Three-dimensional diabetic macular edema thickness maps based on fluid segmentation and fovea detection using deep learning.

AIM: To explore a more accurate quantifying diagnosis method of diabetic macular edema (DME) by displaying detailed 3D morphometry beyond the gold-standard quantification indicator-central retinal thickness (CRT) and apply it in follow-up of DME patients. METHODS: Optical coherence tomography (OCT) scans of 229 eyes from 160 patients were collected. We manually annotated cystoid macular edema (CME), subretinal fluid (SRF) and fovea as ground truths. Deep convolution neural networks (DCNNs) were constructed including U-Net, sASPP, HRNetV2-W48, and HRNetV2-W48+Object-Contextual Representation (OCR) for fluid (CME+SRF) segmentation and fovea detection respectively, based on which the thickness maps of CME, SRF and retina were generated and divided by Early Treatment Diabetic Retinopathy Study (ETDRS) grid. RESULTS: In fluid segmentation, with the best DCNN constructed and loss function, the dice similarity coefficients (DSC) of segmentation reached 0.78 (CME), 0.82 (SRF), and 0.95 (retina). In fovea detection, the average deviation between the predicted fovea and the ground truth reached 145.7±117.8 µm. The generated macular edema thickness maps are able to discover center-involved DME by intuitive morphometry and fluid volume, which is ignored by the traditional definition of CRT>250 µm. Thickness maps could also help to discover fluid above or below the fovea center ignored or underestimated by a single OCT B-scan. CONCLUSION: Compared to the traditional unidimensional indicator-CRT, 3D macular edema thickness maps are able to display more intuitive morphometry and detailed statistics of DME, supporting more accurate diagnoses and follow-up of DME patients.

Rational drug design of indazole-based diarylurea derivatives as anticancer agents.

A series of novel indazole-based diarylurea derivatives targeting c-kit were designed by structure-based drug design. The derivatives were prepared, and their antiproliferative activities were evaluated against human colon cancer HCT-116 cell line and hepatocellular carcinoma PLC/PRF/5 cell line. The antiproliferative activities demonstrated that six of nine compounds exhibited comparable activities with sorafenib against HCT-116. The structure-activity relationship (SAR) analysis indicated that the indazole ring part tolerated different kinds of substituents, and the N position of the central pyridine ring played key roles in antiproliferative activity. The SAR and interaction mechanisms were further explored using molecular docking method. Compound 1i with N-(2-(pyrrolidin-1-yl)ethyl)-carboxamide possessed improved solubility, 596.1 ng/ml and best activities, IC50 at 1.0 µm against HCT-116, and 3.48 µm against PLC/PRF/5. It is a promising anticancer agent for further development.

First total syntheses and antimicrobial evaluation of penicimonoterpene, a marine-derived monoterpenoid, and its various derivatives.

The first total synthesis of marine-derived penicimonoterpene (±)-1 has been achieved in four steps from 6-methylhept-5-en-2-one using a Reformatsky reaction as the key step to construct the basic carbon skeleton. A total of 24 new derivatives of 1 have also been designed and synthesized. Their structures were characterized by analysis of their 1H NMR, 13C NMR and HRESIMS data. Some of them showed significant antibacterial activity against Aeromonas hydrophila, Escherichia coli, Micrococcus luteus, Staphylococcus aureus, Vibrio anguillarum, V. harveyi and/or V. parahaemolyticus, and some showed activity against plant-pathogenic fungi (Alternaria brassicae, Colletotrichum gloeosporioides and/or Fusarium graminearum). Some of the derivatives exhibited antimicrobial MIC values ranging from 0.25 to 4 µg/mL, which were stronger than those of the positive control. Notably, Compounds 3b and 10 showed extremely high selectively against plant-pathogenic fungus F. graminearum (MIC 0.25 µg/mL) and pathogenic bacteria E. coli (MIC 1 µg/mL), implying their potential as antimicrobial agents. SAR analysis of 1 and its derivatives indicated that modification of the carbon-carbon double bond at C-6/7, of groups on the allylic methylene unit and of the carbonyl group at C-1, effectively enhanced the antimicrobial activity.

Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice.

AIM: Fatty acid-binding protein 4 (FABP4) plays an important role in maintaining glucose and lipid homeostasis. The aim of this study was to find new inhibitors of FABP4 for the treatment of type 2 diabetes. METHODS: Human FABP4 protein was expressed, and its inhibitors were detected in 1,8-ANS displacement assay. The effect of the inhibitor on lipolysis activity was examined in mouse 3T3-L1 preadipocytes. The db/db mice were used to evaluate the anti-diabetic activity of the inhibitor. Molecular docking and site-directed mutagenesis studies were carried out to explore the binding mode between the inhibitor and FABP4. RESULTS: From 232 compounds tested, benzbromarone (BBR), an old uricosuric drug, was discovered to be the best inhibitor of FABP4 with an IC50 value of 14.8 µmol/L. Furthermore, BBR (25 µmol/L) significantly inhibited forskolin-stimulated lipolysis in 3T3-L1 cells. Oral administration of BBR (25 or 50 mg/kg, for 4 weeks) dose-dependently reduced the blood glucose level and improved glucose tolerance and insulin resistance in db/db mice. Molecular docking revealed that the residues Ser55, Asp76, and Arg126 of FABP4 formed important interactions with BBR, which was confirmed by site-directed mutagenesis studies. CONCLUSION: BBR is an inhibitor of FABP4 and a potential drug candidate for the treatment of type 2 diabetes and atherosclerosis.