bioavailable multicomponents of PC could contribute to the management of bone health.
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http://dx.doi.org/10.1016/j.biopha.2021.112300DOI Listing
December 2021

Biomarker Rule-in or Rule-out in Patients With Acute Diseases for Validation of Acute Kidney Injury in the Emergency Department (BRAVA): A Multicenter Study Evaluating Urinary TIMP-2/IGFBP7.

Ann Lab Med 2022 03;42(2):178-187

GREAT Network Italy Rome, Italy.

Background: Urine tissue inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein 7 (TIMP-2/IGFBP7) (NephroCheck, Ortho Clinical Diagnostics, Raritan, NJ, USA) is a US Food and Drug Administration-approved biomarker for risk assessment of acute kidney injury (AKI) in critically ill adult patients in intensive care units; however, its clinical impact in the emergency department (ED) remains unproven. We evaluated the utility of NephroCheck for predicting AKI development and short-term mortality in the ED.

Methods: This was a prospective, observational, five-center international study. We consecutively enrolled ED patients admitted with ≥30% risk of AKI development (assessed by ED physician: ED score) or acute diseases. Serum creatinine was tested on ED arrival (T0), day 1, and day 2 (T48); urine for NephroCheck was collected at T0 and T48. We performed ROC curve and reclassification analyses.

Results: Among the 529 patients enrolled (213 females; median age, 65 years), AKI developed in 59 (11.2%) patients. The T0 NephroCheck value was higher in the AKI group than in the non-AKI group (median 0.77 vs. 0.29 (ng/m)/1,000, P=0.001), and better predicted AKI development than the ED score (area under the curve [AUC], 0.64 vs. 0.53; =0.04). In reclassification analyses, adding NephroCheck to the ED score improved the prediction of AKI development (<0.05). The T0 NephroCheck value predicted 30-day mortality (AUC, 0.68; <0.001).

Conclusions: NephroCheck can predict both AKI development and short-term mortality in at-risk ED patients. NephroCheck would be a useful biomarker for early ruling-in or ruling-out of AKI in the ED.
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http://dx.doi.org/10.3343/alm.2022.42.2.178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548247PMC
March 2022

Thermodynamic patterns duringheating of InAs nanowires encapsulated in AlOshells.

Nanotechnology 2021 Oct 22;33(2). Epub 2021 Oct 22.

Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea.

Understanding the dynamic thermal behavior of nanomaterials based on their unique physical and chemical properties is critical for their applications. In this study, the thermal behavior of single-crystalline InAs nanowires in an amorphous AlOshell was investigated by conductingheating experiments in a transmission electron microscope. Two different thermodynamic patterns were observed during theheating experiments: (1) continuous vaporization and condensation simultaneously at temperatures lower than 838.15 K, and (2) pure evaporation at temperatures higher than 878.15 K. During the simultaneous condensation and vaporization in closer areas in a single InAs nanowire, the front edge of the vaporization was flat, while that of the condensation actively changed with time and temperature. Pure vaporization was conducted via layer-by-layer evaporation followed by three-dimensional vaporization at the final stage. The thermal behaviors of the InAs nanowires were demonstrated from a thermodynamic point of view.
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http://dx.doi.org/10.1088/1361-6528/ac2d4bDOI Listing
October 2021

Comparative Analysis of Lenvatinib and Hepatic Arterial Infusion Chemotherapy in Unresectable Hepatocellular Carcinoma: A Multi-Center, Propensity Score Study.

J Clin Med 2021 Sep 7;10(18). Epub 2021 Sep 7.

The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.

The comparative efficacy and safety between lenvatinib and hepatic artery infusion chemotherapy (HAIC) in patients with unresectable hepatocellular carcinoma (HCC) is still unclear. This multicenter historical cohort study enrolled 244 patients who were treated with HAIC ( = 173) or lenvatinib ( = 71) between 2012 and 2020. Propensity score matching (PSM) was performed, and 52 patients were selected per group. Clinical outcomes and safety were compared. Objective response rate (ORR) was not different between the two groups (26.0% vs. 23.1%, = 0.736). Before PSM, the HAIC group had a higher proportion of Child-Pugh B and portal vein tumor, whereas the lenvatinib group had more patients with extrahepatic metastases, which was adjusted after PSM. There were no differences in progression-free survival (PFS) and overall survival (OS) after PSM (HAIC vs. lenvatinib, median PFS, 3.6 vs. 4.0 months, = 0.706; median OS 10.8 vs. 7.9 months, = 0.106). Multivariate Cox-regression showed that alpha-fetoprotein ≤1000 ng/mL was only an associated factor for OS after PSM in all patients (hazard ratio = 0.421, = 0.011). Subgroup analysis for patients with a high tumor burden beyond the REFLECT eligibility criteria revealed that the HAIC group ( = 29) had a significantly longer OS than did the lenvatinib group ( = 30) (10.0 vs. 5.4 months, = 0.004). More patients in the HAIC group achieved better liver function than those in the lenvatinib group at the time of best responses. There was no difference in the incidence of grade 3 and 4 adverse events between the two groups. Therefore, lenvatinib is comparable to HAIC in terms of ORR and OS in unresectable HCC meeting REFLECT eligibility criteria.
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http://dx.doi.org/10.3390/jcm10184045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464794PMC
September 2021

A Novel Cardenolide Glycoside Isolated from Reduces Levels of the Alzheimer's Disease-Associated β-Amyloid Peptides Aβ42 In Vitro.

Pharmaceuticals (Basel) 2021 Jul 29;14(8). Epub 2021 Jul 29.

Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa.

Elevated levels of the amylo β-proteins (Aβ), particularly Aβ42, are associated with a high risk of Alzheimer's disease (AD). The Aβ proteins are produced from cellular processing of the amyloid precursor proteins (APPs). To identify natural products that block the formation of Aβ-proteins from APPs, we previously screened a library of plant extracts and identified (Apocynaceae) as a potential plant for further research. Here, we provide a report on the isolation and identification of the active principles from the plant species using a bioassay-guided fractionation. Fractions and resulting pure compounds from the purification process of the extract of were screened in vitro against APPs transfected HeLa cell lines. Three compounds, acetylated glycosydated crotoxogenin (), xysmalogenin-3, β-d-glucopyranoside (), and crotoxigenin 3--glucopyranoside (), were subsequently isolated and their structures elucidated using NMR and mass spectrometry. Compound , a novel cardenolide, and significantly decreased the Aβ42 levels in a dose-dependent manner while compound was inactive. In silico investigations identified the AD's β-secretase enzyme, BACE1, as a potential target for these compounds with the glycoside moiety being of significance in binding to the enzyme active site. Our study provides the first report of a novel cardenolide and the potential of cardenolides as chemical scaffolds for developing AD treatment drugs.
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http://dx.doi.org/10.3390/ph14080743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400651PMC
July 2021

Water Extract of L. Attenuates Estrogen Deficiency-Induced Bone Loss by Inhibiting Osteoclast Differentiation.

Front Pharmacol 2021 5;12:719602. Epub 2021 Aug 5.

KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea.

L., is an aromatic herb that belongs to the Lamiaceae family and is widely used in medicinal applications, essential oil applications, and food flavoring. The extract of has been reported to exert sedative-hypnotic, anti-inflammatory, anti-fungal, and anti-bacterial effects. However, its effects on bone metabolism have not yet been studied. Here, we investigated the effects of the water extract of (WEMA) on osteoclast formation and bone loss in an ovariectomized mouse model. We found that WEMA inhibited osteoclast differentiation by directly acting on osteoclast precursor cells. WEMA inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced the expression of cellular oncogene fos (c-Fos) and nuclear factor of activated T cells c1 (NFATc1), crucial transcription factors for osteoclast differentiation, by suppressing RANKL-induced activation of early signaling pathways such as those of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). In addition, oral administration of WEMA suppressed ovariectomy-induced trabecular bone loss in mice. We additionally identified phytochemicals in WEMA that are known to have anti-osteoclastogenic or anti-osteoporotic properties. Collectively, these results suggest that WEMA is a promising herbal candidate that can be used to prevent or treat postmenopausal osteoporosis.
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http://dx.doi.org/10.3389/fphar.2021.719602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374437PMC
August 2021

The Association of White Matter Hyperintensities with Frailty in Patients with Very Mild to Moderate Alzheimer's Disease.

J Alzheimers Dis 2021 ;83(3):1281-1289

Department of Psychiatry, Jeju National University School of Medicine, Jeju National University Hospital, Jeju Special Self-Governing Province, South Korea.

Background: Frailty, one of serious global health problems in the elderly, is a growing concern in patients with Alzheimer's disease (AD) because of its high prevalence in AD and its impact on the prognosis.

Objective: To investigate the quantitative association between white matter hyperintensities (WMH) and frailty in AD.

Methods: A total of 144 outpatients were included. All subjects were evaluated by using Korean version of the CERAD assessment battery and diagnosed very mild to moderate AD. WMH volume was calculated using automated segmentation analysis from the 3D MRI image and further partitioned according to the distance from the ventricular surface. Using the Korean Frailty Index, prefrailty was defined by the scores of 3 and 4 and frailty by the score of 5 and higher.

Results: In total, 23.6%were frailty, 32.6%were pre-frailty, and 43.8%were classified as a robust group. The frailty group had higher WMH volume compared to the robust group (p = 0.02), and these trends remained significant after linear regression analyses. According to the subclassification of WMH, using the robust group as a reference, total WMH (OR = 6.297, p = 0.013, 95%CI = 1.463-27.114), juxtaventricular WMH (OR = 12.955, p = 0.014, 95%CI = 1.687-99.509), and periventricular WMH (OR = 3.382, p = 0.025, 95%CI = 1.163-9.8531) volumes were associated with frailty, but deep WMH volume was not.

Conclusions: A quarter of patients with very mild to moderate AD is suffering from frailty. Our study provides the evidence of a cross-sectional relationship between WMH volume and frailty, and there is a difference in the association between the subclassification of WMH volume and frailty.
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http://dx.doi.org/10.3233/JAD-210494DOI Listing
December 2021

Systematic review and meta-analysis of diagnostic performance of CT imaging for assessing resectability of pancreatic ductal adenocarcinoma after neoadjuvant therapy: importance of CT criteria.

Abdom Radiol (NY) 2021 11 31;46(11):5201-5217. Epub 2021 Jul 31.

Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Purpose: To assess the CT diagnostic performance for evaluating resectability of pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy and identify the factor(s) that affect(s) diagnostic performance.

Methods: Databases were searched to identify studies published from January 1, 2000, to November 5, 2019 that evaluated the CT diagnostic performance for assessing resectability of post-neoadjuvant PDAC. Two reviewers independently extracted data and assessed the study quality. A meta-analysis was performed to obtain summary sensitivity and specificity values using a bivariate random-effects model, and heterogeneity across studies was assessed. Univariable meta-regression analysis was performed with eight variables, including the different CT criteria for resectability, conventional National Comprehensive Cancer Network (NCCN) criteria for upfront surgery, and modified criteria for post-neoadjuvant surgery.

Results: Ten studies were included and analyzed. The summary sensitivity and specificity for resectability were 78% (95% CI 68-86%) and 60% (95% CI 44-74%), respectively. No significant heterogeneity was identified (bivariate correlation coefficient ρ = - 1, p-value for hierarchical summary receiver operating characteristics model β = 0.667). The two different CT criteria showed different diagnostic performance (p < 0.01), with higher sensitivity (81% [95% CI 73-90%] vs. 28% [95% CI 15-42%], p < 0.01) and lower specificity (57% [95% CI 41-73%] vs. 90% [95% CI 80-100%], p < 0.01) for the modified criteria. No other variables affected the diagnostic performance.

Conclusion: CT criteria were the factors that affected the diagnostic performance. Modification of the conventional criteria improved sensitivity but lowered specificity. Further modifications are required to improve specificity and uniformity.
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http://dx.doi.org/10.1007/s00261-021-03198-2DOI Listing
November 2021

Early response evaluation of doxorubicin-nanoparticle-microbubble therapy in orthotopic hepatocellular carcinoma rat model using contrast-enhanced ultrasound and intravoxel incoherent motion-diffusion MRI.

Ultrasonography 2022 Jan 10;41(1):150-163. Epub 2021 May 10.

Department of Radiology, Seoul National University Hospital, Seoul National University, Seoul, Korea.

Purpose: This study aimed to apply doxorubicin-loaded nanoparticle microbubble (Dox-NP-MB) therapy in an orthotopic rat model of hepatocellular carcinoma (HCC) and investigate the utility of contrast-enhanced ultrasound (CEUS) and intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DWI) for response evaluation.

Methods: Twenty-eight N1S1 HCC model rats were treated with either Dox-NP-MB (group [G] 1, n=8), doxorubicin (Dox) alone (G2, n=7), nanoparticle microbubbles alone (G3, n=7), or saline (G4, control, n=6) on days 0 and 7, and were sacrificed on day 11. IVIM-DWI and CEUS were performed before each treatment and before euthanasia. Efficacy was estimated by the percentage of tumor volume growth inhibition compared with control. Toxicity was assessed by body weight changes and blood tests. Post-treatment changes in IVIM-DWI and CEUS parameters were analyzed.

Results: Tumor volume growth was inhibited by 48.4% and 90.2% in G1 and G2 compared to G4, respectively. Compared to G2, G1 had a significantly lower degree of body weight change (median, 91.0% [interquartile range, 88.5%-97.0%] vs. 88.0% [82.5%-88.8%], P<0.05) and leukopenia (1.75×103 cells/μL [1.53-2.77] vs. 1.20×103 cells/μL [0.89-1.51], P<0.05). After the first treatment, an increase in peak enhancement, wash-in rate, and wash-in perfusion index on CEUS was observed in G3 and G4 but suppressed in G1 and G2; the apparent diffusion coefficients, true diffusion coefficients, and perfusion fractions significantly increased in G1 and G2 compared to baseline (P<0.05).

Conclusion: Dox-NP-MB showed reduced Dox toxicity. Early changes in some CEUS and IVIM-DWI parameters correlated with the therapeutic response.
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http://dx.doi.org/10.14366/usg.21036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8696148PMC
January 2022

Respiratory Protection Effect of Ear-loop-type KF94 Masks according to the Wearing Method in COVID-19 Pandemic: a Randomized, Open-label Study.

J Korean Med Sci 2021 Jul 19;36(28):e209. Epub 2021 Jul 19.

Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: Ear-loop-type Korean Filter 94 masks (KF94 masks, equivalent to the N95 and FFP2) are broadly used in health care settings in Korea for the coronavirus disease 2019 pandemic.

Methods: A prospective randomized open-label study was designed to identify differences in the fitting performance between mask wearing methods in three different types of KF94 mask with ear loops between January to March 2021. General-fitting involved wearing an ear-loop-type KF94 mask, and tight-fitting involved wearing a mask aided by a clip connecting the ear loops. Each of the 30 participants wore three types of masks according to a randomly assigned order in both methods and performed a total of six quantitative fit tests (QNFTs) according to the occupational safety and health administration protocol.

Results: All fit factors (FFs) measured by the QNFT were significantly higher for tight-fitting method with the clip in all KF94 masks ( < 0.001). However, the total FFs were very low, with a median (interquartile range) of 6 (3-23) and 29 (9-116) for general-fitting and tight-fitting, respectively. When wearing tightly, the horizontal 3-fold type mask with adjustable ear-loop length had the highest FF, with a median of 125, and the QNFT pass rate (FF ≥ 100) increased significantly from 4 (13%) to 18 (60%).

Conclusion: Even with sufficient filter efficiency, ear-loop-type-KF94 masks do not provide adequate protection. However, in relatively low-risk environments, wearing a face-seal adjustable KF94 mask and tight wearing with a clip can improve respiratory protection for healthcare workers.

Trial Registration: ClinicalTrials.gov Identifier: NCT04794556.
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http://dx.doi.org/10.3346/jkms.2021.36.e209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289716PMC
July 2021

Neuroprotective Effect of Astersaponin I against Parkinson's Disease through Autophagy Induction.

Biomol Ther (Seoul) 2021 Nov;29(6):615-629

Natural Product Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea.

An active compound, triterpene saponin, astersaponin I (AKNS-2) was isolated from Nakai (AKNS) and the autophagy activation and neuroprotective effect was investigated on and Parkinson's disease (PD) models. The autophagy-regulating effect of AKNS-2 was monitored by analyzing the expression of autophagy-related protein markers in SHSY5Y cells using Western blot and fluorescent protein quenching assays. The neuroprotection of AKNS-2 was tested by using a 1-methyl-4-phenyl-2,3-dihydropyridium ion (MPP)-induced PD model in SH-SY5Y cells and an MPTP-induced PD model in mice. The compound-treated SH-SY5Y cells not only showed enhanced microtubule-associated protein 1A/1B-light chain 3-II (LC3-II) and decreased sequestosome 1 (p62) expression but also showed increased phosphorylated extracellular signal-regulated kinases (p-Erk), phosphorylated AMP-activated protein kinase (p-AMPK) and phosphorylated unc-51-like kinase (p-ULK) and decreased phosphorylated mammalian target of rapamycin (p-mTOR) expression. AKNS-2-activated autophagy could be inhibited by the Erk inhibitor U0126 and by AMPK siRNA. In the MPP-induced PD model, AKNS-2 reversed the reduced cell viability and tyrosine hydroxylase (TH) levels and reduced the induced α-synuclein level. In an MPTP-induced PD model, AKNS-2 improved mice behavioral performance, and it restored dopamine synthesis and TH and α-synuclein expression in mouse brain tissues. Consistently, AKNS-2 also modulated the expressions of autophagy related markers in mouse brain tissue. Thus, AKNS-2 upregulates autophagy by activating the Erk/mTOR and AMPK/mTOR pathways. AKNS-2 exerts its neuroprotective effect through autophagy activation and may serve as a potential candidate for PD therapy.
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http://dx.doi.org/10.4062/biomolther.2021.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551730PMC
November 2021

Mathematical modeling of the transmission of SARS-CoV-2-Evaluating the impact of isolation in São Paulo State (Brazil) and lockdown in Spain associated with protective measures on the epidemic of CoViD-19.

PLoS One 2021 15;16(6):e0252271. Epub 2021 Jun 15.

Division of Allergy and Immunology, General Hospital of the Medicine School of University of São Paulo, São Paulo, São Paulo, Brazil.

Coronavirus disease 2019 (CoViD-19), with the fatality rate in elder (60 years old or more) being much higher than young (60 years old or less) patients, was declared a pandemic by the World Health Organization on March 11, 2020. A mathematical model considering young and elder subpopulations under different fatality rates was formulated based on the natural history of CoViD-19 to study the transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The model considered susceptible, exposed, asymptomatic, pre-symptomatic, mild CoViD-19, severe CoViD-19, and recovered compartments, besides compartments of isolated individuals and those who were caught by test. This model was applied to study the epidemiological scenario resulting from the adoption of quarantine (isolation or lockdown) in many countries to control the rapid propagation of CoViD-19. We chose as examples the isolation adopted in São Paulo State (Brazil) in the early phase but not at the beginning of the epidemic, and the lockdown implemented in Spain when the number of severe CoViD-19 cases was increasing rapidly. Based on the data collected from São Paulo State and Spain, the model parameters were evaluated, and we obtained a higher estimation for the basic reproduction number R0 (9.24 for São Paulo State, and 8 for Spain) compared to the currently accepted estimation of R0 around 2 using the SEIR (susceptible, exposed, infectious, and recovered compartments) model. In comparison with the lockdown in Spain, the relatively early adoption of the isolation in São Paulo State resulted in enlarging the period of the first wave of the epidemic and delaying its peak. The model allowed to explain the flattening of the epidemic curves by quarantine when associated with the protective measures (face mask, washing hands with alcohol and gel, and social distancing) adopted by the population. The description of the epidemic under quarantine and protections can be a background to foreseen the epidemiological scenarios from the release strategies, which can help guide public health policies by decision-makers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205178PMC
June 2021

The "Intermediate" CD14 + CD16 + monocyte subpopulation plays a role in IVIG responsiveness of children with Kawasaki disease.

Pediatr Rheumatol Online J 2021 May 31;19(1):76. Epub 2021 May 31.

Department of Pediatric, Chonnam National University Children's Hospital, 42 Jaebong ro, Gwangju, South Korea.

Background: Kawasaki disease (KD) is an acute, self-limited febrile illness of unknown cause. Intravenous immunoglobulin (IVIG)-resistance are related to greater risk for permanent cardiac complications. We aimed to determine the correlation between monocytes and the phenotype of KD in relation to IVIG responsiveness in children.

Materials And Methods: The study cohort included 62 patients who were diagnosed with KD, 20 non febrile healthy controls (NFC), and 15 other febrile controls (OFC). In all enrolled patients, blood was taken at least 4 times and laboratory tests were performed. In addition, subtypes of monocytes were characterized via flow cytometry.

Results: The numbers of intermediate monocytes were significantly lower in IVIG-resistant group compared to IVIG-responsive group before IVIG infusion (p < 0.0001). After infusion, intermediate monocytes decreased in the responsive group, while a trend of increase was observed in the resistant group. Only intermediate monocytes were significant in logistic regression with adjusted OR of 0.001 and p value of 0.03.

Conclusions: CD14 + CD16 + intermediate monocyte may play an important role in IVIG responsiveness among KD children. Low starting levels of intermediate monocytes, followed by a dramatic increase post-IVIG infusion during acute phase of KD are associated with IVIG-resistance. Functional studies on intermediate monocyte may help to reveal the pathophysiology.
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http://dx.doi.org/10.1186/s12969-021-00573-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165978PMC
May 2021

Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma.

Int J Mol Sci 2021 Apr 29;22(9). Epub 2021 Apr 29.

The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.

A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68 macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells ( < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8 T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4 and CD8 T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8 T cells in HCC.
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http://dx.doi.org/10.3390/ijms22094710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124544PMC
April 2021

Suppressed estrogen supply extra-ovarian progesterone receptor membrane component 1 in menopause.

J Biomed Res 2021 Jan;35(3):228-237

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea.

In post-menopausal women, intra-mammary estrogen, which is converted from extra-ovarian estrone (E1), promotes the growth of breast cancer. Since the aromatase inhibitor letrozole does not suppress 17β-estradiol (E2) production from E1, high intra-mammary E1 concentrations impair letrozole's therapeutic efficacy. Progesterone receptor membrane component 1 (Pgrmc1) is a non-classical progesterone receptor associated with breast cancer progression. In the present study, we introduced a heterozygous knockout (hetero KO) murine model exhibiting low Pgrmc1 expression, and observed estrogen levels and steroidogenic gene expression. Naïve hetero KO mice exhibited low estrogen (E2 and E1) levels and low progesterone receptor (PR) expression, compared to wild-type mice. In contrast, hetero KO mice that have been ovariectomized (OVX), including letrozole-treated OVX mice (OVX-letrozole), exhibited high estrogen levels and PR expression. Increased extra-ovarian estrogen production in hetero KO mice was observed with the induction of steroid sulfatase (STS). In MCF-7 cell, letrozole suppressed PR expression, but knockdown increased PR and STS expression. Our presented results highlight the important role of in modulating estrogen production when ovary-derived estrogen is limited, thereby suggesting a potential therapeutic approach for letrozole resistance.
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http://dx.doi.org/10.7555/JBR.35.20200172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193715PMC
January 2021

Assessing the effects of diagnostic sensitivity on schistosomiasis dynamics.

J Theor Biol 2021 08 20;523:110727. Epub 2021 Apr 20.

IMECC-UNICAMP, Campinas, SP, Brazil.

Schistosomiasis is a parasite infection that affects millions of people around the world. It is endemic in 13 different states in Brazil and responsible for increasing morbidity in the population. One of its main characteristics is a heterogeneous distribution of worm burden in the human population, which makes the diagnosis difficult. We aimed to investigate how the sensitivity of the diagnostic method may contribute to successful control interventions against infections in a population. In order to do that, we present an ordinary differential equations model that considers three levels of worm burden in the human population, a snail population, and a miracidium reservoir. Through a steady-state analysis and its local stability, we show how this worm-burden heterogeneity can be responsible for the persistence of infection, especially due to reinfection in the highest level of worm burden. The analysis highlights sensitive diagnosis, besides treatment and sanitary improvements, as a key factor for schistosomiasis transmission control.
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http://dx.doi.org/10.1016/j.jtbi.2021.110727DOI Listing
August 2021

The potential impact of systemic anti-inflammatory therapies in psoriasis on major adverse cardiovascular events: a Korean nationwide cohort study.

Sci Rep 2021 04 21;11(1):8588. Epub 2021 Apr 21.

Department of Dermatology, Konkuk University School of Medicine, 120-1 Neungdong-ro, Gwangjin-gu, Seoul, 143-729, Republic of Korea.

This nationwide population-based cohort study aimed to investigate the impact of systemic anti-inflammatory treatment on the major adverse cardiovascular events (MACE) risk in patients with psoriasis from January 2006 to December 2018, using a database provided by the Korean National Health Insurance Service. Patients were grouped based on the following treatment modalities: biologics, phototherapy, methotrexate, cyclosporine, and mixed conventional systemic agents. Patients who had not received any systemic treatment were assigned to the control cohort. The incidence of MACE per 1000 person-year was 3.5, 9.3, 12.1, 28.4, 39.5, and 14.5 in the biologic, phototherapy, methotrexate, cyclosporine, mixed conventional systemic agents, and control cohorts, respectively. During the 36-month follow-up, the cumulative incidence of MACE in the phototherapy and biologic cohorts remained lower than that of other treatment modalities. Cyclosporine (hazard ratio (HR) = 2.11, 95% confidence interval (CI) = 1.64-2.71) and mixed conventional systemic agents (HR = 2.57, 95% CI = 2.05-3.22) treatments were associated with increased MACE risk. Methotrexate treatment was not associated with MACE. Our finding demonstrates that treatment modalities may affect cardiovascular comorbidities in patients with psoriasis. Thus, an appropriate combination of anti-psoriatic therapies should be considered to manage patients with high cardiovascular risk.IRB approval status: Waiver decision was obtained by the institutional review board, Konkuk University Hospital, Seoul, Republic of Korea (KUH1120107).
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http://dx.doi.org/10.1038/s41598-021-87766-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060423PMC
April 2021

Ce=O Terminated CeO.

Angew Chem Int Ed Engl 2021 Jun 11;60(25):13835-13839. Epub 2021 May 11.

Department of Chemistry and London Centre for Nanotechnology, University College London, 20 Gordon Street, London, WC1H 0AJ, UK.

Multiply bonded lanthanide oxo groups are rare in coordination compounds and have not previously been reported for a surface termination of a lanthanide oxide. Here we report the observation of a Ce=O terminated ceria surface in a CeO (111)-( × )R30° reconstruction of ≈3 nm thick ceria islands prepared on Pt(111). This is evidenced by scanning tunnelling microscopy (STM), low energy electron diffraction (LEED) and high-resolution electron energy loss spectroscopy (HREELS) measurements in conjunction with density functional theory (DFT) calculations. A Ce=O stretching frequency of 775 cm is observed in HREELS, compared with 766 cm calculated by DFT. The calculations also predict that the Ce=O bond is weak, with an oxygen vacancy formation energy of 0.85 eV. This could play an important role in the facile removal of lattice oxygen from CeO , accompanied by the reduction of Ce to Ce , which is a key attribute of ceria-based systems in connection with their unique catalytic properties.
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http://dx.doi.org/10.1002/anie.202101771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251574PMC
June 2021

Narciclasine inhibits LPS-induced neuroinflammation by modulating the Akt/IKK/NF-κB and JNK signaling pathways.

Phytomedicine 2021 May 9;85:153540. Epub 2021 Mar 9.

Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Gangwon-do, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea; Department of Integrative Biological Sciences and Industry, Sejong University, Seoul 05006, Republic of Korea. Electronic address:

Background: Neuroinflammation is defined as innate immune system activation in the central nervous system, and is a complex response involved in removing pathogens, toxic components, and dead cells by activating microglial cells. However, over-activated microglia have been implicated in the pathogenesis of neurodegenerative diseases, because they release large amounts of neurotoxic factors. Thus, inhibiting microglial activation may represent an attractive approach for preventing neuroinflammatory disorders. The objective of this study was to investigate the effect of narciclasine (NA) on lipopolysaccharide (LPS)-induced neuroinflammation by evaluating related markers and neurotoxic factors.

Methods: BV-2 cells were pre-incubated with NA at 0.1, 0.2, and 0.3 µM for 1h, and then co-treated with LPS for 12 h. Cellular medium and lysates were measured using a nitric oxide assay, enzyme-link immunosorbent assay (ELISA), western blotting, kinase activity assay, luciferase assay, and immunofluorescence assay. C57BL/6N mice were orally administered NA and intraperitoneally injected with LPS, and the cerebral cortex was examined using western blotting and immunofluorescence assays.

Results: NA showed novel pharmacological activity, inhibiting pro-inflammatory factors, including TNF-α, IL-6, IL-18, NO, and PGE, but increasing the anti-inflammatory cytokines IL-10 and TGF-β1 in LPS-induced microglial cells. Moreover, NA also attenuated the LPS-induced mRNA and proteins of iNOS and COX-2. The mechanistic study indicated that NA attenuates the secretion of pro-inflammatory factor by down-regulating the Akt/IKK/NF-κB and JNK signaling pathways, and directly inhibits the catalytic activity of IKKα/β. Furthermore, we found that NA also reduced the expression of the microglial markers Iba-1, COX-2, and TNF-α in the mouse brain.

Conclusion: NA inhibits the over-expression of pro-inflammatory factors but it promotes anti-inflammatory cytokines by down-regulating the Akt/IKK/NF-κB and JNK signaling pathways in experimental models. Thus, NA may be a potential candidate for relieving neuroinflammation.
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http://dx.doi.org/10.1016/j.phymed.2021.153540DOI Listing
May 2021

Diagnostic Performance of 2018 KLCA-NCC Practice Guideline for Hepatocellular Carcinoma on Gadoxetic Acid-Enhanced MRI in Patients with Chronic Hepatitis B or Cirrhosis: Comparison with LI-RADS Version 2018.

Korean J Radiol 2021 07 9;22(7):1066-1076. Epub 2021 Mar 9.

Department of Radiology, Seoul National University Hospital, Seoul, Korea.

Objective: To evaluate the performance of the 2018 Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) Practice Guidelines (hereafter, PG) for the diagnosis of hepatocellular carcinoma (HCC) using gadoxetic acid-enhanced MRI, compared to the Liver Imaging-Reporting and Data System (LI-RADS) version 2018 (hereafter, v2018).

Materials And Methods: From January 2013 to October 2015, treatment-naïve hepatic lesions (≥ 1 cm) on gadoxetic acid-enhanced MRI in consecutive patients with chronic hepatitis B or cirrhosis were retrospectively evaluated. For each lesion, three radiologists independently analyzed the imaging features and classified the lesions into categories according to the 2018 KLCA-NCC PG and LI-RADS v2018. The imaging features and categories were determined by consensus. Generalized estimating equation (GEE) models were used to compare the per-lesion diagnostic performance of the 2018 KLCA-NCC PG and LI-RADS v2018 using the consensus data.

Results: In total, 422 lesions (234 HCCs, 45 non-HCC malignancies, and 143 benign lesions) from 387 patients (79% male; mean age, 59 years) were included. In all lesions, the definite HCC (2018 KLCA-NCC PG) had a higher sensitivity and lower specificity than LR-5 (LI-RADS v2018) (87.2% [204/234] vs. 80.8% [189/234], < 0.001; 86.2% [162/188] vs. 91.0% [171/188], = 0.002). However, in lesions of size ≥ 2 cm, the definite HCC had a higher sensitivity than the LR-5 (86.8% [164/189] vs. 82.0 (155/189), = 0.002) without a reduction in the specificity (80.0% [48/60] vs. 83.3% [50/60], = 0.15). In all lesions, the sensitivity and specificity of the definite/probable HCC (2018 KLCA-NCC PG) and LR-5/4 did not differ significantly (89.7% [210/234] vs. 91.5% [214/234], = 0.204; 83.5% [157/188] vs. 79.3% [149/188], = 0.071).

Conclusion: For the diagnosis of HCC of size ≥ 2 cm, the definite HCC (2018 KLCA-NCC PG) had a higher sensitivity than LR-5, without a reduction in specificity. The definite/probable HCC (2018 KLCA-NCC PG) had a similar sensitivity and specificity to that those of the LR-5/4.
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http://dx.doi.org/10.3348/kjr.2020.0846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236366PMC
July 2021

3'-O-Acetyl-24-Epi-7,8-Didehydrocimigenol-3-O-β-DXylopryranoside Decreases Amyloid Beta Production in Amyloid Precursor Protein-Transfected HeLa Cells.

Biomol Ther (Seoul) 2021 May;29(3):290-294

Department of Integrative Biological Sciences and Industry, Sejong University, Seoul 05006, Republic of Korea.

Extracellular beta amyloid (Aβ) plaques are the neuropathological hallmarks of Alzheimer's disease (AD). Accordingly, reducing Aβ levels is considered a promising strategy for AD prevention. 3'-O-acetyl-24-epi-7,8-didehydrocimigenol-3-O-β-D-xylopryranoside significantly decreased the Aβ production and this effect was accompanied with reduced sAPPβ production known as a soluble ectodomain APP fragment through β-secretases in HeLa cells overexpressing amyloid precursor proteins (APPs). This compound also increased the level of sAPPα, which is a proteolytic fragment of APP by α-secretases. In addition, 3'-O-acetyl-24-epi-7,8-didehydrocimigenol-3-O-β-D-xylopryranoside decreased the protein level of β-secretases, but the protein levels of A disintegrin and metalloproteinase (ADAM) family, especially ADAM10 and ADAM17, are increased. Thus, 3'-O-acetyl-24-epi-7,8-didehydrocimigenol-3-O-β-D-xylopryranoside could be useful in the development of AD treatment in the aspect of amyloid pathology.
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http://dx.doi.org/10.4062/biomolther.2020.195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094072PMC
May 2021
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