Quercetin Ameliorates Myocardial Injury in Diabetic Rats by Regulating Autophagy and Apoptosis through AMPK/mTOR Signaling Pathway.

A high-glucose environment is involved in the progression of diabetes mellitus (DM). This study aims to explore the regulatory effects of quercetin (QUE) on autophagy and apoptosis after myocardial injury in rats with DM. The type 2 DM rat models were constructed using low-dose streptozotocin (STZ) treatment combined with a high-carbohydrate (HC) diet in vivo. Compared with the control group, the body weight was decreased, whereas blood pressure, blood glucose, and the LVW/BW ratio were increased in the diabetic group. The results showed that the myocardial fibers were disordered in the diabetic group. Moreover, we found that the myocardial collagen fibers, PAS-positive cells, and apoptosis were increased, whereas the mitochondrial structure was destroyed and autophagic vacuoles were significantly reduced in the diabetic group compared with the control group. The expression levels of autophagy-related proteins LC3 and Beclin1 were decreased, whereas the expression levels of P62, Caspae-3, and Bax/Bcl-2 were increased in the diabetic group in vitro and in vivo. Moreover, QUE treatment alleviated the cellular oxidative stress reaction under high-glucose environments. The results of immunoprecipitation (IP) showed that the autophagy protein Beclin1 was bound to Bcl-2, and the binding capacity increased in the HG group, whereas it decreased after QUE treatment, suggesting that QUE inhibited the binding capacity between Beclin1 and Bcl-2, thus leading to the preservation of Beclin1-induced autophagy. In addition, the blood pressure, blood glucose, and cardiac function of rats were improved following QUE treatment. In conclusion, QUE suppressed diabetic myocardial injury and ameliorated cardiac function by regulating myocardial autophagy and inhibition of apoptosis in diabetes through the AMPK/mTOR signaling pathway.

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.

[Mechanism of Liuwei Dihuang Pills in treatment of mice with diminished ovarian reserve based on proteomics].

This study aims to investigate the efficacy and possible mechanism of Liuwei Dihuang Pills in the treatment of diminished ovarian reserve(DOR) by using proteomic techniques. Firstly, cyclophosphamide(60 mg·kg~(-1)) combined with busulfan(6 mg·kg~(-1)) was injected intraperitoneally to establish the mouse model of DOR. After drug injection, the mice were continuously observed and the success of modeling was evaluated by the disturbance of the estrous cycle. After successful modeling, the mice were administrated with the suspension of Liuwei Dihuang Pills by gavage for 28 days. At the end of the gavage, four female mice were selected and caged together with males at a ratio of 2∶1 for the determination of the pregnancy rate. Blood and ovary samples were collected from the remaining mice on the next day after the end of gavage. Hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM) were then employed to observe the morphological and ultrastructural changes in the ovaries. The serum levels of hormones and oxidation indicators were measured by enzyme-linked immunosorbent assay. Quantitative proteomics techniques were used to compare the ovarian protein expression before and after modeling and before and after the intervention with Liuwei Dihuang Pills. The results showed that Liuwei Dihuang Pills regulated the estrous cycle of DOR mice, elevated the serum levels of hormones and anti-oxidation indicators, promoted follicle development, protected the mitochondrial morphology of ovarian granulosa cells, and increased the litter size and survival of DOR mice. Furthermore, Liuwei Dihuang Pills negatively regulated the expression of 12 differentially expressed proteins associated with DOR, which were mainly involved in lipid catabolism, inflammatory response, immune regulation, and coenzyme biosynthesis. These differentially expressed proteins were significantly enriched in sphingolipid metabolism, arachidonic acid metabolism, ribosomes, ferroptosis, and cGMP-PKG signaling pathway. In summary, the occurrence of DOR and the treatment of DOR with Liuwei Dihuang Pills are associated with multiple biological pathways, mainly including oxidative stress response, inflammatory response, and immune regulation. "Mitochondria-oxidative stress-apoptosis" is the key to the treatment of DOR by Liuwei Dihuang Pills. YY1 and CYP4F3 may be the key upstream targets that trigger mitochondrial dysfunction and ROS accumulation, and the metabolism of arachidonic acid is the main signaling pathway of drug action.

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.

Regulation of Monocyte Activation by PPARα Through Interaction With the cGAS-STING Pathway.

Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPARα), has shown robust therapeutic effects on DR in patients with type 2 diabetes. Here we found that PPARα levels were significantly downregulated in monocytes from patients with diabetes and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPARα knockout alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knockout aggravated monocyte activation in diabetes. PPARα knockout impaired mitochondrial function while also increasing glycolysis in monocytes. PPARα knockout increased cytosolic mitochondrial DNA release and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in monocytes under diabetic conditions. STING knockout or STING inhibitor attenuated monocyte activation induced by diabetes or by PPARα knockout. These observations suggest that PPARα negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway.

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.

miRNA-451 regulates rhesus choroid-retinal endothelial cell function and proteome profile.

AIM: To evaluate the effect of miRNA-451 on rhesus macaque choroid-retinal endothelial (RF/6A) cell function and proteome profile. METHODS: The RF/6A cells were transfected with miRNA-451 mimic and inhibitor. The role of miRNA-451 on proliferation ability was evaluated by CCK-8 assay. Furthermore, iTRAQ quantitative proteomic analysis was applied to comprehensively illuminate the change of cellular proteins and biological function between different groups. RESULTS: In miRNA-451 overexpression group, cell proliferation of RF/6A decreased both at 24h and 48h; while in miRNA-451 inhibition group, on the contrary, RF/6A cell proliferation was increased at 48h. Based on iTRAQ quantitative proteomic analysis, 23 differentially expressed proteins (DEPs) were detected in the comparison of miRNA-451 mimic and mimic control-transfected RF/6A cells, and 30 DEPs were identified in the comparison of RF/6A cells transfected with miRNA-451 inhibitor and inhibitor control. DEPs such as GORASP2, KRT1, SLC7A2, RIC8A, DDX42, CAP1, PCBP2 might be closely related to the inhibitory effect of miRNA-451 on RF/6A cell proliferation, while PCYT1A, MGAT1, TUBB, MCU, SIL1, BID, MSH6 might account for the positive effect of miRNA-451 inhibitor on RF/6A cell growth. PTPN1, as the only protein exhibiting an opposite trend between miRNA-451 mimic and inhibitor-transfected cells, was most likely accountable for the inhibition of miRNA-451 mimic on RF/6A cell growth, and the promotion of miRNA-451 inhibitor on RF/6A cell proliferation. CONCLUSION: miRNA-451 overexpression can suppress the growth of RF/6A cells while knockdown of miRNA-451 can promote RF/6A cell viability. Among all DEPs, increased PTPN1 is most likely to account for the negative regulation of miRNA-451 on RF/6A proliferation. miRNA-451 can be a protective factor for neovascular disease of fundus via regulating choroid retinal endothelial cell function.

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.

[Berberine inhibits osteogenic differentiation of aortic valve interstitial cells induced by osteogenic induction medium].

This research focused on the effect and mechanism of berberine on osteogenic differentiation of valve interstitial cells(VICs) induced by osteogenic induction medium, in order to provide new insights into the clinical treatment of calcified aortic valve disease. The expression of osteogenic and fibrotic makers in three cases of calcified valve tissues and one case of normal control was assayed by Western blot. After the porcine aortic VICs were isolated, the effects of different concentrations of berberine on their viability were examined by MTT assay for determining the optimal concentration range. VICs were cultured in osteogenic induction medium and treated with different concentrations of berberine. Western blot and q-PCR were conducted to detect the effects of berberine on the expression of osteogenic and fibrotic makers in VICs. The effects of berberine on osteogenic differentiation of VICs in the early and late stages were separately measured by ALP staining and alizarin red S staining. The effects of berberine on the phosphorylation of ERK1/2 at different time points were assayed by Western blot. And PD98059, an inhibitor of ERK1/2, was added for verification. The results suggested that related osteogenic and fibrotic makers were significantly up-regulated in calcified valve tissues as compared with those in the normal control. The up-regulated fibrosis and osteogenic makers of VICs under osteogenic conditions were reversed by berberine and the ALP activity and calcium deposition in VICs were also reduced obviously. The level of ERK1/2 phosphorylation was decreased. Similarly, the osteogenic and fibrotic makers of VICs induced by osteogenic induction medium were lowered by PD98059. This study has confirmed that berberine is able to inhibit the differentiation of VICs into myofibroblasts or osteoblast-like cells, which may be associated with the inhibition of ERK1/2 signaling pathway.

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.

Artificial intelligence can assist with diagnosing retinal vein occlusion.

AIM: To assist with retinal vein occlusion (RVO) screening, artificial intelligence (AI) methods based on deep learning (DL) have been developed to alleviate the pressure experienced by ophthalmologists and discover and treat RVO as early as possible. METHODS: A total of 8600 color fundus photographs (CFPs) were included for training, validation, and testing of disease recognition models and lesion segmentation models. Four disease recognition and four lesion segmentation models were established and compared. Finally, one disease recognition model and one lesion segmentation model were selected as superior. Additionally, 224 CFPs from 130 patients were included as an external test set to determine the abilities of the two selected models. RESULTS: Using the Inception-v3 model for disease identification, the mean sensitivity, specificity, and F1 for the three disease types and normal CFPs were 0.93, 0.99, and 0.95, respectively, and the mean area under the curve (AUC) was 0.99. Using the DeepLab-v3 model for lesion segmentation, the mean sensitivity, specificity, and F1 for four lesion types (abnormally dilated and tortuous blood vessels, cotton-wool spots, flame-shaped hemorrhages, and hard exudates) were 0.74, 0.97, and 0.83, respectively. CONCLUSION: DL models show good performance when recognizing RVO and identifying lesions using CFPs. Because of the increasing number of RVO patients and increasing demand for trained ophthalmologists, DL models will be helpful for diagnosing RVO early in life and reducing vision impairment.

Human umbilical cord-derived mesenchymal stem cells treatment for refractory uveitis: a case series.

AIM: To evaluate therapeutic outcomes of human umbilical cord-derived mesenchymal stem cells (HUC-MSCs) treatment in patients with refractory uveitis. METHODS: A retrospective and noncomparative review was performed on four patients with refractory uveitis from December 2013 to December 2017. HUC-MSCs were administered intravenously at a dose of 1×106 cells/kg. Clinical response, relapse rate, change of visual acuity, and other metrics were evaluated. RESULTS: All four patients presented with responses to HUC-MSCs treatment, with three males and one female. The numbers of uveitis attacks per year after the HUC-MSCs treatment (0, 2, 0, 0 respectively) all decreased compared with the numbers before the treatment (3, 6, 4, 4 respectively). The oral steroid and immunosuppressive agents were tapered in all patients without recrudescence of ocular inflammation, and three patients discontinued their oral medicine at the last visit. The best corrected visual acuity (BCVA) of 3 patients was improved to varying degrees, and the BCVA of 1 patient remained at 20/20 (Snellen chart) from the first to the last consultation. CONCLUSION: The study provides an effective therapy of HUC-MSCs in maintaining remission in patients affected by uveitis refractory to previous immunosuppressant treatments.

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.

Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with macular edema secondary to uveitis.

AIM: To assess the correlation between disorganization of the retinal inner layers (DRIL) and best-corrected visual acuity (BCVA) in patients with uveitis and macular edema (UME) who underwent systemic treatment using optical coherence tomography (OCT). METHODS: A retrospective clinical study of 23 patients (30 eyes) with DRIL and 23 patients (31 eyes) without DRIL secondary to UME were included. All patients underwent comprehensive ophthalmic examinations at baseline, 3, 6, and 12mo after local and systemic treatment. The OCT-based parameters included foveal center point thickness (FCPT), mean thickness (MT), and diameters of DRIL in horizontal and vertical directions. BCVA and OCT-based parameters were compared between the two groups. The relationship between each OCT parameter and BCVA was evaluated using linear correlation and regression analysis. RESULTS: At the initial visit, the mean baseline FCPT was 441.03±128.68 µm in the eyes with DRIL and 337.26±99.31 µm in the eyes without DRIL (P=0.001). No significant differences were observed in MT (P=0.357). The mean size of transverse and vertical diameters of DRIL was 684.07±267.51 and 267.07±104.61 µm at baseline, respectively. There was significant improvement in BCVA and OCT-based parameters at 3, 6, and 12mo in all cases (P<0.001 for each timepoint). In addition, significant differences were detected in BCVA and OCT parameters between eyes with and without DRIL at each time point (P<0.01 for each timepoint). A greater DRIL range at baseline was associated with a worse baseline BCVA (transverse diameter of DRIL: r=0.875, P<0.001; vertical diameter of DRIL: r=0.622, P<0.001). The transverse diameter of baseline DRIL was found to be significantly correlated with the final BCVA (P=0.003). CONCLUSION: The improvement in BCVA is associated with DRIL in patients with UME. DRIL is an easy-to-determine and robust imaging biomarker that could help predict BCVA prognosis in eyes with UME.

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.