Efficacy of Topical Cyclosporine Combined with Punctal Plugs in Treating Dry Eye Disease and Inflammation.

PURPOSE: To evaluate the effect of punctal plugs combined with cyclosporine eye drops on dry eye disease (DED) and ocular surface inflammation. METHODS: In a clinical trial, 73 patients were randomly allocated into three groups: punctal plug group, combination therapy group, and cyclosporine group. At the baseline and four weeks after treatment, the Schirmer I test score, fluorescein tear film break-up time (FBUT), ocular surface staining score and dry eye symptoms were assessed. Tear samples were collected to detect the level of inflammatory factors (interleukins, matrix metalloproteinase 9 (MMP-9) and tumor necrosis factor alpha (TNF-α)). In an animal experiment, a New Zealand rabbit dry eye model was induced. The rabbits were randomly divided into control group, punctal plug group, and combination therapy group (n = 6). Conjunctival goblet cell density, protein level of MMP-9 in conjunctiva and mRNA levels of inflammatory factors in conjunctiva and cornea were measured before and after treatment. RESULTS: In combination therapy group of the clinical trial, the following results were observed: significant improvement in Schirmer I test scores and FBUT compared to the cyclosporine group and punctal plug group, respectively; a decrease in the tear levels of IL-6, IL-1, and MMP-9 compared to the punctal plug group; and a decrease in the tear levels of IL-1α, IL-6, and IL-17 compared to the baseline (all p < 0.05). In the animal experiment, rabbits in combination therapy group had a higher goblet cell density (p < 0.01) and lower mRNA levels of IL-16 (p < 0.05), IL-17 (p < 0.05), and MMP-9 (p < 0.01) in conjunctiva and that of MMP-9 (p < 0.01) in cornea compared to punctal plug group. CONCLUSION: Cyclosporine eye drops combined with degradable punctal plugs is a more optimized clinical treatment strategy for DED compared with degradable punctal plugs or cyclosporine eye drops alone, considering the influence of comprehensive clinical efficacy and ocular surface inflammation.

Key genes and regulatory networks for diabetic retinopathy based on hypoxia-related genes: a bioinformatics analysis.

AIM: To prevent neovascularization in diabetic retinopathy (DR) patients and partially control disease progression. METHODS: Hypoxia-related differentially expressed genes (DEGs) were identified from the GSE60436 and GSE102485 datasets, followed by gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Potential candidate drugs were screened using the CMap database. Subsequently, a protein-protein interaction (PPI) network was constructed to identify hypoxia-related hub genes. A nomogram was generated using the rms R package, and the correlation of hub genes was analyzed using the Hmisc R package. The clinical significance of hub genes was validated by comparing their expression levels between disease and normal groups and constructing receiver operating characteristic curve (ROC) curves. Finally, a hypoxia-related miRNA-transcription factor (TF)-Hub gene network was constructed using the NetworkAnalyst online tool. RESULTS: Totally 48 hypoxia-related DEGs and screened 10 potential candidate drugs with interaction relationships to upregulated hypoxia-related genes were identified, such as ruxolitinib, meprylcaine, and deferiprone. In addition, 8 hub genes were also identified: glycogen phosphorylase muscle associated (PYGM), glyceraldehyde-3-phosphate dehydrogenase spermatogenic (GAPDHS), enolase 3 (ENO3), aldolase fructose-bisphosphate C (ALDOC), phosphoglucomutase 2 (PGM2), enolase 2 (ENO2), phosphoglycerate mutase 2 (PGAM2), and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Based on hub gene predictions, the miRNA-TF-Hub gene network revealed complex interactions between 163 miRNAs, 77 TFs, and hub genes. The results of ROC showed that the except for GAPDHS, the area under curve (AUC) values of the other 7 hub genes were greater than 0.758, indicating their favorable diagnostic performance. CONCLUSION: PYGM, GAPDHS, ENO3, ALDOC, PGM2, ENO2, PGAM2, and PFKFB3 are hub genes in DR, and hypoxia-related hub genes exhibited favorable diagnostic performance.

Lipidomics combined with random forest machine learning algorithms to reveal freshness markers for duck eggs during storage in different rearing systems.

The differences in lipids in duck eggs between the 2 rearing systems during storage have not been fully studied. Herein, we propose untargeted lipidomics combined with a random forest (RF) algorithm to identify potential marker lipids based on ultra-performance liquid chromatography‒mass spectrometry (UPLPC-MS/MS). A total of 106 and 16 differential lipids (DL) were screened in egg yolk and white, respectively. In yolk, metabolic pathway analysis of DLs revealed that glycerophospholipid metabolism and sphingolipid metabolism were the key metabolic pathways in the traditional free-range system (TFS) during storage, glycosylphosphatidylinositol-anchored biosynthesis and glyceride metabolism were the key pathways in the floor-rearing system (FRS). In egg white, the key pathway in both systems is the biosynthesis of unsaturated fatty acids. Combined with RF algorithm, 12 marker lipids were screened during storage. Therefore, this study elucidates the changes in lipids in duck eggs during storage in 2 rearing systems and provides new ideas for screening marker lipids during storage. This approach is highly important for evaluating the quality of egg and egg products and provides guidance for duck egg production.

Sepsis caused by Phytobacter diazotrophicus complicated with galactosemia type 1 in China: a case report.

BACKGROUND: Phytobacter diazotrophicus (P. diazotrophicus) is an opportunistic pathogen that causes nosocomial outbreaks and sepsis. However, there are no reports of P. diazotrophicus isolated from human blood in China. CASE PRESENTATION: A 27-day-old female infant was admitted to our hospital with fever and high bilirubin levels. The clinical features included jaundice, abnormal coagulation, cholestasis, fever, convulsions, weak muscle tension, sucking weakness, ascites, abnormal tyrosine metabolism, cerebral oedema, abnormal liver function, clavicle fracture, and haemolytic anaemia. The strain isolated from the patient's blood was identified as P. diazotrophicus by whole-genome sequencing (WGS). Galactosemia type 1 (GALAC1) was diagnosed using whole-exome sequencing (WES). Based on drug sensitivity results, 10 days of anti-infective treatment with meropenem combined with lactose-free milk powder improved symptoms. CONCLUSION: P. diazotrophicus was successfully identified in a patient with neonatal sepsis combined with galactosemia. Galactosemia may be an important factor in neonatal sepsis. This case further expands our understanding of the clinical characteristics of GALAC1.

MUP1 mediates urolithin A alleviation of chronic alcohol-related liver disease via gut-microbiota-liver axis.

Alcohol-related liver disease (ALD) is recognized as a global health crisis, contributing to approximately 20% of liver cancer-associated fatalities. Dysbiosis of the gut microbiome is associated with the development of ALD, with the gut microbial metabolite urolithin A (UA) exhibiting a potential for alleviating liver symptoms. However, the protective efficacy of UA against ALD and its underlying mechanism mediated by microbiota remain elusive. In this study, we provide evidence demonstrating that UA effectively ameliorates alcohol-induced metabolic disorders and hepatic endoplasmic reticulum (ER) stress through a specific gut-microbiota-liver axis mediated by major urinary protein 1 (MUP1). Moreover, UA exhibited the potential to restore alcohol-induced dysbiosis of the intestinal microbiota by enriching the abundance of Bacteroides sartorii (B. sartorii), Parabacteroides distasonis (P. distasonis), and Akkermansia muciniphila (A. muciniphila), along with their derived metabolite propionic acid. Partial attenuation of the hepatoprotective effects exerted by UA was observed upon depletion of gut microbiota using antibiotics. Subsequently, a fecal microbiota transplantation (FMT) experiment was conducted to evaluate the microbiota-dependent effects of UA in ALD. FMT derived from mice treated with UA exhibited comparable efficacy to direct UA treatment, as it effectively attenuated ER stress through modulation of MUP1. It was noteworthy that strong associations were observed among the hepatic MUP1, gut microbiome, and metabolome profiles affected by UA. Intriguingly, oral administration of UA-enriched B. sartorii, P. distasonis, and A. muciniphila can enhance propionic acid production to effectively suppress ER stress via MUP1, mimicking UA treatment. Collectively, these findings elucidate the causal mechanism that UA alleviated ALD through the gut-microbiota-liver axis. This unique mechanism sheds light on developing novel microbiome-targeted therapeutic strategies against ALD.

Hepatitis B virus X protein promotes tumor glycolysis by downregulating lncRNA OIP5-AS1/HKDC1 in HCC.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, with Hepatitis B virus (HBV) infection being the leading cause. This study aims to investigate the role of HBV in HCC pathogenesis involving glucose metabolism. Long non-coding RNA (lncRNA) OIP5-AS1 was significantly downregulated in HBV-positive HCC patients, and its low expression indicated a poor prognosis. This lncRNA was primarily localized in the cytoplasm, acting as a tumor suppressor. HBV protein X (HBx) repressed OIP5-AS1 expression by inhibiting a ligand-activated transcriptional factor peroxisome proliferator-activated receptor α (PPARα). Furthermore, mechanistic studies revealed that OIP5-AS1 inhibited tumor growth by suppressing Hexokinase domain component 1 (HKDC1)-mediated glycolysis. The expression of HKDC1 could be enhanced by transcriptional factor sterol regulatory element-binding protein 1 (SREBP1). OIP5-AS1 facilitated the ubiquitination and degradation of SREBP1 to suppress HKDC1 transcription, which inhibited glycolysis. The results suggest that lncRNA OIP5-AS1 plays an anti-oncogenic role in HBV-positive HCC via the HBx/OIP5-AS1/HKDC1 axis, providing a promising diagnostic marker and therapeutic target for HBV-positive HCC patients.

Hepatitis B Virus-Mediated m6A Demethylation Increases Hepatocellular Carcinoma Stemness and Immune Escape.

Hepatitis B viral (HBV) persistent infection plays a significant role in hepatocellular carcinoma (HCC) tumorigenesis. Many studies have revealed the pivotal roles of N6-methyladenosine (m6A) in multiple cancers, while the regulatory mechanism in stemness maintenance of HBV persistent infection-related HCC remains elusive. Here, we demonstrated that the level of m6A modification was downregulated by HBV in HBV-positive HCC, through enhanced stability of ALKBH5 mRNA. More specifically, we also identified that ALKBH5 mRNA was functionally required for the stemness maintenance and self-renewal in the HBV-positive HCC, but dispensable in HBV-negative HCC. Mechanistically, ALKBH5 demethylated the m6A modification in the 3' untranslated region of the oncogenic gene SNAI2 to prevent the recognition of YTHDF2 therewith stabilize SNAI2 transcripts, contributing to cancer stem cell traits in HBV-positive HCC. Moreover, the expression of SNAI2 reversed the suppression of stemness properties by knocking down ALKBH5. In addition, ALKBH5/SNAI2 axis accelerates tumor immune evasion through activated ligand of immune checkpoint CD155. Our study unveiled that the ALKBH5 induces m6A demethylation of the SNAI2 as a key regulator in HBV-related HCC, and identifies the function of ALKBH5/SNAI2/YTHDF2 axis in promoting the stem-like cells phenotype and immune escape during HBV infection. IMPLICATIONS: HBV promotes HCC stemness maintenance through elevate m6A modification of SNAI2 in an ALKBH5-YTHDF2-dependent manner and increases the expression of the ligand of immune checkpoint CD155.

Water-Free Cyclosporine Ophthalmic Solution vs Vehicle for Dry Eye Disease: A Randomized Clinical Trial.

Importance: Dry eye disease (DED) is a prevalent eye disorder. Cyclosporine is an effective immunomodulator that is widely used in DED; however, due to its highly hydrophobic nature, delivery of cyclosporine to the ocular surface is challenging. Objective: To evaluate the efficacy and safety of SHR8028, a water-free cyclosporine ophthalmic solution, 0.1%, compared with vehicle in Chinese participants with DED. Design, Setting, and Participants: This was a multicenter, double-blind, vehicle-controlled, phase 3 randomized clinical trial conducted from March 4, 2021, to July 22, 2022. Adult participants with moderate to severe DED were recruited from 12 hospitals in China. Study data were analyzed April 2, 2022, for the primary analysis. Interventions: Following a 14-day run-in period with an artificial tear, participants were randomly assigned (1:1) to receive water-free cyclosporine or vehicle (1 eye drop in each eye twice daily). After a 29-day treatment, participants of both groups were given the option to receive water-free cyclosporine for an additional 12 weeks for longer-term safety assessment. Main Outcomes and Measures: The primary end points were changes from baseline in total corneal fluorescein staining (tCFS) using the National Eye Institute scale and in dryness score on a visual analog scale at day 29. Results: A total of 206 participants (mean [SD] age, 47.8 [14.2] years; 185 female [90%]) were enrolled, with 103 each in the cyclosporine group and the vehicle group. At day 29, the cyclosporine group experienced improved tCFS compared with vehicle (change [Δ] = -1.8; 95% CI, -2.7 to -1.0; P < .001), with a tCFS score decrease from baseline of -4.8 in the cyclosporine group and -3.0 in the vehicle group. Dryness score decreased from baseline in both groups (-19.2 vs -15.4; Δ = -3.8; 95% CI, -9.2 to 1.6; P = .17). During the 29-day treatment, treatment-related adverse events were reported in 15 participants (14.6%) in the cyclosporine group and 11 participants (10.7%) in the vehicle group. Conclusions And Relevance: Results demonstrated superiority of a water-free cyclosporine, 0.1%, eye solution over vehicle in improving tCFS score at day 29 in Chinese participants with DED. However, dryness score (VAS) was not improved at day 29. Trial Registration: ClinicalTrials.gov Identifier: NCT05841043.

FASN Inhibition Decreases MHC-I Degradation and Synergizes with PD-L1 Checkpoint Blockade in Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICI) transformed the treatment landscape of hepatocellular carcinoma (HCC). Unfortunately, patients with attenuated MHC-I expression remain refractory to ICIs, and druggable targets for upregulating MHC-I are limited. Here, we found that genetic or pharmacologic inhibition of fatty acid synthase (FASN) increased MHC-I levels in HCC cells, promoting antigen presentation and stimulating antigen-specific CD8+ T-cell cytotoxicity. Mechanistically, FASN inhibition reduced palmitoylation of MHC-I that led to its lysosomal degradation. The palmitoyltransferase DHHC3 directly bound MHC-I and negatively regulated MHC-I protein levels. In an orthotopic HCC mouse model, Fasn deficiency enhanced MHC-I levels and promoted cancer cell killing by tumor-infiltrating CD8+ T cells. Moreover, the combination of two different FASN inhibitors, orlistat and TVB-2640, with anti-PD-L1 antibody robustly suppressed tumor growth in vivo. Multiplex IHC of human HCC samples and bioinformatic analysis of The Cancer Genome Atlas data further illustrated that lower expression of FASN was correlated with a higher percentage of cytotoxic CD8+ T cells. The identification of FASN as a negative regulator of MHC-I provides the rationale for combining FASN inhibitors and immunotherapy for treating HCC. SIGNIFICANCE: Inhibition of FASN increases MHC-I protein levels by suppressing its palmitoylation and lysosomal degradation, which stimulates immune activity against hepatocellular carcinoma and enhances the efficacy of immune checkpoint inhibition.

Need to Increase the Number of Intense Pulsed Light (IPL) Treatment Sessions for Patients with Moderate to Severe Meibomian Gland Dysfunction (MGD) Patients.

PURPOSE: To evaluate whether patients with moderate-to-severe meibomian gland dysfunction (MGD) will benefit from increasing the number of intense pulsed light (IPL) treatment sessions. METHODS: Ninety Asian adult with MGD (stages 3-4) were enrolled in this retrospective study. In Group1, 30 patients completed the five-session IPL treatment, 63.33% of which also received meibomian gland expression (MGX). In Group 2, 60 patients received three-session IPL treatment, 60.0% of which also accepted MGX. Both intragroup and intergroup analyses were conducted. RESULTS: The population characteristics, clinical baseline characteristics and therapeutic regimen were comparable between Group1 and Group2. The symptoms and most clinical indices improved after IPL treatment finished in both two groups. No statistical difference was found in any improvement level of all symptomatic and physical indices, including the Ocular surface disease index, tear break-up time, Demodex, corneal staining, meibum quality, meibomian gland expressibility, and MGD stage (all p ≥ 0.05) between the two groups at any time, not only month by month, but also at the terminal visit. However, the response rate of Group1 after the five-session treatment (70.00%) was increased compared to that of Group2 after the three-session treatment (63.33%). CONCLUSIONS: Increasing the number of IPL sessions is beneficial for patients with moderate to severe MGD to increase the response rate of treatment, rather than the improvement level. However, there is no need for patients who respond well to a routine number of IPL treatments to undergo additional IPL sessions.

Clinical and Morphological in Vivo Confocal Microscopy Findings following a Modified Biphasic Higher Fluence Transepithelial Corneal Crosslinking.

Purpose: To compare the refractive efficacy and morphological changes in the cornea following a novel biphasic higher fluence transepithelial corneal crosslinking (BI-TE-CXL) and transepithelial corneal crosslinking (TE-CXL) in adults keratoconus.Methods: Patients with progressive keratoconus who required corneal crosslinking were assigned to the BI-TE-CXL group (32 eyes, phase 1: 7.2 J/cm2 for 5 min and 20 s of pulsed-light exposure, KXL, Glaukos-Avedro; phase 2: 3.6 J/cm2 for 6 min and 40 s of continuous light exposure at the front curvature apex with a 6 mm diameter light spot, UVX-2000, IROC) or the TE-CXL group (32 eyes, uniform 7.2 J/cm2 for 5 min and 20 s of pulsed-light exposure, KXL, Glaukos-Avedro). Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), corneal fluorescein staining (CFS), corneal topography, anterior segment optical coherence tomography (AS-OCT), and in vivo corneal confocal microscopy (IVCM) were performed 3, 6, 12 and 24 months after surgery.Results: The CFS scores in the BI-TE-CXL group were significantly higher than those in the TE-CXL group on the first two days after surgery (p < 0.001). The Kmax (at 12 and 24 months) and CDVA (logMAR) were significantly lower in the BI-TE-CXL group than those in the TE-CXL group (p < 0.05). The corneal demarcation line under AS-OCT was visible in 81.3% of patients in the BI-TE-CXL group and 15.6% in the TE-CXL group. The depth of the demarcation line under IVCM was significantly deeper in the BI-TE-CXL group (248.3 ± 25.0 µm) than that of the TE-CXL group (136.5 ± 15.6 µm) in the central cornea (p < 0.001). The cross-linked collagen structures in the central cornea were still present after 12 months in the BI-TE-CXL group. No significant difference in sub-basal nerve density between the two groups (p > 0.05).Conclusions: Following BI-TE-CXL, CDVA was significantly improved, accompanied by deeper demarcation line depth and persistent crosslinked structures in the central corneal stroma.

Relation Between Corneal Dendritic Cell Density and Tear Film Stability in Patients with Epidemic Keratoconjunctivitis Associated Dry Eye.

PURPOSE: To clarify the ocular surface features of patients with recent history of epidemic keratoconjunctivitis (EKC) and the relation between corneal dendritic cells (DCs) and ocular discomfort. METHODS: Normal controls (NC) and dry eye (DE) patients without EKC were recruited. Patients with recent EKC history (onset >4 weeks, but <20 weeks) were recruited as EKC + DE group (with dry eye) or EKC-DE group (without dry eye). Ocular surface disease index (OSDI) questionnaire, tear film parameters including lipid layer thickness, first tear break-up time (fBUT), average tear break-up time (aBUT), tear meniscus height and Schirmer I test, meibomian gland parameters, and in vivo corneal confocal microscopy were evaluated. RESULTS: 50 subjects in the NC group, 83 patients in the DE group, 76 patients in the EKC + DE group, and 38 patients in the EKC-DE group were included. Compared with the NC, DE, and EKC-DE groups, the EKC + DE group represented higher OSDI, lid margin, and meibum score (p < 0.05). In the EKC + DE group, the tear volume (10.5 ± 3.7 mm) was significantly higher than in the DE group (8.1 ± 2.8 mm, p < 0.001). The DC density in the EKC + DE group (29.98 ± 15.38 cells/image) was significantly higher than in NC, DE, and EKC-DE groups (4.68 ± 4.05 cells/image) (p < 0.001). The DC density was positively correlated with OSDI, lid margin, and meibum score (all p < 0.01) while inversely correlated with fBUT, aBUT (all p < 0.001) in the EKC + DE group. CONCLUSIONS: Corneal DC density significantly correlates to ocular discomfort and tear film instability in patients with recent EKC history who suffer from DE without aqueous tear deficiency.

A Novel Bifidobacterium/Klebsiella Ratio in Characterization Analysis of the Gut and Bile Microbiota of CCA Patients.

Cholangiocarcinoma (CCA) is a serious health problem worldwide. The gut and bile microbiota have not been clearly characterized in patients with CCA, and better noninvasive diagnostic approaches for CCA need to be established. The aim of this study was to investigate the characteristics of the gut and bile microbiota in CCA patients. Forty-two CCA patients and 16 healthy normal controls (HNCs) were enrolled. DNA was extracted from fecal and bile samples and subjected to 16S rRNA gene analysis. We found that there were significant differences in the species diversity, structure, and composition of the microbial communities between the CCA group and the HNC grouAt the phylum level, compared with that in the HNC group, the relative abundance of Firmicutes and Actinobacteriota was significantly decreased in the CCA group, whereas Proteobacteria and Bacteroidota were significantly enriched. The Firmicutes/Bacteroidota (F/B) ratio significantly decreased in the CCA group compared to the HNC grouThe relative abundance of Klebsiella in the CCA group was significantly higher than that in the HNC group, while the relative abundance of Bifidobacterium was significantly decreased. The Bifidobacterium/Klebsiella (B/K) ratio was established as a novel biomarker and was found to be significantly decreased in the CCA group compared with the HNC grouOur findings provide evidence supporting the use of Klebsiella and Bifidobacterium as noninvasive intestinal microbiomarkers for improving the diagnosis of CCA.

Nonlinear effects of humidex on risk of outpatient visit for allergic conjunctivitis among children and adolescents in Shanghai, China: A time series analysis.

Background: Various epidemiological studies have focused on the adverse health outcomes of meteorological factors. However, there has been little research on the impact of humidex on allergic conjunctivitis, especially in child and adolescent populations. We aimed to explore the impact of humidex, a comprehensive index of relative humidity and temperature, on child and adolescent allergic conjunctivitis admissions. Methods: Outpatient visit data for allergic conjunctivitis, meteorological factors and air pollutants in Shanghai for the 2017-2022 period were retrieved. For the purpose of analysing the nonlinear connection and lag impact between humidex and admissions for paediatric and adolescent allergic conjunctivitis, the distributed lag nonlinear model (DLNM) was fitted. Results: A total of 147 090 cases were included in our cohort. We found a significantly nonlinear effect on humidex and allergic conjunctivitis. In the single-day lag pattern, the relative risks (RR) of allergic conjunctivitis were significant at lag 0 (RR = 1.08, 95% confidence interval (CI) = 1.05-1.11) to lag 2 (RR = 1.01, 95% CI = 1.00-1.01), lag 5 (RR = 1.01, 95% CI = 1.00-1.01) to lag 9 (RR = 1.01, 95% CI = 1.00-1.01), and lag 14 (RR = 1.02, 95% CI: 1.01-1.03). In the cumulative-lag day pattern, the RR of allergic conjunctivitis were significant at lag 0-0 (RR = 1.08, 95% CI = 1.05-1.11) to lag 0-14 (RR = 1.21, 95% CI = 1.13-1.28). We found that boys, children aged 7-17 years, and children in the warm season were more vulnerable to humidex. In addition, the highest attributable fraction (AF) and attributable number (AN) of humidex are at lag 0-14 (AF = 0.17, AN = 25 026). Conclusions: Humidex exposure markedly increased the risk of allergic conjunctivitis, especially in highly high humidex. Appropriate public health management is needed for disease management and early intervention.

Urolithin A Protects Neuronal Cells against Stress Damage and Apoptosis by Atp2a3 Inhibition.

SCOPE: This study aims to investigate the effect and mechanism of Urolithin A (UA) on neuronal stress damage on cognitive impairment in type 2 diabetes mellitus (T2DM) mouse model induced by high-fat diet (HFD) and streptozotocin (STZ). METHODS AND RESULTS: T2DM mice fed with UA display an attenuated cognitive impairment along with suppressed endoplasmic reticulum (ER) stress and Tau hyperphosphorylation in brain. Similar restraint effect of UA on Tau hyperphosphorylation and ER stress is also observed in high glucose-treated primary hippocampal neurons. Moreover, UA ameliorates oxidative stress, ER stress, aberrant energy metabolism, and apoptosis in 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) induced HT22 cells. Atp2a3 is identified as a potential target gene of UA which is closely related to intracellular calcium homeostasis, ER stress, and apoptosis, so that UA significantly down-regulated Atp2a3 expression in DMNQ-induced cells. Furthermore, the protection effect of UA against ER stress and apoptosis is abolished by Atp2a3 over-expression in HT22 cells. Taken together, these data suggest that UA performs anti-stress effect by suppressing the expression of Atp2a3 in damaged neuronal cells and thus attenuates diabetes-associated cognitive impairment in T2DM mice. CONCLUSION: The study implies UA as a potential novel pharmaceutic target for neurodegeneration and stress damage through regulating the expression of Atp2a3.

Relations between nonmotor manifestations and motor disorders in patients with benign essential blepharospasm.

PURPOSE: To evaluate the relations between nonmotor manifestations (dry eye, mood disorders, and sleep disturbance) and motor disorders in patients with benign essential blepharospasm (BEB), and to determine whether relieving motor disorders by botulinum neurotoxin can improve the nonmotor manifestations. METHODS: In this prospective case series study, 123 BEB patients were enrolled for evaluations. Among them, 28 patients underwent botulinum neurotoxin therapy and attended another two postoperative visits at 1 month and 3 months. Motor severity was measured with Jankovic Rating Scale (JRS) and Blepharospasm Disability Index (BSDI). We assessed dry eye using OSDI questionnaire, Schirmer test, tear break-up time (TBUT), tear meniscus height, lipid layer thickness (LLT) and corneal fluorescence staining. Zung's Self-rating Anxiety and Depression Scale (SAS, SDS) and Pittsburgh Sleep Quality Index (PSQI) were for mood status and sleep quality evaluations. RESULTS: Patients with dry eye or mood disorders had higher JRS scores (5.78 ± 1.13, 5.97 ± 1.30) than those without (5.12 ± 1.40, 5.50 ± 1.16; P = 0.039, 0.019, respectively). BSDI values of patients with sleep disturbance (14.61 ± 4.71) was higher than those without (11.89 ± 5.44, P = 0.006). Correlations were found between JRS, BSDI and SAS, SDS, PSQI, OSDI, TBUT. Botulinum neurotoxin effectively relieved JRS, BSDI and improved PSQI, OSDI, TBUT, LLT (8.11 ± 5.81, 21.77 ± 15.76, 5.04 ± 2.15 s, 79.61 ± 24.11 nm) at the 1-month visit compared to baseline (9.75 ± 5.60, 33.58 ± 13.27, 4.14 ± 2.21 s, 62.33 ± 22.01 nm; P = 0.006, < 0.001, = 0.027, < 0.001, respectively). CONCLUSIONS: The BEB patients with dry eye, mood disorders, or sleep disturbance had more severe motor disorders. Motor severity was associated with the severity of the nonmotor manifestations. Relieving motor disorders by botulinum neurotoxin was effective in improving dry eye and sleep disturbance.

Administration of serotonin and norepinephrine reuptake inhibitors tends to have less ocular surface damage in a chronic stress-induced rat model of depression than selective serotonin reuptake inhibitors.

Depressed patients who medicate with selective serotonin reuptake inhibitors (SSRIs) often report ocular dryness. Epidemiological studies have found that serotonin and norepinephrine reuptake inhibitors (SNRIs) are not risk factors for dry eye in depressed patients. However, the effect of SNRIs on the ocular surface is unknown. A depression rat model was induced by chronic unpredictable mild stress (CUMS), and SNRIs or SSRIs were administered to the rats for 3 or 6 weeks. The levels of norepinephrine (NE) and serotonin in tear fluid were tested by ELISA. The corneal fluorescence and lissamine green staining were used to evaluate ocular surface damage. NE and/or serotonin were administered to human corneal epithelial cells in vitro. RNA sequencing (RNA-seq) analysis was performed to investigate the mRNA expression profiles. Tear NE levels were higher in the SNRIs group, and ocular surface inflammation and apoptosis were significantly reduced compared to the SSRIs group. RNA-Seq indicated that NE significantly activate MAPK signaling pathway. NE can inhibit serotonin-induced activation of the NF-κB signaling pathway through α-1 adrenergic receptors and promotes the proliferation of corneal epithelial cells through activation of the MAPK signaling pathway. SNRIs administration have less ocular surface damage than SSRIs. NE protects human corneal epithelial cells from damage, and reduce inflammation on the ocular surface via activating the MAPK signaling pathway. SNRIs might be used as an appropriate treatment for depression-related DED.

A Review of Applications and Intracellular Mechanisms of Intense Pulsed Light in Eyelid Inflammatory Diseases.

Objective: To evaluate relevant clinical outcomes and conclude possible mechanisms of intense pulsed light (IPL) in eyelid inflammation. Background: IPL devices were primarily applied in cutaneous vascular malformations and have been used in ocular diseases for about 20 years, mostly including meibomian gland dysfunction (MGD), blepharitis, and ocular rosacea. Recent findings: Seventy-two original clinical researches were included, 57 for MGD, 4 for blepharitis or blepharitis-related keratoconjunctivitis, and 11 for rosacea. Dry eye symptoms, (tear) break-up time (BUT), and meibomian structure and/or functions were improved in most patients, but production of reactive oxygen species is an important link in the photobiomodulation mediated by IPL, which can influence numerous signal pathways to achieve anti-inflammatory, anti-infective, and prodifferentiation effects. Conclusions: The evidence suggests that IPL is an effective therapeutic tool for most patients with MGD, but more clinical evidence is needed for other indications.

Comprehensive Analysis of Antimicrobial, Heavy Metal, and Pesticide Residues in Commercial Organic Fertilizers and Their Correlation with Tigecycline-Resistant tet(X)-Variant Genes.

With the issue of the antimicrobial additive ban in feed in Chinese animal husbandry, it is important to determine the potential drivers of the spread of the newly discovered tigecycline-resistant tet(X)-variant genes. Here, we investigated the correlations between residues of heavy metals, antimicrobials, and pesticides and the relative abundance of tet(X)-variant genes in 94 commercial organic-fertilizer samples collected from 9 Chinese provinces. A total of 5 heavy metals (mercury, lead, arsenic, chromium, and cadmium), 10 antimicrobials, and 18 pesticides were detected. The tet(X)-variant genes, including tet(X)/(X2), tet(X3), tet(X4), tet(X5), and tet(X6) were detected in 39 (41.5%) samples. Although tet(X)-variant-carrying bacteria were not isolated from these samples, the tet(X4)-carrying plasmids could be captured by exogenous Escherichia coli. Correlation analysis revealed that heavy metals, other than antimicrobials, showed a significant positive association with the relative abundance of the tet(X)-variant genes, especially tet(X3) and tet(X4) (R = 0.346 to 0.389, P < 0.001). The correlation was attributed to the coselection of the tet(X3)/tet(X4) gene on the same plasmid and the conjugation-promoting effect of tet(X3)/tet(X4)-carrying plasmids by subinhibitory concentrations of heavy metals. The heavy metals increased the permeability of the bacterial outer membrane and upregulated the transcription of type IV secretion system (T4SS)-encoding genes on tet(X)-variant-carrying plasmids, therefore enhancing the bacterial conjugation rates. Taken together, our findings have indicated that heavy metals may play an important role in spreading tet(X)-variant genes within the animal manure-related environment. IMPORTANCE An antimicrobial resistance gene (ARG) is considered a novel contaminant for the environment. Most animal feces are usually made into commercial organic fertilizers in China and will pose a threat to the farmland soil and agricultural product if fertilizers harboring clinically significant antimicrobial-resistant (AMR) genes are applied on farmland. This study has indicated that heavy metals may play an important role in the transmission of transferable tigecycline resistance genes [tet(X3) and tet(X4)]. The mechanism was that heavy metals posed a coselection effect of the tet(X3)/tet(X4) gene on the same plasmid and could increase the conjugation ability of tet(X3)/tet(X4)-carrying plasmids. The conjugation-promoting concentrations of heavy metals are lower than the maximal limits defined in the national standard for fertilizers, indicating a high transmission risk of tet(X3)/tet(X4) genes within the animal manure-related environment. The findings in this study will provide scientific evidence for the future development of effective measures to reduce AMR dissemination.