Exosome-mediated secretion of miR-127-3p regulated by RAB27A accelerates metastasis in renal cell carcinoma.

BACKGROUND: The exosome-mediated extracellular secretion of miRNAs occurs in many cancers, and RAB27A is a potent regulator of exosome secretion. For metastatic renal cell carcinoma (RCC), this study examines the mechanisms of cancer metastasis via the RAB27A-regulated secretion of specific miRNAs. METHODS: RAB27A knockdown (KD) and overexpressing (OE) RCC cells were used to examine cell migration and adhesion. The particle counts and sizes of exosomes in RAB27A OE cells were analyzed using Exoview, and those of intraluminal vesicles (ILV) and multivesicular bodies (MVB) were measured using an electron microscope. Analysis of RNA sequences, protein-protein interaction networks, and the competing endogenous RNA (ceRNA) network were used to identify representative downregulated miRNAs that are likely to undergo cargo-sorting into exosomes and subsequent secretion. A molecular beacon of miR-137-3p, one of the most representatively downregulated genes with a fold change of 339, was produced, and its secretion was analyzed using Exoview. RAB27A OE and control cells were incubated in an exosome-containing media to determine the uptake of tumor suppressor miRNAs that affect cancer cell metastasis. RESULTS: Migration and cell adhesion were higher in RAB27A OE cells than in RAB27A KD cells. Electron microscopy revealed that the numbers of multivesicular bodies and intraluminal vesicles per cell were higher in RAB27A OE cells than in control cells, suggesting their secretion. The finding revealed that miR-127-3p was sorted into exosomes and disposed of extracellularly. Protein-protein interaction analysis revealed MYCN to be the most significant hub for RAB27A-OE RCC cells. ceRNA network analysis revealed that MAPK4 interacted strongly with miR-127-3p. CONCLUSION: The disposal of miR-127-3p through exosome secretion in RAB27A overexpressing cells may not inhibit the MAPK pathway to gain metastatic potential by activating MYCN. The exosomes containing miRNAs are valuable therapeutic targets for cancer treatment.

Longitudinal Rates of Change in Structural Parameters of Optical Coherence Tomography in Primary Angle Closure Glaucoma following Laser Iridotomy along with Peripheral Iridoplasty.

Background: This study aimed to investigate longitudinal rates of change (LRCs) of structural parameters from optical coherence tomography (OCT) in patients with primary angle closure glaucoma (PACG) after laser iridotomy (LI) along with laser peripheral iridoplasty (PI). Methods: Among 146 patients diagnosed with PACG, thirty-two subjects (32 eyes) who underwent LI plus PI and accomplished more than five times of reliable OCT tests were included in the current retrospective study. Retinal nerve fiber layer (RNFL) and Bruch's membrane opening-minimum rim width (BMO-MRW) were measured by spectral-domain OCT with three month interval. LRCs of global and six Garway-Heath sectors were investigated using the linear mixed-effects model which adjusted BMO area, sex, and age. Imaging of dual Scheimpflug analyzer was performed before and at 1 week after LI with PI and yearly thereafter. Results: The mean follow-up period was 32.28 ± 13.34 months with a mean number of 10.18 ± 3.33 OCT images. Baseline characteristics are as follows: age, 63 ± 7.9 years; female, 62.5%; intraocular pressure(IOP), 15.48 ± 4.79 mmHg; anterior chamber depth, 2.09 ± 0.18 mm; and mean deviation, -7.97 ± 8.48 dB. Global LRC of BMO-MRW was 0.86 ± 1.34 µm/yr and RNFL was -0.64 ± 0.22 µm/yr. IOP decreased significantly to 13.06 ± 2.21 mmHg (p=0.001) while anterior chamber volume (p=0.011) and mean anterior chamber angle (p=0.022) increased significantly after LI along with PI compared to the baseline at the final visit. Conclusions: LRC of a new parameter, BMO-MRW, and LRC of RNFL were relatively low in patients with PACG, following LI along with PI. After widening of the anterior chamber angle and decrease of IOP due to LI plus PI, PACG might show stable structural prognosis assessed by OCT.

Deep learning visual field global index prediction with optical coherence tomography parameters in glaucoma patients.

The aim of this study was to predict three visual filed (VF) global indexes, mean deviation (MD), pattern standard deviation (PSD), and visual field index (VFI), from optical coherence tomography (OCT) parameters including Bruch's Membrane Opening-Minimum Rim Width (BMO-MRW) and retinal nerve fiber layer (RNFL) based on a deep-learning model. Subjects consisted of 224 eyes with Glaucoma suspects (GS), 245 eyes with early NTG, 58 eyes with moderate stage of NTG, 36 eyes with PACG, 57 eyes with PEXG, and 99 eyes with POAG. A deep neural network (DNN) algorithm was developed to predict values of VF global indexes such as MD, VFI, and PSD. To evaluate performance of the model, mean absolute error (MAE) was determined. The MAE range of the DNN model on cross validation was 1.9-2.9 (dB) for MD, 1.6-2.0 (dB) for PSD, and 5.0 to 7.0 (%) for VFI. Ranges of Pearson's correlation coefficients were 0.76-0.85, 0.74-0.82, and 0.70-0.81 for MD, PSD, and VFI, respectively. Our deep-learning model might be useful in the management of glaucoma for diagnosis and follow-up, especially in situations when immediate VF results are not available because VF test requires time and space with a subjective nature.

Association between atrial fibrillation and the risk of glaucoma development: a 12-year Nationwide cohort study.

OBJECTIVE: To investigate the risk of glaucoma development in patients with atrial fibrillation (A-fib) using Korean National Health Insurance Service data. METHODS: The present study used a National Sample Cohort consisting of approximately one million random subjects who were tracked from 2002 to 2013 (12 years). Newly diagnosed glaucoma and A-fib were included based on the Korean Classification of Disease codes. The A-fib group consisted of patients who received an initial A-fib diagnosis between January 2003 and December 2007 as an index period (n = 8765). The control group (n = 43,352) was selected using a 1:5 propensity-score matching for social and demographic factors. Each subject was followed up until 2013. Multivariate Cox proportional hazard regression analysis was performed to compare the risk of glaucoma development between the A-fib group and the control group. RESULTS: The rate of glaucoma development was 3.54% in the A-fib group and 2.96% in the control group (P < 0.0001). A-fib increased the risk of glaucoma development [hazard ratio = 1.31; 95% confidence interval (CI): 1.15 to 1.48] after adjusting for age, sex, comorbidities, residence, household income, and year of enrollment. In multivariable Cox regression analysis, patients with comorbidity of diabetes mellitus and chronic renal failure and those aged ≥50 years showed significantly higher risk of glaucoma development (all P < 0.001). CONCLUSIONS: A-fib was significantly associated with the development of glaucoma after adjusting for potential confounding factors. Physicians may need to monitor patients with A-fib carefully for possible glaucoma development.

Deep learning classification of early normal-tension glaucoma and glaucoma suspect eyes using Bruch's membrane opening-based disc photography.

Purpose: We aimed to investigate the performance of a deep learning model to discriminate early normal-tension glaucoma (NTG) from glaucoma suspect (GS) eyes using Bruch's membrane opening (BMO)-based optic disc photography. Methods: 501 subjects in total were included in this cross-sectional study, including 255 GS eyes and 246 eyes of early NTG patients. BMO-based optic disc photography (BMO overview) was obtained from spectral-domain optical coherence tomography (OCT). The convolutional neural networks (CNN) model built from scratch was used to classify between early NTG and GS. For diagnostic performances of the model, the accuracy and the area under the curve (AUC) of the receiver operating characteristic curve (ROC) were evaluated in the test set. Results: The baseline demographics were age, 48.01 ± 13.03 years in GS, 54.48 ± 11.28 years in NTG (p = 0.000); mean deviation, -0.73 ± 2.10 dB in GS, -2.80 ± 2.40 dB in NTG (p = 0.000); and intraocular pressure, 14.92 ± 2.62 mmHg in GS, 14.79 ± 2.61 mmHg in NTG (p = 0.624). Our CNN model showed the mean AUC of 0.94 (0.83-1.00) and the mean accuracy of 0.91 (0.82-0.98) with 10-fold cross validation for discriminating between early NTG and GS. Conclusion: The performance of the CNN model using BMO-based optic disc photography was considerably good in classifying early NTG from GS. This new disc photography of BMO overview can aid in the diagnosis of early glaucoma.

Quantitative analysis of exosomes in the aqueous humor of Korean patients with pseudoexfoliation glaucoma.

We aimed to quantitatively analyze the exosome and its cargo in individual aqueous humor (AH) samples from pseudoexfoliation (PEX) glaucoma patients compared to controls using a novel detection platform. We investigated the size distribution and measured the quantitative exosome particle counts in each AH sample. AH (80-120 µL) was obtained during cataract surgery or glaucoma filtering surgery from 12 Korean subjects (six with PEX glaucoma and six age-matched controls). The mean size of the exosomes was 58.9 ± 18.5 nm measured by a tangential flow filtration system using single-particle interferometric reflectance imaging sensor. Exosome particle count in each CD 63, CD 81, and CD9 spot was significantly greater in PEX glaucoma than in controls in total, CD 63, CD9, syntenin, and scattering(all p < 0.003). The CD63 spot showed a particle count of 8319.1 ± 797.7 in PEX glaucoma patients and 4786.8 ± 1302.1 in controls (p = 1.88E-11). Individual fluorescent capture spot images also revealed denser exosome particles in PEX patients than in controls. Syntenin, indicating exosomal origin, was detected in all AH samples. Exosomes differentially detected in AH suggest the possible role of exosomes in the pathogenesis of PEX glaucoma.

MicroRNA profiles in aqueous humor between pseudoexfoliation glaucoma and normal tension glaucoma patients in a Korean population.

We aimed to obtain microRNA (miRNA) profiles of patients with pseudoexfoliation (PEX) glaucoma or normal-tension glaucoma (NTG) compared to normal controls using individual aqueous humor (AH) samples and investigate the role of miRNAs in the pathogenesis of PEX glaucoma compared to NTG in Korean. AH (80-120 µl) was collected before cataract surgery or trabeculectomy from 26 Korean subjects (eleven with PEX glaucoma, age-matched eight NTG, and seven controls). RNA sequencing was conducted for RNA samples extracted from 26 AH samples. Bioinformatics analysis was performed for targets and related pathways. A total of 334 and 291 discrete miRNAs were detected in AH samples of PEX glaucoma and NTG patients, respectively. Two significantly upregulated miRNAs (hsa-miR-30d-5p and hsa-miR-320a) and ten significantly downregulated miRNAs (hsa-miR-3156-5p, hsa-miR-4458, hsa-miR-6717-5p, hsa-miR-6728-5p, hsa-miR-6834-5p, hsa-miR-6864-5p, hsa-miR-6879-5p, hsa-miR-877-3p, hsa-miR-548e-3p, and hsa-miR-6777-5p) in PEX glaucoma patients compared to control (fold-change > 2, p < 0.05) were found. In NTG patients, ten significantly upregulated and two downregulated miRNAs compared to control were found. Only hsa-miR-6777-5p was commonly downregulated in both PEX glaucoma and NTG patients. Related pathways were proteoglycans in cancer, glioma, and TGF-beta signaling pathway in PEX glaucoma. These differentially expressed miRNAs between PEX glaucoma and NTG samples suggest the possible role of miRNA in the pathogenesis of glaucoma, further implying that pathogenic mechanisms may differ between different types of glaucoma.

Resveratrol prevents hypoxia-induced retinal ganglion cell death related with ErbB2.

AIM: To confirm the changes in proteins related with hypoxia-induced retinal cell death and to assess the effects of resveratrol (Res). METHODS: The therapeutic effect of Res was verified using an ischemic/reperfusion (I/R) model in vivo and a hypoxia modelin retinal ganglion cells (RGCs) in vitro. Death of RGCs were confirmed by TUNEL assay. Protein expression was confirmed by Western blotting and immunohistochemistry. In addition, flow cytometric analysis was used to confirm the response in the cell unit to obtain more accurate data. RESULTS: ErbB2 expression and apoptosis in the ganglion cell layer (GCL) increased after I/R injury. Treatment of Res rescued I/R-induced ganglion cell death, downregulated apoptosis and ErbB2 protein expression in the retina. In subsequent in vitro models, Res affects apoptosis by regulating the phosphorylation and expression of mouse double minute 2 homolog (MDM2), along with those of ErbB2. These results suggest that Res reverses GCL-specific apoptosis via downregulation of ErbB2 in ischemic injury. CONCLUSION: In light of Res favorable properties, it should be evaluated in the treatment of RGC death and related retinal disease characterized by ErbB2 and MDM2 expression. Therefore, Res is appropriate therapeutic agent for treating ischemic injury-related eye diseases by targeting the expression of ErbB2 and MDM2.

Long-Term Outcome of Corneal and Anterior Chamber Angle Parameters after Combined Laser Iridotomy and Iridoplasty Using Dual Scheimpflug Analyzer: 1 Year Results.

BACKGROUND: To investigate the outcomes of corneal and anterior chamber angle (ACA) parameters after laser iridotomy (LI) combined with peripheral iridoplasty (PI) using dual Scheimpflug analyzer in the long term. METHODS: Fifty-eight eyes (58 subjects) with shallow AC were included in this prospective cohort study. Images of the Dual Scheimpflug analyzer were obtained before, 1 week, and 1 year after LI and PI. Pachymetry from three zones (central, middle, and peripheral), corneal aberration, and spherical equivalent (SE) were acquired. AC depth (ACD), AC volume (ACV), ACA from four quadrants, and intraocular pressure (IOP) were also obtained. For comparison of the results, the linear mixed-effects model was employed. RESULTS: ACD significantly increased from 2.09 ± 0.25 mm to 2.10 ± 0.23 mm at 1 year after laser (all p < 0.05). ACV and ACA increased significantly after laser at 1 year (all p < 0.05). IOP significantly decreased from 15.97 ± 4.20 mmHg to 13.73 ± 2.63 mmHg at 1 year (all p < 0.0001). No significant changes were found in the coma, trefoil, total corneal aberration, pachymetry from three zones, corneal volume, central corneal thickness, and SE after LI and PI until 1 year (all p > 0.05). CONCLUSIONS: LI plus PI ameliorated parameters of ACA efficiently and significantly reduced IOP in eyes with shallow AC until 1 year of long-term follow-up. However, parameters of the cornea and SE were not influenced by LI with PI until after 1 year.

Sphingosine 1-Phosphate Receptor 4 Promotes Nonalcoholic Steatohepatitis by Activating NLRP3 Inflammasome.

BACKGROUND & AIMS: Sphingosine 1-phosphate receptors (S1PRs) are a group of G-protein-coupled receptors that confer a broad range of functional effects in chronic inflammatory and metabolic diseases. S1PRs also may mediate the development of nonalcoholic steatohepatitis (NASH), but the specific subtypes involved and the mechanism of action are unclear. METHODS: We investigated which type of S1PR isoforms is activated in various murine models of NASH. The mechanism of action of S1PR4 was examined in hepatic macrophages isolated from high-fat, high-cholesterol diet (HFHCD)-fed mice. We developed a selective S1PR4 functional antagonist by screening the fingolimod (2-amino-2-[2-(4- n -octylphenyl)ethyl]-1,3- propanediol hydrochloride)-like sphingolipid-focused library. RESULTS: The livers of various mouse models of NASH as well as hepatic macrophages showed high expression of S1pr4. Moreover, in a cohort of NASH patients, expression of S1PR4 was 6-fold higher than those of healthy controls. S1pr4+/- mice were protected from HFHCD-induced NASH and hepatic fibrosis without changes in steatosis. S1pr4 depletion in hepatic macrophages inhibited lipopolysaccharide-mediated Ca++ release and deactivated the Nod-like receptor pyrin domain-containning protein 3 (NLRP3) inflammasome. S1P increased the expression of S1pr4 in hepatic macrophages and activated NLRP3 inflammasome through inositol trisphosphate/inositol trisphosphate-receptor-dependent [Ca++] signaling. To further clarify the biological function of S1PR4, we developed SLB736, a novel selective functional antagonist of SIPR4. Similar to S1pr4+/- mice, administration of SLB736 to HFHCD-fed mice prevented the development of NASH and hepatic fibrosis, but not steatosis, by deactivating the NLRP3 inflammasome. CONCLUSIONS: S1PR4 may be a new therapeutic target for NASH that mediates the activation of NLRP3 inflammasome in hepatic macrophages.

Long noncoding RNAs associated with nonalcoholic fatty liver disease in a high cholesterol diet adult zebrafish model.

The mechanism of nonalcoholic fatty liver disease (NAFLD) has not been completely revealed. In this study, we investigated the association of liver histological changes and long noncoding RNAs (lncRNAs) in the NAFLD zebrafish model. Forty zebrafish were fed a high-cholesterol diet (1.5 g per day) for 8 weeks. We measured fatty liver changes in the zebrafish liver using oil red O staining and divided them into two groups based on high and low scores. We pooled each group of zebrafish livers and identified lncRNAs, miRNAs, and mRNAs using Next-generation sequencing. Human homologs of lncRNAs were identified using ZFLNC, Ensembl, and NONCODE. We found several significant genes, including 32 lncRNAs, 5 miRNA genes, and 8 protein-coding genes, that were associated with liver metabolism and NAFLD-related functions in zebrafish. In particular, eight conserved human homologs of lncRNAs were found. We discovered the human homologs of eight lncRNA candidates from fatty liver zebrafish for the first time. The spectrum of biological mechanisms by which lncRNAs mediate their functional roles in NAFLD in a high cholesterol diet adult zebrafish model remains to be uncovered.

Profiles of microRNA in aqueous humor of normal tension glaucoma patients using RNA sequencing.

We aimed to identify and compare microRNAs (miRNAs) from individual aqueous humor samples between normal-tension glaucoma (NTG) patients and normal controls. Aqueous humor (80 to 120 µl) was collected before cataract surgery. Six stable NTG patients and seven age-matched controls were included in the final analysis. RNA sequencing was conducted for RNA samples extracted from the 13 aqueous humor samples, and bioinformatics analysis was employed for the miRNA targets and related pathways. Two hundred and twenty-eight discrete miRNAs were detected in the aqueous humor and consistently expressed in all samples. Eight significantly upregulated miRNAs were found in the NTG patients compared to the controls (fold-change > 2, p < 0.05). They were hsa-let-7a-5p, hsa-let-7c-5p, hsa-let-7f-5p, hsa-miR-192-5p, hsa-miR-10a-5p, hsa-miR-10b-5p, hsa-miR-375, and hsa-miR-143-3p. These miRNAs were predicted to be associated with the biological processes of apoptosis, autophagy, neurogenesis, and aging in the gene ontology categories. The related Kyoto encyclopedia of genes and genomes pathways were extracellular matrix-receptor interaction, mucin-type O-glycan biosynthesis, biotin metabolism, and signaling pathways regulating the pluripotency of stem cells. The differentially expressed miRNA in the NTG samples compared to the controls suggest the possible roles of miRNA in the pathogenesis of NTG. The underlying miRNA-associated pathways further imply novel targets for the pathogenesis of NTG.

Association Between Chronic Renal Disease and the Risk of Glaucoma Development: A 12-year Nationwide Cohort Study.

Purpose: The purpose of this study was to present the results of our investigation into the risk of glaucoma development in patients with chronic renal disease (CRD). Methods: The present retrospective cohort study used the Korean National Health Insurance Service data, which consisted of 1,025,340 random subjects who were tracked from 2002 to 2013. Newly diagnosed glaucoma and CRD were included on the basis of the Korean Classification of Disease codes. The CRD group consisted of patients who received an initial CRD diagnosis between January 2003 and December 2007 as an index period (n = 3640). The control group (n = 17,971) was selected using 1:5 propensity-score matching using social and demographic factors, along with the year of enrollment. Each group subject was followed until 2013. We used multivariate Cox proportional hazard regression analysis to compare the risk of glaucoma development between the two groups. Results: Glaucoma consecutively developed in 4.3% in the CRD group and 2.8% in the control group (P < 0.0001). CRD increased the risk of glaucoma development (hazard ratio [HR] = 1.63, 95% confidence interval [CI] = 1.34-1.98] after adjusting for age, sex, comorbidities, residence, household income, and the year of enrollment. In multivariate Cox regression analysis, patients with comorbidity of hypertension, diabetes mellitus, or aged ≥ 50 years showed a significantly higher risk of glaucoma development (all P < 0.008). Conclusions: A significant association between CRD and following development of glaucoma was revealed after adjusting the potential confounding factors.

Deep learning classification of early normal-tension glaucoma and glaucoma suspects using Bruch's membrane opening-minimum rim width and RNFL.

We aimed to classify early normal-tension glaucoma (NTG) and glaucoma suspect (GS) using Bruch's membrane opening-minimum rim width (BMO-MRW), peripapillary retinal nerve fiber layer (RNFL), and the color classification of RNFL based on a deep-learning model. Discriminating early-stage glaucoma and GS is challenging and a deep-learning model may be helpful to clinicians. NTG accounts for an average 77% of open-angle glaucoma in Asians. BMO-MRW is a new structural parameter that has advantages in assessing neuroretinal rim tissue more accurately than conventional parameters. A dataset consisted of 229 eyes out of 277 GS and 168 eyes of 285 patients with early NTG. A deep-learning algorithm was developed to discriminate between GS and early NTG using a training set, and its accuracy was validated in the testing dataset using the area under the curve (AUC) of the receiver operating characteristic curve (ROC). The deep neural network model (DNN) achieved highest diagnostic performance, with an AUC of 0.966 (95%confidence interval 0.929-1.000) in classifying either GS or early NTG, while AUCs of 0.927-0.947 were obtained by other machine-learning models. The performance of the DNN model considering all three OCT-based parameters was the highest (AUC 0.966) compared to the combinations of just two parameters. As a single parameter, BMO-MRW (0.959) performed better than RNFL alone (0.914).

Rate of Change in Bruch's Membrane Opening-Minimum Rim Width and Peripapillary RNFL in Early Normal Tension Glaucoma.

BACKGROUND: to investigate the rate of change (ROC) of Bruch's membrane opening minimum rim width (BMO-MRW) and peripapillary retinal nerve fiber layer (RNFL) thickness in early normal tension glaucoma (NTG) patients. METHODS: in this longitudinal cohort study, 115 subjects (115 eyes) diagnosed as early NTG (mean deviation > -6.0 dB) and who had completed more than five times of spectral-domain optical coherence tomography (OCT) tests with acceptable quality were included. Measurement of BMO-MRW and RNFL were performed at 3-month intervals by OCT. Linear mixed-effects model was employed to calculate the ROC in global region and six Garway-Heath sectors with adjusting age, sex, and BMO area. RESULTS: Average follow-up was 20.99 ± 6.99 months with OCT number of 7.54 ± 2.12. Baseline intraocular pressure was 14.72 ± 2.70 mmHg and MD was -2.73 ± 2.26 dB. ROC of global BMO-MRW was -2.06 ± 0.65 µm/yr and RNFL was -0.96 ± 0.16 µm/yr (p = 0.098). The most rapid ROC was in inferotemporal sector (BMO-MRW: -3.02 ± 0.88 µm/yr, RNFL: -1.96 ± 0.36 µm/yr) followed by superotemporal sector. CONCLUSION: The ROC of BMO-MRW, the new parameter along with that of RNFL should be considered in the management of early NTG. BMO-MRW may show visible reduction ROC better than RNFL to detect early progression in early NTG when visual field may not show significant change.

NED416, a novel synthetic Sirt1 activator, promotes cutaneous wound healing via the MAPK/Rho pathway.

Cutaneous wound healing is a highly complex biological process involving major events such as cell migration, angiogenesis, and tissue development. Sirtuin 1 (Sirt1) and its regulators have been suggested to play a role in cell migration and tissue repair. The aim of the present study was to determine the effects of a novel Sirt1 activator, the piper amide derivative (E)­3­(2,4­dichlorophenyl)­N­phenylacrylamide, also known as NED416, on cutaneous wound healing. The effects of NED416 on Sirt1 activity, Sirt1 expression, and angiogenesis were measured in skin and endothelial cells (epidermal keratinocytes, dermal fibroblasts and vascular endothelial cells) using a Sirt1 activity assay kit, western blot analysis and tube formation assays, respectively. The effects of NED416 on the rate of wound closure and collagen deposition were measured via H&E staining and Masson's trichrome staining, respectively. Levels of migration­related [Rac1, cell division cycle 42 (Cdc42) and α­p21­activated kinase] and mitogen­activated protein kinase (MAPK) signaling pathway proteins were measured in hairless mice via western blot analysis. NED416 significantly increased Sirt1 activity in dermal fibroblasts and epidermal keratinocytes to a greater extent than resveratrol, leading to increased cell migration and angiogenesis through Rac1/Cdc42 and ERK/JNK activation. Furthermore, NED416 accelerated wound closure, macrophage infiltration, and epithelium and collagen formation in vivo. The present study demonstrated a role of Sirt1 in cutaneous wound healing, and suggested that NED416 as a Sirt1 activator is more potent than resveratrol in promoting wound healing through Rac1/Cdc42 and MAPK signaling without toxicity, thus serving as a promising candidate for treatment.

Comparison of Rate of Change between Bruch's Membrane Opening Minimum Rim Width and Retinal Nerve Fiber Layer in Eyes Showing Optic Disc Hemorrhage.

PURPOSE: To investigate and compare the longitudinal rate of change of Bruch's membrane opening minimum rim width (BMO-MRW) and peripapillary retinal nerve fiber layer (RNFL) thickness in eyes showing optic disc hemorrhage(DH). DESIGN: Observational case series. METHODS: A total of 82 subjects(82 eyes) showing DH who had undergone more than five reliable spectral-domain optical coherence tomography (OCT) tests were included. BMO-MRW and RNFL were measured with OCT at 3-month intervals. The rates of change in global and each Garway-Heath sector were calculated with a linear mixed-effects model after adjusting for age, sex, and BMO area. RESULTS: The mean follow-up period was 21.57 ± 7.88 months with a mean number of 7.88 ± 2.39 OCT tests. Baseline demographics were age (58.37 ± 10.65 y); 46.3% were female; and the mean deviation was -4.41 ± 5.04 dB. The global rate of change in BMO-MRW was -3.507 ± 0.675 µm/y and in -1.404 ± 0.208 µm/y in RNFL. The rate of change was the greatest in the inferotemporal sector, which was -9.141 ± 1.254 µm/y in BMO-MRW and -4.204 ± 0.490 µm/y in the RNFL. The rate of change was significantly greater in BMO-MRW than in the RNFL in all sectors, except for the nasal sector (P < .05). Percentage of reduction was significantly greater in BMO-MRW than in RNFL in the inferotemporal and superotemporal sectors (P < .05). CONCLUSIONS: BMO-MRW showed a significantly greater rate of change than RNFL in eyes showing DH, especially in the inferotemporal and superotemporal sectors in percentage of reduction. Thus, it may be more advantageous to detect glaucomatous progression earlier in BMO-MRW than in the RNFL in eyes showing DH that are more likely to progress.

Identification of a New Chemotype of Anti-Obesity Compounds by Ensemble Screening.

Despite the increasing prevalence of overweight or obesity in the global population, most of the approved drugs for obesity are still not ideal for long-term use due to severe cardiovascular and/or neurological side effects. Therefore, we designed a library-implemented virtual screening (VS) approach to discover new anti-obesity agents without significant toxicity. The Bayesian classification and 3D pharmacophore model for the VS process were built by using the screening results of our in-house library of natural piper amide-like compounds, which possess a wide range of biological activities and relatively low toxicities. The VS process identified six compounds of different classes with enhanced inhibitory activities against lipid accumulation and without toxicity. Moreover, the most active compound with an oxadiazole scaffold resulted in weight loss and improved the fatty liver condition of mice with overnutrition in animal experiments.

Ocular complications of Garcinia cambogia extract diet pills: Case report.

BACKGROUND: Garcinia cambogia contains hydroxycitric acid. Hydroxycitric acid is a potent competitive inhibitor of adenosine triphosphate citrate lyase which is a key enzyme in the synthesis of fatty acids. Hydroxycitric acid also regulates the level of serotonin. In these regards, hydroxycitric acid has been reported to exhibit weight loss activity. Adverse reactions of G. cambogia from numerous clinical studies demonstrated relatively mild reactions. However, there are some complications of G. cambogia reported in the past: acute liver injury, acute hepatitis, and hepatic failure. However, ocular complications of G. cambogia have not been reported yet. CASE PRESENTATION: A 35-year-old female visited our clinic with decreased vision in the left eye and ocular pain in both eyes for the last 6 days. She also complained of headache, dizziness, and nausea. She had taken G. cambogia extract more than the recommended dose. There was myopic shift with anterior chamber shallowing in both eyes, especially in the left eye. Moreover, swelling and retinal folds of peripapillary retinal nerve fiber layer and macula were observed in both eyes. These ocular complications of G. cambogia extract resolved after discontinuation of the extract and topical and oral steroid treatment. Herein, we report the first case of ocular complications of G. cambogia extract diet pill assessed with optical coherence tomography of optic disk and macula along with dual Scheimpflug analyzer. CONCLUSION: It is necessary that physicians dealing with obesity advice patients about possible visual disturbance of this extract when taken in overdose so that they can see an ophthalmologist immediately.