AIM: To evaluate the inflammasome activation and the effect of peroxisome proliferator-activated receptors(PPAR)-δ agonist treatment in nonalcoholic fatty liver disease(NAFLD) models.METHODS: Male ...C57BL/6J mice were classified according to control or high fat diet(HFD) with or without PPAR-δ agonist(GW) over period of 12 wk control, HFD, HFD + lipopolysaccharide(LPS), HFD + LPS + GW group. Hep G2 cells were exposed to palmitic acid(PA) and/or LPS in the absence or presence of GW.RESULTS: HFD caused glucose intolerance and hepatic steatosis. In mice fed an HFD with LPS, caspase-1 and interleukin(IL)-1β in the liver were significantly increased. Treatment with GW ameliorated the steatosis and inhibited overexpression of pro-inflammatory cytokines. In Hep G2 cells, PA and LPS treatment markedly increased m RNA of several nucleotide-binding andoligomerization domain-like receptor family members(NLRP3, NLRP6, and NLRP10), caspase-1 and IL-1β. PA and LPS also exaggerated reactive oxygen species production. All of the above effects of PA and LPS were reduced by GW. GW also enhanced the phosphorylation of AMPK-α.CONCLUSION: PPAR-δ agonist reduces fatty acidinduced inflammation and steatosis by suppressing inflammasome activation. Targeting the inflammasome by the PPAR-δ agonist may have therapeutic implication for NAFLD.
Non-synonymous SNPs and protein coding SNPs within the promoter region of genes (regulatory SNPs) might have a significant effect on carcass traits. Imputed sequence level data of 10,215 Hanwoo ...bulls, annotated and filtered to include only regulatory SNPs (450,062 SNPs), were used in a genome-wide association study (GWAS) to identify loci associated with backfat thickness (BFT), carcass weight (CWT), eye muscle area (EMA), and marbling score (MS). A total of 15, 176, and 1 SNPs were found to be significantly associated (
< 1.11 × 10
) with BFT, CWT, and EMA, respectively. The significant loci were BTA4 (CWT), BTA6 (CWT), BTA14 (CWT and EMA), and BTA19 (BFT). BayesR estimated that 1.1%~1.9% of the SNPs contributed to more than 0.01% of the phenotypic variance. So, the GWAS was complemented by a gene-set enrichment (GSEA) and protein-protein interaction network (PPIN) analysis in identifying the pathways affecting carcass traits. At
< 0.005 (~2,261 SNPs), 25 GO and 18 KEGG categories, including calcium signaling, cell proliferation, and folate biosynthesis, were found to be enriched through GSEA. The PPIN analysis showed enrichment for 81 candidate genes involved in various pathways, including the PI3K-AKT, calcium, and FoxO signaling pathways. Our finding provides insight into the effects of regulatory SNPs on carcass traits.
Short-term hydroponic-cultured ginseng (sHCG), which is 1-year-old ginseng seedlings cultivated for 4 weeks in a hydroponic system, is a functional food item with several biological effects. However, ...the optimal extraction conditions for sHCG, and the bioactivity of its extracts, have not been evaluated.
Chlorogenic acid (CGA) and ginsenoside contents were evaluated in sHCG, white ginseng (WG), and red ginseng (RG) using high-performance liquid chromatography. Response surface methodology (RSM) was used to optimize the extraction conditions (temperature and ethanol concentration) to maximize the yield of dry matter, CGA, and four ginsenosides (Re, Rg1, Rb1, and Rd) from sHCG. The optimal extraction conditions were applied to pilot-scale production of sHCG extracts. The expression levels of tumor necrosis factor (TNF)-α/interferon (IFN)-γ-induced thymic and activation-regulated chemokines (TARC/CCL17) were measured after treatment with sHCG, WG, and RG extracts, and the effects of their bioactive compounds (CGA and four ginsenosides) on human skin keratinocytes (HaCaTs) were evaluated.
CGA and four ginsenosides, which are bioactive compounds of sHCG, significantly inhibited TNF-α/IFN-γ-induced TARC/CCL17 expression. The optimal sHCG extraction conditions predicted by the RSM models were 80 °C and 60% ethanol (v/v). The sHCG extracts produced at the pilot scale under optimal conditions greatly alleviated TNF-α/IFN-γ-induced TARC/CCL17 production compared with WG and RG extracts.
Pesticide-free sHCG extracts, which contain high levels of CGA and the ginsenosides Re, Rg1, Rb1, and Rd as bioactive compounds, may have therapeutic potential for atopic diseases.
Display omitted
Hepatoma arterial-embolization prognostic (HAP) score and its modifications (modified HAP mHAP and mHAP-II), consisting of some or all of the following factors of tumor size, number, ...alpha-fetoprotein, bilirubin, and serum albumin, have been found to predict outcomes after trans-arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). We investigated the feasibility of using HAP-related risk scores for dynamic risk assessment during repeated TACE.
A total of 619 HCC patients treated with TACE from two institutions between 2003 and 2010 were included.
Patients with A-B class risk scores showed significantly better survival than those with C-D class risk scores at the first (median 43.7 vs. 21.5 months for mHAP-II, 35.2 vs. 10.2 months for mHAP, and 39.8 vs. 18.6 months for HAP; all P < 0.001) and the second rounds of TACE (38.6 vs. 17.2 months for mHAP-II, 30.0 vs. 8.5 months for mHAP, and 32.6 vs. 17.3 months for HAP; all P < 0.001). Sequential assessment of risk scores at the second TACE round was applied for patients with A-B class risk scores at the first TACE round, which further identified two subgroups of A-B and C-D class risk scores with different outcomes (median survival 40.6 vs. 19.6 months for mHAP-II, 31.2 vs. 16.9 months for mHAP, and 35.8 vs. 21.0 months for HAP; all P < 0.001). Compared with mHAP and HAP, mHAP-II showed the highest likelihood ratio (22.61 vs. 14.67 and 13.97, respectively), highest linear trend (24.43 vs. 19.67 and 14.19, respectively), and lowest Akaike information criteria value (1432.51 vs. 3412.29 and 2296.98, respectively).
All HAP-related risk scores dynamically predicted outcomes during repeated TACE. Sequential risk assessment using mHAP-II best identified optimal candidates for repeated TACE.
Ornithine decarboxylase (ODC) is a rate-limiting enzyme in the first step of polyamine biosynthesis that is associated with cell growth and tumor formation. Existing catalytic inhibitors of ODC have ...lacked efficacy in clinical testing or displayed unacceptable toxicity. In this study, we report the identification of an effective and nontoxic allosteric inhibitor of ODC. Using computer docking simulation and an in vitro ODC enzyme assay, we identified herbacetin, a natural compound found in flax and other plants, as a novel ODC inhibitor. Mechanistic investigations defined aspartate 44 in ODC as critical for binding. Herbacetin exhibited potent anticancer activity in colon cancer cell lines expressing high levels of ODC. Intraperitoneal or oral administration of herbacetin effectively suppressed HCT116 xenograft tumor growth and also reduced the number and size of polyps in a mouse model of APC-driven colon cancer (ApcMin/+). Unlike the well-established ODC inhibitor DFMO, herbacetin treatment was not associated with hearing loss. Taken together, our findings defined the natural product herbacetin as an allosteric inhibitor of ODC with chemopreventive and antitumor activity in preclinical models of colon cancer, prompting its further investigation in clinical trials.
Background: Serum asialo α1-acid gycoprotein (AsAGP) is a novel biomarker specific to liver fibrosis. Aim: To evaluate the diagnostic efficacy of serum AsAGP levels in classifying the severity of ...liver fibrosis and differentiating liver cirrhosis (LC) in patients with chronic hepatitis B (CHB) from healthy controls. Methods: Overall, 206 subjects were prospectively enrolled. LC was diagnosed based on liver stiffness levels (>11 kPa) measured using transient elastography. Serum AsAGP levels were measured using an antibody-lectin sandwich immunoassay. We investigated the diagnostic performance by comparing serum AsAGP levels among healthy control, CHB, and CHB with LC groups. Sensitivity, specificity, and optimal AsAGP cut-off values were also calculated. Results: Serum AsAGP levels were significantly different between healthy controls, CHB patients, and CHB patients with LC (1.04 ± 0.31 µg/mL, 1.12 ± 0.34 µg/mL, 1.51 ± 0.43 µg/mL respectively; p < 0.001). Serum AsAGP levels positively correlated with liver stiffness (r = 0.46, p < 0.001). AUROC of healthy control versus CHB with LC was 0.821 (p < 0.001, optimal cut-off 1.036 µg/mL). AUROC of healthy control versus CHB was 0.624 (p = 0.049, optimal cut-off level 0.934 µg/mL). AUROC of CHB versus CHB with LC was 0.765, (p < 0.001, optimal cut-off 1.260 µg/mL). Conclusions: Serum AsAGP levels in CHB patients with LC were significantly higher than those in healthy controls and CHB patients. AsAGP levels showed good diagnostic performance in predicting advanced fibrosis and cirrhosis, which suggests a potential role as a biomarker for predicting the progression of liver disease in CHB.
To evaluate the clinical and imaging characteristics of SARS-CoV-2 breakthrough infection in hospitalized immunocompromised patients in comparison with immunocompetent patients.
This retrospective ...study analyzed consecutive adult patients hospitalized for COVID-19 who received at least one dose of the SARS-CoV-2 vaccine at two academic medical centers between June 2021 and December 2022. Immunocompromised patients (with active solid organ cancer, active hematologic cancer, active immune-mediated inflammatory disease, status post solid organ transplantation, or acquired immune deficiency syndrome) were compared with immunocompetent patients. Multivariable logistic regression analysis was performed to evaluate the effect of immune status on severe clinical outcomes (in-hospital death, mechanical ventilation, or intensive care unit admission), severe radiologic pneumonia (≥ 25% of lung involvement), and typical CT pneumonia.
Of 2218 patients (mean age, 69.5 ± 16.1 years), 274 (12.4%), and 1944 (87.6%) were immunocompromised an immunocompetent, respectively. Patients with active solid organ cancer and patients status post solid organ transplantation had significantly higher risks for severe clinical outcomes (adjusted odds ratio = 1.58 95% confidence interval {CI}, 1.01-2.47,
= 0.042; and 3.12 95% CI, 1.47-6.60,
= 0.003, respectively). Patient status post solid organ transplantation and patients with active hematologic cancer were associated with increased risks for severe pneumonia based on chest radiographs (2.96 95% CI, 1.54-5.67,
= 0.001; and 2.87 95% CI, 1.50-5.49,
= 0.001, respectively) and for typical CT pneumonia (9.03 95% CI, 2.49-32.66,
< 0.001; and 4.18 95% CI, 1.70-10.25,
= 0.002, respectively).
Immunocompromised patients with COVID-19 breakthrough infection showed an increased risk of severe clinical outcome, severe pneumonia based on chest radiographs, and typical CT pneumonia. In particular, patients status post solid organ transplantation was specifically found to be associated with a higher risk of all three outcomes than hospitalized immunocompetent patients.
Background and objectives: Ocular ultrasound is a core application of point-of-care ultrasound (POCUS) to assist physicians in promptly identifying various ocular diseases at the bedside; however, ...hands-on POCUS training is challenging during a pandemic. Materials and Methods: A randomized controlled non-inferiority trial was conducted in an academic emergency department from October 2020 to April 2021. Thirty-two participants were randomly assigned to one of two groups. Group H (hands-on learning group) participated individually in a hands-on session with a standardized patient for 30 min, whereas Group O (online learning group) learned training materials and video clips for 20 min. They scanned four eyeballs of two standardized patients sequentially following the ocular POCUS scan protocol. Repeated POCUS scans were performed 2 weeks later to assess skill maintenance. Both groups completed the pre- and post-surveys and knowledge tests. Two emergency medicine faculty members blindly evaluated the data and assigned a score of 0−25. The primary endpoint was the initial total score of scan quality evaluated using non-inferiority analysis (generalized estimating equation). The secondary endpoints were total scores for scan quality after 2 weeks, scan time, and knowledge test scores. Results: The least squares means of the total scores were 21.7 (0.35) for Group O and 21.3 (0.25) for Group H, and the lower bound of the 95% confidence interval (CI) was greater than the non-inferiority margin of minus 2 (95% CI: −0.48−1.17). The second scan scores were not significantly different from those of the first scan. The groups did not differ in scanning time or knowledge test results; however, Group H showed higher subjective satisfaction with the training method (p < 0.001). Conclusion: This study showed that basic online ocular ultrasound education was not inferior to hands-on education, suggesting that it could be a useful educational approach in the pandemic era.
Alcoholic liver disease (ALD) is a worldwide health problem and hepatocyte apoptosis has been associated with the development/progression of ALD. However, no definite effective pharmacotherapy for ...ALD is currently available. Cilostazol, a selective type III phosphodiesterase inhibitor has been shown to protect hepatocytes from ethanol-induced apoptosis. In the present study, the underlying mechanisms for the protective effects of cilostazol were examined. Primary rat hepatocytes were treated with ethanol in the presence or absence of cilostazol. Cell viability and intracellular cAMP were measured. Apoptosis was detected by Hoechst staining, TUNEL assay, and caspase-3 activity assay. The roles of cAMP and AMP-activated protein kinase (AMPK) pathways in the action of CTZ were explored using pharmacological inhibitors and siRNAs. Liver from mice received ethanol (5 g/kg body weight) by oral gavage following cilostazol treatment intraperitoneally was obtained for measurement of apoptosis and activation of AMPK pathway. Cilostazol inhibited ethanol-induced hepatocyte apoptosis and potentiated the increases in cAMP level induced by forskolin. However, the anti-apoptotic effect of cilostazol was not reversed by an inhibitor of adenylyl cyclase. Interestingly, cilostazol activated AMPK and increased the level of LC3-II, a marker of autophagy. The inhibition of AMPK abolished the effects of cilostazol on LC3-II expression and apoptosis. Moreover, the inhibition of LKB1 and CaMKK2, upstream kinases of AMPK, dampened cilostazol-inhibited apoptosis as well as AMPK activation. In conclusion, cilostazol protected hepatocytes from apoptosis induced by ethanol mainly via AMPK pathway which is regulated by both LKB1 and CaMKK2. Our results suggest that cilostazol may have potential as a promising therapeutic drug for treatment of ALD.
Magnetic resonance imaging (MRI) has become a crucial tool for evaluating mediastinal masses considering that several lesions that appear indeterminate on computed tomography and radiography can be ...differentiated on MRI. Using a three-compartment model to localize the mass and employing a basic knowledge of MRI, radiologists can easily diagnose mediastinal masses. Here, we review the use of MRI in evaluating mediastinal masses and present the images of various mediastinal masses categorized using the International Thymic Malignancy Interest Group's three-compartment classification system. These masses include thymic hyperplasia, thymic cyst, pericardial cyst, thymoma, mediastinal hemangioma, lymphoma, mature teratoma, bronchogenic cyst, esophageal duplication cyst, mediastinal thyroid carcinoma originating from ectopic thyroid tissue, mediastinal liposarcoma, mediastinal pancreatic pseudocyst, neurogenic tumor, meningocele, and plasmacytoma.
PDF
