Identification and characterization of two O-methyltransferases involved in biosynthesis of methylated 2-(2-phenethyl)chromones in agarwood.

The 2-(2-phenethyl)chromones (PECs) are the signature constituents responsible for the fragrance and pharmacological properties of agarwood. O-Methyltransferases (OMTs) are necessary for the biosynthesis of methylated PECs, but there is little known about OMTs in Aquilaria sinensis. In this study, we identified 29 OMT genes from the A. sinensis genome. Expression analysis showed they were differentially expressed in different tissues and responded to drill wounding. Comprehensive analysis of the gene expression and methylated PEC content revealed that AsOMT2, AsOMT8, AsOMT11, AsOMT16, and AsOMT28 could potentially be involved in methylated PECs biosynthesis. In vitro enzyme assays and functional analysis in Nicotiana benthamiana demonstrated that AsOMT11 and AsOMT16 could methylate 6-hydroxy-2-(2-phenylethyl)chromone to form 6-methoxy-2-(2-phenylethyl)chromone. A transient overexpression experiment in the variety 'Qi-Nan' revealed that AsOMT11 and AsOMT16 could significantly promote the accumulation of three major methylated PECs. Our results provide candidate genes for the mass production of methylated PECs using synthetic biology.

A FRET-based multifunctional fluorescence probe for the simultaneous detection of sulfite and viscosity in living cells.

Viscosity and sulfur dioxide derivatives were significant indicators for the assessment of health threat and even cancers, therefore, on-site and real time detection of viscosity and sulfur dioxide derivatives has obtained considerable attentions. An FRET-based fluorescence probe JZX was designed and synthesized based on a novel energy donor of N,N-diethyl-4-(1H-phenanthro[9,10-d]imidazol-2-yl)benzamide fluorophore. JZX exhibited a large Stokes shift (230 nm), high energy transfer efficiency, wide emission channel gap (135 nm) and excellent stability and biocompatibility. JZX detected sulfur dioxide with low detection limit (55 nM), fast responding (16 min), high selectivity and sensitivity. Additionally, JZX tend to target endoplasmic reticulum of which normal metabolism will be disturbed by the abnormal levels of viscosity and sulfur dioxide derivatives. Prominently, JZX could concurrently detect viscosity and sulfur dioxide derivatives depending on different fluorescence signals in living cells for the screening of cancer cells. Hence, probe JZX will be a promising candidate for the detection of viscosity and sulfur dioxide derivatives, and even for the diagnosis of liver cancers.

Quercetin nanocrystals prepared using a microfluidic chip with improved in vitro dissolution.

OBJECTIVE: In order to improve the dissolution property of quercetin (QCT), the quercetin nanocrystals (QNCs) were prepared in this study. METHODS: QNCs were prepared by a 100 µm diameter Y-shape microfluidic channel. Some impact factors affecting the generation of QNCs such as concentration and flow rate were investigated. Furthermore, the fluid mixing in the microfluidic channel was simulated by fluid software. RESULTS: XRPD and DSC analyses indicated that the prepared QNCs were amorphous. Stable QNCs with a particle size of 77.9 ± 3.63 nm and polydispersity index of 0.26 ± 0.02 were obtained. TEM showed that the as-prepared QNCs had a uniform spherical shape with an average particle size of about 100-300 nm. In the dissolution medium without cosolvent Tween -80, the dissolution of QCT was poor, its final accumulated dissolution was only 3.95%, while that of QNCs was 66%. CONCLUSION: When QCT was changed to QNCs by microfluidic technology, its dissolution property could be obviously improved. Therefore, microfluidic technology as a new method to prepare nanocrystals has a good applying prospect in improving dissolution property for poorly water-soluble drugs.

pH-Triggered Charge Reversible Fluorescent Probe for Simultaneous Imaging of Lipid Droplets and Nucleoli in Living Cells.

Cooperation between organelles is essential to maintain the normal functions of cells. Lipid droplets (LDs) and nucleoli, as important organelles, play an important role in the normal activities of cells. However, due to the lack of appropriate tools, in situ observation of the interaction between them has been rarely reported. In this work, taking into full consideration the pH and charge differences between LDs and nucleoli, a pH-triggered charge reversible fluorescent probe (LD-Nu) was constructed based on a cyclization-ring-opening mechanism. The in vitro pH titration experiment and 1H NMR showed that LD-Nu gradually transferred from the charged form to the electroneutral form with the increase of pH, and thus, the conjugate plane was reduced and its fluorescence blue-shifted. Most importantly, the physical contact between LDs and nucleoli was visualized for the first time. Meanwhile, the relationship between LDs and nucleoli was also further investigated, and the results showed that their interaction was more liable to be affected by the abnormality of LDs than those of nucleoli. Moreover, the cell imaging results displayed that the LDs both in the cytoplasm and nucleus were observed using the probe LD-Nu, and interestingly, the LDs in the cytoplasm were more susceptible to external stimuli than those in the nucleus. In a word, the probe LD-Nu can serve as a powerful tool for further exploration of the interaction mechanism between LDs and nucleoli in living cells.

Constructing Spatially Separated Cage-Like Z-scheme Heterojunction Photocatalyst for Enhancing Photocatalytic H2 Evolution.

Heterojunctions coupled into micro-mesoscopic structures is an attractive strategy to optimize the light harvesting and carrier separation of semiconductor photocatalysts. A self-templating method of ion exchange is reported to synthesize an exquisite hollow cage-structured Ag2 S@CdS/ZnS that direct Z-scheme heterojunction photocatalyst. On the ultrathin shell of the cage, Ag2 S, CdS, and ZnS with Zn-vacancies (VZn ) are arranged sequentially from outside to inside. Among them, the photogenerated electrons are excited by ZnS to the VZn energy level and then recombine with the photogenerated holes that are generated by CdS, while the electrons remained in the CdS conduction band are further transferred to Ag2 S. The ingenious cooperation of the Z-scheme heterojunction with the hollow structure optimizes the photogenerated charges transport channel, spatially separated the oxidation and reduction half-reactions, decreases the charge recombination probability, and simultaneously improves the light harvesting efficiency. As a result, the photocatalytic hydrogen evolution activity of the optimal sample is 136.6 and 17.3 times higher than that of cage-like ZnS with VZn and CdS by, respectively. This unique strategy demonstrates the tremendous potential of the incorporation of heterojunction construction to morphology design of photocatalytic materials, and also provided a reasonable route for designing other efficient synergistic photocatalytic reactions.

Simplified stepwise anatomical ablation strategy for mitral isthmus: efficacy, efficiency, safety, and outcome.

AIMS: Bidirectional and durable block of mitral isthmus (MI) is essential for catheter ablation of persistent atrial fibrillation (PeAF) and perimitral flutter (PMF), but it remains a challenge. The aim of this study was to create a simple anatomical ablation strategy with minimal fluoroscopy that would yield a high success rate for MI block. METHODS AND RESULTS: Patients with PeAF or PMF were included. Mitral isthmus was ablated in a stepwise strategy. In Step 1, endocardial MI linear ablation was performed; in Step 2, ablation was targeted to the posterolateral portion of the left atrium along the MI line; in Step 3, epicardial ablation within the coronary sinus (CS) was performed across the MI line to the ostium of the vein of Marshall (VOM) or performed within the VOM if available; in Step 4, the catheter was rotated and ablated in the CS to isolate the CS; and in Step 5, the early activation site with complex component potential above the MI line during distal CS pacing was considered as the ablation target. All patients were followed up. A total of 178 (17 patients with mechanical prosthetic mitral valve) were included. One hundred and sixty-six patients achieved a confirmed MI bidirectional conduction block (93%). One patient had cardiac tamponade. Four patients showed re-conduction across the MI line during a repeated ablation. In the latest follow-up [12 (7, 16) months], 161 of 178 (90%) patients maintained their sinus rhythm. CONCLUSION: A simple stepwise anatomical ablation strategy for MI shows a high success rate with low fluoroscopy exposure.

Applying lysozyme, alkaline protease, and sodium hypochlorite to reduce bioclogging during managed aquifer recharge: A laboratory study.

Alleviating bacterial-induced clogging is of great importance to improve the efficiency of managed aquifer recharge (MAR). Enzymes (lysozyme and alkaline protease) and sodium hypochlorite (NaClO) are common biological and chemical reagents for inhibiting bacterial growth and activity. To investigate the applicability of these reagents to reduce bioclogging, percolation experiments were performed to simulate a weak alkaline recharge water infiltration through laboratory-scale sand columns, with adding 10 mg/L lysozyme, alkaline protease, and NaClO, respectively. The results showed that, with the addition of lysozyme, alkaline protease, and NaClO, the average clogging rates (the reduced percentages of relative saturated hydraulic conductivity of the sand columns per hour during the percolation experiments) were 0.53%/h, 0.32%/h and 0.06%/h, respectively, which were much lower than that in the control group (0.99%/h). This implied that bioclogging could be alleviated to some extent following the treatments. For further analyzing the mechanisms of the regents on alleviating bioclogging, the bacterial cell amount and extracellular polymeric substances (EPS) concentration were also measured to study the effects of lysozyme, alkaline protease, and NaClO on bacterial growth and EPS secretion. Lysozyme and alkaline protease could disintegrate bacterial EPS by hydrolyzing polysaccharides and proteins, respectively, while they had little effect on the bacterial cell amount. The addition of NaClO significantly decreased the bacterial cell amount (P < 0.05) and thus greatly alleviated bioclogging. Although the lowest average clogging rate was achieved in the NaClO group, it can generate disinfection by-products that are potentially harmful to the environment and human health. Therefore, the biological-based method, i.e., enzyme treatment, could be a promising option for bioclogging control. Our results provide insights for understanding the mechanisms of lysozyme, alkaline protease, and NaClO to alleviate bioclogging, which is of great importance for addressing the clogging problem during MAR activities and achieving groundwater resources sustainable utilization.

Bilayer nanofibrous wound dressing prepared by electrospinning containing gallic acid and quercetin with improved biocompatibility, antibacterial, and antioxidant effects.

OBJECTEIVES: The purpose of this study was to prepare an antibacterial, antioxidant, and biocompatible bilayer nanofibrous wound dressing by using electrospinning. METHODS: The micromorphology and bilayer structure characteristics of the GA-Qe-PVP-PCL nanofibers were analyzed by SEM. The physicochemical characteristics were analyzed by XRD and FTIR. The uptake, mechanical properties, water contact angle, water vapor transmission and in vitro drug release were evaluated. In addition, the effect of antibacterial, antioxidant and biocompatability of the nanofibers were evaluated, respectively. RESULTS: The SEM results showed that the GA-Qe-PVP-PCL nanofibers had a smooth surface, no beading phenomenon, and a prominent bilayer structure. The diameter and porosity of the drug-loading layer and waterproof support layer of the nanofibers were 842 ± 302 nm, 242 ± 50 nm, and 88.56 ± 1.67%, 94.49 ± 1.57%, respectively. Moreover, the water uptake, mechanical properties, water contact angle, and water vapor transmission showed ideal performance. The results of in vitro drug release indicated that GA and Qe were both released rapidly, which was conducive to accelerating wound healing. The GA-Qe-PVP-PCL nanofibers exhibited antibacterial effects against both bacteria as well as high antioxidant activity. Additionally, the GA-Qe-PVP-PCL nanofibers possessed good compatibility, could promote the proliferation, adhesion, and migration of L929 fibroblast cells. CONCLUSION: The nanofibers we developed met the requirements of ideal materials for wound dressing, which makes the nanofibers the potential to be a wound dressing for wound care.

Chitosan/Polylactic Acid Nanofibers Containing Astragaloside IV as a New Biodegradable Wound Dressing for Wound Healing.

The ideal wound dressing should adequately protect the wound from bacterial infection and provide a suitable healing environment for the wound. Thus, we prepared a biodegradable functional nanofiber dressing with good antibacterial and biocompatibility by electrospinning technology. The average diameter of the dressing was 354 ± 185 nm, and the porosity was 93.27%. Scanning electron microscopy (SEM) showed that the dressing was smooth without beading. It was also characterized by Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The wettability and water vapor permeability of the dressing were tested; the results showed that the dressing had good wettability and permeability. The ability of drug release indicates that continuous release over a period of time is beneficial to wound healing. Finally, the antibacterial effect and in vivo pharmacodynamic evaluation of AS/CS/PLA nanofiber dressing were studied; the result showed that it had significant antibacterial activity and the ability to promote wound healing.

Finite element analysis of the angle range in trans-inferior alveolar nerve implantation at the mandibular second molar.

BACKGROUND: Trans- inferior alveolar nerve (IAN) implantation technique was wildly used while the potential appropriate angle range in which the residual alveolar bone can bear the stress without absorption are currently unclear. This study aimed to evaluate the stress distribution pattern of the interface between bone and implant by finite element analysis (FEA) to determine the appropriate range of the implant tilt angle. METHODS: Cone beam computed tomography (CBCT) images of 120 patients with missing mandibular second molars and vertical bone height < 9 mm in the edentulous area were selected. The distances from the mandibular nerve canal to the buccal cortex, the lingual cortex and the alveolar ridge crest were measured by using a combination of software. The angular ranges of the buccal-lingual inclination of simulated trans-IAN implants were measured and three-dimensional finite element models were constructed in the mandibular second molar area according to the differences of the inclination angles. A vertical load (200N) was then applied to analyze the biomechanical conditions of the implant-bone interface during median occlusion. RESULTS: The distance at the second molar from the nerve canal to the buccal cortex, lingual cortex and alveolar crest were 6.861 ± 1.194 mm, 2.843 ± 0.933 mm and 7.944 ± 0.77 mm. Trans-IAN implantation was feasible in 73.33% of patients. The minimum angle and maximum angles of the buccal-lingual inclination of the simulated implant were 19.135 ± 6.721° and 39.282 ± 6.581°. When a vertical static load of 200N was applied, the tensile stress in cortical bone gradually increased with the increase of the implant tilt angle. When the inclination angle reached 30°, the tensile stress (105.9 MPa) exceeded the yield strength (104 MPa) of cortical bone. Compared with the conventional implants, the stress peak value of the vertical ultra-short implant in cortical bone was greater than the stress peak value of the conventional implants at 10°(79.81 MPa) and 20°(82.83 MPa) and was smaller than the stress of the implant at 30°(105.9 MPa) and 40°(107.8 MPa). Therefore, when the bone mass allows, conventional-length implants should be selected whenever possible, and an operative range of the trans-IAN implantation in the mandibular second molar could be retained with an inclination angle of < 30°. CONCLUSIONS: The mandibular nerve canal at the mandibular second molar was obviously biased to the lingual side, which ensured sufficient bone mass at the buccal side. In most patients with severe mandibular atrophy, it was possible to maintain a safe distance from the nerve canal with conventional-length implants via the trans-IAN implantation technique.

Paper-Based Distance Sensor for the Detection of Lipase via a Phase Separation-Induced Viscosity Change.

Human pancreatic lipase is a symbolic biomarker for the diagnosis of acute pancreatitis, which has profound significance for clinical detection and disease treatment. Herein, we first demonstrate a paper-based lipase sensor via a phase separation-induced viscosity change. Lipase catalyzes triolein to produce oleic acid and glycerol. Adding an excess of Ca2+ produces calcium oleate. The remaining Ca2+ binds with sodium alginate, triggering hydrogelation with an "egg-box" structure. The viscosity change of the aqueous solution induced by the phase separation process can be quantified by measuring the solution flow distance on a pH test paper. The paper-based lipase sensor has high sensitivity with a detection limit of 0.052 U/mL and also shows excellent specificity. Additionally, it is also utilized for quantitative lipase analysis in human serum samples to exhibit its potency in acute pancreatitis detection. This method overcomes the drawbacks of low sensitivity, slow response, and poor reproducibility caused by the nonuniform distribution of the highly viscous hydrogel on the sensing interface in existing approaches. In conclusion, thanks to the prominent characteristics of high portability, low cost, and easy operation, it is prospective for simple quantitative detection of lipase and has great potential for commercialization.

Large scale application of pulse oximeter and auscultation in screening of neonatal congenital heart disease.

PURPOSE: To conduct a retrospective evaluation of a large clinical implementation of combined pulse oximeter (POX) and cardiac auscultation as a fast-screening device for congenital heart disease (CHD). METHODS: Every newborn in a large maternity healthcare center received auscultation and POX screening within 24 hours after delivery. When an abnormal heart murmur or SpO2 level was detected, an echocardiogram was ordered to confirm the diagnosis of CHD. RESULTS: From January 1, 2018 to December 31, 2019, there were 44,147 livebirths at the studied hospital where 498 suspected CHD were identified: 27 newborns by POX screening and 471 by cardiac auscultation. The diagnosis was further confirmed in 458 neonates through echocardiogram. This result put forth an overall diagnosis rate of 92.0%. Cardiac auscultation detected the majority of CHD cases 438 (95.6%) while POX only screened 20 (4.4%) cases. Interestingly, no CHD case was detected by both auscultation examination and POX screening. Auscultation detected most of the common types of CHD, but POX excelled in identifying rare and critical cases. POX screening alone had a very low accuracy of 74.07% in positive predict value (PPV). On the other hand, auscultation functioned well in terms of PPV and negative predict value (NPV) (92.99 and 99.95%, respectively), but the addition of POX improved the overall screening performance resulting in 100% NPV. We also validate the finding with the data 6 months after the study period. CONCLUSION: Our study demonstrated that addition of pulse oximetry to routine cardiac auscultation could be used as an accurate and feasible screening for early screening of CHD in newborns in large-scale clinical practice.

Characteristics and origin of clogging-functional bacteria during managed aquifer recharge: A laboratory study.

Owing to serious influences on well performance, bacteria-induced clogging has become a dilemma for managed aquifer recharge (MAR). During MAR, surface river water is inoculated into aquifer and mixed with groundwater. Therefore, the clogging-functional bacteria may originate from the river water or the groundwater. However, the origin of the clogging-functional bacteria in the aquifer has not yet been well understood. This study conducted a series of laboratory-scale column experiments involving different recharge modes (using river water, groundwater) to simulate the processes of bacteria-induced clogging and used the high-throughput sequencing technology, aiming to elucidate the community characteristics and the origin of the clogging-functional bacteria involved in MAR bioclogging. Analyses of the bacterial-community characteristics showed significant differences between the river water and groundwater. The bacterial-community characteristics of the clogging aquifer in the different recharge modes were similar to each other and have common genera, namely, Acinetobacter, Brevundimonas, Exiguobacterium, Porphyrobacter, Cloacibacterium, and Sphingobium, which suggests that MAR activity could promote bacterial communities to become identical during surface water infiltration into aquifers, despite differences in the bacterial communities present in the subsurface- and surface systems. This knowledge will assist greatly in targeted treatment and prophylaxis of clogging-functional bacteria during managed aquifer recharge.

Screening of Xanthine Oxidase Inhibitors by Liquid Crystal-Based Assay Assisted with Enzyme Catalysis-Induced Aptamer Release.

Small-molecule drugs play an important role in the treatment of various diseases. The screening of enzyme inhibitors is one of the most important means in developing therapeutic drugs. Herein, we demonstrate a liquid crystal (LC)-based screening assay assisted with enzyme catalysis-induced aptamer release for screening xanthine oxidase (XOD) inhibitors. The oxidation of xanthine by XOD prevents the specific binding of xanthine and its aptamer, which induces a bright image of LCs. However, when XOD is inhibited, xanthine specifically binds to the aptamer. Correspondingly, LCs display a dark image. Three compounds are identified as potent XOD inhibitors by screening a small library of triazole derivatives using this method. Molecular docking verifies the occupation of the active site by the inhibitor, which also exhibits excellent biocompatibility to HEK293 cells and HeLa cells. This strategy takes advantages of the unique aptamer-target binding, specific enzymatic reaction, and simple LC-based screening assay, which allows high-throughput and label-free screening of inhibitors with high sensitivity and remarkable accuracy. Overall, this study provides a competent and promising approach to facilitate the screening of enzyme inhibitors using the LC-based assay assisted with the enzyme catalysis-induced aptamer release.

Mixed ionic/electronic conducting nanosheet arrays for stable lithium storage.

Lithium metal batteries (LMBs) have received extensive attention and research interest as high specific energy systems. However, the issues of Li dendrites growth in LMBs restrict their practical applications. The development of lithiophilic collectors can effectively solve the issues of Li dendrites growth. This study reports excellent lithium storage performance of lithiophilic nanosheet arrays which consist of electronic conductor Ni and ionic conductor Li2O (Ni-LONSs) on Ni foil (NF) fabricated via a simple preparation method for LMBs. The ionic conductor Li2O of the Ni-LONSs layer is lithiophilic and can induce uniform Li deposition on the Ni-LONSs collector. In addition, the nanosheet array structure of the Ni-LONSs collector is beneficial to slow down the volume change of the Li plating/stripping. In comparison with the NF collector, due to the specific nanosheet array structure of Ni-LONSs collector, the Ni-LONSs collector demonstrates excellent coulombic efficiency of 97.2% after 280 cycles (95.7% after 100 cycles of NF collector) and satisfactory cycling lifespan of 340 h (about 120 h of NF collector) at 0.5 mA cm-2with 1.0 mAh cm-2. Furthermore, the Ni-LONSs collector shows superior electrochemical performance in Ni-LONS/Li∣LiFePO4full cells. The excellent lithium storage performance of Ni-LONSs collector with mixed ionic/electronic conductor is conducive to the development and practical applications of LMBs.

Comparison of the prognostic value of SYNTAX score and clinical SYNTAX score on outcomes of Chinese patients underwent percutaneous coronary intervention.

BACKGROUND: Previous studies have validated the capability of SYNTAX score (SS) and clinical SYNTAX score (CSS) in the prediction of clinical outcomes in patients who have undergone PCI; however, studies on comparison of these two scoring systems in Chinese population have been sparse. METHODS: To study the ability of SS and CSS in prediction of clinical outcomes of Chinese patients underwent percutaneous coronary intervention (PCI). We retrospectively calculated SS and CSS for 547 Chinese patients from a single center who underwent PCI. Patients were stratified into tertiles according to their SS and CSS. We compared the 2-year clinical outcomes in these patients stratified separately by SS and CSS tertiles. RESULTS: The incidence of major adverse cardiac and cerebro-vascular events (MACCE) was the highest in patients with SSHIGH (13.5%), comparing to 6.8% in SSMED and 0% in SSLOW (p < 0.0001). The Cox multivariable analysis showed that the SS and CSS were both strong independent predictors for MACCE [1.100 (1.069-1.133), 1.017 (1.010-1.025), both p < 0.0001]. The receiver operating characteristic (ROC) curves showed the areas-under-the-curves for all-cause death by CSS was slightly larger comparing to SS but not significantly (AUC SS, 0.64; AUC CSS, 0.71; p = 0.23). CONCLUSION: We concluded that both the SS and CSS were capable of risk stratification of clinical outcomes in all-comers population as well as in low and moderate risk Chinese patients undergoing PCI with CSS showing slightly better advantage.

Basic fibroblast growth factor promotes human dental pulp stem cells cultured in 3D porous chitosan scaffolds to neural differentiation.

AIM/PURPOSE: Dental pulp stem cells (DPSCs) were widely used as seed cells in the field of tissue engineering and regenerative medicine, including spinal cord injury (SCI) repair and other neuronal degenerative diseases, due to their easy isolation, multiple differentiation potential, low immunogenicity and low rates of rejection during transplantation. Various studies have shown that bFGF can enhance peripheral nerve regeneration after injury, and phospho-ERK (p-ERK) activation as a major mediator may be involved in this process. Previous studies also have proved that a suitable biomaterial scaffold can carry and transport the therapeutic cells effectively to the recipient area. It has showed in our earlier experiments that 3D porous chitosan scaffolds exhibited a suitable circumstance for survival and neural differentiation of DPSCs in vitro. The purpose of the study was to evaluate the influence of chitosan scaffolds and bFGF on differentiation of DPSCs. MATERIALS AND METHODS: In current study, DPSCs were cultured in chitosan scaffolds and treated with neural differentiation medium for 7 days. The neural genes and protein markers were analyzed by western blot and immunofluorescence. Meanwhile, the relevant signaling pathway involved in this process was also tested. RESULTS: Our study revealed that the viability of DPSCs was not influenced by co-culture with the chitosan scaffolds as well as bFGF. Compared with the control and DPSC/chitosan-scaffold groups, the levels of GFAP, S100ß and ß-tubulin III significantly increased in the DPSC/chitosan-scaffold+bFGF group. CONCLUSION: Chitosan scaffolds were non-cytotoxic to the survival of DPSCs, and chitosan scaffolds combined with bFGF facilitated the neural differentiation of DPSCs. The transplantation of DPSCs/chitosan-scaffold+bFGF might be a secure and effective method of treating SCI and other neuronal diseases.

Brivanib, a multitargeted small-molecule tyrosine kinase inhibitor, suppresses laser-induced CNV in a mouse model of neovascular AMD.

In age-related macular degeneration (AMD), choroidal neovascularization (CNV), a major pathologic feature of neovascular AMD (nAMD), affects 10% of patients, potentially causing serious complications, including vision loss. Vascular endothelial growth factor receptor 2 (VEGFR2) and fibroblast growth factor receptor 1 (FGFR1) contribute to the pathogenesis of CNV. Brivanib is an oral selective dual receptor tyrosine kinase (RTK) inhibitor of FGFRs and VEGFRs, especially VEGFR2 and FGFR1. In this study, brivanib inhibited zebrafish embryonic angiogenesis without impairing neurodevelopment. In a mouse CNV model, brivanib intravitreal injection blocked phosphorylation of FGFR1 and VEGFR2 and reduced CNV leakage, area, and formation without causing intraocular toxicity. Moreover, brivanib oral gavage reduced CNV leakage and area. Accordingly, brivanib remained at high concentrations (above 14,000 ng/ml) in retinal/choroidal/scleral tissues following intravitreal injection. Similarly, brivanib remained at high concentrations (over 10,000 ng/ml) in retinal/choroidal/scleral tissues following oral gavage. Finally, in vitro cell experiments demonstrated that brivanib inhibited the proliferation, migration and tube formation of microvascular endothelial cells. In conclusion, our study suggested that brivanib treatment could be a novel therapeutic strategy for nAMD.

Andrographolide attenuates choroidal neovascularization by inhibiting the HIF-1α/VEGF signaling pathway.

Choroidal neovascularization (CNV), a characteristic of wet age-related macular degeneration (AMD), leads to severe vision loss amongst the elderly in the developed countries. Currently, the premier treatment for AMD is anti-VEGF therapy, which has limited efficacy, and is still controversial. Previous studies have showed that Andrographolide (Andro) had various biological effects, including anti-angiogenesis, anti-inflammation, and antioxidant. However, the effect of Andro on the formation of CNV has not been studied thus far. Here our results showed that Andro reduced the expression levels of HIF-1α and VEGF in the RF/6A cells chemical hypoxia model and the laser-induced CNV mouse model. Moreover, Andro inhibited the tube formation activity of RF/6A cells under hypoxic conditions. Furthermore, intraperitoneal injection of Andro reduced the severity of choroidal vascular leakage and the size of CNV in the laser-induced CNV mouse model, indicating that Andro attenuated the development of CNV by inhibiting the HIF-1α/VEGF signaling pathway. These results suggest that Andro could be a potential novel therapeutic agent for AMD.

A Novel Geometric Morphometric Analytical Method for Classifying Mandibular Morphology in Infants With Isolated Pierre Robin Sequence.

PURPOSE: There is a lack of uniformity in the diagnostic criteria and system for the morphologic classification of micrognathia in infants with isolated Pierre Robin sequence (IPRS). Therefore, the aim of this study was to create a morphologic classification system for IPRS-affected mandibles that may guide surgical management and osteotomy design. PATIENTS AND METHODS: We designed and implemented a retrospective cross-sectional study. The study sample included infants with IPRS. The predictor variables included shape variables of the IPRS-affected mandibles. The outcome of interest was morphologic differences among the IPRS-affected mandibles in the infancy stage. The original coordinate data of the mandibular images were analyzed by a generalized Procrustes analysis and 2-block partial least squares analysis to identify the focal and nonfocal areas in the IPRS-affected mandibles. The original feature points were modified according to the results of 2-block partial least squares analysis. The modified feature points were further analyzed by principal component analysis, K-means cluster analysis, and canonical variate analysis to obtain a morphologic classification of the IPRS-affected mandibles. RESULTS: One hundred fifty infants with IPRS were enrolled in this study. Principal component analysis showed that the variations among IPRS-affected mandibles were mostly in terms of the shapes of the mandibular ramus, mandibular body, and angle of the mandible. On the basis of the results of K-means cluster analysis and canonical variate analysis, the mandibles in group A3 showed characteristics such as a simply shorter mandibular body. Group B3 was adjusted to show characteristics such as a shorter mandibular body with a more obtuse mandibular angle, whereas group C3 showed characteristics such as a shorter mandibular body with a shorter mandibular ramus. CONCLUSIONS: Our study confirmed the hypothesis that there are quantifiable morphologic differences among the IPRS-affected mandibles, and it provided a morphologic classification of the IPRS-affected mandibles that will help to promote the clinical diagnosis and treatment.