ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.

Background: Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. Methods: We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. Results: Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate. Conclusions: This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.

Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.

OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss. METHODS: We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mutant leukemia using RNA sequencing, mass spectrometry, and computational modeling. RESULTS: D2-HG impairs NADH redox homeostasis in myotubes. Increased NAD+ levels drive activation of nuclear deacetylase Sirt1, which causes deacetylation and activation of LC3, a key regulator of autophagy. Using LC3 mutants, we confirm that deacetylation of LC3 by Sirt1 shifts its distribution from the nucleus into the cytosol, where it can undergo lipidation at pre-autophagic membranes. Sirt1 silencing or p300 overexpression attenuated autophagy activation in myotubes. In vivo, we identified increased muscle atrophy and reduced grip strength in response to D2-HG in male vs. female mice. In male mice, glycolytic intermediates accumulated, and protein expression of oxidative phosphorylation machinery was reduced. In contrast, female animals upregulated the same proteins, attenuating the phenotype in vivo. Network modeling and machine learning algorithms allowed us to identify candidate proteins essential for regulating oncometabolic adaptation in mouse skeletal muscle. CONCLUSIONS: Our multi-omics approach exposes new metabolic vulnerabilities in response to D2-HG in skeletal muscle and provides a conceptual framework for identifying therapeutic targets in cachexia.

Emergence of Stable Meron Quartets in Twisted Magnets.

The investigation of twist engineering in easy-axis magnetic systems has revealed remarkable potential for generating topological spin textures. Implementing twist engineering in easy-plane magnets, we introduce a novel approach to achieving fractional topological spin textures, such as merons. Through atomistic spin simulations on twisted bilayer magnets, we demonstrate the formation of a stable double Meron pair, which we refer to as the "Meron Quartet" (MQ). Unlike a single pair, the merons within the MQ exhibit exceptional stability against pair annihilation due to the protective localization mechanism induced by the twist that prevents collision of the Meron cores. Furthermore, we showcase that the stability of the MQ can be enhanced by adjusting the twist angle, resulting in an increased resistance to external perturbations such as external magnetic fields. Our findings highlight the twisted magnet as a promising platform for achieving merons as stable magnetic quasiparticles in van der Waals magnets.

Endometriosis-Related Chronic Pelvic Pain.

Endometriosis, which is the presence of endometrial stroma and glands outside the uterus, is one of the most frequently diagnosed gynecologic diseases in reproductive women. Patients with endometriosis suffer from various pain symptoms such as dysmenorrhea, dyspareunia, and chronic pelvic pain. The pathophysiology for chronic pain in patients with endometriosis has not been fully understood. Altered inflammatory responses have been shown to contribute to pain symptoms. Increased secretion of cytokines, angiogenic factors, and nerve growth factors has been suggested to increase pain. Also, altered distribution of nerve fibers may also contribute to chronic pain. Aside from local contributing factors, sensitization of the nervous system is also important in understanding persistent pain in endometriosis. Peripheral sensitization as well as central sensitization have been identified in patients with endometriosis. These sensitizations of the nervous system can also explain increased incidence of comorbidities related to pain such as irritable bowel disease, bladder pain syndrome, and vulvodynia in patients with endometriosis. In conclusion, there are various possible mechanisms behind pain in patients with endometriosis, and understanding these mechanisms can help clinicians understand the nature of the pain symptoms and decide on treatments for endometriosis-related pain symptoms.

Thermal Gradient Infrared Spectroscopy for Diffusion in Polymers.

Time-resolved Fourier transform infrared-attenuated total reflectance spectroscopy (FTIR-ATR) was used to measure diffusion in opaque and translucent samples. FTIR-ATR was used to measure the change in the absorbance near the heated ATR crystal surface. The infrared absorbance was then related to the concentration through the Beer-Lambert law. The sample used is a polymer electrolyte composed of lithium bis-trifluoromethanesulfonylimide (LiTFSI) salt in a block copolymer polystyrene-poly(ethylene oxide) (SEO). A new approach to introduce concentration gradients is presented using a temperature gradient that creates a small salt concentration gradient due to thermally driven mass diffusion (the Soret effect). This first method was compared to a second method that we reported using two laminated polymer electrolyte films of different salt concentrations. The thermal gradient study (method 1) covered three temperature differences of 10, 15, and 20 °C, while the second study (method 2) used three average molar ratios across isothermal temperatures ranging from 80 to 120 °C. The benefits and limitations of the new approach are reported, as is the activation energy for salt diffusion in this and similar SEO electrolytes. Developing new techniques to measure diffusion coefficients effectively will aid in the development of a variety of devices, including solid-state batteries and thermogalvanic cells, that are able to convert waste heat into electricity and improve the efficiency of power-generating systems. FTIR-ATR overcomes previous limitations in experimental techniques measuring diffusion coefficients. The results prove that thermal gradient FTIR-ATR is an effective and repeatable approach for determining Fickian diffusion coefficients in viscoelastic solids.

Ab Initio Spin Hamiltonian and Topological Noncentrosymmetric Magnetism in Twisted Bilayer CrI3.

Twist engineering of van der Waals magnets has emerged as an outstanding platform for manipulating exotic magnetic states. However, the complicated form of spin interactions in the large moiré superlattice obstructs a concrete understanding of such spin systems. To tackle this problem, for the first time, we developed a generic ab initio spin Hamiltonian for twisted bilayer magnets. Our atomistic model reveals that strong AB sublattice symmetry breaking due to the twist introduces a promising route to realize the novel noncentrosymmetric magnetism. Several unprecedented features and phases are uncovered including the peculiar domain structure and skyrmion phase induced by noncentrosymmetricity. The diagram of those distinctive magnetic phases has been constructed, and the detailed nature of their transitions analyzed. Further, we established the topological band theory of moiré magnons relevant to each of these phases. By respecting the full lattice structure, our theory provides the characteristic features that can be detected in experiments.

Calibration of BRDF Based on the Field Goniometer System Using a UAV Multispectral Camera.

The bidirectional reflectance distribution function (BRDF) is important for estimating the physical properties of a surface in remote sensing. In the laboratory, the BRDF can be estimated quickly and accurately using a goniometer, but it is very difficult to operate in the field. The purpose of this study was to evaluate whether estimating the BRDF with reasonable accuracy using an unmanned aerial vehicle (UAV) with a multispectral camera is possible in the field. Hemispherical reflectance was created from images taken using an UAV multispectral camera. The ground targets were four calibrated reference tarps (CRTs) of different reflectance, and the UAV was operated five times. Down-welling irradiance for reflectance calculation was measured in two ways: a sunlight sensor was mounted on a UAV, and a spectroradiometer with a remote cosine receptor (RCR) was installed on the ground. The BRDF was assessed through the anisotropy factor (ANIF) of the CRT reflectance derived from the collected data. As a result, the irradiance data for the reflectance calculation were more effective from the spectroradiometer with RCR on the ground than from the sunlight sensor mounted on an UAV. Furthermore, the high reflectance CRTs, ANIF, and BRDF had similar results. Therefore, when analyzing the BRDF, the effectiveness can be guaranteed when the reflectance of the target is over 21~46%, because a low reflectance tendency differs due to the adjacency effect. In addition, weather affects irradiance, so it is more effective to conduct fieldwork in clear weather.

Fabrication of Highly Porous and Pure Zinc Oxide Films Using Modified DC Magnetron Sputtering and Post-Oxidation.

Porous films of metals and metal oxides exhibit larger surface areas and higher reactivities than those of dense films. Therefore, they have gained growing attention as potential materials for use in various applications. This study reports the use of a modified direct current magnetron sputtering method to form porous Zn-ZnO composite films, wherein a subsequent wet post-oxidation process is employed to fabricate pure porous ZnO films. The porous Zn-ZnO composite films were initially formed in clusters, and evaluation of their resulting properties allowed the optimal conditions to be determined. An oxygen ratio of 0.3% in the argon gas flow resulted in the best porosity, while a process pressure of 14 mTorr was optimal. Following deposition, porous ZnO films were obtained through rapid thermal annealing in the presence of water vapor, and the properties and porosities of the obtained films were analyzed. An oxidation temperature of 500 °C was optimal, with an oxidation time of 5 min giving a pure ZnO film with 26% porosity. Due to the fact that the films produced using this method are highly reliable, they could be employed in applications that require large specific surface areas, such as sensors, supercapacitors, and batteries.

Automatically Attributing Mobile Threat Actors by Vectorized ATT&CK Matrix and Paired Indicator.

During the past decade, mobile attacks have been established as an indispensable attack vector adopted by Advanced Persistent Threat (APT) groups. The ubiquitous nature of the smartphone has allowed users to use mobile payments and store private or sensitive data (i.e., login credentials). Consequently, various APT groups have focused on exploiting these vulnerabilities. Past studies have proposed automated classification and detection methods, while few studies have covered the cyber attribution. Our study introduces an automated system that focuses on cyber attribution. Adopting MITRE's ATT&CK for mobile, we performed our study using the tactic, technique, and procedures (TTPs). By comparing the indicator of compromise (IoC), we were able to help reduce the false flags during our experiment. Moreover, we examined 12 threat actors and 120 malware using the automated method for detecting cyber attribution.

Effects of the methanol fraction of modified Seonghyangjeongki-san water extract on transient ischaemic brain injury in mice.

CONTEXT: Recently in Korean medicine, the antioxidant and anti-inflammatory activities of Seonghyangjeongki-san (SHJKS) were reported. However, studies on the specific mechanisms of action of SHJKS for the treatment of ischaemic stroke are still lacking. OBJECTIVE: This study investigates the mechanism of action of the water extract methanol fraction of modified SHJKS (SHJKSmex) on cerebral ischaemic injury. MATERIALS AND METHODS: C57BL/6 male mice were orally administered SHJKSmex (30, 100, or 300 mg/kg) for 3 consecutive days (2 days, 1 day, and 1 h, respectively) before middle cerebral artery occlusion (MCAO). Twenty-four hours after MCAO, the infarct volumes were measured, brain edoema indices were calculated, and neurological deficit scores were determined. Inflammation-related substances in the ipsilateral hemisphere were determined by western blotting, dichlorofluorescin diacetate, thiobarbituric acid-reactive substances assay, and enzyme-linked immunosorbent assay. RESULTS: SHJKSmex pre-treatment at 300 mg/kg decreased infarct volume by 87% and mean brain water content by 90% of the MCAO control group. Moreover, SHJKSmex effectively suppressed the expression of inducible nitric oxide synthase, reactive oxygen species, interleukin 1, and caspases-8 and -9 and increased the B-cell lymphoma 2/Bcl-2-associated X protein ratio (Bcl-2/Bax) in ischaemic mouse brain. The hippocampal pyramidal cell densities were significantly increased in the 300 mg/kg SHJKSmex-administered group compared to the MCAO control group. DISCUSSION AND CONCLUSIONS: SHJKSmex protected the brain from ischaemic stroke in mice through its antioxidant, anti-inflammatory, and antiapoptotic activities. Our findings suggest that SHJKSmex is a promising therapeutic candidate for the development of a new formulation for ischaemia-induced brain damage.

The Reliability and Validity of the Korean Version of the Mood and Feelings Questionnaire for Depression in Youth: A Cross-Cultural Perspective.

We aimed to assess cross-cultural differences in depressive symptoms and the validity of the Korean version of the Mood and Feelings Questionnaire (MFQ). Four hundred and sixty-four children and adolescents (aged 7-19, 278 girls) with any psychiatric diagnosis, 290 of whom had major depressive disorder, were included. The levels of depressive symptoms in children and adolescents were evaluated by children/adolescents and their parents. We conducted Pearson's r and Cronbach's α, confirmative factor analysis and item response theory tests. The Korean version of the MFQ demonstrated excellent criterion validity and discriminant validity. There were no cultural differences in the clinical manifestations of depression in youth from Western countries and Korea. Korean youths with depression were more likely to complain of cognitive and emotional symptoms than somatic symptoms. The Korean version of the MFQ demonstrated promising psychometric properties in a clinical sample of children and adolescents.

Lithium Salt Diffusion in Diblock Copolymer Electrolyte Using Fourier Transform Infrared Spectroscopy.

The diffusion of a lithium salt through a diblock copolymer electrolyte was studied using vibrational spectroscopy. Lithium bis-trifluoromethylsulfonimide (LiTFSI) was dissolved in a lamellar-structured, high-molecular-weight polystyrene-poly(ethylene oxide) diblock copolymer at various concentrations (0-4.51 molLiTFSI/kgPEO). The diffusion coefficient of LiTFSI was determined from time-resolved Fourier Transform infrared spectroscopy attenuated total reflectance (FTIR-ATR) as a function of the salt concentration. By the application of the Beer-Lambert law, FTIR-ATR was used to detect concentration changes. Mutual diffusion was driven by putting in contact two polymer electrolyte membranes with different salt concentrations. Thus, mutual diffusion coefficients were obtained without the influence of electric fields or electrode interfaces. The accuracy of the simple experimental approach and straightforward analysis was validated by comparison to diffusion coefficients reported from measurements in electrochemical cells. Both methods yield mutual diffusion coefficients of lithium salt that are only weakly (and nonmonotonically) dependent on salt concentration. There is some indication in the spectra that there exist two populations of salt with different dissociation states. This could explain the observed nonmonotonic concentration dependence of the mutual diffusion coefficient of the salt. This hypothesis will be examined quantitatively with complementary measurements in future work.

Interferometric time- and energy-resolved photoemission electron microscopy for few-femtosecond nanoplasmonic dynamics.

We report a time-resolved normal-incidence photoemission electron microscope with an imaging time-of-flight detector using ∼7-fs near-infrared laser pulses and a phase-stabilized interferometer for studying ultrafast nanoplasmonic dynamics via nonlinear photoemission from metallic nanostructures. The interferometer's stability (35 ± 6 as root-mean-square from 0.2 Hz to 40 kHz) as well as on-line characterization of the driving laser field, which is a requirement for nanoplasmonic near-field reconstruction, is discussed in detail. We observed strong field enhancement and few-femtosecond localized surface plasmon lifetimes at a monolayer of self-assembled gold nanospheres with ∼40 nm diameter and ∼2 nm interparticle distance. A wide range of plasmon resonance frequencies could be simultaneously detected in the time domain at different nanospheres, which are distinguishable already within the first optical cycle or as close as about ±1 fs around time-zero. Energy-resolved imaging (microspectroscopy) additionally revealed spectral broadening due to strong-field or space charge effects. These results provide a clear path toward visualizing optically excited nanoplasmonic near-fields at ultimate spatiotemporal resolution.

Efficacy and Safety of Switching to Teneligliptin in Patients with Type 2 Diabetes Inadequately Controlled with Dipeptidyl Peptidase-4 Inhibitors: A 12-Week Interim Report.

INTRODUCTION: Teneligliptin, an antidiabetic agent classified as a class III dipeptidyl peptidase-4 (DPP-4) inhibitor, has a unique structural feature that provides strong binding to DPP-4 enzymes. We investigated the efficacy and safety of switching patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control on a stable dose of other DPP-4 inhibitors to teneligliptin. METHODS: Patients with T2DM whose glycosylated hemoglobin (HbA1c) levels were ≥ 7% despite taking DPP-4 inhibitors other than teneligliptin, with or without other hypoglycemic agents, for at least 3 months were enrolled. The DPP-4 inhibitors taken before participating in the study were switched to 20 mg qd teneligliptin, and this was to be maintained for 52 weeks. The primary end point was the change in HbA1c levels after 12 weeks. Metabolic parameters including fasting plasma glucose (FPG) and blood lipids were assessed also. To assess safety, adverse and hypoglycemic events were monitored. The data from baseline to week 12 were used for analysis in this interim report. RESULTS: The mean change in HbA1c levels from baseline to week 12 was - 0.44%. At week 12, the percentage of patients achieving HbA1c < 7.0% was 31.6% and that of achieving HbA1c < 6.5% was 11.4%, respectively. In 41.2% of patients, the HbA1c levels decreased by at least 0.5% at 12 weeks. The mean change in FPG levels from baseline to week 12 was - 11.5 mg/dl. No severe hypoglycemia was reported. CONCLUSION: After switching to teneligliptin, HbA1c levels decreased significantly in patients with T2DM inadequately controlled with other DPP-4 inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03793023. FUNDING: Handok Inc.

Psychometric Properties and Factor Structures of the Korean Version of Children's Depression Rating Scale-Revised.

OBJECTIVE: The Children's Depression Rating Scale-Revised (CDRS-R) is a valid instrument for the assessment of depressive symptoms in youth, but this measure is yet to be validated in Korea. Thus, the present study aimed to evaluate the validity of the Korean version of the CDRS-R and to determine its factor structures. METHODS: This study included 66 youths between 12 and 17 years of age who participated as part of an ongoing study investigating biomarkers of the antidepressant response and suicidal events in depressed youth. At baseline, the participants were assessed using the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version (K-SADS-PL), CDRS-R, Children's Depression Inventory (CDI), Beck Depression Inventory (BDI), Clinical Global Impressions-Severity (CGI-S), Children's Global Assessment Scale (CGAS), and Child Behavior Checklist (CBCL). Based on their diagnosis, each participant was assessed either five (major depressive disorder [MDD], n = 36) or two (non-MDD, n = 30) more times with the CDRS-R, CDI, BDI, CGI-S, and CGAS; thus, 306 assessments were included in the final analyses of the present study. Pearson's r and Cronbach's α values were used to determine validity and internal consistency, and exploratory factor analysis was performed to determine the factor structures of the Korean version of the CDRS-R. RESULTS: The CDRS-R score was significantly correlated with scores on the K-SADS-PL depression subscale (r = 0.93, p < 0.01), CDI (r = 0.86, p < 0.01), BDI (r = 0.85, p < 0.01), CGI-S (r = 0.84, p < 0.01), and CGAS (r = -0.86, p < 0.01), indicating that this measure has strong criterion validity. In addition, the high correlation of the CDRS-R with the depression subscale of the CBCL (r = 0.67, p < 0.01) and lower correlations with the subscales of the CBCL that assess delinquent behavior, aggressive behavior, and externalizing problem support the discriminant validity of this instrument (rs ≤ 0.50, p < 0.01). Internal consistency was high, as evidenced by a Cronbach's α of 0.91, and the exploratory factor analysis revealed that the Korean version of the CDRS-R comprised three factors as follows: subjective depressed mood, daily functional impairment, and observed depressive affect. These factors differed from those used in previous studies, which were performed with the English version of the CDRS-R. CONCLUSIONS: This study of the Korean version of the CDRS-R provides initial promising data regarding its criterion validity, discriminant validity, internal consistency, and factor structures. These properties were significantly strong, which suggests that the Korean version of the CDRS-R is a valid and reliable instrument for the assessment of depressive symptoms in youth.

Effects of pretreatment with methanol extract of Peucedani Radix on transient ischemic brain injury in mice.

BACKGROUND: Stroke is the second most common cause of death and may result in various disabilities; thus, identification of neuroprotective therapeutic agents is important. Peucedani Radix (PR), the root of Angelica decursiva, is a well-known remedy for damp and phlegm in Korean medicine and has also been shown to exert antioxidant and anti-inflammatory activities. This study was performed to investigate the mechanism underlying the anti-inflammatory effect of methanol extract of PR (PRex) on cerebral ischemic injury. METHODS: C57BL/6 male mice were orally administered PRex (20, 60, or 200 mg/kg) at 2 days, 1 day, and 1 h prior to middle cerebral artery occlusion (MCAO). Twenty-four hours after MCAO, the infarct volume was measured and the neurological deficit score was assessed. The inflammatory-related substances in the ipsilateral hemisphere were determined by western blotting, DCFH-DA assay, TBARS assay, and ELISA. RESULTS: PRex pretreatment significantly decreased the infarct volume at 24 h after MCAO. Moreover, PRex effectively suppressed the expression of iNOS, ROS, MDA, and pro-inflammatory cytokines, such as IL-1ß and TNF-α, in brain tissue of mice with MCAO-induced brain injury. CONCLUSIONS: PRex protected neurons from ischemic brain injury in mice through its antioxidant and anti-inflammatory activities. Our results suggested that PR could be a promising candidate in the therapy of ischemia-induced brain damage.

Cytotoxicity, Intestinal Transport, and Bioavailability of Dispersible Iron and Zinc Supplements.

Iron or zinc deficiency is one of the most important nutritional disorders which causes health problem. However, food fortification with minerals often induces unacceptable organoleptic changes during preparation process and storage, has low bioavailability and solubility, and is expensive. Nanotechnology surface modification to obtain novel characteristics can be a useful tool to overcome these problems. In this study, the efficacy and potential toxicity of dispersible Fe or Zn supplement coated in dextrin and glycerides (SunActive FeTM and SunActive ZnTM) were evaluated in terms of cytotoxicity, intestinal transport, and bioavailability, as compared with each counterpart without coating, ferric pyrophosphate (FePP) and zinc oxide (ZnO) nanoparticles (NPs), respectively. The results demonstrate that the cytotoxicity of FePP was not significantly affected by surface modification (SunActive FeTM), while SunActive ZnTM was more cytotoxic than ZnO-NPs. Cellular uptake and intestinal transport efficiency of SunActive FeTM were significantly higher than those of its counterpart material, which was in good agreement with enhanced oral absorption efficacy after a single-dose oral administration to rats. These results seem to be related to dissolution, particle dispersibility, and coating stability of materials depending on suspending media. Both SunActiveTM products and their counterpart materials were determined to be primarily transported by microfold (M) cells through the intestinal epithelium. It was, therefore, concluded that surface modification of food fortification will be a useful strategy to enhance oral absorption efficiency at safe levels.

Biokinetics of food additive silica nanoparticles and their interactions with food components.

Nanomaterials have been widely utilized in the food industry in production, packaging, sensors, nutrient delivery systems, and food additives. However, research on the interactions between food-grade nanoparticles and biomolecules as well as their potential toxicity is limited. In the present study, the in vivo solubility, oral absorption, tissue distribution, and excretion kinetics of one of the most extensively used food additives, silica (SiO2) were evaluated with respect to particle size (nano vs bulk) following single-dose oral administration to rats. Intestinal transport mechanism was investigated using a 3D culture system, in vitro model of human intestinal follicle-associated epithelium (FAE). The effect of the presence of food components, such as sugar and protein, on the oral absorption of nanoparticles was also evaluated with focus on their interactions. The results obtained demonstrated that the oral absorption of nanoparticles (3.94±0.38%) was greater than that of bulk materials (2.95±0.37%), possibly due to intestinal transport by microfold (M) cells. On the other hand, particle size was found to have no significant effect on in vivo dissolution property, biodistribution, or excretion kinetics. Oral absorption profile of silica nanoparticles was highly dependent on the presence of sugar or protein, showing rapid absorption rate in glucose, presumably due to their surface interaction on nanoparticles. These findings will be useful for predicting the potential toxicity of food-grade nanoparticles and for understanding biological interactions.

Stable fluorescence conjugation of ZnO nanoparticles and their size dependent cellular uptake.

We evaluated size dependent cellular uptake of ZnO nanoparticles utilizing stably introduced Cy5.5, which emits long-wavelength fluorescence. Through (3-aminopropyl)triethoxysilane modification, ZnO nanoparticles of different sizes (20 and 70nm) were functionalized with amine moiety, which was further reacted with Cy5.5-N-hydroxylsuccinimide ester to make covalently conjugated Cy5.5 dye on ZnO nanoparticles. Field emission-scanning electron microscopic images revealed that average particle size as well as particle morphology of ZnO nanoparticles were not altered by Cy5.5 conjugation. Zeta potential measurement confirmed that the positive surface charge of ZnO nanoparticles was well preserved after successive conjugation reactions. Based on infrared, ultraviolet-visible light and photoluminescence spectroscopies, we verify that the Cy5.5 was stably introduced to ZnO nanoparticles without serious aggregation. Surface conjugated Cy5.5 showed high stability in deionized water, phosphate buffered saline and cell culture medium, showing less than 2% of release during 85h. Confocal microscopy and fluorescence-activated cell sorting analysis demonstrated that smaller ZnO nanoparticles were more taken up in greater quantities by HaCaT cells. Moreover, systematic study on cellular uptake pathway showed that smaller ZnO nanoparticles were internalized into cells mainly by clathrin-mediated endocytosis, while larger ZnO nanoparticles entered cells via several pathways.

Titanium Dioxide Nanoparticle-Biomolecule Interactions Influence Oral Absorption.

Titanium dioxide (TiO2) nanoparticles (NPs) have been widely applied in various industrial fields, such as electronics, packaging, food, and cosmetics. Accordingly, concerns about the potential toxicity of TiO2 NPs have increased. In order to comprehend their in vivo behavior and potential toxicity, we must evaluate the interactions between TiO2 NPs and biomolecules, which can alter the physicochemical properties and the fate of NPs under physiological conditions. In the present study, in vivo solubility, oral absorption, tissue distribution, and excretion kinetics of food grade TiO2 (f-TiO2) NPs were evaluated following a single-dose oral administration to rats and were compared to those of general grade TiO2 (g-TiO2) NPs. The effect of the interactions between the TiO2 NPs and biomolecules, such as glucose and albumin, on oral absorption was also investigated, with the aim of determining the surface interactions between them. The intestinal transport pathway was also assessed using 3-dimensional culture systems. The results demonstrate that slightly higher oral absorption of f-TiO2 NPs compared to g-TiO2 NPs could be related to their intestinal transport mechanism by microfold (M) cells, however, most of the NPs were eliminated through the feces. Moreover, the biokinetics of f-TiO2 NPs was highly dependent on their interaction with biomolecules, and the dispersibility was affected by modified surface chemistry.