Investigating small molecule compounds targeting psoriasis based on cMAP database and molecular dynamics simulation.

OBJECTIVE: Psoriasis (PSO) is a chronic inflammatory skin disease that severely affects the physical and mental health of patients. Drug resistance has been developed upon current drug treatments, and there is no specific therapy. The aim of this study was to screen promising novel drug candidates for PSO using molecular dynamics (MD) simulations. METHODS: The data of PSO were downloaded from gene expression omnibus (GEO) database and subjected to variance analysis. Target proteins and small molecule compounds targeting PSO were predicted in the connective map (cMAP) database. Molecular docking, MD simulation, and trajectory analysis were conducted to predict the binding of target proteins to compounds. RESULTS: 1999 differentially expressed genes in PSO were obtained by differential analysis. Through cMAP database prediction, a low Score value of -45.69 for lymphocyte cell-specific protein-tyrosine kinase (LCK) was revealed, and aminogenistein was identified as the compound targeting LCK, and LCK was notably highly expressed in the PSO samples. The drugScore of the binding pocket P_0 was 0.814656, which was docked with aminogenistein. The results showed that there were more than one binding site between LCK and aminogenistein with binding energy less than -7.0 kJ/mol, and the docking was relatively stable. The results of root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), Gyrate, number of hydrogen bonds and total free binding energy in MD simulations showed that the binding of aminogenistein to LCK was relatively solid. CONCLUSION: Aminogenistein has good protein-ligand interaction and stability with LCK, a target of PSO, and is a novel drug candidate for PSO.

Inhibition of Ferroptosis Ameliorates Photoreceptor Degeneration in Experimental Diabetic Mice.

Diabetic retinopathy (DR) is a leading cause of vision impairment in the working-age population worldwide. Various modes of photoreceptor cell death contribute to the development of DR, including apoptosis and autophagy. However, whether ferroptosis is involved in the pathogenesis of photoreceptor degeneration in DR is still unclear. High-glucose (HG)-stimulated 661W cells and diabetic mice models were used for in vitro and in vivo experiments, respectively. The levels of intracellular iron, glutathione (GSH), reactive oxygen species (ROS), lipid peroxidation (MDA), and ferroptosis-related proteins (GPX4, SLC7A11, ACSL4, FTH1, and NCOA4) were quantified to indicate ferroptosis. The effect of ferroptosis inhibition was also assessed. Our data showed the levels of iron, ROS, and MDA were enhanced and GSH concentration was reduced in HG-induced 661W cells and diabetic retinas. The expression of GPX4 and SLC7A11 was downregulated, while the expression of ACSL4, FTH1, and NCOA4 was upregulated in the 661W cells cultured under HG conditions and in the photoreceptor cells in diabetic mice. Furthermore, the administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1) obviously alleviated ferroptosis-related changes in HG-cultured 661W cells and in retinal photoreceptor cells in diabetic mice. Taken together, our findings suggest that ferroptosis is involved in photoreceptor degeneration in the development of the early stages of DR.

Virtual Screening of Natural Chemical Databases to Search for Potential ACE2 Inhibitors.

The angiotensin-converting enzyme II (ACE2) is a multifunctional protein in both health and disease conditions, which serves as a counterregulatory component of RAS function in a cardioprotective role. ACE2 modulation may also have relevance to ovarian cancer, diabetes, acute lung injury, fibrotic diseases, etc. Furthermore, since the outbreak of the coronavirus disease in 2019 (COVID-19), ACE2 has been recognized as the host receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The receptor binding domain of the SARS-CoV-2 S-protein has a strong interaction with ACE2, so ACE2 may be a potent drug target to prevent the virus from invading host cells for anti-COVID-19 drug discovery. In this study, structure- and property-based virtual screening methods were combined to filter natural product databases from ChemDiv, TargetMol, and InterBioScreen to find potential ACE2 inhibitors. The binding affinity between protein and ligands was predicted using both Glide SP and XP scoring functions and the MM-GBSA method. ADME properties were also calculated to evaluate chemical drug-likeness. Then, molecular dynamics (MD) simulations were performed to further explore the binding modes between the highest-potential compounds and ACE2. Results showed that the compounds 154-23-4 and STOCK1N-07141 possess potential ACE2 inhibition activities and deserve further study.

Automatic Segmentation of Hemorrhages in the Ultra-wide Field Retina: Multi-scale Attention Subtraction Networks and An Ultra-wide Field Retinal Hemorrhage Dataset.

Ultra-wide field (UWF) retinal imaging can improve the detection rate of retinal hemorrhage as compared with conventional fundus images. However, hemorrhages in UWF retinal images can also become smaller and more widely distributed, which can be time consuming and labor intensive. With the development of computer technology, automatic segmentation techniques can assist physicians in diagnosis. However, the lack of publicly available UWF retinal hemorrhage segmentation datasets has limited the development of automatic hemorrhage segmentation techniques in UWF retinal images. We present a large-scale high-quality UWF retinal hemorrhage segmentation dataset, named UWF-RHS Dataset, for public use. To the best of our knowledge, we are the first team to make the UWF retinal hemorrhage segmentation dataset publicly available. In addition, we propose a multi-scale attention subtraction network (MASNet) for UWF retinal hemorrhage segmentation. Specifically, highly focused lesion features are extracted by using the proposed multi-scale attention subtraction (MAS) module at the progress of the skip-connection. Several comparative experiments and ablation experiments were performed at the UWF-RHS Dataset, and all experiments state that our proposed method is effective in diagnosing retinal hemorrhages with state-of-the-art results. The proposed UWF-RHS dataset and MASNet will greatly facilitate the development of automated segmentation techniques for UWF retinal hemorrhages. Links to the UWF-RHS dataset and the MASNet model code are available from https://github.com/wurenkai/UWF-RHS-Dataset-and-MASNet.

Bilateral ciliochoroidal detachment: Drug- or COVID-19-related? A case report and literature review.

Background: This report describes a case of bilateral transient myopia with a shallow anterior chamber and ciliochoroidal detachment following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and indapamide intake. Case presentation: A 37-year-old man with coronavirus disease 2019 (COVID-19) was referred to our department due to bilateral blurred vision. The patient had been treated with ibuprofen for fever and indapamide for uncontrolled blood pressure. After four days of indapamide intake, the patient complained of bilateral visual blurring. On ocular examination, his uncorrected visual acuity was 20/400 in both eyes. Slit-lamp examination revealed shallow anterior chambers. The following day, the patient experienced pain and redness in both eyes, which began the previous night. Ocular examination revealed a significant decrease in intraocular pressure (IOP) compared to the previous day: 11 mmHg and 12 mmHg in the right eye (OD) and left eye (OS), respectively. Slit-lamp examination revealed conjunctival injection and the presence of inflammatory cells (2+) in the shallow anterior chambers of both eyes. Ultrasound biomicroscopy revealed ciliary body detachment and B-scan ultrasonography showed peripheral shallow choroidal detachment in both eyes. Discontinuing indapamide and initiating treatment with oral prednisolone, topical tobramycin dexamethasone and tropicamide phenylephrine eye drops resulted in the rapid recovery of signs and symptoms after three days. Discussion and conclusions: Indapamide intake may contribute to bilateral ciliochoroidal detachment, with SARS-CoV-2 infection possibly increasing susceptibility to drug-induced side effects. Timely drug withdrawal and symptomatic treatment can result in a good prognosis.

The effect of electrical stimulation in critical patients: a meta-analysis of randomized controlled trials.

Objectives: While electrical stimulation has been demonstrated to improve medical research council (MRC) scores in critically ill patients, its effectiveness remains a subject of debate. This meta-analysis aimed to discuss recent insights into the effectiveness of electrical stimulation in improving muscle strength and its effects on different clinical outcomes in critically ill adults. Methods: A comprehensive search of major electronic databases, including PubMed, Cochrane Library, and Embase, was conducted from inception to June 15, 2024, to identify randomized controlled trials (RCTs) that evaluated the effects of electrical stimulation in critically ill patients. The analysis focused on comparing electrical stimulation to standard care, sham interventions, or placebo. Outcomes of interest included MRC scores, duration of mechanical ventilation (MV), mortality rate, and intensive care unit (ICU) and hospital length of stay (LOS). Results: A total of 23 RCTs, including 1798 patients, met the inclusion criteria. The findings demonstrated a significant benefit of electrical stimulation over usual care in enhancing global muscle strength, as measured by MRC scores (MD =3.62, 95% CI 0.94 to 6.30, p = 0.0008, I2 = 87%). While subgroup analysis of electrical muscle stimulation (EMS) demonstrated no significant effect on ICU LOS, sensitivity analysis indicated a potential reduction in ICU LOS for both EMS (MD = -11.0, 95% CI -21.12 to -0.88, p = 0.03) and electrical stimulation overall (MD = -1.02, 95% CI -1.96 to -0.08, p = 0.03) compared to the control group. In addition, sensitivity analysis suggested that both electrical stimulation (MD = -2.38, 95% CI -3.81 to -0.94, p = 0.001) and neuromuscular electrical stimulation (NMES) specifically (MD = -2.36, 95% CI -3.85 to -0.88, p = 0.002) may contribute to a decrease in hospital LOS. No statistically significant differences were observed in mortality or duration of MV. Conclusion: Electrical stimulation appears to be an effective intervention for improving MRC scores in critically ill patients. However, further research is warranted to explain the potential effects of electrical stimulation on hospital LOS and ICU LOS. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails.

TMCO1 promotes ferroptosis and ECM deposition in glaucomatous trabecular meshwork via ERK1/2 signaling.

Glaucoma, a leading cause of global blindness, is marked by irreversible retinal ganglion cells (RGCs) loss, elevated intraocular pressure (IOP), and extracellular matrix (ECM) deposition in the trabecular meshwork (TM). Transmembrane and coiled-coil domain protein 1 (TMCO1), implicated in calcium regulation, has potential links to primary open-angle glaucoma (POAG). Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, is also observed in glaucoma. This study investigates the role of TMCO1 in POAG, focusing on its involvement in TM ECM deposition via ferroptosis induction and ERK1/2 phosphorylation inhibition. In both in vivo and in vitro models, we demonstrated that dexamethasone (DEX) stimulation upregulates TMCO1, leading to increased ECM deposition and ferroptosis in human trabecular meshwork cells (HTMCs). Furthermore, treatment with ferrostatin-1 (Fer-1), a ferroptosis inhibitor, significantly reduced ECM deposition and ferroptosis in HTMCs. These findings establish TMCO1 as a critical regulator of ferroptosis and ECM deposition through the ERK/MAPK pathway, positioning it as a promising therapeutic target for glaucoma.

Macular changes following cataract surgery in eyes with early diabetic retinopathy: an OCT and OCT angiography study.

Background: To evaluate changes in macular status and choroidal thickness (CT) following phacoemulsification in patients with mild to moderate nonproliferative diabetic retinopathy (NPDR) using optical coherence tomography. Methods: In this prospective study, all of the patients underwent uncomplicated phacoemulsification. Retinal superficial capillary plexus vascular density (SCP-VD), macular thickness (MT), and CT were measured pre- and postoperatively. Results: Twenty-two eyes of 22 cataract patients with mild to moderate NPDR without diabetic macular edema (DME) and 22 controls were enrolled. BCVA increased in two groups at 3 months postoperatively. At 1 and 3 months postoperatively, SCP-VD in the diabetic retinopathy (DR) group significantly increased; changes in SCP-VD in parafovea were significantly greater in the DR group than in the control group. MT and CT in the DR group significantly increased at all visits postoperatively in the fovea and perifovea. Changes in parafoveal MT were significantly greater in the DR group than in the control group at all visits postoperatively. Changes in CT and MT in the fovea were significantly greater in patients with DR than in the controls 1 and 3 months postoperatively. Conclusion: Uncomplicated phacoemulsification resulted in greater increases in SCP-VD, MT and CT in patients with early DR without preoperative DME than in controls.

Monitoring multi-temporal and spatial variations of water transparency in the Jiaozhou Bay using GOCI data.

Water transparency, commonly measured as Secchi disk depth (SDD), is essential for describing the optical properties of coastal waters. We proposed a regional linear corrected SDD estimation model based on the North Sea Mathematical Models for GOCI and the mechanical model developed by Lee et al. (2015) in the Jiaozhou Bay. Combined with the multiple variable linear regression analysis, the diurnal SDD variations of the bay inside and the bay mouth are controlled by the solar zenith angle (SZA) and tides. The bay outside mainly varies with SZA. From GOCI observations between 2011 and 2021, wind force influenced the entire area on the inner-annual SDD variations. It exhibits an increasing trend in the inter-annual dynamics, which was more stable inside the bay with an annual increase of 0.035 m, and air temperature was the most significant contribution. However, human activities cannot be ignored in causing water environment changes.

LncRNA BBOX1-AS1 Aggravates the Development of Ovarian Cancer by Sequestering miR-361-3p to Augment PODXL Expression.

Ovarian cancer (OC) is a kind of common gynecological malignancy around the world. Mounting literatures have confirmed the implication of lncRNAs in the development of various cancers. Long non-coding RNA (LncRNA) BBOX1-AS1 has not been reported in most cancer types including OC. Presently, we aimed at exploring the function and regulatory mechanism of BBOX1-AS1 in OC. As a result, we demonstrated the extremely high BBOX1-AS1 expression in OC tissues and cells. BBOX1-AS1 silence inhibited OC progression by suppressing cell proliferation and promoting cell apoptosis. Importantly, BBOX1-AS1 was verified to bind to miR-361-3p, which presented a low expression trend in OC cells. Subsequently, PODXL was testified as the downstream target of miR-361-3p. Of note, BBOX1-AS1 positively regulated PODXL through their competition in binding with miR-361-3p. Furthermore, miR-361-3p inhibition facilitated the growth of BBOX1-AS1-deficient OC cells, while such facilitating effect was then counteracted in response to PODXL depletion. All the results above explained that BBOX1-AS1 was overexpressed in OC and that BBOX1-AS1 caused carcinogenic influences on OC cell growth via miR-361-3p/PODXL pathway, highlighting BBOX1-AS1 as a novel potential target for OC treatment.

Effect of erythropoietin on the survival of retinal neurocytes in culture upon serum withdrawal.

OBJECTIVES: To clarify whether erythropoietin (EPO) could substitute for the serum component in cultured retinal neurocytes suffering from serum withdrawal. METHODS: The study was performed in the Shanghai Institute of Traumatology and Orthopedics, Shanghai, China between April 2008 and March 2009. A total of 160 postnatal 2-3 day-old Sprague-Dawley rats were used for this study. After the retinal neurocytes were cultured for 48 hours, the culture media was replaced with serum-free media, and the cells were exposed to 1 U/ml, 3 U/ml, and 6 U/ml EPO for another 24 or 48 hours, the cell body diameter was then assessed using a computerized image-analysis system, and the survival and apoptosis rates of those cells were estimated by method of transcription and translation assay and flow cytometry. Immunocytochemistry was used to detect EPO and erythropoietin receptor (EPOR) expression. RESULTS: The retinal neurocytes had obvious EPO/ EPOR expression. The early (p = 0.002) and total (p = 0.049) apoptosis rates of retinal neurocytes cultured with serum withdrawal were significantly higher than that of neurocytes cultured with serum, and the cell viability of neurocytes cultured with serum withdrawal was significantly lower than that of neurocytes cultured with serum (p = 0.047). The EPO had no effect on the cell body diameter of cultured retinal neurocytes. The cell viability and the apoptosis rates of retinal neurocytes were not significantly different from that of simple serum-withdrawal culture at any EPO concentration. CONCLUSION: As the addition of EPO immediately after serum withdrawal had no effect in preventing retinal neurocytes apoptosis induced by serum withdrawal, EPO cannot substitute for the serum component.

Choroidal Structural Changes Assessed with Swept-Source Optical Coherence Tomography after Cataract Surgery in Eyes with Diabetic Retinopathy.

OBJECTIVE: To determine the influence of phacoemulsification on choroidal vasculature in patients with diabetic retinopathy (DR) undergoing cataract surgery using swept-source optical coherence tomography (SS-OCT). METHODS: The study was conducted in 23 eyes of 23 cataract patients with mild/moderate nonproliferative diabetic retinopathy (NPDR) without diabetic macular edema (DME) and 23 age-matched controls. Choroidal thickness (CT) and choroidal vascularity index (CVI) were measured at baseline and 1 week, 1 month, and 3 months after surgery. RESULTS: The baseline CVI in the DR group was significantly lower than that in the control group (P=0.001). CVI in DR patients after surgery significantly increased compared with preoperative values (all P < 0.001 for 1 week, 1 month, and 3 months after surgery). Postoperative increase of CVI and CT in the DR group was more than in the control group, and the difference was significant 1 month and 3 months after surgery (all P < 0.05). CONCLUSION: Patients with mild/moderate NPDR have reduced CVI compared with nondiabetic patients at baseline; diabetic cataract surgery tended to induce more increase in CVI and CT as compared with nondiabetic patients. This trial is registered with NCT04499768.

Examining the need assessment process by identifying the need profiles of elderly care recipients in the Ten-year Long-Term Care Project (TLTCP) of Taiwan.

OBJECTIVE: To deal with the increasing long-term care (LTC) needs of elderly people in Taiwan, the government launched the Ten-year Long-term Care Project (TLTCP) in 2007, and through the care management system, care plans for those in need were distributed and implemented by care managers according to the single assessment process. Based on the emphasis of linking the right need assessment to the care plan, this study aimed to explore the need profiles of LTC recipients with regard to their health indicators to serve as a validity check on the identified dependency levels and care plans in the current care management system. DESIGN: A model based on latent class analysis (LCA) was used for dealing with the issue of health heterogeneity. LCA provides an empirical method that examines the interrelationships among health indicators and characterizes the underlying set of mutually exclusive latent classes that account for the observed indicators. The analysis included a total of 2901 elderly care recipients in the LTC dataset from a southern city, 1 of the 5 major metropolitan areas in Taiwan. The identified dependency levels of the samples and their care plans in need assessment were compared and discussed. RESULTS: Four need profiles were explored in the LTC dataset. Apart from the low (LD) (32.95%) and moderate dependent groups (MD) (17.48%), there were 2 groups identified among the high-dependency levels, including the severe physical and psychological dependency (SPP) (26.37%) and the comorbidities and severe dependency (CSD) groups (23.20%), which in sum were approximately identified as high dependency (HD) by care managers in the LTC dataset. In addition, the CSD group currently costs more for their care plans on average in LTC services (NT. 277,081.15, approximately 9200 USD) than the SPP group (NT. 244,084.21) and the other groups. CONCLUSION: Need assessment is a key to success in care management in LTC. The results of this study showed the importance of focusing on multifacet indicators, especially the mental and social health indicators in need assessments by improving the unified assessment process to sensitively detect those with various needs and then link them to the right care plan.

The heterogeneous health latent classes of elderly people and their socio-demographic characteristics in Taiwan.

The health care needs of elderly people were influenced by their heterogeneity. This study aimed to identify the health latent classes of elderly people by using latent class analysis to deal with heterogeneity and examine their socio-demographic characteristics. Data came from the 2005 National Health Interview Survey (NHIS) in Taiwan. In total, 2449 elderly individuals with available health indicators were examined in latent class analysis (LCA), and 2217 elderly community-dwellings with complete socio-demographic data were analyzed by multinomial logistic regression. Four health latent classes were identified which included 1066 (43.5%) people in the High Comorbidity (HC), 152 (6.2%) in the Functional Impairment (FI), 252 (10.3%) in the Frail (FR), and 979 (40.0%) in the Relatively Healthy (RH) group. Multinomial logistic regressions revealed socio-demographic characteristics among health classes. The variables associated with an increased likelihood of being in the FR group were age, female, and living with families. They were also correlated to ethnicity and educations. Apart from age and gender, the Functional Impairment group was less likely to be ethnicity of Hakka, more likely to live with others than were the RH group. The HC group tended to be younger, with higher educations, and more likely to live in urban area than the Functional Impairment group. The correlations between health classes and socio-demographic factors were discussed. The health status of elderly people includes a variety of health indicators. A person-centered approach is critical to identify the health heterogeneity of elderly people and manage their care needs by targeting differential aging.

Utilization of health care services by elderly people with National Health Insurance in Taiwan: the heterogeneous health profile approach.

OBJECTIVES: Taiwan is now facing an increased prevalence of aging related diseases and escalating healthcare costs. Within the context of the health care system and NHI in Taiwan, the aim of this study was to examine the health profiles of elderly people by using Latent Class Analysis to determine the effects of different health profiles on the health care services utilization and expenditures, and to examine the factors associated with by controlling for the health profiles of elderly people. METHODS: Data came from the 2005 National Health Interview Survey in Taiwan. Among those who were interviewed, 2449 elderly individuals with available health indicators were identified, and 1491 of these had complete socio-economic data and linkage to their utilization of health care services from 2004 to 2007 were analyzed. RESULTS: Four health profiles were identified. The effect of the different health profiles of elderly people on the likelihood of utilization and expenditure on health care services was significant. While comparing with Relative Healthy group, the High Comorbidity group tended to utilize more services in the ambulatory care. The functional impairment group had relatively high probabilities of needing care assistance and the Frail group had higher health care expenditures. Age and gender did not have a significant effect and other associated socio-economic factors were also discussed. CONCLUSIONS: The health status of elderly people includes a variety of health indicators. We suggest that a person-centered approach is needed in order to satisfy needs and forecast expenditures in the future.

Ocular findings in a patient with virus-associated hemophagocytic syndrome.

PURPOSE: To describe a case of virus-associated hemophagocytic syndrome with ocular changes resembling Vogt-Koyanagi-Harada disease prior to the systemic changes. METHODS: A 51-year-old man presented with a sudden decline in vision. The patient was examined by fluorescein angiography, bone marrow biopsy, abdominal ultrasound, ocular examinations, and laboratory examinations. RESULTS: Fluorescein angiography revealed uveitis resembling Vogt-Koyanagi-Harada disease. Bone marrow biopsy specimen demonstrated histiocytic hyperplasia and some hemophagocytes. Abdominal ultrasound findings indicated hepato-splenomegaly. And ocular examinations revealed hematocytopenia and hypoproteinemia. CONCLUSION: The ocular changes resembling Vogt-Koyanagi-Harada disease observed in this study could be a kind of manifestation of virus-associated hemophagocytic syndrome in retina.

Promotion of neurite outgrowth and protective effect of erythropoietin on the retinal neurons of rats.

OBJECTIVE: To clarify the effect of erythropoietin (EPO) on neurite outgrowth of the cultured retinal neurocytes, and investigate whether EPO might potentially be beneficial in protecting cultured retinal neurocytes suffering from glutamate-induced cytotoxity. METHODS: After the retinal neurocytes were cultured for 48 hours, the culture media was replaced with serum-free media, and the cultured retinal cells were exposed to 1.0 U/ml, 3.0 U/ml and 6.0 U/ml EPO for another 48 hours; then the cells were stained with Sudan Black B, and the neurite outgrowth of those cells were evaluated by an image-analysis system. After the retinal neurocytes were cultured for 48 hours, the cells were cultured in serum-free media containing 5 mM or 10 mM glutamate, and the cells were incubated in the presence or absence of Epo (1.0 U/ml, 3.0 U/ml, 6.0 U/ml respectively) for another 48 hours. The survival and apoptosis rates of those cells were estimated by MTT assay and fluorescein isothiocyanate (FITC)-annexin V/propidium Iodide (PI) flow cytometry respectively. RESULTS: EPO induced a stable improvement of neurite outgrowth of retinal neurocytes in a dose-dependent manner. Compared with the control group, the neurite outgrowth length increased to 162.8% at 6.0 U/ml EPO exposure. EPO had no any significant effect on the survival and apoptosis rates of the retinal neurocytes cultured in serum-free media, but it was beneficial in promoting the survival and decreasing the early and total apoptosis rates of the cultured retinal neurocytes suffering from glutamate-induced cytotoxicity. CONCLUSION: EPO had a significant biological effect on neurite outgrowth of the dissociated retinal neurocytes in vitro. EPO was beneficial in promoting the survival and decreasing the apoptosis rates of the cultured retinal neurocytes suffering from glutamate-induced cytotoxicity.