Survival Benefit of Anticoagulation Therapy in End Stage Kidney Disease Patients with Atrial Fibrillation: A Single Center Retrospective Study.

Background and Objectives: Although the need for anticoagulation to prevent thromboembolism is increasing and non-vitamin K antagonist oral anticoagulants (NOACs) have been tried, there is still controversy about the efficacy of anticoagulation in patients with dialysis. Materials and Methods: We retrospectively analyzed the risk and benefit of anticoagulation in dialysis patients with atrial fibrillation (AF). We retrospectively analyzed all data of 89 patients who received dialysis therapy and were diagnosed with AF. Among them, 27 received anticoagulation (11 warfarin and 16 apixaban 2.5 mg twice a day), while 62 received no anticoagulation. Results: In multivariate Cox regression analysis, compared to no anticoagulation treatment, anticoagulation treatment was associated with a low incidence of all-cause mortality (hazard ratios (HR) 0.36; 95% confidence interval (CI) 0.15-0.88). Compared to no anticoagulation treatment, more anticoagulation treatment patients experienced severe bleeding (HR 4.67; 95% CI 1.26-17.25) and any bleeding (HR 2.79; 95% CI 1.01-7.74). Compared to no anticoagulation, warfarin treatment patients were associated with a low incidence of all-cause mortality (HR 0.26; 95% CI 0.09-0.81) and a high incidence of severe bleeding (HR 4.85; 95% CI 1.12-21.10). All-cause mortality and bleeding were not significantly different between no anticoagulation and apixaban treatment patients. Conclusions: In dialysis patients with AF, anticoagulation therapy is associated with an increased incidence of severe bleeding, but anticoagulation therapy is associated with a low incidence of all-cause mortality. Individualized anticoagulation therapy with careful bleeding monitoring is needed in dialysis patients with AF.

Targeted Delivery of Recombinant Heat Shock Protein 27 to Cardiomyocytes Promotes Recovery from Myocardial Infarction.

Ischemic heart disease, especially myocardial infarction (MI), is the leading cause of death worldwide. Apoptotic mechanisms are thought to play a significant role in cardiomyocyte death after MI. Increased production of heat shock proteins (Hsps) in cardiomyocytes is a normal response to promote tolerance and to reduce cell damage. Hsp27 is considered to be a therapeutic option for the treatment of ischemic heart disease due to its protective effects on hypoxia-induced apoptosis. Despite its antiapoptotic effects, the lack of strategies to deliver Hsp27 to the heart tissue in vivo limits its clinical applicability. In this study, we utilized an antibody against the angiotensin II type 1 (AT1) receptor, which is expressed immediately after ischemia/reperfusion in the heart of MI rats. To achieve cardiomyocyte-targeted Hsp27 delivery after ischemia/reperfusion, we employed the immunoglobulin-binding dimer ZZ, a modified domain of protein A, in conjunction with the AT1 receptor antibody. Using the AT1 receptor antibody, we achieved systemic delivery of ZZ-TAT-GFP fusion protein into the heart of MI rats. This approach enabled selective delivery of Hsp27 to cardiomyocytes, rescued cells from apoptosis, reduced the area of fibrosis, and improved cardiac function in the rat MI model, thus suggesting its applicability as a cardiomyocyte-targeted protein delivery system to inhibit apoptosis induced by ischemic injury.

Antitumor Activity of Ohmyungsamycin A through the Regulation of the Skp2-p27 Axis and MCM4 in Human Colorectal Cancer Cells.

Ohmyungsamycin A (1), a novel cyclic peptide discovered from a marine Streptomyces sp., was previously reported with antibacterial and anticancer activities. However, the antitumor activities and the underlying molecular mechanisms of 1 remain to be elucidated. Compound 1 inhibited the proliferation and tumor growth of HCT116 human colorectal cancer cells based on both in vitro cell cultures and an in vivo animal model. A cDNA microarray analysis revealed that 1 downregulated genes involved in cell cycle checkpoint control. Compound 1 also induced G0/G1 cell cycle arrest that was mediated by the regulation of S-phase kinase-associated protein 2 (Skp2)-p27 axis and minichromosome maintenance protein 4 (MCM4). Furthermore, a longer exposure of 1 exhibited an accumulation of a sub-G1 phase cell population, which is characteristic of apoptotic cells. The induction of apoptosis by 1 was also associated with the modulation of caspase family proteins. Compound 1 effectively suppressed tumor growth in a xenograft mouse model subcutaneously implanted with HCT116 cells. In addition, analysis of tumors revealed that 1 upregulated the expression of the CDK inhibitor p27 but downregulated the expression of Skp2 and MCM4. These findings demonstrate the involvement of 1 in cell cycle regulation and the induction of apoptosis in human colorectal cancer cells.

Synthesis of fluorenes via tandem copper-catalyzed [3 + 2] cycloaddition and rhodium-catalyzed denitrogenative cyclization in a 5-exo mode from 2-ethynylbiaryls and N-sulfonyl azides in one pot.

An efficient synthetic method of fluorenes having an enamine moiety at C-9 methylene bridge is developed from N-sulfonyl-4-biaryl-1,2,3-triazole derivatives via Rh-catalyzed denitrogenative cyclization in a 5-exo mode. Rh-catalyzed denitrogenative cyclization followed by catalytic hydrogenation produces N-tosylaminomethyl-substituted fluorenes in one pot. Moreover, fluorenes are synthesized via tandem Cu-catalyzed [3 + 2] cycloaddition and Rh-catalyzed denitrogenative cyclization in a 5-exo mode starting from 2-ethynylbiaryls and N-sulfonyl azides in one pot.

Systemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-ß Accumulation in Alzheimer's Disease.

Amyloid-ß (Aß) peptide aggregation in the brain is a key factor in Alzheimer's disease. However, direct inhibition of ß-secretase or γ-secretase proves ineffective in reducing Aß accumulation and improving cognition in Alzheimer's. Recent findings suggest that inhibiting gamma-secretase activating protein (GSAP) can decrease Aß generation without affecting crucial γ-secretase substrates. Dimerization of Lep9R3LC (diLep9R3LC) was confirmed by Ellman's test. The peptide-small interfering RNA (siRNA) complex ratio, particle size, and surface charge were analyzed using electrophoretic mobility shift assay, and dynamic light scattering, respectively. In a 3xTg mice model of Alzheimer's disease, diLep9R3LC:siRNA complexes were intravenously administered twice a week for 8 weeks. Assessments included gene silencing, protein expression, and behavioral improvement using reverse transcription polymerase chain reaction, quantitative polymerase chain reaction, western blotting, Y-maze, and object recognition tests. The efficacy of Lep9R3LC dimerization was ~80% after a 3-d reaction by Ellman's test. In N2a cells, diLep9R3LC:siGSAP complexes achieved ~70% silencing at 48 h posttransfection. In 7-month-old male 3xTg mice, GSAP knockdown was ~30% in the cortex and ~50% in the hippocampus. The behavior improved in mice treated with diLep9R3LC:siGSAP complexes, showing a 60% increase in entries and an 80% increase object recognition. A novel dipeptide, diLep9R3LC, complexed with siRNA targeting GSAP (siGSAP), efficiently delivers siRNA to the mouse brain, targeting the hippocampus. The treatment inhibits Aß accumulation, reduces GSK-3ß-associated with tau hyperphosphorylation, and improves Alzheimer's behavior. Our findings highlight diLep9R3LC:siGSAP's potential for Alzheimer's and as a siRNA carrier for central nervous system-related diseases.

Comparison of physicochemical properties and oxidative stability of microencapsulated perilla oil powder prepared by freeze-drying and spray-drying.

Perilla oil is vulnerable to lipid oxidation owing to its high linolenic acid content. Microencapsulation using freeze- and spray-drying methods was applied to enhance the oxidative stability and change the physicochemical properties of perilla oil. Freeze-dried powder (FDP) possessed 11.77 to 38.48% oil content, whereas spray-dried powder (SDP) had 8.90-27.83% oil content. Encapsulation efficiency ranged from 51.22 to 85.71% by freeze-drying and from 77.38 to 90.74% by spray-drying. The oxidative stability of powders depends on the oil content and production methods. Generally, FDP had higher oxidative stability and water solubility, and lower moisture content and water activity than SDP. The particle size of FDP (154.00-192.00 µm) in volume-weight mean diameter was 2.56-24.49 times larger than that of SDP (7.84-72.03 µm). SDP had a lower volatile content at the initial time of storage than FDP, while more volatiles were observed in SDP as storage time increased. The microencapsulation method should be selected appropriately depending on the target property or usage in food applications.

Distribution of aldehydes compared to other oxidation parameters in oil matrices during autoxidation.

Distribution of aldehydes between headspace (HS) and inner matrix (IM) of bulk oil or oil-in-water (O/W) emulsion was determined and contents of aldehydes were compared with other oxidation parameters in soybean oil or O/W emulsion during 50 °C autoxidation. Bulk oil matrix had higher portion of IM aldehydes than O/W emulsion. HS aldehydes in O/W emulsion reflected aldehyde content better than in bulk oil. Moisture content in soybean oil increased distinctively before the generation of oxidation products including hydroperoxides and volatiles. HS aldehydes and other oxidation parameters were simultaneously increased in soybean oil. In case of O/W emulsion, HS aldehydes had a sudden increase point while lipid hydroperoxides and conjugated did not show such increase during autoxidation. HS aldehydes reflected oxidation stage better in O/W emulsion than in bulk oil based on partition distribution and linear changes during autoxidation.

Enhancing oxidative stability of tocopherol-enriched edible oils using short-term exposure to microwave irradiation.

The effect of microwave irradiation on the oxidative stability of tocopherol-enriched corn oil at temperatures of 60 or 100°C was evaluated using the Rancimat assay. Short durations of microwave treatment (1 min) on 10-g oil aliquots were found to increase the induction period of corn oil samples containing 500 and 1000 ppm tocopherol by 7.7% and 9.9%, respectively compared to control oils. The moisture content of tocopherol-enriched corn oil decreased by 15% compared to that of corn oil after 1 min of microwave treatment. At 100°C, 1000 ppm tocopherol-enriched corn oil received 3 min of microwave treatment had 5.8% and 9.9% lower primary and secondary oxidation products than control groups, respectively while this effect was not clearly observed for oils stored at 60°C. However, 15 min of microwave irradiation accelerated the rates of lipid oxidation in corn oils irrespective of the addition of tocopherol. Content of α- and γ-tocopherols in 1 min of microwave irradiated samples remained more by 28.8 and 5.8%, respectively than those of controls after 9 h heat treatment at 100°C. Overall, microwave irradiation within 3 min can increase the oxidative stability of 10 g-corn oils, especially at 100°C, which could be due to the reduced moisture content in the bulk oil matrix. Practical Application: A microwave oven is an irreplaceable home appliance and is widely used in households. Short time exposure to microwave irradiation can remove moisture efficiently from edible oils without the formation of oxidation products, which could increase the oxidative stability of these oils, especially under frying conditions. The results of this study can be utilized to ensure a longer shelf-life of fried products in the food industry by short time treatment of microwave irradiation.

Prediction Models of Early Childhood Caries Based on Machine Learning Algorithms.

In this study, we developed machine learning-based prediction models for early childhood caries and compared their performances with the traditional regression model. We analyzed the data of 4195 children aged 1-5 years from the Korea National Health and Nutrition Examination Survey data (2007-2018). Moreover, we developed prediction models using the XGBoost (version 1.3.1), random forest, and LightGBM (version 3.1.1) algorithms in addition to logistic regression. Two different methods were applied for variable selection, including a regression-based backward elimination and a random forest-based permutation importance classifier. We compared the area under the receiver operating characteristic (AUROC) values and misclassification rates of the different models and observed that all four prediction models had AUROC values ranging between 0.774 and 0.785. Furthermore, no significant difference was observed between the AUROC values of the four models. Based on the results, we can confirm that both traditional logistic regression and ML-based models can show favorable performance and can be used to predict early childhood caries, identify ECC high-risk groups, and implement active preventive treatments. However, further research is essential to improving the performance of the prediction model using recent methods, such as deep learning.

Chemical changes and antioxidant activities of heated whole barley extracts.

Chemical profiles of ethanolic (70%) and aqueous extracts of whole barley heated at 150, 190, and 230 °C were analyzed by GC-MS and their antioxidant properties were studied in vitro, in bulk oil, or in an oil-in-water (O/W) emulsion systems. More chemicals were detected in the ethanolic extract than in the aqueous extract from heated barley; heating decreased the contents of detected chemicals. Organic acids, mono- and di-saccharides, sugar alcohols, and glycerol were the major chemicals detected in both the extracts. Ethanolic extracts possessed higher in vitro antioxidant activities than the aqueous extracts. However, this trend was not clearly observed in the bulk oil and O/W emulsion. For O/W emulsions, ethanolic extracts obtained following heating at 150 °C prevented lipid oxidation better than others. Therefore, heat treatment at 150 °C is recommended to enhance the antioxidant activities of whole barley.

Effects of 1,2-dioleoyl-sn-glycero-3-phosphocholine on moisture content and oxidative stability in soybean oil-water system at different interfaces.

Effects of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) on the oxidative stability were determined in soybean oil-water system at different locations including at the interface of air-oil, in the middle of oil, and at the interface of oil-water. Also, profile changes of tocopherols were determined during UV irradiation for 18 days. Although no significant changes in tocopherol profiles were observed at three different locations irrespective of DOPC from 0 to 1250 µmol/kg oil, addition of DOPC increased total tocopherols, α-tocopherol, and δ-tocopherol whereas content of ß + γ tocopherols did not increase at any locations. Moisture content in water-oil interface was higher than other locations while those were not consistent at different DOPC concentration. Added DOPC significantly decreased oxidative stability from 250 to 830 µmol/kg oil compared to controls (p < 0.05) whereas 1250 µmol/kg oil DOPC increased oxidative stability. Stabilities of tocopherols especially α-tocopherol were lower in oil-water system than those in bulk oil at UV irradiation.

Protective effect of daidzin against D-galactosamine and lipopolysaccharide-induced hepatic failure in mice.

This study examined the effects of daidzin, a major isoflavone from Puerariae Radix, on D-galactosamine (D-GalN) and lipopolysaccharide (LPS)-induced liver failure. Mice were given an intraperitoneal injection of daidzin (25, 50, 100 and 200 mg/kg) 1 h before receiving an injection of D-GalN (700 mg/kg)/LPS (10 microg/kg). Daidzin markedly reduced the elevated serum aminotransferase activity and the levels of lipid peroxidation and tumor necrosis factor-alpha. The glutathione content was lower in the D-GalN/LPS group, which was attenuated by daidzin. The daidzin pretreatment attenuated the swollen mitochondria observed in the d-GalN/LPS group. Daidzin attenuated the apoptosis of hepatocytes, which was confirmed using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling method and a caspase-3 assay. Overall, these results suggest that the liver protection of daidzin is due to reduced oxidative stress and its antiapoptotic activity.

Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most intractable cancer in women with a high risk of metastasis. While hyper-methylation of histone H3 catalyzed by disruptor of telomeric silencing 1-like (DOT1L), a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), is reported as a potential target for TNBCs, early developed nucleoside-type DOT1L inhibitors are not sufficient for effective inhibition of growth and metastasis of TNBC cells. We found that TNBC cells had a high expression level of DOT1L and a low expression level of E-cadherin compared to normal breast epithelial cells and non-TNBC cells. Here, a novel psammaplin A analog (PsA-3091) exhibited a potent inhibitory effect of DOT1L-mediated H3K79 methylation. Consistently, PsA-3091 also significantly inhibited the proliferation, migration, and invasion of TNBC cells along with the augmented expression of E-cadherin and the suppression of N-cadherin, ZEB1, and vimentin expression. In an orthotopic mouse model, PsA-3091 effectively inhibited lung metastasis and tumor growth by the regulation of DOT1L activity and EMT biomarkers. Together, we report here a new template of DOT1L inhibitor and suggest that targeting DOT1L-mediated H3K79 methylation by a novel PsA analog may be a promising strategy for the treatment of metastatic breast cancer patients.

Cytoprotective effects of melatonin against necrosis and apoptosis induced by ischemia/reperfusion injury in rat liver.

Melatonin protects against organ ischemia; this effect has mainly been attributed to the antioxidant properties of the indoleamine. This study examined the cytoprotective properties of melatonin against injury to the liver caused by ischemia/reperfusion (I/R). Rats were subjected to 60 min of ischemia followed by 5 hr of reperfusion. Melatonin (10 mg/kg) or the vehicle was administered intraperitoneally 15 min before ischemia and immediately before reperfusion. The serum aminotransferase activity and lipid peroxidation levels were increased markedly by hepatic I/R, which were suppressed significantly by melatonin. In contrast, the glutathione content, which is an index of the cellular redox state, and mitochondrial glutamate dehydrogenase activity, which is a maker of the mitochondrial membrane integrity, were lower in the I/R rats. These decreases were attenuated by melatonin. The rate of mitochondrial swelling, which reflects the extent of the mitochondrial permeability transition, was higher after 5 hr of reperfusion but was attenuated by melatonin. Melatonin limited the release of cytochrome c into the cytosol and the activation of caspase-3 observed in the I/R rats. The melatonin-treated rats showed markedly fewer apoptotic (TUNEL positive) cells and DNA fragmentation than did the I/R rats. These results suggest that melatonin ameliorates I/R-induced hepatocytes damage by inhibiting the level of oxidative stress and the apoptotic pathway. Consequently, melatonin may provide a new pharmacological intervention strategy for hepatic I/R injuries.

Oxidative Stability in Oil-in-Water Emulsions with Quercetin or Rutin Under Iron Catalysis or Riboflavin Photosensitization.

The effects of quercetin and rutin on the oxidative stability of oil-in-water (O/W) emulsions were tested under riboflavin (RF) photosensitization in the presence or absence of FeCl2 . The degree of oxidation in O/W emulsions was determined by headspace oxygen content, conjugated dienes, and lipid hydroperoxides. Quercetin chelated more metal than did rutin in iron catalyzed O/W emulsions. Generally, 0.1 mM quercetin and rutin was oxidative while 0.5 and 1.0 mM quercetin and rutin was antioxidative in O/W emulsions under RF photosensitization. Depending on the analysis method, the antioxidants had different strengths. The antioxidative or oxidative properties of quercetin and rutin vary in O/W emulsions and depend the quercetin and rutin concentrations and oxidative forces like transition metals, RF photosensitization, or a combination thereof.

Cobalt-Catalyzed Carbonylative Cyclization of Pyridinyl Diazoacetates for the Synthesis of Pyridoisoquinolinones.

Dicobalt octacarbonyl-catalyzed carbonylative cyclization of pyridinyl diazoacetates is developed for the synthesis of pyridoisoquinolinones under mild conditions (room temperature) in a carbon monoxide atmosphere. Moreover, a synthetic method for various pyridoisoquinolinones from ethylpyridinyl aryl acetates is demonstrated through diazotization using TsN3 and DBU followed by Co-catalyzed carbonylation to generate ketene intermediates, which can subsequently undergo intramolecular cyclization under mild conditions in a carbon monoxide atmosphere in a semi-one-pot fashion.

Synthesis of Cinnolin-3(2H)-one Derivatives from Rh-Catalyzed Reaction of Azobenzenes with Diazotized Meldrum's Acid.

A synthetic method of a wide range of cinnolin-3(2H)-one derivatives is developed from the reaction of symmetrical as well as unsymmetrical azobenzenes with diazotized Meldrum's acid via Rh-catalyzed C-H alkylation followed by cyclization.

Derivation of the center-wavelength shift of narrow-bandpass filters under temperature change.

We derive a simple equation to predict the center-wavelength shift of a Fabry-Perot type narrow-bandpass filter by using the conventional characteristic matrix method and the elastic strain model as the temperature varies. We determine the thermal expansion coefficient of substrate from the zero-shift condition of the center wavelength of the filter. The calculated shifts are in a good agreement with the experimental ones, in which the narrow-bandpass filters are prepared by plasma ion-assisted deposition on four substrates with different thermal expansion coefficients.

DNA-PCR and RT-PCR for the 18-kDa gene of Mycobacterium leprae to assess the efficacy of multi-drug therapy for leprosy.

DNA-PCR and reverse transcription (RT)-PCR for the 18-kDa protein of Mycobacterium leprae were used to examine the efficacy of multi-drug therapy (MDT) in leprosy. MDT was administered for 0-24 months. Fourteen (63.6%) of 22 patients showed positive PCR results after treatment for 12 months and the positive results decreased to 30% after 24 months of MDT. These results did not correlate with the bacterial index (BI) or the IgM antibody titre for the phenolic glycolipid (PGL)-1. One-dimensional densitometric analysis of agarose gels from PCR from the longitudinal study showed a gradual reduction of the 360-bp band after 12-24 months of MDT. RT-PCR for mRNA of the 18-kDa protein successfully tracked bacterial RNA changes in the biopsies and confirmed a decrease in the RNA of M. leprae in patients after MDT for 12 months. Thus, DNA- and RT-PCR for the 18-kDa protein of M. leprae are effective in assessing the efficacy of MDT for leprosy.