HDAC6 preserves BNIP3 expression and mitochondrial integrity by deacetylating p53 at lysine 320.

HDAC6 has been reported as a deacetylase of p53 at multiple lysine residues, associated with the canonical functions of p53, such as apoptosis and tumor suppression. We have previously reported that p53 acetylation at the lysine 320 site accumulates due to the genetic ablation of HDAC6 in mice liver. However, the biological processes affected by K320 acetylation of p53 are yet to be elucidated. In this study, we demonstrate that K320 acetylation of p53 is regulated by HDAC6 deacetylase activity. HDAC6 knockout mouse brains exhibit a significant accumulation of K320 acetylated p53 compared to other tissues. The level of K320 acetylation of p53 inversely correlates with the level of BNIP3, a direct target of p53 and essential for mitophagy. Notably, overexpressing the deacetylation mimic K320R mutant p53 restored BNIP3 expression in HDAC6 knockout MEFs. Furthermore, we observed that neurons are particularly susceptible to the genetic ablation of HDAC6, impacting BNIP3 expression, which inversely correlates with the accumulation of abnormal mitochondria characterized by swollen cristae. Our findings suggest that HDAC6 plays a crucial role in maintaining BNIP3 expression by deacetylating p53 at the K320 site, which is linked to the structural integrity of mitochondria.

Brimonidine-montmorillonite hybrid formulation for topical drug delivery to the eye.

Brimonidine (BMD) is often prescribed as an eye drop to reduce the intraocular pressure (IOP) for glaucoma treatment. However, eye drops are limited by rapid clearance from the preocular surface, and hence a low ocular drug bioavailability. Therefore, in this study, we propose montmorillonite (MMT), as a delivery carrier, hybridized with BMD (BMD-MMT) for topical drug delivery to the eye. The BMD-MMT hybrid was prepared by intercalating the BMD molecules in the interlayer space of the MMT lattice via ion-exchange reaction; it was then formulated with polyvinyl alcohol (PVA) to produce a dry tablet (i.e., BMD-MMT@PVA). The BMD-MMT@PVA hybrid drug released BMD in a sustained manner for more than 5 h under in vitro conditions. When the hybrid drug was administered to rabbit eyes in vivo, 43% and 18.5% BMD-MMT still remained on the preocular surface for 10 and 60 min after administration, respectively. Thus, the BMD-MMT@PVA hybrid drug exhibited a prolonged decrease in IOP, that is, for 12 h, which was approximately two times longer than that observed with the commercially available BMD eye drop, Alphagan® P.

Alendronate-Anionic Clay Nanohybrid for Enhanced Osteogenic Proliferation and Differentiation.

BACKGROUND: Alendronate (AL), a drug for inhibiting osteoclast-mediated bone-resorption, was intercalated into an inorganic drug delivery nanovehicle, layered double hydroxide (LDH), to form a new nanohybrid, AL-LDH, with 1:1 heterostructure along the crystallographic C-axis. Based on the intercalation reaction strategy, the present AL-LDH drug delivery system (DDS) was realized with an enhanced drug efficacy of AL, which was confirmed by the improved proliferation and osteogenic differentiation of osteoblast-like cells (MG63). METHODS: The AL-LDH nanohybrid was synthesized by conventional ion-exchange reaction and characterized by powder X-ray diffraction (PXRD), high-resolution transmission electron microscopy (HR-TEM), and Fourier transform infrared (FT-IR) spectroscopy. Additionally, in vitro efficacy tests, such as cell proliferation and alkaline phosphatase (ALP) activity, were analyzed. RESULTS: The AL was successfully intercalated into LDH via ion-exchange reaction, and thus prepared AL-LDH DDS was X-ray single phasic and chemically well defined. The accumulated AL content in MG63 cells treated with the AL-LDH DDS nanoparticles was determined to be 10.6-fold higher than that within those treated with the intact AL after incubation for 1 hour, suggesting that intercellular permeation of AL was facilitated thanks to the hybridization with drug delivery vehicle, LDH. Furthermore, both in vitro proliferation level and ALP activity of MG63 treated with the present hybrid drug, AL-LDH, were found to be much more enhanced than those treated with the intact AL. This is surely due to the fact that LDH could deliver AL drug very efficiently, although LDH itself does not show any effect on proliferation and osteogenic differentiation of MG63 cells. CONCLUSION: The present AL-LDH could be considered as a promising DDS for improving efficacy of AL.

Moral distress as experienced by hospital social workers in South Korea and Australia.

This exploratory, qualitative research explored the ethical problems faced by hospital social workers in South Korea and Australia, and what and who influenced their decision making using a focus group design. Although dilemmas of boundaries, confidentiality, self-determination, and other complex scenarios found in practice were identified, moral distress, a consequence of the unresolvable conflicts, dominated participants' narratives. This was particularly the case for the Korean social workers in this sample. A thematic analysis of the data yielded three main themes: 'Under pressure-"It's very uncomfortable"'; 'Failing our patients'; and 'Coping and codes'.

Theranostic Bioabsorbable Bone Fixation Plate with Drug-Layered Double Hydroxide Nanohybrids.

A bioabsorbable polymeric bone plate enabled with both diagnostic and therapeutic functionalities (radiopacity and sustained drug release, respectively) is proposed. To this end, a drug-inorganic nanohybrid (RS-LDH) is examined as a theranostic agent by intercalating an anti-resorptive bone remodeling drug, risedronate (RS) into a layered double hydroxide (LDH) via an ion-exchange reaction. The RS-LDH is prepared as a sheet with a biodegradable polymer, poly(lactic-co-glycolic acid), and is then attached onto the clinically approved bioabsorbable bone plate to produce the theranostic plate. Because of the presence of the metals in the LDH, the theranostic plate results in discernible in vivo X-ray images for up to four weeks after implantation. Concurrently, bone regeneration is also significantly improved compared with the other control groups, likely because of this material's sustained drug-release property. The theranostic plate is also largely biocompatible, similar to the plate already approved for clinical use. It is concluded that the combination of a biodegradable bone plate with RS-LDH nanohybrids can constitute a promising system with theranostic ability in both X-ray diagnosis and expedited bone repair.

A Longitudinal Study of Association between Adiposity Markers and Intraocular Pressure: The Kangbuk Samsung Health Study.

IMPORTANCE: Intraocular pressure (IOP) reduction or stabilization is the only proven method for glaucoma management. Identifying risk factors for IOP is crucial to understand the pathophysiology of glaucoma. OBJECTIVE: To examine the associations of change in body mass index (BMI), waist circumference, and percent fat mass with change in intraocular pressure (IOP) in a large sample of Korean adults. DESIGN, SETTING AND PARTICIPANTS: Cohort study of 274,064 young and middle age Korean adults with normal fundoscopic findings who attended annual or biennial health exams from January 1, 2002 to Feb 28, 2010 (577,981 screening visits). EXPOSURES: BMI, waist circumference, and percent fat mass. MAIN OUTCOME MEASURE(S): At each visit, IOP was measured in both eyes with automated noncontact tonometers. RESULTS: In multivariable-adjusted models, the average increase in IOP (95% confidence intervals) over time per interquartile increase in BMI (1.26 kg/m2), waist circumference (6.20 cm), and percent fat mass (3.40%) were 0.18 mmHg (0.17 to 0.19), 0.27 mmHg (0.26 to 0.29), and 0.10 mmHg (0.09 to 0.11), respectively (all P < 0.001). The association was stronger in men compared to women (P < 0.001) and it was only slightly attenuated after including diabetes and hypertension as potential mediators in the model. CONCLUSIONS AND RELEVANCE: Increases in adiposity were significantly associated with an increase in IOP in a large cohort of Korean adults attending health screening visits, an association that was stronger for central obesity. Further research is needed to understand better the underlying mechanisms of this association, and to establish the role of weight gain in increasing IOP and the risk of glaucoma and its complications.

Bioabsorbable bone plates enabled with local, sustained delivery of alendronate for bone regeneration.

We prepared a bone plate enabled with the local, sustained release of alendronate, which is a drug known to inhibit osteoclast-mediated bone resorption and also expedite the bone-remodeling activity of osteoblasts. For this, we coated a bone plate already in clinical use (PLT-1031, Inion, Finland) with a blend of alendronate and a biocompatible polymer, azidobenzoic acid-modified chitosan (i.e., Az-CH) photo-crosslinked by UV irradiation. As we performed the in vitro drug release study, the drug was released from the coating at an average rate of 4.03µg/day for 63days in a sustained manner. To examine the effect on bone regeneration, the plate was fixed on an 8mm cranial critical size defect in living rats and the newly formed bone volume was quantitatively evaluated by micro-computed tomography (micro-CT) at scheduled times over 8weeks. At week 8, the group implanted with the plate enabled with sustained delivery of alendronate showed a significantly higher volume of newly formed bone (52.78±6.84%) than the groups implanted with the plates without drug (23.6±3.81%) (p<0.05). The plate enabled with alendronate delivery also exhibited good biocompatibility on H&E staining, which was comparable to the Inion plate already in clinical use. Therefore, we suggest that a bone plate enabled with local, sustained delivery of alendronate can be a promising system with the combined functionality of bone fixation and its expedited repair.

Cadmium exposure and age-related macular degeneration.

Cadmium (Cd) has been proposed as a risk factor for age-related macular degeneration (AMD), but the association between Cd exposure and AMD risk in large population studies is unknown. This study evaluated the association of Cd exposure with AMD in a large representative sample of Korean men and women. This was a cross-sectional study of 3865 Korean adults ≥ 40 years of age who participated in the Korean National Health and Nutrition Examination Survey (KNHANES) during 2008-2011. Cd concentrations in whole blood were measured by graphite-furnace atomic absorption spectrometry. The presence of AMD was determined in digital non-mydriatic fundus photographs. Cd levels were higher in participants with AMD compared with those without AMD (1.3 vs 1.1 µg/l, respectively, P<0.001). In fully adjusted models, the odds ratio for AMD comparing the highest with the lowest Cd quartiles was 1.92 (95% CI=1.08-3.39; P for trend 0.029). In restricted cubic spline models, the association between Cd and AMD was approximately linear, with no evidence of threshold effects. Blood Cd concentrations were independently associated with the prevalence of AMD. If the association is proven causal, population-based preventive strategies to decrease Cd exposure could reduce the population burden of AMD.

Growth Comparison of Israeli Carp (Cyprinus carpio) to Different Breeding Combination.

The purpose of this study was to investigate the improvement of growth in Israeli carp (Cyprinus carpio), and the cross experiment was carried out with two strains of Israeli carp. Four combinations of Israeli carp from Jeonbuk fisheries farm and Songpu mirror carp from Heilong Jiang, China (KK; Jeonbuk ♀ × Jeonbuk ♂, KC; Jeonbuk ♀ × China ♂, CC; China ♀ × China ♂ and CK; China ♀ × Jeonbuk ♂) were developed and reared. Body length, body weight and condition factor were determined at 20, 40, 60 and 170 days post-hatch (DPH). The results showed that there were differences in growth rate of the four groups. Body length of four groups were CK > CC > KC > KK and body weight were CC > CK > KC > KK at 170 DPH. The growth perfomance of four groups were statistically significant difference (P<0.05). During the rearing, CC group had longer length and higher weight at 170 DPH compared to other three groups and also condition factor was highest in the CC group, but there was no significant difference in a survival rate. These results indicated that the growth performance mainly depended upon brooder combination but survival rate could not significantly affect brooder.

Gonadogenesis and Sex Differentiation in the Korean Rose Bitterling, Rhodeus uyekii).

This report describes the sex differentiation of the Korean rose bitterling, Rhodeus uyekii, from hatching to 170 days post-hatch (DPH) in relation to total length (TL), body weight (BW), and integral water temperature (IWT). The growth curve of TL from just hatching to 83 DPH was 5.144e0.045t (R² = 0.961; t, time), and that of BW was 2.398e0.086t (R² = 0.725). Primordial germ cells (PGCs) were observed at 17 DPH (7.9 mm TL, 3.74 mg BW, 374°C IWT), and thereafter began to protrude into the peritoneal cavity. At 21 DPH (9.2±0.14 mm TL, 4.8±0.07 mg BW, 462°C IWT), some PGCs contained condensed chromatin and oocyte were observed in meiotic prophase. In contrast to the ovaries, which grew gradually after sexual differentiation, testes began multiplying at 25 DPH (10.1 mm TL, 5.42 mg BW, 550°C IWT), when testicular differentiation was first identified, and multiplied continuously thereafter. At 33 DPH (11.2 mm TL, 10.5 mg BW, 726°C IWT), the developing testes contained spermatogonia that exhibited mitotic activity. No spermatocyte or sperm cell was observed until 83 DPH (18.9 TL, 48.2 mg BW, 1,826°C IWT). At 170 DPH (32.5 mm TL, 270.1 mg BW, 3,740°C IWT), which was the end point of this study, the mature ovaries showed germinal vesicle breakdown, while the mature testes contained observable spermatocytes and sperm cells. These results allow us to identify the sex differentiation type of the Korean rose bitterling as differentiated gonochoristic.

Review of Clay-Drug Hybrid Materials for Biomedical Applications: Administration Routes.

Focus here is placed on the pharmaceutical and biomedical applications of novel clay-drug hybrid materials categorized by methods of administration. Clay minerals have been used for many years as pharmaceutical and medicinal ingredients for therapeutic purposes. A number of studies have attempted to explore clay-drug hybrid materials for biomedical applications with desired functions, such as sustained release, increased solubility, enhanced adsorption, mucoadhesion, biocompatibility, targeting, etc. The present review attempts not only to summarize the state-of-the-art of clay-drug hybrid materials and their advantages, depending on the methods of administration, but also to deal with challenges and future perspectives of clay mineral-based hybrids for biomedical applications.

Nanoparticle coating on the silane-modified surface of magnesium for local drug delivery and controlled corrosion.

In this study, we proposed a potential method for the preparation of a magnesium-based medical device for local drug delivery and controlled corrosion. A magnesium surface was modified with 3-aminopropyltrimethoxy silane, and the resulting surface was then coated with drug-loaded nanoparticles made of poly (lactic-co-glycolic acid) via electrophoretic deposition. The drug-loaded nanoparticles (i.e., Tr_NP) exhibited a size of 250 ± 67 nm and a negative zeta potential of -20.9 ± 2.75 mV. The drug was released from the nanoparticles in a sustained manner for 21 days, and this did not change after their coating on the silane-modified magnesium. The silane-modified surface suppressed magnesium corrosion. When immersed in phosphate buffered saline at pH 7.4, the average rate of hydrogen gas generation was 0.41-0.45 ml/cm(2)/day, compared to 0.58-0.6 ml/cm(2)/day from a bare magnesium surface. This corrosion profile was not significantly changed after nanoparticle coating under the conditions employed in this work. The in vitro cell test revealed that the drug released from the coating was effective during the whole release period of 21 days, and both the silane-modified surface and carrier nanoparticles herein were not cytotoxic.

Mucoadhesive microparticles with a nanostructured surface for enhanced bioavailability of glaucoma drug.

Topical drug administration to the eye is limited by low drug bioavailability due to its rapid clearance from the preocular surface. Thus, multiple daily administrations are often needed, but patient compliance is low, hence a high chance of unsatisfactory treatment of ocular diseases. To resolve this, we propose mucoadhesive microparticles with a nanostructured surface as potential carriers for delivery of brimonidine, an ocular drug for glaucoma treatment. For sustained drug delivery, the microparticles were composed mainly of a diffusion-wall material, poly(lactic-co-glycolic acid) and a mucoadhesive polymer, polyethylene glycol, was used as an additive. Due to their nanostructured surface, the microparticles with a mucoadhesive material exhibited a 13-fold increase in specific surface area and could thus adhere better to the mucous layer on the eye, as compared with the conventional spherical microparticles. When loaded with brimonidine, the mucoadhesive microparticles with a nanostructured surface increased both drug bioavailability and its activity period by a factor of more than 2 over Alphagan P, a marketed eye drop of brimonidine.

The Association Between Menarche and Myopia: Findings From the Korean National Health and Nutrition Examination, 2008-2012.

PURPOSE: The purpose of this study was to analyze the relationship between age at menarche and myopia in Korean adult females. METHODS: A total of 8398 women of at least 19 years of age, who participated in the Korean National Health and Nutrition Examination Survey from 2008 to 2012, underwent a refractive examination using an autorefractor. The association between age at menarche and the severity of myopia was evaluated using a four-level multinomial logistic regression analysis. RESULTS: The prevalence of myopia was 61.77% (95% confidence interval [CI], 60.46-63.08), including 40.02% with low, 15.46% with moderate, and 6.29% with high myopia. The mean age at menarche was 14.09 ± 0.03 years. Age at menarche was inversely associated with the severity of myopia. In fully adjusted models, older age at menarche decreased the risk of moderate myopia (odds ratio [OR], 0.93; 95% CI, 0.86-0.99; P = 0.0261), and high myopia (OR, 0.85; 95% CI, 0.77-0.95; P = 0.0012). CONCLUSIONS: Later age at menarche is associated with a decreased risk of moderate and high myopia. The effects of female sex hormones on ocular structures and growth spurts may mediate this relationship between age at menarche and myopia.

The Heritability of Corneal and Ocular Higher-Order Aberrations in Koreans: The Healthy Twin Study.

PURPOSE: To estimate the genetic influences on corneal and ocular higher-order aberrations (HoAs) in the Korean population. METHODS: This was a prospective, family-based twin cohort study. A total of 1272 adult twins and their family members, who were part of the Korean Healthy Twin Study from 2007-2011, were included. Corneal and ocular HoAs were measured. The genetic influences on HoAs were investigated by using variance-component methods after adjusting for age and sex. Narrow-sense heritability was calculated. Intraclass correlation coefficients (ICCs) were used to calculate degrees of resemblance among different types of family relationships. RESULTS: A total of 269 monozygotic (MZ) twin pairs (including 176 MZ twin pairs and 93 orphan twins), 50 dizygotic (DZ) twin pairs (including 38 DZ twin pairs and 12 orphan twins), and 739 adult first-degree relatives of twins in 358 families were included. For more than half of corneal HoAs, the narrow-sense heritability estimates were not significant. Horizontal coma was highly heritable among corneal HoAs. The ICCs of horizontal coma from MZ twin pairs, pooled first-degree pairs, and spouse pairs were 0.41, 0.05, and 0.00, respectively. Among ocular HoAs, the estimated narrow-sense heritability of SA was 0.71 with the highest estimates. The ICCs of spherical aberration (SA) from MZ twins, pooled first-degree pairs, and spouse pairs were 0.76, 0.25, and 0.06, respectively. CONCLUSIONS: Both corneal and ocular HoAs demonstrated smaller heritability. Corneal HoAs showed low heritability, suggesting individual environmental factors explain most of the variance of these HoAs in the Korean population. Ocular HoAs were moderately heritable.

Diabetes, fasting glucose, and the risk of glaucoma: a meta-analysis.

TOPIC: We performed a systematic review to summarize the association of diabetes and blood glucose levels with glaucoma, intraocular pressure (IOP), and ocular hypertension in the general population. CLINICAL RELEVANCE: Diabetes has been proposed as a risk factor for glaucoma, but epidemiologic studies have been inconsistent, and the association is still controversial. Furthermore, no systematic reviews evaluated other metabolic abnormalities, such as the metabolic syndrome, with the risk of glaucoma. METHODS: We identified the studies by searching the PubMed and EMBASE databases. We used inverse-variance weighted random-effects models to summarize relative risks across studies. RESULTS: We identified 47 studies including 2 981 342 individuals from 16 countries. The quality of evidence generally was higher in the cohort compared with case-control or cross-sectional studies. The pooled relative risk for glaucoma comparing patients with diabetes with those without diabetes was 1.48 (95% confidence interval [CI], 1.29-1.71), with significant heterogeneity across studies (I(2) = 82.3%; P < 0.001). The risk of glaucoma increased by 5% (95% CI, 1%-9%) for each year since diabetes diagnosis. The pooled average difference in IOP comparing patients with diabetes with those without diabetes was 0.18 mmHg (95% CI, 0.09-0.27; I(2) = 73.2%), whereas the pooled average increase in IOP associated with an increase in 10 mg/dl in fasting glucose was 0.09 mmHg (95% CI, 0.05-0.12; I(2) = 34.8%). CONCLUSIONS: Diabetes, diabetes duration, and fasting glucose levels were associated with a significantly increased risk of glaucoma, and diabetes and fasting glucose levels were associated with slightly higher IOP.

Illite improves memory impairment and reduces Aß level in the Tg-APPswe/PS1dE9 mouse model of Alzheimer׳s disease through Akt/CREB and GSK-3ß phosphorylation in the brain.

ETHNOPHARMACOLOGICAL RELEVANCE: The use of illite in Korean medicine has a long history as a therapeutic agent for various cerebrovascular diseases. According to Dongui Bogam, illite can be used for Qi-tonifying, phlegm dispersing and activation of blood circulation which is an important principle for the treatment of brain-associated diseases. AIM OF THE STUDY: This study was undertaken to evaluate beneficial effects of illite on the neurodegenerative diseases such as Alzheimer׳s disease (AD). MATERIAL AND METHODS: The transgenic mice of AD, Tg-APPswe/PS1dE9, were fed with 1% or 3% of illite for 3 months. Behavioral, immunological and ELISA analyses were used to assess memory impairment with additional measurement of Aß accumulation and plaque deposition in the brain. Other in vitro studies were performed to examine whether illite inhibits the Aß-induced neurotoxicity in human neuroblastoma cell line, SH-SY5Y cells. RESULTS: Illite treatment rescued Aß-induced neurotoxicity on SH-SY5Y cells, which was dependent on the PI3K/Akt activation. Intake of illite improved the Aß-induced memory impairment and suppressed Aß levels and plaque deposition in the brain of Tg-APPswe/PS1dE9 mice. Illite increased CREB, Akt, and GSK-3ß phosphorylation and suppressed tau phosphorylation in the AD-like brains. Moreover, 1% of illite reduced weight gain and suppressed glucose level in the blood. CONCLUSION: The present study suggests that illite has the potential to be a useful adjunct as a therapeutic drug for the treatment of AD.

Acute suppression of TGF-ß with local, sustained release of tranilast against the formation of fibrous capsules around silicone implants.

We propose the acute, local suppression of transforming growth factor beta (TGF-ß), a major profibrotic cytokine, to reduce fibrosis around silicone implants. To this end, we prepared silicone implants that were able to release tranilast, a TGF-ß inhibitor, in a sustained manner for 5 days or 15 days. We performed histologic and immunohistochemical analyses for 12 weeks after the implantation of the implants in living rats. The capsule thicknesses and collagen densities significantly decreased compared with those around the non-treated silicone implants. Notably, early suppression of TGF-ß affected the fibrogenesis that actually occurs at the late stage of wound healing. This change may be ascribed to the decrease in monocyte recruitment mediated by early TGF-ß during the acute inflammatory reaction. Thus, a significant decrease in differentiated macrophages was observed along with a decrease in the quantity of TGF-ß and fibroblasts during the subsequent inflammation stage; these changes led to a diminished fibrotic capsule formation.

Bioabsorbable bone fixation plates for X-ray imaging diagnosis by a radiopaque layer of barium sulfate and poly(lactic-co-glycolic acid).

Bone fixation systems made of biodegradable polymers are radiolucent, making post-operative diagnosis with X-ray imaging a challenge. In this study, to allow X-ray visibility, we separately prepared a radiopaque layer and attached it to a bioabsorbable bone plate approved for clinical use (Inion, Finland). We employed barium sulfate as a radiopaque material due to the high X-ray attenuation coefficient of barium (2.196 cm(2) /g). The radiopaque layer was composed of a fine powder of barium sulfate bound to a biodegradable material, poly(lactic-co-glycolic acid) (PLGA), to allow layer degradation similar to the original Inion bone plate. In this study, we varied the mass ratio of barium sulfate and PLGA in the layer between 3:1 w/w and 10:1 w/w to modulate the degree and longevity of X-ray visibility. All radiopaque plates herein were visible via X-ray, both in vitro and in vivo, for up to 40 days. For all layer types, the radio-opacity decreased with time due to the swelling and degradation of PLGA, and the change in the layer shape was more apparent for layers with a higher PLGA content. The radiopaque plates released, at most, 0.5 mg of barium sulfate every 2 days in a simulated in vitro environment, which did not appear to affect the cytotoxicity. The radiopaque plates also exhibited good biocompatibility, similar to that of the Inion plate. Therefore, we concluded that the barium sulfate-based, biodegradable plate prepared in this work has the potential to be used as a fixation device with both X-ray visibility and biocompatibility.