Incorporation of Lactococcus lactis and Chia Mucilage for Improving the Physical and Biological Properties of Gelatin-Based Coating: Application for Strawberry Preservation.

In this work, a gelatin/chia mucilage (GN/CM) composite coating material doped with Lactococcus lactis (LS) was developed for strawberry preservation applications. The results of the scanning electron microscope and Fourier transform infrared spectroscopy stated that the enhanced molecular interaction between the CM and GN matrix strengthened the density and compactness of the GN film. Antifungal results indicated that the addition of LS significantly (p < 0.05) improved the ability of the GN coating to inhibit the growth of Botrytis cinerea (inhibition percentage = 62.0 ± 4.6%). Adding CM significantly (p < 0.05) decreased the water vapour permeability and oxygen permeability of the GN coating by 32.7 ± 4.0% and 15.76 ± 1.89%, respectively. In addition, the incorporated CM also significantly (p < 0.05) improved the LS viability and elongation at break of the film by 13.11 ± 2.05% and 42.58 ± 1.21%, respectively. The GN/CM/LS composite coating material also exhibited an excellent washability. The results of this study indicated that the developed GN/CM/LS coating could be used as a novel active material for strawberry preservation.

Lactobacillus bulgaricus-loaded and chia mucilage-rich gum arabic/pullulan nanofiber film: An effective antibacterial film for the preservation of fresh beef.

In recent years, the development of probiotic film by incorporating probiotics into edible polymers has attracted significant research attention in the field of active packaging. However, the influence of the external environment substantially reduces the vitality of probiotics, limiting their application. Therefore, to improve the probiotic activity, this study devised a novel nanofiber film incorporating chia mucilage protection solution (CPS), gum arabic (GA), pullulan (PUL), and Lactobacillus bulgaricus (LB). SEM images indicated the successful preparation of the nanofiber film incorporating LB. CPS incorporation significantly improved the survival ability of LB, with a live cell count reaching 7.62 log CFU/g after 28 days of storage at 4 °C - an increase of 1 log CFU/g compared to the fiber film without CPS. The results showed that the fiber film containing LB inhibited Escherichia coli and Staphylococcus aureus. Finally, the novel probiotic nanofiber film was applied to beef. The results showed that the shelf life of the beef during the experiments was extended for 2 days at 4 °C. Therefore, the novel probiotic film containing LB was suitable for meat preservation.

Design, synthesis, and bioactivity evaluation of novel indole-selenide derivatives as P-glycoprotein inhibitors against multi-drug resistance in MCF-7/ADR cell.

The inhibition of P-glycoprotein (P-gp) has emerged as an intriguing strategy for circumventing multidrug resistance (MDR) in anticancer chemotherapy. In this study, we have designed and synthesized 30 indole-selenides as a new class of P-gp inhibitors based on the scaffold hopping strategy. Among them, the preferred compound H27 showed slightly stronger reversal activity (reversal fold: 271.7 vs 261.6) but weaker cytotoxicity (inhibition ratio: 33.7% vs 45.1%) than the third-generation P-gp inhibitor tariquidar on the tested MCF-7/ADR cells. Rh123 accumulation experiments and Western blot analysis demonstrated that H27 displayed excellent MDR reversal activity by dose-dependently inhibiting the efflux function of P-gp rather than its expression. Besides, UIC-2 reactivity shift assay revealed that H27 could bind to P-gp directly and induced a conformation change of P-gp. Moreover, docking study revealed that H27 matched well in the active pockets of P-gp by forming some key H-bonding interactions, arene-H interactions and hydrophobic contacts. These results suggested that H27 is worth to be a starting point for the development of novel Se-containing P-gp inhibitors for clinic use.

Ultra-Wide-Field Optical Coherence Tomography and Gaussian Curvature to Assess Macular and Paravascular Retinoschisis in High Myopia.

PURPOSE: To evaluate the severity and related factors of macular retinoschisis (MRS) and paravascular retinoschisis (PVRS) in high myopia (HM) using ultra-wide-field optical coherence tomography (UWF-OCT) and a novel Gaussian curvature (K). DESIGN: A cross-sectional study. METHODS: Patients diagnosed with HM in Peking Union Medical College Hospital were recruited between January 2022 and November 2022. The presence and severity of retinoschisis, along with the three highest K values, were assessed using UWF-OCT and en face images. Logistic regressions were employed to identify factors associated with MRS, PVRS, and the severity of retinoschisis in the 24 × 20 mm scan region. RESULTS: A total of 108 HM eyes from 55 patients were recruited. The highest Gaussian curvature (K1) was predominantly found in the vascular arcade (43, 40%). Multivariable logistic regression found that age and PVRS were significant risk factors for MRS occurrence (P < .05), while MRS and higher K1 were significantly associated with the presence of PVRS in HM patients (P < .05). The axial length (AL) and spherical equivalent were associated with the severity of MRS, while AL and K1 values were associated with the severity of retinoschisis in the 24 × 20 mm scan region (P < .05). CONCLUSIONS: An association existed between large Gaussian curvature and the presence of MRS and PVRS, as well as the severity of retinoschisis in a wide field of view. UWF-OCT, which enables visualization of the central and peripheral retinal areas, holds promise as an imaging technique for the early detection of extrafoveal retinoschisis.

Structure-Activity Relationship of FL118 Platform Position 7 Versus Position 9-Derived Compounds and Their Mechanism of Action and Antitumor Activity.

Structurally, FL118 is a camptothecin analogue and possesses exceptional antitumor efficacy against human cancer through a novel mechanism of action (MOA). In this report, we have synthesized and characterized 24 FL118 Position 7-substituted and 24 FL118 Position 9-substituted derivatives. The top compounds were further characterized for their MOA in colorectal cancer (CRC) models using CRC patient-derived xenograft (PDX) models and pancreatic cancer PDX models to evaluate their antitumor activities. Four FL118 Position 7-substituted derivatives showed significantly better antitumor efficacy than the FL118 Position 9-substituted derivatives. The four identified compounds also appeared to have better antitumor activity than their parental platform FL118. Interestingly, RNA-Seq analyses indicated that three of the four compounds exerted antitumor effects via an MOA similar to FL118, which provided an intriguing opportunity for follow-up studies. Extended in vivo studies revealed that FL77-6 (7-(4-ethylphenyl)-FL118), FL77-9 (7-(4-methoxylphenyl)-FL118), and FL77-24 (7-(3, 5-dimethoxyphenyl)-FL118) exhibit potential for further development toward clinical trials.

Enantioselective Synthesis of 2,3,3a,8a-Tetrahydrofuro[2,3-b]benzofuran Scaffolds Enabled by Cu(II)/SPDO-Catalyzed [3+2] Cycloaddition of 2,3-Dihydrofuran and Quinone Esters.

An asymmetric [3+2] cycloaddition of quinone esters with 2,3-dihydrofuran has been realized via a newly developed Cu(II)/SPDO complex. It provides straightforward access to 2,3,3a,8a-tetrahydrofuro[2,3-b]benzofurans (TFB) with high enantioselectivity (up to 97.5:2.5 er) and diastereoselectivity (all >20:1 dr). The resulting adducts contain two adjacent stereocenters and a continuously functionalized benzene ring. Additionally, this transformation could be easily performed on a gram scale, allowing for expedient synthesis of natural dihydroaflatoxin D2 and aflatoxin B2.

KPNB1-mediated nuclear import in cancer.

Dysregulation of nucleocytoplasmic shuttling impairs cellular homeostasis and promotes cancer development. KPNB1 is a member of karyopherin ß family, mediating the transportation of proteins from the cytoplasm to the nucleus. In a variety of cancers, the expression of KPNB1 is upregulated to facilitate tumor growth and progression. Both downregulation of KPNB1 level and inhibition of KPNB1 activity prevent the entry of cancer-related transcription factors into the nucleus, subsequently suppressing the proliferation and metastasis of cancer cells. Currently, five KPNB1 inhibitors have been reported and exhibited good efficacy against cancer. This paper provides an overview of the role and mechanism of KPNB1 in different cancers and KPNB1-targeted anticancer compounds which hold promise for the future.

New retinal findings in NLRP3-associated autoinflammatory disease.

PURPOSE: To determine whether the rare NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) is associated with retinal changes and to assess the ocular involvement. METHODS: A retrospective cohort study of 20 patients(40 eyes) diagnosed with rare NLRP3-AID at Peking Union Medical College Hospital, from April 2015 to August 2022. Patients underwent a comprehensive ophthalmological examination, including visual acuity, intraocular pressure examination, slit-lamp examination, fundus photography, optical coherence tomography(OCT), and fluorescence angiography (FA). Some patients also underwent optical coherence tomography angiography (OCTA). RESULTS: This study analyzed 40 eyes of 20 patients (11 [55.0%] male; median age, 25.0 years [range, 12-52 years]) and 13 patients (26 eyes, 65%) demonstrated ocular involvement. The most common ophthalmologic manifestation was conjunctivitis (22 eyes, 84.6%), followed by papilledema (14 eyes, 53.8%), retinopathy (10 eyes, 38.5%), optic atrophy (6 eyes, 23.1%), uveitis (4 eyes, 15.4%), reduced pupil light reflex (3 eyes, 11.5%) and cataracts (2 eyes, 7.7%). Ocular involvement was bilateral in 11 patients (55.0%). Five kinds of retinal lesions were seen in 5 patients (10 eyes, 25%) with NLRP3-AID, including peripheral retinal vascular leakage, microaneurysms, macular ischemia, macular epiretinal membrane formation and drusen. CONCLUSIONS: Peripheral retinal vascular leakage, macular ischemia, microaneurysms and drusen are newly identified retinal findings in patients with NLRP3-AID, which suggests the importance of detailed retinal examination in these patients.

Comparison of the adjuvant effect of conbercept intravitreal injection at different times before vitrectomy for proliferative diabetic retinopathy.

Purpose: To assess the optimal time of intravitreal conbercept (IVC) treatment prior to pars plana vitrectomy (PPV) in patients with severe proliferative diabetic retinopathy (PDR). Method: This study was exploratory in nature. Forty-eight consecutive patients (48 eyes) with PDR were divided into four groups according to different IVC times (0.5 mg/0.05 mL) before PPV: group A (3 days), group B (7 days), group C (14 days), and group D (non-IVC). Intraoperative and postoperative effectiveness were assessed, and vitreous VEGF concentrations were detected. Result: For intraoperative effectiveness, groups A and D had a higher incidence of intraoperative bleeding than groups B and C (P = 0.041). Furthermore, groups A-C required less surgical time than group D (P < 0.05). For postoperative effectiveness, group B had a significantly higher proportion of visual acuity that improved or remained unchanged than group D (P = 0.014), and groups A-C had lower proportions of postoperative bleeding than group D. The vitreous VEGF concentration of group B (67.04 ± 47.24 pg/mL) was significantly lower than that of group D (178.29 ± 110.50 pg/mL) (P = 0.005). Conclusion: IVC treatment that was administered 7 days preoperatively was associated with better effectiveness and a lower vitreous VEGF concentration than its administration at other time points.

Design, Synthesis, and Biological Evaluation of Phenyloxadiazole Sulfoxide Derivatives as Potent Pseudomonas aeruginosa Biofilm Inhibitors.

With the development of antimicrobial agents, researchers have developed new strategies through key regulatory systems to block the expression of virulence genes without affecting bacterial growth. This strategy can minimize the selective pressure that leads to the emergence of resistance. Quorum sensing (QS) is an intercellular communication system that plays a key role in the regulation of bacterial virulence and biofilm formation. Studies have revealed that the QS system controls 4-6% of the total number of P. aeruginosa genes, and quorum sensing inhibitors (QSIs) could be a promising target for developing new prevention and treatment strategies against P. aeruginosa infection. In this study, four series of phenyloxadiazole and phenyltetrazole sulfoxide derivatives were synthesized and evaluated for their inhibitory effects on P. aeruginosa PAO1 biofilm formation. Our results showed that 5b had biofilm inhibitory activity and reduced the production of QS-regulated virulence factors in P. aeruginosa. In addition, silico molecular docking studies have shown that 5b binds to the P. aeruginosa QS receptor protein LasR through hydrogen bond interaction. Preliminary structure-activity relationship and docking studies show that 5b has broad application prospects as an anti-biofilm compound, and further research will be carried out in the future to solve the problem of microbial resistance.

Entrapment of probiotic (Bifidobacterium longum) in bilayer emulsion film with enhanced barrier property for improving viability.

The gelatin/gellan gum based-bilayer emulsion film was developed in this work to improve the survivability of Bifidobacterium longum during the storage process. The baobab seed oil (BO) was added to the gelatin (GE) matrix to develop emulsion film as the barrier outer layer. The blueberry anthocyanin extract (BE) was incorporated into the gellan gum (GG)-based inner layer to enhance the viability of B. longum. The SEM and FTIR results revealed that the probiotics were successfully entrapped in BO/BE-loaded bilayer film. The greatest survivability and viable cell numbers of the B. longum during the storage period were observed in the BO/BE loaded bilayer film. Furthermore, the stability of the colorful patterns by electrochemical writing was also evaluated in this work. Finally, the GE/BO-GG/BE/BM maintain satisfactory probiotic viability in steamed bread coating application. Hence, the GE/BO-GG/BE/BM bilayer film could be considered a novel material to deliver and protect the probiotics in food applications.

Mendelian Randomization and Transcriptome-Wide Association Analysis Identified Genes That Were Pleiotropically Associated with Intraocular Pressure.

BACKGROUND: Intraocular pressure (IOP) is a major modifiable risk factor for glaucoma. However, the mechanisms underlying the controlling of IOP remain to be elucidated. OBJECTIVE: To prioritize genes that are pleiotropically associated with IOP. METHODS: We adopted a two-sample Mendelian randomization method, named summary-based Mendelian randomization (SMR), to examine the pleiotropic effect of gene expression on IOP. The SMR analyses were based on summarized data from a genome-wide association study (GWAS) on IOP. We conducted separate SMR analyses using Genotype-Tissue Expression (GTEx) and Consortium for the Architecture of Gene Expression (CAGE) expression quantitative trait loci (eQTL) data. Additionally, we performed a transcriptome-wide association study (TWAS) to identify genes whose cis-regulated expression levels were associated with IOP. RESULTS: We identified 19 and 25 genes showing pleiotropic association with IOP using the GTEx and CAGE eQTL data, respectively. RP11-259G18.3 (PSMR = 2.66 × 10-6), KANSL1-AS1 (PSMR = 2.78 × 10-6), and RP11-259G18.2 (PSMR = 2.91 × 10-6) were the top three genes using the GTEx eQTL data. LRRC37A4 (PSMR = 1.19 × 10-5), MGC57346 (PSMR = 1.19 × 10-5), and RNF167 (PSMR = 1.53 × 10-5) were the top three genes using the CAGE eQTL data. Most of the identified genes were found in or near the 17q21.31 genomic region. Additionally, our TWAS analysis identified 18 significant genes whose expression was associated with IOP. Of these, 12 and 4 were also identified by the SMR analysis using the GTEx and CAGE eQTL data, respectively. CONCLUSIONS: Our findings suggest that the 17q21.31 genomic region may play a critical role in the regulation of IOP.

Double Optic Disc Pit With Retinal Pigmentation in a Woman With High Myopia.

This case report discusses a diagnosis of 2 optic disc pits in an otherwise asymptomatic woman with high myopia.

Discovery of 2,5-disubstituted furan derivatives featuring a benzamide motif for overcoming P-glycoprotein mediated multidrug resistance in MCF-7/ADR cell.

P-glycoprotein (P-gp) is one of the drug efflux transporters that triggers multidrug resistance (MDR) in cells. Herein, by utilizing the strategies of active skeleton splicing and structural optimization on the lead compound 5 m, a total of 50 novel 2,5-disubstituted furan derivatives were designed, synthesized, and screened for P-gp inhibitory activity. The structure-activity relationship analysis enabled the identification of an important pharmacophore N-phenylbenzamide, which resulted in the discovery of a promising drug lead compound Ⅲ-8. Ⅲ-8 possesses broad-spectrum reversal activity and low toxicity in MCF-7/ADR cells. Western blot and Rh123 accumulation assay demonstrated that Ⅲ-8 displayed the reversal activity by inhibiting P-gp efflux. Molecular docking analysis indicated a potent affinity of Ⅲ-8 to P-gp by forming H-bond interactions with residues Asn 721 and Met 986. Ⅲ-8 was determined to be a highly effective and safe P-gp inhibitor in an MCF-7/ADR xenograft mouse model.

Novel Benzo Five-Membered Heterocycle Derivatives as P-Glycoprotein Inhibitors: Design, Synthesis, Molecular Docking, and Anti-Multidrug Resistance Activity.

A proposed strategy to overcome multidrug resistance (MDR) of anticancer drugs in chemotherapy is to disable the efflux function of P-glycoprotein (P-gp). In this study, based on ring-merging and fragment-growing strategies, 105 novel benzo five-membered heterocycle derivatives were designed, synthesized, and screened. Exploration of the structure-activity relationship (SAR) led to the identification of d7 with low cytotoxicity and promising reversal activity to doxorubicin in MCF-7/ADR cells. Furthermore, the mechanism studies revealed that the reversal activity of d7 stemmed from the inhibition of P-gp efflux. Molecular docking further clarified the observed trends in SAR with d7 displaying potent affinity to P-gp. Additionally, coadministration of d7 with doxorubicin achieved stronger antitumor activity in a xenograft model than doxorubicin alone. These results suggest that d7 is a potential MDR reveal agent acting as a P-gp inhibitor and provides guidelines for the future development of new P-gp inhibitors.

Novel gellan gum-based probiotic film with enhanced biological activity and probiotic viability: Application for fresh-cut apples and potatoes.

A novel probiotic film based on gellan gum (GN), cranberry extract (CE), and Lactococcus lactis (LA) was developed in the present study. The fluorescence and SEM image results showed that GN/CE film containing LA was successfully fabricated. The incorporation of LA significantly enhanced the antibacterial activity of the film. The presence of CE strengthened the antioxidant activity and LA survivability in the film. The combination of LA (0-1.0 %) and CE (0.5-1.0 %) improved the mechanical property of the film through the formation of density structure. The best comprehensive properties were obtained with the film containing 2.0 %LA and 0.5 %CE. The GN/2.0 %LA/0.5 %CE film also showed the optimal preservation effect on fresh-cut potatoes and apples. Hence, GN/2.0 %LA/0.5 %CE probiotic film has proved to be suitable for fruit and vegetable preservation.

Design, synthesis, and biological evaluation of benzoheterocyclic sulfoxide derivatives as quorum sensing inhibitors in Pseudomonas aeruginosa.

Six series of benzoheterocyclic sulfoxide derivatives were designed and synthesised as Pseudomonas aeruginosa (P. aeruginosa) quorum sensing inhibitors in this paper. We experimentally demonstrated that 6b significantly inhibited the formation of P. aeruginosa PAO1 biofilm without affecting the growth. Further mechanistic studies showed that 6b affected the luminescence of quorum sensing reported strain PAO1-lasB-gfp and the production of P. aeruginosa PAO1 elastase virulence factor which was regulated by las system. These experimental results indicate that 6b acts as a quorum sensing inhibitor mainly through the las system. Furthermore, silico molecular docking studies demonstrated that 6b and the P. aeruginosa quorum sensing receptor LasR were molecularly bound via hydrogen bonding interactions. Preliminary structure-activity relationship and docking studies illustrated that 6b shows great promise as anti-biofilm compounds for further studies in order to solve the problem of microbial resistance in future.

Effects of Pulsed Pressure Curing on Beef Quality.

The study was proposed to investigate the effects of pulsed pressure curing on the beef absorption of the curing solution, cooking loss, moisture content, centrifugal loss, salt content, sensory attributes, texture, microstructures and volatile compounds. Curing methods include the following four treatments: (1) control group 1-static curing (SC); (2) control group 2-vacuum curing (VC); (3) control group 3-pressurized curing (PC); and (4) treatment group-pulsed pressure curing (PPC). The acquired results revealed that pulsed pressure curing significantly boosts the curing efficiency and moisture content, decreases cooking loss in beef, brightens meat color, and enhances texture compared to static curing, vacuum curing, and pressurized curing. Additionally, centrifugal losses were not impaired, and sensory findings revealed that PPC significantly improved the saltiness of beef. TPA results showed that the springiness and cohesiveness of PPC were greatly increased, and hardness and chewiness were significantly reduced. Moreover, PPC significantly reduced the content of 1-octen-3-ol and 1-hexanol. Scanning electron microscopy (SEM) images documented that pulsed pressure curing can effectively increase the tenderness of beef. This study demonstrates that processed meat product efficiency and sensory attributes should be taken into account when selecting a curing technique, and the PPC technique has an advantage in both areas.

Design, synthesis and biological evaluation of novel phenylfuran-bisamide derivatives as P-glycoprotein inhibitors against multidrug resistance in MCF-7/ADR cell.

The co-administration of anticancer drugs and P-glycoprotein (P-gp) inhibitors was a treatment strategy to surmount multidrug resistance (MDR) in anticancer chemotherapy. In this study, novel phenylfuran-bisamide derivatives were designed as P-gp inhibitors based on target-based drug design, and 31 novel compounds were synthesized and screened on MCF-7/ADR cells. The result of bioassay revealed that compound y12d exhibited low cytotoxicity and promising MDR reversal activity (IC50 = 0.0320 µM, reversal fold = 1163.0), 3.64-fold better than third-generation P-gp inhibitor tariquidar (IC50 = 0.1165 µM, reversal fold = 319.3). The results of Western blot and rhodamine 123 accumulation verified that compound y12d exhibited excellent MDR reversal activity by inhibiting the efflux function of P-gp but not expression. Furthermore, molecular docking showed that compound y12d bound to target P-gp by forming the double H-bond interactions with residue Gln 725. These results suggest that compound y12d might be a potential MDR reveal agent acting as a P-gp inhibitor in clinical therapeutics, and provide insight into design strategy and skeleton optimization for the development of P-gp inhibitors.

Early onset drusen and RPE dysfunction in a patient with NLRP3-AID.

Retinal pigment epithelium (RPE) dysfunction, manifested as drusen formation and RPE mottling, is a characteristic lesion of aging. The mechanism of RPE dysfunction remains unknown. Previous animal studies have proven that the activation of NLRP3 inflammasome in RPE leads to apoptosis and pyroptosis, which may play a very important role in the development of age-related macular degeneration (AMD). However, there is a lack of clinical evidence to support the above hypothesis. Herein, we report a 38-year-old Chinese Han woman who had NLRP3-associated autoinflammatory disease (NLRP3-AID) with widely scattered drusen at the posterior pole in both eyes. NLRP3-AID is a rare disease caused by mutations of the NLRP3 gene, leading to NLRP3 inflammasome activation. This report of early-onset drusen provides clinical evidence that the NLRP3 inflammasome might contribute to the occurrence of RPE dysfunction and is a potential cause of age-related macular degeneration (AMD).