Cryptochinones from Cryptocarya chinensis act as farnesoid X receptor agonists.

Cryptochinones A-D are tetrahydroflavanones isolated from the leaves of Cryptocarya chinensis, an evergreen tree whose extracts are believed to have a variety of health benefits. The origin of their possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and for hyperglycemia. We studied whether cryptochinones A-D, which are structurally similar to known FXR ligands, may act at this target. Indeed, in mammalian one-hybrid and transient transfection reporter assays, cryptochinones A-D transactivated FXR to modulate promoter action including GAL4, SHP, CYP7A1, and PLTP promoters in dose-dependent manner, while they exhibited similar agonistic activity as chenodeoxycholic acid (CDCA), an endogenous FXR agonist. Through molecular modeling docking studies we evaluated their ability to bind to the FXR ligand binding pocket. Our results indicate that cryptochinones A-D can behave as FXR agonists.

Cryptocaryone induces apoptosis in human hepatocellular carcinoma cells by inhibiting aerobic glycolysis through Akt and c-Src signaling pathways.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, with the second highest mortality rate in all cancer. Energy reprogramming is one of the hallmarks of cancer, and emerging evidence showed that targeting glycolysis is a promising strategy for HCC treatment. Cryptocaryone has been shown to display promising anti-cancer activity against numerous types of cancer. Previous study also indicated that cryptocaryone induces cytotoxicity by inhibiting glucose transport in cancer cells, but the detailed mechanism still needs to be elucidated. Therefore, this study aimed to investigate the relationship between the anti-cancer effect and glycolytic metabolism of cryptocaryone in human HCC cells. In this study, we found that cryptocaryone potently induced growth inhibition by apoptotic cell death in HCC cells. Cryptocaryone also suppressed the ATP synthesis, lactate production and glycolytic capacity of HCC cells. Mechanistic investigations showed that phosphorylation of Akt and c-Src, as well as the expression of HK1 were impeded by cryptocaryone. Moreover, cryptocaryone markedly increased the expression level of transcription factor FoxO1. Importantly, clinical database analysis confirmed the negative correlation between HK1 and FoxO1. High expression levels of HK-1 were positively correlated with poorer survival in patients with HCCs. These results suggest that cryptocaryone may promote cell apoptosis by inhibiting FoxO1-mediated aerobic glycolysis through Akt and c-Src signaling cascades in human HCC cells. This is the first study to indicate that cryptocaryone exerts anti-cancer property against human HCC cells. Cryptocaryone is a potential natural product worthy of further development into a promising candidate for HCC treatment.

Orthoquinone and naphthalenone derivatives from Berrya ammonilla and their anti-inflammatory activity.

A new orthoquinone, berryammone A (1), and four new naphthalenone derivatives, berryammone B (2), berryammone C (3), 6-O-methylberryammone C (4), and 4-O-methylberryammone C (5), have been isolated from the stem of Berrya ammonilla, together with eleven known compounds (6-16). The structures of these new compounds were determined through spectroscopic and MS analyses. Among the isolates, compounds 1-3, 5, (+)-pinoresinol (6), and betulinic acid (12) exhibited inhibition (IC50 ≤ 4.41 µM) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds 1, 2, and 5 also inhibited fMLP/CB-induced elastase release with IC50 values ≤ 3.95 µM.

New flavanones from the leaves of Cryptocarya chinensis and their antituberculosis activity.

Four new flavanones, cryptoflavanones A-D (1-4, resp.), together with eight known compounds, were isolated from the leaves of Cryptocarya chinensis. The structures of these new compounds were determined by spectral analyses. Among the isolated compounds, pinocembrin (5) and cryptocaryone (6) exhibited antituberculosis activity against Mycobacterium tuberculosis H(37) Rv strain in vitro with MIC values of 3.5 and 25.0 µg/ml, respectively.

A new ferulic acid ester, a new ellagic acid derivative, and other constituents from pachycentria formosana: effects on neutrophil pro-inflammatory responses.

A new ferulic acid ester derivative, tetracosane-1,24-diyl di[(Z)-ferulate] (1), and a new ellagic acid derivative, 3,4 : 3',4'-bis(O,O-methylene)ellagic acid (2), have been isolated from leaves and twigs of Pachycentria formosana, together with eight known compounds. Their structures were determined by in-depth spectroscopic and mass-spectrometric analyses. Among the isolated compounds, oleanolic acid (6), ursolic acid acetate (7), and 3-epibetulinic acid (9) exhibited potent inhibition (IC(50) values ≤ 21.8 µM) of O2(-) generation by human neutrophils in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). In addition, oleanolic acid (6), 3-O-[(E)-feruloyl]ursolic acid (8), 3-epibetulinic acid (9), and lawsonic acid (10) also inhibited fMLP/CB-induced elastase release with IC(50) values ≤ 18.6 µM.

Deep learning for abdominal ultrasound: A computer-aided diagnostic system for the severity of fatty liver.

BACKGROUND: The prevalence of nonalcoholic fatty liver disease is increasing over time worldwide, with similar trends to those of diabetes and obesity. A liver biopsy, the gold standard of diagnosis, is not favored due to its invasiveness. Meanwhile, noninvasive evaluation methods of fatty liver are still either very expensive or demonstrate poor diagnostic performances, thus, limiting their applications. We developed neural network-based models to assess fatty liver and classify the severity using B-mode ultrasound (US) images. METHODS: We followed standards for reporting of diagnostic accuracy guidelines to report this study. In this retrospective study, we utilized B-mode US images from a consecutive series of patients to develop four-class, two-class, and three-class diagnostic prediction models. The images were eligible if confirmed by at least two gastroenterologists. We compared pretrained convolutional neural network models, consisting of visual geometry group (VGG)19, ResNet-50 v2, MobileNet v2, Xception, and Inception v2. For validation, we utilized 20% of the dataset resulting in >100 images for each severity category. RESULTS: There were 21,855 images from 2,070 patients classified as normal (N = 11,307), mild (N = 4,467), moderate (N = 3,155), or severe steatosis (N = 2,926). We used ResNet-50 v2 for the final model as the best ones. The areas under the receiver operating characteristic curves were 0.974 (mild steatosis vs others), 0.971 (moderate steatosis vs others), 0.981 (severe steatosis vs others), 0.985 (any severity vs normal), and 0.996 (moderate-to-severe steatosis/clinically abnormal vs normal-to-mild steatosis/clinically normal). CONCLUSION: Our deep learning models achieved comparable predictive performances to the most accurate, yet expensive, noninvasive diagnostic methods for fatty liver. Because of the discriminative ability, including for mild steatosis, significant impacts on clinical applications for fatty liver are expected. However, we need to overcome machine-dependent variation, motion artifacts, lacking of second confirmation from any other tools, and hospital-dependent regional bias.

Cryptocaryone, a natural dihydrochalcone, induces apoptosis in human androgen independent prostate cancer cells by death receptor clustering in lipid raft and nonraft compartments.

PURPOSE: Androgen refractory prostate cancer is a major clinical challenge. Treatment approaches to prostate cancer are based on various mechanisms that cause malignant cell apoptosis. Of these strategies the anticancer effect of triggering death receptors is well substantiated. MATERIALS AND METHODS: Several pharmacological and biochemical assays were used to characterize the apoptotic signaling pathways of the natural dihydrochalcone cryptocaryone in prostate cancer cells. RESULTS: Cryptocaryone induced antiproliferative and apoptotic effects in human androgen independent prostate cancer cells. It induced caspase-8 and 3 activation but did not change total protein levels of death receptors and their ligands. DR5 surface expression was moderately increased by cryptocaryone. Confocal immunofluorescence examination showed that cryptocaryone induced Fas clustering and the association of downstream signaling molecules, including FADD and procaspase-8. DR4 and DR5 aggregation was also induced by cryptocaryone. Data were confirmed by protein profile analysis of detergent resistant membranes showing that Fas, DR4, DR5, FADD and procaspase-8 levels were increased 1.3, 3.5, 4.1, 13.1 and 4.1-fold, respectively, in the lipid raft compartment. Cryptocaryone mediated clustering of death receptors and associated molecules was also detected in nonraft compartments. The distribution between lipid raft and nonraft compartments was validated by the cholesterol depleting agent methyl-beta-cyclodextrin. Cryptocaryone significantly potentiated FasL induced apoptosis in PC-3 cells. CONCLUSIONS: We suggest that cryptocaryone has anticancer activity via the stimulation of death receptor and associated molecule clustering, leading to caspase-8 and 3 activation, and apoptosis in prostate cancer cells.

Cytotoxic flavonoids from the leaves of Cryptocarya chinensis.

Bioassay-guided fractionation led to the isolation of six new tetrahydroflavanones, cryptochinones A-F (1-6), from the neutral CHCl(3) fraction of Cryptocarya chinensis leaves, together with 14 known compounds (7-20). The structures of these new compounds were determined through spectroscopic analyses, including 2D-NMR, MS, CD, and X-ray crystallographic analysis. Among the isolates, infectocaryone (7) showed cytotoxic activities with IC(50) values of 11.0 and 3.7 µM against NCI-H460 and SF-268 cell lines, respectively, and cryptocaryanone A (9) showed cytotoxic activities with IC(50) values of 5.1, 4.3, and 5.0 µM against MCF-7, NCI-H460, and SF-268 cell lines, respectively.

Phthalides from Pittosporum illicioides var. illicioides with inhibitory activity on superoxide generation and elastase release by neutrophils.

Six new phthalides, (S)-3-ethyl-7-hydroxy-6-methoxyphthalide (1), (S)-3-ethyl-7-hydroxy-5,6-dimethoxyphthalide (2), (S)-3-ethyl-5,6,7-trimethoxyphthalide (3), (R)-3-ethyl-7-hydroxy-6-methoxyphthalide (4), (Z)-3-ethylidene-7-hydroxy-6-methoxyphthalide (5), and (Z)-3-ethylidene-6,7-dimethoxyphthalide (6), have been isolated from the root of Pittosporum illicioides var. illicioides, together with seven known compounds. The structures of these new compounds were determined through spectroscopic and MS analyses. Compounds 1-4 exhibited inhibition (IC50

A new dihydroagarofuranoid sesquiterpene and antituberculosis constituents from the root of Microtropis japonica.

A new dihydroagarofuran-based sesquiterpene, 15-acetoxyorbiculin A, was isolated from the root of Microtropis japonica, together with 13 known compounds. Their structures were determined through in-depth spectroscopic and mass-spectrometric analyses. Among the isolated compounds, celahin C and salasol A exhibited potent in vitro antituberculosis activity, both with an MIC value of 15.0 microg/ml against Mycobacterium tuberculosis H(37)Rv.

A new dihydroagarofuranoid sesquiterpene from Microtropis fokienensis with antituberculosis activity.

A new dihydroagarofuran-based sesquiterpene, 8-acetoxymutangin (1), was isolated from the stems of Microtropis fokienensis, together with eight known compounds, including mutangin (2). Their structures were determined through in-depth spectroscopic and mass-spectrometric analyses. Among the isolated compounds, 1 exhibited potent in vitro antituberculosis activity, with an MIC value of 10.0 microg/ml against Mycobacterium tuberculosis 90-221387, which is considerably better than that of mutangin (2). The activity of 1 lies in the same range as that of the clinic drug ethambutol (MIC 6.25 microg/ml), despite completely different chemical structures, which indicates different modes of action.

Antitubercular dihydroagarofuranoid sesquiterpenes from the roots of Microtropis fokienensis.

Four new dihydroagarofuranoid sesquiterpenes (1-4) and a new hydroxybenzylsalicylaldehyde, forkienin (5), together with nine known compounds have been isolated from the roots of Microtropis fokienensis. The structures of the new compounds were determined through analyses of physical data. Compounds 3, 4, 7, and 8 exhibited potent antitubercular activities (MICs < or = 26.0 microM) against Mycobacterium tuberculosis 90-221387 in vitro.

New dihydrochalcones and anti-platelet aggregation constituents from the leaves of Muntingia calabura.

Two new dihydrochalcones, 2,3-dihydroxy-4,3',4',5'-tetramethoxydihydrochalcone (1) and 4,2',4'-trihydroxy-3'-methoxydihydrochalcone (2), and a new flavanone, (2R,3R)-(-)-3,5-dihydroxy-6,7-dimethoxyflavanone (3), together with nineteen known compounds have been isolated from the leaves of Muntingia calabura. The structures of three new compounds were determined through spectral analyses including extensive 2D-NMR data. Among the isolates, 2,3-dihydroxy-4,3',4',5'-tetramethoxydihydrochalcone, 5,7-dihydroxy-3-methoxyflavone, 5,7-dihydroxy-6-methoxyflavone, 5,4'-dihydroxy-3,7-dimethoxyflavone, (2S)-7,8,3',4',5'-pentamethoxyflavan, (2S)-5'-hydroxy-7,8,3',4'-tetramethoxyflavan, and methyl gallate exhibited significant anti-platelet aggregation activity in vitro.

Cytotoxic dihydroagarofuranoid sesquiterpenes from the stem of Microtropis fokienensis.

Four dihydroagarofuran sesquiterpene polyesters (1-4) have been isolated from the stem of Microtropis fokienensis. The structures of these new compounds were determined through spectroscopic analyses. Compound 1, 2, 3, and 4 exhibited cytotoxicities (IC(50) values < 0.1 microg/mL) against P-388 and HT-29 cell lines in vitro.