Structure elucidation and antiviral activity of a cold water-extracted mannogalactofucan Ts1-1A from Trametes sanguinea against human cytomegalovirus in vitro.

In this study, we purified a partially acetylated heteropolysaccharide (Ts1-1A) from the fruit bodies of Trametes sanguinea Lloyd through cold water extraction and serial chromatographic separation. The purified polysaccharide Ts1-1A (12.8 kDa) was characterized as a branched mannogalactofucan with a backbone of alternately connected 1,3-linked α-Fucp and 1,6-linked α-Galp, which was partially substituted by non-reducing end units of ß-Manp at O-2 and O-3 positions of 1,6-linked α-Galp. Ts1-1A showed pronounced anti-human cytomegalovirus activity at the concentration of 200 and 500 µg/mL in systematical assessments including morphological changes, western blotting, qPCR, indirect immunofluorescence and tissue culture infective dose assays. Moreover, Ts1-1A exerted its antiviral activity at two distinct stages of viral proliferation manifesting as significantly inhibiting viral protein (IE1/2 and p52) expression and reducing viral gene (UL123, UL44 and UL32) replication in the HCMV-infected WI-38 cells. At viral attachment stage, Ts1-1A interacted with HCMV and prevented HCMV from attaching to its host cells. While at early phase of viral replication stage, Ts1-1A suppressed HCMV replication by downregulating NQO1 and HO-1 proteins related to oxidative stress as an antioxidant. To sum up, Ts1-1A is a promising anti-HCMV agent which could be developed for HCMV infection prevention and therapy.

DNA damage response(DDR): a link between cellular senescence and human cytomegalovirus.

The DNA damage response (DDR) is a signaling cascade that is triggered by DNA damage, involving the halting of cell cycle progression and repair. It is a key event leading to senescence, which is characterized by irreversible cell cycle arrest and the senescence-associated secretory phenotype (SASP) that includes the expression of inflammatory cytokines. Human cytomegalovirus (HCMV) is a ubiquitous pathogen that plays an important role in the senescence process. It has been established that DDR is necessary for HCMV to replicate effectively. This paper reviews the relationship between DDR, cellular senescence, and HCMV, providing new sights for virus-induced senescence (VIS).

Efficacy and safety of primary customized phacoemulsification combined with goniosynechialysis for refractory acute primary angle closure.

PURPOSE: To assess the safety, efficacy, and long-term clinical outcomes of primary customized phacoemulsification (phaco) combined with goniosynechialysis (GSL; phaco-GSL) in refractory acute primary angle closure (APAC) eyes with uncontrolled high intraocular pressure (IOP). METHODS: This retrospective case series comprised 51 eyes of 42 consecutive patients with refractory APAC and high IOP who were treated using primary customized phaco-GSL at 3 hospitals in China, from 2014 to 2021. Preoperative and postoperative IOP, corrected distant visual acuity (CDVA), corneal endothelial cell density (CECD), intraoperative and postoperative complications were recorded. The safety, efficacy and subsequent long-term clinical outcomes were analyzed. RESULTS: The mean CDVA (LogMAR) was improved from 1.67 ± 0.94 preoperatively to 0.23 ± 0.26 postoperatively (P < 0.001). Preoperative CECD was 2309.39 ± 541.03 cells/mm2 in 33 eyes and inaccessible in 18 eyes due to severe corneal edema; at the final follow-up, the mean CECD of all patients was 1823.50 ± 533.40 cells/mm2 (P < 0.001). The mean IOP decreased from 48.51 ± 6.25 mmHg preoperatively to 15.66 ± 2.27 mmHg at the final follow-up (P < 0.001). Among 51 eyes, additional customized procedures performed were corneal indentation in 42 eyes, epithelial debridement in 9 eyes, giant epithelial bullae view in 4 eyes, pars-plana fluid aspiration in 3 eyes, and secondary intraocular lens implantation in 7 eyes. The IOP of all eyes was well controlled eventually and 47 eyes (92.16%) were successfully treated by phaco-GSL alone. No significant intraoperative or postoperative complications were observed. CONCLUSIONS: Primary customized phaco-GSL is a safe and effective surgical management strategy for patients with refractory APAC and high IOP.

NINJ2 deficiency inhibits preadipocyte differentiation and promotes insulin resistance through regulating insulin signaling.

OBJECTIVE: Genetic variants in ninjurin-2 (NINJ2; nerve injury-induced protein 2) confer risk of ischemic strokes and coronary artery disease as well as endothelial activation and inflammation. However, little is known about NINJ2's in vivo functions and underlying mechanisms. METHODS: The phenotypes of NINJ2 knockout mice were analyzed, and mechanisms of NINJ2 that regulate body weight, insulin resistance, and glucose homeostasis and lipogenesis were investigated in vivo and in vitro. RESULTS: This study found that mice lacking NINJ2 showed impaired adipogenesis, increased insulin resistance, and abnormal glucose homeostasis, all of which are risk factors for strokes and coronary artery disease. Mechanistically, NINJ2 directly interacts with insulin receptor/insulin-like growth factor 1 receptor (INSR/IGF1R), and NINJ2 knockdown can block insulin-induced mitotic clonal expansion during preadipocyte differentiation by inhibiting protein kinase B/extracellular signal-regulated kinase (AKT/ERK) signaling and by decreasing the expression of key adipocyte transcriptional regulators CCAAT/enhancer-binding protein ß (C/EBP-ß), C/EBP-α, and peroxisome proliferator-activated receptor γ (PPAR-γ). Furthermore, the interaction between NINJ2 and INSR/IGF1R is needed for maintaining insulin sensitivity in adipocytes and muscle via AKT and glucose transporter type 4. Notably, adenovirus-mediated NINJ2 overexpression can ameliorate diet-induced insulin resistance in mice. CONCLUSIONS: In conclusion, these findings reveal NINJ2 as an important new facilitator of insulin receptors, and the authors propose a unique regulatory mechanism between insulin signaling, adipogenesis, and insulin resistance.

Hepatocyte Ninjurin2 promotes hepatic stellate cell activation and liver fibrosis through the IGF1R/EGR1/PDGF-BB signaling pathway.

BACKGROUND: Liver fibrogenesis is orchestrated by the paracrine signaling interaction between several resident cell types regulating the activation of hepatic stellate cells (HSCs). However, the molecular mechanisms underlying paracrine regulation are largely unknown. The aim of this study is to elucidate the role of Ninjurin2 in the crosstalk between hepatocytes and HSCs and better understand the implications of Ninjurin2 in liver fibrosis. METHODS: Ninj2 knockout mice (Ninj2-/-) and hepatocyte-specific Ninj2 overexpression mice (Ninj2Hep-tg) were constructed and followed by the induction of liver fibrosis using methionine- and choline-deficient (MCD) diet. The relationship between Ninjurin2 and liver fibrosis phenotype was evaluated in vivo by measurement of fibrotic markers and related genes. We used an in vitro transwell cell co-culture model to examine the impact of Ninjurin2 in hepatocytes on the crosstalk to HSCs. The interaction of Ninjurin2 and IGF1R and the regulation of PI3K-AKT-EGR1 were analyzed in vivo and in vitro. Finally, an inhibitory Ninjurin2 peptide was injected intravenously via the tail vein to investigate whether inhibiting of Ninjurin2 cascade can attenuate MCD diet-induced liver fibrosis in mice. RESULTS: We found that hepatic Ninjurin2 expression was significantly increased in fibrotic human liver and MCD diet-induced liver injury mouse models. In the mouse model, hepatocyte-specific overexpression of Ninj2 exacerbates MCD-induced liver fibrosis, while global Ninj2 knockout reverses the phenotype. To mimic hepatocyte-HSC crosstalk during liver fibrosis, we used co-culture systems containing hepatocytes and HSCs and determined that Ninjurin2 overexpression in hepatocytes directly activates HSCs in vitro. Mechanistically, Ninjurin2 directly interacts with insulin-like growth factor 1 receptor (IGF1R) and increases the hepatocyte secretion of the fibrogenic cytokine, platelet-derived growth factor-BB (PDGF-BB) through IGF1R-PI3K-AKT-EGR1 cascade. Inhibition of PDGFRB signaling in HSCs can abolish the profibrogenic effect of Ninjurin2. In addition, we demonstrated that a specific inhibitory Ninjurin2 peptide containing an N-terminal adhesion motif mitigates liver fibrosis and improves hepatic function in the mouse models by negatively regulating the sensitivity of IGF1R to IGF1 in hepatocytes. CONCLUSION: Hepatic Ninjurin2 plays a key role in liver fibrosis through paracrine regulation of PDGF-BB/PDGFRB signaling in HSCs, and the results suggesting Ninjurin2 may be a potential therapeutic target.

Three-dimensional assessment of posterior capsule-intraocular lens interaction with and without primary posterior capsulorrhexis: an intraindividual randomized trial.

PURPOSE: To assess the morphologic and clinical features of posterior capsule-intraocular lens (IOL) interaction following cataract surgery with and without primary posterior continuous curvilinear capsulorrhexis (PPCCC) at a three-dimensional (3-D) level using Scheimpflug imaging. METHODS: This prospective intraindividual randomized comparative study comprised 56 patients (112 eyes) with age-related cataract who had bilateral cataract surgery and hydrophobic acrylic IOLs implantation. In randomized order, cataract surgery with PPCCC was performed in 1 eye (PPCCC group), and the posterior capsule was left intact in the fellow eye (NPCCC group). Scheimpflug imaging containing 25 images distributed in 360° was taken 1 day, 1 week, 1 month, and 3 months postoperatively. RESULTS: 46 patients completed 3 months follow-up. Posterior capsule-IOL interaction can be morphologically classified into two types including complete adhesion and floppy shape in PPCCC group, and six types including full area wave, full area flat, concentric ring wave, concentric ring flat, sector, and complete adhesion in NPCCC group. The adhesion index (AI), defined as the proportion of complete adhesion of posterior capsule-IOL in 25 cross-section tomograms, was 0.45 ± 0.45, 0.79 ± 0.37, 0.92 ± 0.26 and 1.00 ± 0.00 in PPCCC group, while 0.05 ± 0.18, 0.41 ± 0.47, 0.87 ± 0.34, and 0.96 ± 0.21 in NPCCC group at 1 day, 1 week, 1 month and 3 months postoperatively, respectively (p = 0.001, 0.001, 0.338 and 0.151). CONCLUSIONS: 3-D Scheimpflug imaging was favorable in observing of posterior capsule-IOL interaction. Faster posterior capsule adhesion to the IOL was found in PPCCC group than in NPCCC group.

Outcomes and Complications of Sutured Scleral-Fixated Foldable Intraocular Lens Implantation: A Retrospective Study of 5-Year Follow-Up.

PURPOSE: To evaluate long-term outcomes and complications of sutured scleral-fixated foldable intraocular lens (IOL) implantation. DESIGN: Retrospective study. METHODS: Patients who underwent sutured scleral-fixated foldable IOL implantation using 10-0 polypropylene suture were followed up for at least 5 years at one Chinese tertiary hospital and two primary hospitals. RESULTS: 52 eyes among 48 patients (35 male and 13 female) were evaluated. The mean age (years) was 50.27 ± 20.08 (range: 6 to 81). The mean postoperative follow-up time (months) was 79.70 ± 18.84 (range: 60 to 121). The mean best-corrected visual acuity (BCVA) improved from 0.83 ± 0.69 logarithm of the minimum angle of resolution (logMAR) at baseline to 0.50 ± 0.45 logMAR at the last follow-up visit. There was improved or unchanged BCVA in 44 eyes (84.62%) and reduced BCVA in 8 eyes (15.38%). Mild intraoperative intravitreal hemorrhage was observed in 3 eyes (5.77%). Early postoperative complications included transient elevated intraocular pressure (IOP) in 5 eyes (9.62%) and hypotony in 1 eye (1.92%). Secondary epimacular membrane occurred in 5 eyes (9.62%) and retinal detachment (RD; 3 years postsurgery), subconjunctival suture knot exposure (5 years postsurgery), and persistent elevated IOP (in a GRAVES patient) occurred in 1 eye (1.92%) each. No suture erosion or breakage nor IOL dislocation was observed. No visually threatening IOL tilt or decentration was reported in any patient. CONCLUSION: Sutured scleral-fixated foldable IOL implantation demonstrated satisfactory long-term outcomes and rare suture-related complications. This technology was safe and did not require complicated equipment and is of considerable interest in the setting of aphakia without adequate capsule support.

Clinical Outcomes of Primary Posterior Continuous Curvilinear Capsulorhexis in Postvitrectomy Cataract Eyes.

PURPOSE: To evaluate the safety and outcomes of primary posterior continuous curvilinear capsulorhexis (PPCCC) combined with phacoemulsification in postvitrectomy eyes. DESIGN: Retrospective case series. METHODS: Twenty-one postvitrectomy eyes of 21 patients with cataract between April 2017 and December 2019 were enrolled. PPCCC through the cornea incision was performed before in-the-bag intraocular lens implantation. All patients were followed up for at least 3 months postoperatively. The outcome measures were corrected distance visual acuity (CDVA), intraocular pressure (IOP), corneal endothelium cell counts (CECC), central macular thickness (CMT), the occurrence of intraoperative or postoperative complications, and the incidence of posterior capsular opacification (PCO). RESULTS: The mean age was 56.14 ± 9.76 years (ranging from 31 to 68). The mean Snellen CDVA was 20/400 preoperatively and improved to 20/67 postoperatively (P < 0.001). No significant differences were found between IOP (P = 0.96) and CMT (P = 0.42) preoperatively and postoperatively. The mean CECC was 2571.8 ± 319.3 cells/mm2 preoperatively and 2498.2 ± 346.3 cells/mm2 postoperatively (P < 0.05). Lens epithelium cells proliferation was confined to the peripheral capsular bag during a mean follow-up of 12.9 ± 10.5 months (ranging from 3 to 28 months). Intraoperative posterior capsule extension occurred in 1 eye (4%), although it did not affect the patient's vision. No serious complications, including retinal detachment or endophthalmitis, were detected in any of the 21 cases. CONCLUSION: PPCCC through cornea incision combined with phacoemulsification may be a safe and practical alternative to prevent PCO in postvitrectomy eyes with cataract.