Construction and validation of a neovascular glaucoma nomogram in patients with diabetic retinopathy after pars plana vitrectomy.

BACKGROUND: Neovascular glaucoma (NVG) is likely to occur after pars plana vitrectomy (PPV) for diabetic retinopathy (DR) in some patients, thus reducing the expected benefit. Understanding the risk factors for NVG occurrence and building effective risk prediction models are currently required for clinical research. AIM: To develop a visual risk profile model to explore factors influencing DR after surgery. METHODS: We retrospectively selected 151 patients with DR undergoing PPV. The patients were divided into the NVG (NVG occurrence) and No-NVG (No NVG occurrence) groups according to the occurrence of NVG within 6 months after surgery. Independent risk factors for postoperative NVG were screened by logistic regression. A nomogram prediction model was established using R software, and the model's prediction accuracy was verified internally and externally, involving the receiver operator characteristic curve and correction curve. RESULTS: After importing the data into a logistic regression model, we concluded that a posterior capsular defect, preoperative vascular endothelial growth factor ≥ 302.90 pg/mL, glycosylated hemoglobin ≥ 9.05%, aqueous fluid interleukin 6 (IL-6) ≥ 53.27 pg/mL, and aqueous fluid IL-10 ≥ 9.11 pg/mL were independent risk factors for postoperative NVG in patients with DR (P < 0.05). A nomogram model was established based on the aforementioned independent risk factors, and a computer simulation repeated sampling method was used to internally and externally verify the nomogram model. The area under the curve (AUC), sensitivity, and specificity of the model were 0.962 [95% confidence interval (95%CI): 0.932-0.991], 91.5%, and 82.3%, respectively. The AUC, sensitivity, and specificity of the external validation were 0.878 (95%CI: 0.746-0.982), 66.7%, and 95.7%, respectively. CONCLUSION: A nomogram constructed based on the risk factors for postoperative NVG in patients with DR has a high prediction accuracy. This study can help formulate relevant preventive and treatment measures.

Folic acid conjugated palygorskite/Au hybrid microgels: Temperature, pH and light triple-responsive and its application in drug delivery.

Herein, folic acid conjugated poly (NIPAM-co-functional palygorskite-Au-co-acrylic acid) (FA-PNFA) hybrid microgels were fabricated by emulsion polymerization. The introduction of acrylic acid can increase the low critical solution temperature (LCST) of FA-PNFA from 36 °C at pH 5.5-42 °C at pH 7.4. Doxorubicin hydrochloride (DOX) was chosen as the load drug, the results show that the DOX release behavior is driven by temperature, pH and light. Cumulative drug release rate can reach 74 % at 37 °C and pH 5.5 while only 20 % at 37 °C and pH 7.4, which effectively avoided the early leakage of the drug. In addition, by exposing FA-PNFA hybrid microgels to laser irradiation, the cumulative release rate was increased by 5 % compared to the release rate under dark conditions. Functional palygorskite-Au as physical crosslinkers not only improves the drug loading content of microgels but also promotes the release of DOX through light drive. Methyl thiazolyl tetrazolium bromide (MTT) assay demonstrated that the FA-PNFA are nontoxic up to 200 µg mL-1 towards 4T1 breast cancer cell. Meanwhile, DOX-loaded FA-PNFA show more significant cytotoxicity than the free DOX. Confocal laser scanning microscope (CLSM) revealed that the DOX-loaded FA-PNFA could be efficiently taken by 4T1 breast cancer cells. FA-PNFA hybrid microgels not only improve the LCST of PNIPAM, but also endow the microgels with photostimulation responsiveness, which can release drugs in response to the triple stimulation response of temperature, pH and light, thus effectively reducing the activity of cancer cells, making them more promising for wider medical applications.

Analysis of postoperative ocular surface changes and intervention effect after pars plana vitrectomy in meibomian gland dysfunction dry eye patients.

AIM: To observe ocular surface changes after phacovitrectomy in patients with mild to moderate meibomian gland dysfunction (MGD)-type dry eye and track clinical treatment response using a Keratograph 5M and a LipiView interferometer. METHODS: Forty cases were randomized into control group A and treatment group B; the latter received meibomian gland treatment 3d before phacovitrectomy and sodium hyaluronate before and after surgery. The average non-invasive tear film break-up time (NITBUTav), first non-invasive tear film break-up time (NITBUTf), non-invasive measured tear meniscus height (NTMH), meibomian gland loss (MGL), lipid layer thickness (LLT) and partial blink rate (PBR) were measured preoperatively and 1wk, 1 and 3mo postoperatively. RESULTS: The NITBUTav values of group A at 1wk (4.38±0.47), 1mo (6.76±0.70), and 3mo (7.25±0.68) were significantly lower than those of group B (7.45±0.78, 10.46±0.97, and 11.31±0.89; P=0.002, 0.004, and 0.001, respectively). The NTMH values of group B at 1wk (0.20±0.01) and 1mo (0.22±0.01) were markedly higher than those of group A (0.15±0.01 and 0.15±0.01; P=0.008 and P<0.001, respectively); however, there was no difference at 3mo. The LLT of group B at 3mo [91.5 (76.25-100.00)] significantly exceeded that of group A [65.00 (54.50-91.25), P=0.017]. No obvious intergroup difference was found in MGL or PBR (P>0.05). CONCLUSION: Mild to moderate MGD dry eye worsens in the short term after phacovitrectomy. Preoperative cleaning, hot compresses, and meibomian gland massage as well as preoperative and postoperative sodium hyaluronate promote the rapid recovery of tear film stability.

ALDH2 attenuates ischemia and reperfusion injury through regulation of mitochondrial fusion and fission by PI3K/AKT/mTOR pathway in diabetic cardiomyopathy.

The function of mitochondrial fusion and fission is one of the important factors causing ischemia-reperfusion (I/R) injury in diabetic myocardium. Aldehyde dehydrogenase 2 (ALDH2) is abundantly expressed in heart, which involved in the regulation of cellular energy metabolism and stress response. However, the mechanism of ALDH2 regulating mitochondrial fusion and fission in diabetic myocardial I/R injury has not been elucidated. In the present study, we found that the expression of ALDH2 was downregulated in rat diabetic myocardial I/R model. Functionally, the activation of ALDH2 resulted in the improvement of cardiac hemodynamic parameters and myocardial injury, which were abolished by the treatment of Daidzin, a specific inhibitor of ALDH2. In H9C2 cardiomyocyte hypoxia-reoxygenation model, ALDH2 regulated the dynamic balance of mitochondrial fusion and fission and maintained mitochondrial morphology stability. Meanwhile, ALDH2 reduced mitochondrial ROS levels, and apoptotic protein expression in cardiomyocytes, which was associated with the upregulation of phosphorylation (p-PI3KTyr458, p-AKTSer473, p-mTOR). Moreover, ALDH2 suppressed the mitoPTP opening through reducing 4-HNE. Therefore, our results demonstrated that ALDH2 alleviated the ischemia and reperfusion injury in diabetic cardiomyopathy through inhibition of mitoPTP opening and activation of PI3K/AKT/mTOR pathway.

Short-term Outcomes of Elective Surgery Following Self-Expandable Metallic Stent and Neoadjuvant Chemotherapy in Patients With Left-Sided Colon Cancer Obstruction.

BACKGROUND: Colonic stenting reduces morbidity and stoma formation for left-sided colon cancer obstruction, and a prolonged interval between stenting and surgery with neoadjuvant chemotherapy administered might result in a lower stoma rate and tumor reduction. OBJECTIVE: The study aimed to evaluate the short-term outcomes of elective surgery following colonic stenting compared with elective surgery following colonic stenting and neoadjuvant chemotherapy in patients with left-sided colon cancer obstruction. DESIGN: This is a prospective multicenter cohort study. SETTINGS: This study was conducted at 5 medical centers. PATIENTS: Patients ( n = 100) with acute left-sided colon cancer obstruction undergoing colonic stenting between December 2015 and December 2019 were included. INTERVENTIONS: Patients were assigned to the stenting-alone or chemotherapy group. MAIN OUTCOME MEASURES: The primary outcomes measured were laparoscopic surgery and stoma rate. RESULTS: Of the 100 patients who underwent colonic stenting, 52 were assigned to the stenting group and 48 were assigned to the chemotherapy group. No statistically significant differences were detected in stent-related complications. The adverse events associated with neoadjuvant chemotherapy were well tolerated. The level of hemoglobin (117.2 vs 107.6 g/L; p = 0.008), albumin (34.2 vs 31.5 g/L; p < 0.001), and prealbumin (0.19 vs 0.16 g/L; p = 0.001) was significantly increased, and the bowel wall thickness (1.09 vs 2.04 mm; p < 0.001) was significantly decreased preoperatively in the chemotherapy group compared with the stenting group. The number of mean harvested lymph nodes was greater in the chemotherapy group than in the stenting group (25.6 vs 21.8; p = 0.04). Laparoscopic surgery was performed more frequently (77.1% vs 40.4%; p < 0.001) and a stoma was created less frequently (10.4% vs 28.8%; p = 0.02) in the chemotherapy group than in the stenting group. LIMITATIONS: This trial was limited by the nonrandomized design and a short follow-up period. CONCLUSIONS: This study suggests that elective surgery following neoadjuvant chemotherapy and colonic stenting is a safe, effective, and well-tolerated treatment approach with a high laparoscopic resection rate and a low stoma rate. See Video Abstract at http://links.lww.com/DCR/B980 . RESULTADOS A CORTO PLAZO DE LA CIRUGA ELECTIVA SEGUIDO DE STENT METLICO AUTOEXPANDIBLE Y QUIMIOTERAPIA NEOADYUVANTE EN PACIENTES CON OBSTRUCCIN POR CNCER DE COLON IZQUIERDO: ANTECEDENTES:La colocación de stents colónicos reduce la morbilidad y la formación de estomas por obstrucción por cáncer de colon izquierdo, y el intervalo prolongado entre la colocación de stents y la cirugía con quimioterapia neoadyuvante administrada podría resultar en una menor tasa de estomas y reducción del tumor.OBJETIVO:Evaluar los resultados a corto plazo de la cirugía electiva después de la colocación de stent en el colon en comparación con la cirugía electiva después de la colocación de stent en el colon y la quimioterapia neoadyuvante en pacientes con obstrucción por cáncer de colon izquierdo.DISEÑO:Estudio prospectivo de cohorte multicéntrico.ENTORNO CLINICO:Este estudio se realizó en 5 centros médicos.PACIENTES:Se incluyeron pacientes (n=100) con obstrucción aguda por cáncer de colon izquierdo que se sometieron a colocación de stent colónico entre diciembre de 2015 y diciembre de 2019.INTERVENCIONES:Los pacientes fueron asignados al grupo de stent solo o quimioterapia.MEDIDAS DE RESULTADO PRINCIPALES:Los resultados primarios medidos fueron la cirugía laparoscópica y la tasa de ostomía.RESULTADOS:De los 100 pacientes que se sometieron a la colocación de stent colónico, 52 fueron asignados al grupo de colocación de stent y 48 al grupo de quimioterapia. No se detectaron diferencias estadísticamente significativas en las complicaciones relacionadas con el stent. Los eventos adversos asociados con la quimioterapia neoadyuvante fueron bien tolerados. Hemoglobina (117,2 g/l vs. 107,6 g/l; p = 0,008), albúmina (34,2 g/l vs. 31,5 g/l; p < 0,001) y prealbúmina (0,19 g/l vs. 0,16 g/l; p = 0,001) aumentaron significativamente y el grosor de la pared intestinal (1,09 mm vs. 2,04 mm; p < 0,001) disminuyó significativamente antes de la operación en el grupo de quimioterapia en comparación con el grupo de colocación de stent. El número medio de ganglios linfáticos extraídos fue mayor en el grupo de quimioterapia que en el grupo de stent (25,6 vs. 21,8; p = 0,04). La cirugía laparoscópica se realizó con mayor frecuencia (77,1 % vs. 40,4 %; p < 0,001) y se creó un estoma con menos frecuencia (10,4 % vs. 28,8 % ; p = 0,02) en el grupo de quimioterapia que en el grupo de colocación de stent.LIMITACIONES:Este ensayo estuvo limitado por el diseño no aleatorio y el corto período de seguimiento.CONCLUSIONES:Este estudio sugiere que la cirugía electiva después de la quimioterapia neoadyuvante y la colocación de stent colónico es un tratamiento seguro, efectivo y bien tolerado, con una alta tasa de resección laparoscópica y una baja tasa de estoma. Consulte Video Resumen en http://links.lww.com/DCR/B980 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Negative effects of enlarging internal limiting membrane peeling for idiopathic macular hole surgery.

AIM: To observe the effects of the different extents of internal limiting membrane (ILM) peeling on the surgical success and anatomical and functional outcomes of idiopathic macular hole (IMH). METHODS: In this retrospective cohort study, 36 patients were reviewed and divided into two groups according to the extent of ILM peeling: group A (18 patients), with the peeling area within one-half of the optic disc macular distance as the radius; group B (18 patients), with the peeling area larger than that of group A but did not exceed the optic disc macular distance as the radius. The main outcomes included the best corrected visual acuity (BCVA), light-adaptive electroretinography, macular hole (MH) closure rate, central macular thickness (CMT), retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness [nine regions based on the Early Treatment of Diabetic Retinopathy Study (ETDRS) ring] before and 1, 3, and 6mo after surgery. RESULTS: The closure rate was 94.4% (17/18) both in groups A and B. The BCVA in both groups improved significantly compared with the preoperative values, but there was no difference between the two groups. The b-wave amplitude of the electroretinogram analysis was significantly improved in both groups compared to that of the preoperative period, with a greater increase in group A than in group B at 6mo (P=0.017). The CMT in both groups gradually decreased after surgery, and there was no difference between the two groups. The RNFL thickness of the temporal outer ring region in group B was significantly lower than that in group A at 3 and 6mo after surgery (P=0.010, 0.032). The GCC thickness of the temporal outer ring region in group B was significantly lower than that in group A at 6mo after surgery (P=0.038). CONCLUSION: Enlarging the extent of ILM peeling doesn't affect the IMH closure rate and visual acuity recovery, but the greater the extent of peeling, the greater the damage to the inner retinal structures.

Changes in the peripapillary vasculature and macular thickness after cataract surgery using two phacoemulsification systems with optical coherence tomography angiography.

AIM: To assess the changes in the peripapillary vasculature and macular thickness after cataract surgery using two phacoemulsification systems with optical coherence tomography angiography (OCTA). METHODS: Fifty-two eyes of 52 patients with age-related cataract were randomized into two groups for phacoemulsification: Infiniti group (26 patients) using the Infiniti phacoemulsification system with gravity-fluidics and Centurion group (26 patients) using the Centurion phacoemulsification system with active-fluidics. The peripapillary vessel density (PVD) and macular thickness were examined using OCTA at baseline and at 1d, 1 and 3mo after cataract surgery. RESULTS: In the Infiniti group, the PVD was significantly reduced at 1d after the cataract surgery (P<0.001). However, the retinal nerve fiber layer (RNFL) thickness showed no significant change during the follow-up. Change in PVD 1d postoperatively was significantly negatively correlated to the cumulative dissipated energy (CDE), estimated fluid usage (EFU), effective phacoemulsification time (EPT), intraocular pressure (IOP), and total operating time (TOT; P<0.05). The macular thickness was significantly increased in all regions after the cataract surgery (P<0.05). However, no significant changes were found in the macular vessel density (VD) during the follow-up (P>0.05). In the Centurion group, the VD and thickness in the optic papilla and macula did not significantly change in all regions during the follow-up (all P>0.05). The best-corrected visual acuity (BCVA) significantly improved in both groups postoperatively (P<0.001). CONCLUSION: Using the Infiniti phacoemulsification system, OCTA provides a promising analysis of retinal vascular alterations, demonstrating a reduction of the PVD and an increase in the macular thickness. The Centurion phacoemulsification system can provide better retinal vasculature preservation during cataract surgery.

A BRCA1 Splice Site Variant Responsible for Familial Ovarian Cancer in a Han-Chinese Family.

OBJECTIVE: Ovarian cancer (OC) is one of the most common and most lethal gynecological malignancies. OC has an age-dependent incidence and occurs more commonly in females older than 50 years old. Most OC patients are diagnosed at an advanced stage and have a poor prognosis. Germline mutations in the BRCA1 DNA repair associated gene (BRCA1) and the BRCA2 DNA repair associated gene (BRCA2) account for 20%-25% of epithelial ovarian cancer (EOC). BRCA1 germline mutations are more common in Chinese EOC patients. METHODS: This study reported a three-generation Han-Chinese family containing four EOC patients and a rectal adenocarcinoma patient. Whole-exome sequencing was performed on two EOC patients and an unaffected individual. Variant validation was also performed in all available members by Sanger sequencing. RESULTS: A heterozygous splice site variant, c.4358-2A>G in the BRCA1 gene, was identified. Bioinformatic analysis showed that the variant may change the splicing machinery. CONCLUSION: The BRCA1 splice site variant, c.4358-2A>G was identified as the likely genetic cause for EOC, and may also be associated with the increased risk of rectal adenocarcinoma in the family. The findings were beneficial for genetic counseling, helpful for cancer prevention in other family members, and may facilitate therapy decision-making in the future to reduce cancer lethality.

Fabrication of attapulgite-based dual responsive composite hydrogel and its efficient adsorption for methyl violet.

In this work, attapulgite (ATP)-based dual sensitive poly (N-isopropylacrylamide-co-acrylic acid) composite hydrogel, P(NIPAM-co-AA)/ATP, was prepared by free radical polymerization. The prepared composite hydrogel was characterized via methods of scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), zeta potential analysis and Brunauer, Emmett, and Teller (BET) etc. The composite hydrogel showed pH and temperature sensitive behaviour, with lower critical solution temperature (LCST) of 35°C and highest swelling occurred at pH 8.0. The adsorption of methyl violet (MV) can be controlled by the hydrogel responsiveness, and 95.78% of MV can be removed at pH 8.0 and 35°C. The addition of a small amount of ATP (3 Wt%) can improve the swelling ratio and adsorption capacity. Kinetic analysis demonstrated that the experimental data were best fitted to the pseudo-second order model. Isotherm analysis showed that the equilibrium data followed Langmuir model with the adsorption capacity of 168.35 mg g-1. In addition, the composite hydrogel has high adsorption selectivity for cationic dyes, and MV-loaded hydrogel is easy to regenerate, which can be used for successive adsorption cycles. These results demonstrate that the composite hydrogel has potential application in dye wastewater treatment.

The bioinformatics and metabolomics research on anti-hypoxic molecular mechanisms of Salidroside via regulating the PTEN mediated PI3K/Akt/NF-κB signaling pathway.

Salidroside (SAL), a major bioactive compound of Rhodiola crenulata, has significant anti-hypoxia effect, however, its underlying molecular mechanism has not been elucidated. In order to explore the protective mechanism of SAL, the lactate dehydrogenase (LDH), reactive oxygen species (ROS), superoxide dismutase (SOD) and hypoxia-induced factor 1α (HIF-1α) were measured to establish the PC12 cell hypoxic model. Cell staining and cell viability analyses were performed to evaluate the protective effects of SAL. The metabolomics and bioinformatics methods were used to explore the protective effects of salidroside under hypoxia condition. The metabolite-protein interaction networks were further established and the protein expression level was examined by Western blotting. The results showed that 59 endogenous metabolites changed and the expression of the hub proteins of CK2, p-PTEN/PTEN, PI3K, p-Akt/Akt, NF-κB p65 and Bcl-2 were increased, suggesting that SAL could increase the expression of CK2, which induced the phosphorylation and inactivation of PTEN, reduced the inhibitory effect on PI3K signaling pathways and activated the PI3K/Akt/NF-κB survival signaling pathway. Our study provided an important insight to reveal the protective molecular mechanism of SAL as a novel drug candidate.

Utilizing dexamethasone intravitreal implant to control postoperative inflammation in refractory uveitis undergoing cataract surgery.

AIM: To report the effectiveness of intravitreal implantation of dexamethasone implant (Ozurdex) after phacoemulsification and intraocular lens implantation in refractory uveitis patients. METHODS: This single-center retrospective study conducted for refractory pan-uveitis patients who underwent cataract surgery combined with intravitreal Ozurdex implantation. The main outcome measurements were best-corrected visual acuity (BCVA), central retinal thickness (CRT), grade of anterior chamber cell (AAC), intraocular pressure (IOP), and systemic/ocular adverse events. RESULTS: Ten eyes of 7 patients were included. BCVA showed significant improvement at 1mo (P=0.004), 3mo (P=0.0004), and 6mo (P=0.001) post operation. There were no statistically significant differences in the postoperative CRT among follow-up groups (P>0.05). No significant differences were observed in the baseline IOP when compared to 1, 3, and 6mo (all P>0.05) post operation. One patient developed a transient elevated IOP post injection. Two eyes (20%) developed posterior capsular opacifications and underwent neodymium-doped yttrium aluminum garnet (Nd:YAG) laser capsulotomy. In six patients (8 eyes, 71.4%), the systemic steroid usage was reduced to below 10 mg/d. The patients experienced a mean of 1.4±0.52 recurrences of inflammation in the 6mo before operation and 0.7±0.48 in the 6mon post operation. The mean recurrence time was 13±0.58wk (range 12-14wk) post operation. In five of seven patients (7 out of 10 eyes), inflammation relapse was developed postoperatively. Only one patient (2 eyes) needed increased amounts of oral corticosteroids. Intraocular inflammation recurrence in the remaining patients was controlled by topical steroids. CONCLUSION: Ozurdex is considered a safe and effective approach to control postoperative inflammation in cataract surgery for patients with refractory uveitis in our study. After the disappearance of Ozurdex's anti-inflammatory effects over time, in most cases the recurrent inflammation can be controlled by topical steroids.

Protective Effect and Mechanism of Bone Morphogenetic Protein-4 on Apoptosis of Human Lens Epithelium Cells under Oxidative Stress.

Bone morphogenetic proteins (BMPs), a member of the transforming growth factor ß (TGF-ß) superfamily, are abundant in human ocular tissues and play an important role in lens development. Targeted deletion of BMP-4 in mice results in failure of lens placode formation. Following lens maturation, the formation of senile cataracts is demonstrably associated with free radical-related oxidative stress. Previous studies reported that BMPs play an antiapoptotic role in cells under oxidative stress, and the BMP-4 signal is important in inflammation regulation and homeostasis. BMP-4 evidently suppressed the apoptosis of human lens epithelial cells (HLECS) under oxidative stress induced by H2O2. This protective antiapoptotic effect is partly due to a decrease in caspase-3 activity and reactive oxygen species (ROS) level. Furthermore, the expression of activating transcription factor- (ATF-) 6 and Krüppel-like factor- (KLF-) 6 increased under oxidative stress and decreased after BMP-4 treatment.

Detection and Quantification of Retinal Neovascularization Using BrdU Incorporation.

Purpose: The retina is a commonly used model for angiogenesis research due to its special characteristics. Oxygen-induced retinopathy (OIR) provides a useful model to study ischemia-induced neovascularization (NV) and to develop anti-angiogenic therapeutics. The purpose of this study was to develop a simple, accurate, and less-subjective quantification method for retinal NV in the OIR model. Methods: To address this challenge, we combined the conventional vascular staining and BrdU labeling of newly formed vascular cells to detect and analyze retinal NV. With daily injections of BrdU, which was incorporated into the DNA of newly formed retinal vessels under the OIR condition, ischemia-induced retinal neovasculature with BrdU labeling was distinguished from pre-existing vasculature and accurately quantified using the ImageJ program. Results: Compared with conventional quantification methods using isolectin B4 staining of the entire vascular network, BrdU labeling allowed us to distinguish newly formed vessels from the pre-existing vessels and to objectively quantify the newly formed vessels, which was verified in OIR mice with intravitreal injections of an antibody-neutralizing vascular endothelial growth factor. Conclusions: BrdU labeling provides a useful and sensitive method for studying retinal NV and evaluating the therapeutic effects of medical interventions against pathological angiogenesis. Translational Relevance: Quantitative, straightforward, and objective observation and evaluation of pathologic neovasculature are important to study the pathogenesis of NV and therapeutic effects using animal models.

Mesenchymal stem cell-derived extracellular vesicles as a new therapeutic strategy for ocular diseases.

Mesenchymal stem cells (MSCs) have attracted considerable attention for their activity in the treatment of refractory visual disorders. Since MSCs were found to possess the beneficial effects by secreting paracrine factors rather than direct differentiation, MSC-derived extracellular vesicles (EVs) were widely studied in various disease models. MSCs generate abundant EVs, which act as important mediators by exchanging protein and genetic information between MSCs and target cells. It has been confirmed that MSC-derived EVs possess unique anti-inflammatory, anti-apoptotic, tissue repairing, neuroprotective, and immunomodulatory properties, similar to their parent cells. Upon intravitreal injection, MSC-derived EVs rapidly diffuse through the retina to alleviate retinal injury or inflammation. Due to possible risks associated with MSC transplantation, such as vitreous opacity and pathological proliferation, EVs appear to be a better choice for intravitreal injection. Small size EVs can pass through biological barriers easily and their contents can be modified genetically for optimal therapeutic effect. Hence, currently, they are also explored for the possibility of serving as drug delivery vehicles. In the current review, we describe the characteristics of MSC-derived EVs briefly, comprehensively summarize their biological functions in ocular diseases, and discuss their potential applications in clinical settings.

A fluorogenic probe for tracking GSH flux in developing neurons.

Understanding GSH flux in developing neurons is prerequisite to reveal its role in neuronal development but necessiates an ultrasensitive assay. By systematically exploring key structural factors determing probe sensitivity in live cells, we developed a fluorogenic probe capable of imaging subtle GSH fluctuations in developing neurons.

A Protective Effect of PPARα in Endothelial Progenitor Cells Through Regulating Metabolism.

Deficiency of endothelial progenitor cells, including endothelial colony-forming cells (ECFCs) and circulating angiogenic cells (CACs), plays an important role in retinal vascular degeneration in diabetic retinopathy (DR). Fenofibrate, an agonist of peroxisome proliferator-activated receptor α (PPARα), has shown therapeutic effects on DR in both patients and diabetic animal models. However, the function of PPARα in ECFC/CACs has not been defined. In this study, we determined the regulation of ECFC/CAC by PPARα. As shown by flow cytometry and Seahorse analysis, ECFC/CAC numbers and mitochondrial function were decreased in the bone marrow, circulation, and retina of db/db mice, correlating with PPARα downregulation. Activation of PPARα by fenofibrate normalized ECFC/CAC numbers and mitochondrial function in diabetes. In contrast, PPARα knockout exacerbated ECFC/CAC number decreases and mitochondrial dysfunction in diabetic mice. Primary ECFCs from PPARα -/- mice displayed impaired proliferation, migration, and tube formation. Furthermore, PPARα -/- ECFCs showed reduced mitochondrial oxidation and glycolysis compared with wild type, correlating with decreases of Akt phosphorylation and expression of its downstream genes regulating ECFC fate and metabolism. These findings suggest that PPARα is an endogenous regulator of ECFC/CAC metabolism and cell fate. Diabetes-induced downregulation of PPARα contributes to ECFC/CAC deficiency and retinal vascular degeneration in DR.

miRNA-451a regulates RPE function through promoting mitochondrial function in proliferative diabetic retinopathy.

The purpose of this study was to explore the role of microRNA-451a (miR-451a) in diabetic retinopathy through activating transcription factor 2 (ATF2). The epiretinal membrane samples from patients with proliferative diabetic retinopathy (PDR) were immunolabeled with an antibody for Ki-67 to identify the proliferative cells. The expression of miR-451a was measured by qRT-PCR in the retina of Akita mice and in RPE cells under diabetic conditions. The potential downstream targets of miR-451a were predicted by bioinformatics and confirmed by dual luciferase assay, qRT-PCR, and Western blotting. Mitochondrial function, cell proliferation, and migration assays were used to detect the functional change after transfection of miR-451a mimic and inhibitor. Proliferative RPE cells were identified in the epiretinal membrane from PDR patients. The expression of miR-451a was downregulated both in the retina of Akita mice and 4-hydroxynonenal (4-HNE)-treated RPE cells. Bioinformatic analysis and luciferase assay identified ATF2 as a potential target of miR-451a. miR-451a inhibited proliferation and migration of RPE cells. The mitochondrial function was enhanced by miR-451a mimic, but suppressed by miR-451a inhibitor. In diabetic conditions, miR-451a showed a protective effect on mitochondrial function. The results of qRT-PCR and Western blotting revealed that overexpression of miR-451a downregulated the expression of ATF2 and its downstream target genes CyclinA1, CyclinD1, and MMP2. In conclusion, miR-451a/ATF2 plays a vital role in the regulation of proliferation and migration in RPE cells through regulation of mitochondrial function, which may provide new perspectives for developing effective therapies for PDR.

Involvement of methylation-associated silencing of formin 2 in colorectal carcinogenesis.

AIM: To investigate whether promoter methylation is responsible for the silencing of formin 2 (FMN2) in colorectal cancer (CRC) and to analyze the association between FMN2 methylation and CRC. METHODS: We first identified the expression levels and methylation levels of FMN2 in large-scale human CRC expression datasets, including GEO and TCGA, and analyzed the relationship between the expression and methylation levels. Then, the methylation levels in four CpG regions adjacent to the FMN2 promoter were assessed by MethylTarget™ assays in CRC cells and in paired colorectal tumor samples and adjacent nontumor tissue samples. Furthermore, we inhibited DNA methylation in CRC cells with 5-Aza-2'-deoxycytidine and assessed the expression of FMN2 by qRT-PCR. Last, the association between FMN2 methylation patterns and clinical indicators was analyzed. RESULTS: A statistically significant downregulation of FMN2 expression in large-scale human CRC expression datasets was found. Subsequent analysis showed that a high frequency of hypermethylation occurred in the FMN2 gene promoter in CRC tissues; operating characteristic curve analysis revealed that FMN2 gene methylation had a good capability for discriminating between CRC and nontumor tissue samples (AUC = 0.8432, P < 0.0001). MethylTarget™ assays showed that CRC cells and tissues displayed higher methylation of these CpG regions than nontumor tissue samples. Correlation analysis showed a strong inverse correlation between methylation and FMN2 expression, and the inhibition of DNA methylation with 5-Aza significantly increased endogenous FMN2 expression. Analysis of the association between FMN2 methylation patterns and clinical indicators showed that FMN2 methylation was significantly associated with age, N stage, lymphovascular invasion, and pathologic tumor stage. Notably, the highest methylation of FMN2 occurred in tissues from cases of early-stage CRC, including cases with no regional lymph node metastasis (N0), cases in stages I and II, and cases with no lymphovascular invasion, but the methylation level began to decrease with tumor progression. Additionally, FMN2 promoter hypermethylation was more common in patients > 60 years old and in colon cancer tissue. CONCLUSION: FMN2 promoter hypermethylation may be an important early event in CRC, most likely playing a critical role in cancer initiation, and can serve as an ideal diagnostic biomarker in elderly patients with early-stage colon cancer.

The prevalence of vision impairment and refractive error in 3654 first year students at Tianjin Medical University.

AIM: To determine the prevalence of vision impairment (VI) and refractive error in first year university students at the Tianjin Medical University. METHODS: This is a cross-sectional observational cohort study of VI and refractive error among first year university students at the Tianjin Medical University. The first year university students were involved in this study and were given a detailed questionnaire including age, birth date, and spectacle wearing history. A standardized ophthalmologic examination including visual acuity (VA), slit-lamp examination, non-cycloplegic auto-refraction, objective refraction, fundus photography, and examination of their spectacles were recorded. RESULTS: A total of 3654 participants were included in this study. Totally 3436 (94.03%) individuals had VI in this population. Totally 150 (4.10%) individuals had VI due to ocular disease, including amblyopia, congenital cataract, retinal atrophy or degeneration, strabismus, congenital nystagmus, refractive surgery orthokeratology. Totally 3286 (89.93%) subjects had VI due to refractive error. Only 218 (5.97%) students were emmetropia. Moreover, refractive error was the main cause for the VI (95.63%). Totally 3242 (92.52%) students were myopia and the prevalence of mild, moderate, and high myopia subgroup was 27.05%, 44.35%, and 21.26% respectively. Totally 44 (1.29%) subjects were hyperopic. The rates of uncorrected visual acuity (UCVA), presenting visual acuity (PVA) and best corrected visual acuity (BCVA) which better than 20/20 in both eyes were 5.65%, 22.32% and 82.13% respectively. The rates of correction, under correction and well correction in myopia subjects were 82.73%, 84.39% and 15.61%, respectively. CONCLUSION: We present a high prevalence of refractive errors and high rates of under correction refractive error among first year university students. These results may help to promote vision protection work in young adults.