Growth differentiation factor 15: Emerging role in liver diseases.

Growth differentiation factor 15 (GDF15) is a cell stress-response cytokine within the transforming growth factor-ß (TGFß) superfamily. It is known to exert diverse effects on many metabolic pathways through its receptor GFRAL, which is expressed in the hindbrain, and transduces signals through the downstream receptor tyrosine kinase Ret. Since the liver is the core organ of metabolism, summarizing the functions of GDF15 is highly important. In this review, we assessed the relevant literature regarding the main metabolic, inflammatory, fibrogenic, tumorigenic and other effects of GDF15 on different liver diseases, including Metabolic dysfunction-associated steatotic liver disease(MASLD), alcohol and drug-induced liver injury, as well as autoimmune and viral hepatitis, with a particular focus on the pathogenesis of MASLD progression from hepatic steatosis to MASH, liver fibrosis and even hepatocellular carcinoma (HCC). Finally, we discuss the prospects of the clinical application potential of GDF15 along with its research and development progress. With better knowledge of GDF15, increasing in-depth research will lead to a new era in the field of liver diseases.

A novel endoscopic artificial intelligence system to assist in the diagnosis of autoimmune gastritis: a multicenter study.

BACKGROUND & AIMS: Autoimmune gastritis (AIG), distinct from Helicobacter pylori-associated atrophic gastritis (HpAG), is underdiagnosed due to limited awareness. This multicenter study aims to develop a novel endoscopic artificial intelligence (AI) system assisting in AIG diagnosis. METHODS: Patients diagnosed with AIG, as well as HpAG and non-atrophic gastritis (NAG), were retrospectively enrolled from six centers. Endoscopic images with relevant demographic and medical data, were collected for the development of AI-assisted system, SEER-SCOPE AI, based on multi-site feature fusion model. The diagnostic performance of SEER-SCOPE AI was evaluated in the internal and external datasets. Endoscopists' performance with and without AI support was tested and compared using Mann-Whitney U test. Heatmap analysis was performed to interpret SEER-SCOPE AI. RESULTS: 1 070 patients (294 AIG, 386 HpAG, 390 NAG) with 18 828 endoscopy images were collected. SEER-SCOPE AI achieved strong performance for identifying AIG, with 96.9% sensitivity, 92.2% specificity and an AUROC of 0.990 internally, and 90.3% sensitivity, 93.1% specificity and an AUROC of 0.973 externally. The performance of SEER-SCOPE AI (sensitivity 91.3%) was comparable to experts (87.3%) and significantly outperformed non-experts (70.0%). With AI support, the overall performance of endoscopists was improved (sensitivity: 90.3% [95% CI 86.0%-93.2%] vs. 78.7% [95% CI 73.6%-83.2%], p=0.008). Heatmap analysis revealed consistent focus of SEER-SCOPE AI on regions corresponding to atrophic areas. CONCLUSIONS: SEER-SCOPE AI demonstrated expert-level performance in identifying AIG, and enhanced the diagnostic ability of endoscopists. Its application holds promise as a potent endoscopy-assisted tool for guiding biopsy sampling and early detection of AIG.

Idiopathic mesenteric phlebosclerotic colitis associated with Chinese herbal medicine.

Idiopathic mesenteric phlebosclerotic colitis(IMP) is a rare disease. At present, the etiology and pathogenesis are not clear, but the main patients are Asian people, and most of them have a history of taking Chinese herbal medicines. The disease has characteristic endoscopic and imaging manifestations. This paper shares a case of IMP, The patient came to our hospital for one year because of intermittent abdominal pain and diarrhea. It conforms to the typical manifestations of IMP. For patients who take Chinese herbal medicine for a long time, if they have clinical manifestations of gastrointestinal tract, it is necessary to consider the possibility of the disease to avoid serious consequences due to missed diagnosis.

Alkaloids and Polyacetylenes from Hippobroma longiflora with Antiangiogenesis Properties.

Four new alkaloids, hippobrines A-D (1-4), along with three new polyacetylenes, hippobrenes A-C (5-7), were isolated from Hippobroma longiflora. Compounds 1-3 possess an unprecedented carbon skeleton. All of the new structures were determined by analyzing their mass and NMR spectroscopic data. The absolute configurations of 1 and 2 were confirmed by single-crystal X-ray analyses, and the absolute configurations of 3 and 7 were deduced using their ECD spectra. Plausible biogenetic pathways of 1 and 4 were proposed. In regard to bioactivities, all compounds (1-7) exhibited weak antiangiogenic activity against human endothelial progenitor cells, with IC50 values ranging from 21.1 ± 1.1 to 44.0 ± 2.3 µg/mL.

2,6-Disubstituted Piperidine Alkaloids with Neuroprotective Activity from Hippobroma longiflora.

Three new alkaloids, hipporidine A (1: ), hipporidine B (2: ), and (-)-lobeline N-oxide (3: ), were discovered from the whole plant of Hippobroma longiflora together with five known compounds (4: -8: ). Their 2,6-disubstituted piperidine structures were established based on the HRESIMS, NMR (COSY, HMBC, HSQC, NOESY), and UV spectroscopic data. Hipporidines A (1: ) and B (2: ) possess a rare 1,3-oxazinane moiety. Compound 3: is the N-oxide derivative of (-)-lobeline (6: ). Moreover, the absolute configuration of norlobeline (5: ) was established by single-crystal X-ray diffraction analysis. Three major secondary metabolites (6: -8: ) were evaluated for their neuroprotective effect against paclitaxel-induced neurotoxicity. Consequently, pretreatment with compound 8: at a concentration of 1.0 µM displayed significant attenuation on paclitaxel-damaged neurite outgrowth of dorsal root ganglion neurons without interfering with the cytotoxicity of paclitaxel on cervical cancer SiHa cells.

Recombinant expression and surface display of a zearalenone lactonohydrolase from Trichoderma aggressivum in Escherichia coli.

Zearalenone (ZEN), one of the most dangerous mycotoxins, causes enormous economic losses in the food and feed industries. To solve the problem of ZEN pollution, ZEN detoxifying enzymes are in emergent need. In this study, a zearalenone lactonohydrolase from Trichoderma aggressivum, denoted as ZHD-P, was heterologously expressed and characterized. The intracellular ZHD-P from E. coli BL21(DE3) exhibited high activity for ZEN degradation (191.94 U/mg), with the optimal temperature and pH of 45 °C and 7.5-9.0, respectively. With excellent temperature stability, the intracellular ZHD-P retained 100% activity when it was incubated at 25-40 °C for 1 h. Furthermore, we firstly constructed an E. coli cell surface display system for ZHD-P. The surface-displayed ZHD-P exhibited high activity against ZEN and showed optimal activity at 40 °C and pH 9.0. With superior pH stability, the surface-displayed ZHD-P retained 80% activity when it was incubated at pH 5.0-11.0 for 12 h. Interestingly, the metal ions tolerance of the surface-displayed ZHD-P was better than the intracellular form. Additionally, the surface-displayed ZHD-P could be reused four times with the residual enzyme activity of more than 50%. The biotoxicity assessment using P. phosphoreum T3 indicated that ZEN could be degraded into hypotoxic products by the intracellular or surface-displayed ZHD-P. ZHD-P could be feasible for ZEN detoxification.

Additional alkaloids from Zoanthus vietnamensis with neuroprotective and anti-angiogenic effects.

A chemical investigation of the zoantharian Zoanthus vietnamensis, collected off Taiwan, yielded eleven new alkaloids, 7α-hydroxykuroshine J (1), 18ß-hydroxykuroshine J (2), 5α-hydroxyzoanthenamine (3), 5ß-hydroxyzoanthenamine (4), 14α-hydroxyzoanthenamine (5), 30-hydroxyzoanthenamine (6), 11-dehydroxy-18-epi-kuroshine A (7), 5α-hydroxykuroshine A (8), 7ß-hydroxykuroshine A (9), 11-keto-oxyzoanthamine (10), and 30-hydroxyzoanthamine (11), along with eight known compounds (12-19). The structures of these compounds were identified by detailed spectroscopic data, including HRESIMS, IR, NMR, and UV spectra. All secondary metabolites isolated from Z. vietnamensis were investigated for the anti-angiogenic effect in human endothelial progenitor cells (EPCs). Compounds 6, 7, 11, and 13 exhibited mild anti-angiogenic effect by blocking cell growth and tube formation of EPCs. The neuroprotective potential of four major compounds 12, 14, 15, and 19 against paclitaxel-induced neurotoxicity was evaluated. Pretreatment of 14 and 15 protected paclitaxel-damaged neurite outgrowth of dorsal root ganglion (DRG) neurons, without interfering the cytotoxic activity of paclitaxel on cervical cancer SiHa cells.

Targeted Isolation of Xenicane Diterpenoids from Taiwanese Soft Coral Asterospicularia laurae.

Application of LC-MS/MS-based molecular networking indicated the ethanol extract of octocoral Asterospicularia laurae is a potential source for the discovery of new xenicane derivatives. A natural product investigation of this soft coral resulted in the isolation of four new xenicane diterpenoids, asterolaurins O‒R (1‒4), together with six known compounds, xeniolide-A (5), isoxeniolide-A (6), xeniolide-B (7), 7,8-epoxyxeniolide-B (8), 7,8-oxido-isoxeniolide-A (9), and 9-hydroxyxeniolide-F (10). The structures of isolated compounds were characterized by employing spectroscopic analyses, including 2D-NMR (COSY, HMQC, HMBC, and NOESY) and high-resolution electrospray ionization mass spectrometry (HRESIMS). Asterolaurin O is the first case of brominated tricarbocyclic type floridicin in the family Xeniidae. Concerning bioactivity, the cytotoxic activity of those isolates was evaluated. As a result, compounds 1 and 2 demonstrated a selective cytotoxic effect against the MCF-7 cell line at IC50 of 14.7 and 25.1 µM, respectively.

Correction: Ou-Yang, F. et al. Antiproliferation for Breast Cancer Cells by Ethyl Acetate Extract of Nepenthes thorellii x (ventricosa x maxima). Int. J. Mol. Sci. 2019, 20, 3238.

The authors would like to make corrections to their published paper [...].

Zoanthamine Alkaloid Derivatives from the Zoantharian Zoanthus vietnamensis with Antimetastatic Activity.

A novel compound zoanone A (1), together with eight new alkaloids, 3ß,14α-dihydroxy-28-deoxyzoanthenamine (2), 7α-hydroxy-28-deoxyzoanthenamine (3), 3α-hydroxyzoanthenamine (4), 7ß-hydroxyzoanthenamine (5), 28α-methoxyzoanthenamine (6), 28α-methoxykuroshine A (7), 30-hydroxykuroshine A (8), and 3ß-hydroxy-11-deketo-kuroshine B (9), was isolated from the zoantharian Zoanthus vietnamensis. Their structures were elucidated by the comprehensive analyses of IR, mass spectrometry, NMR, and UV spectroscopic data. The absolute configuration of 1 was established by single-crystal X-ray crystallographic analysis using Cu Kα radiation. A plausible biosynthetic pathway of 1 was proposed. Antiangiogenic and antilymphangiogenic activities of the isolated metabolites were tested and evaluated. The results showed that all isolated compounds had weak antimetastatic activity.

Cytotoxic and anti-inflammatory effects of lignans and diterpenes from Cupressus macrocarpa.

Cupressus macrocarpa is a windbreak tree and is reported to have various cytotoxic effects. A natural product study on the leaves of C. macrocarpa has yielded ten secondary metabolites, including three new diterpenoids (1-3), four known diterpenoids (4-7), and three known lignans (8-10). The structures of all isolated compounds were elucidated via the interpretation of spectroscopic methods, especially 2D NMR and mass analyses. In the cytotoxic assays, compounds 1-3 and 7-10 showed inhibition effect against HepG2, MDA-MB-231, and A549 cells with IC50 values ranging from 0.004 to 19.9 µg/mL. Moreover, the anti-inflammatory assays revealed that (-)-matairesinol (8) had significant inhibitory activities on superoxide anion generation (IC50 = 2.7 ± 0.3 µM) and elastase release (IC50 = 6.6 ± 0.7 µM).

Aleuritin, a novel dinor-diterpenoid from the twigs of Aleurites moluccanus with an anti-lymphangiogenic effect.

A phytochemical investigation of Aleurites moluccanus yielded one novel dinor-diterpenoid, aleuritin (1), along with a rare diterpenoid, aleuritone (2). Compound 1 has an unprecedented skeleton with a 6/6/5-fused tricyclic ring system. Compound 2 possesses a rare 6/6/5/3-fused tetracyclic skeleton, which is probably an artifact formed photochemically by the Norrish reaction. The structures of 1 and 2 were determined by spectroscopic methods (ECD, IR, mass, and NMR) and confirmed by single-crystal X-ray diffraction analyses. A plausible biogenetic pathway of 1 is proposed. Pharmacological study showed that these two compounds possessed mild in vitro anti-lymphangiogenic activity, which suppressed tube formation with IC50 values of 48.1 ± 1.8 and 34.2 ± 0.8 µg mL-1, respectively.

New Hydroquinone Monoterpenoid and Cembranoid-Related Metabolites from the Soft Coral Sarcophyton tenuispiculatum.

Chemical investigation of the marine soft coral Sarcophyton tenuispiculatum resulted in the isolation of a 1,4-dihydrobenzoquinone, sarcotenuhydroquinone (1), three new cembranoids, sarcotenusenes A‒C (2‒4), and ten previously reported metabolites 5-14. The chemical structures of all isolated metabolites were determined by detailed spectroscopic analyses. In biological assays, anti-inflammatory, cytotoxic, and peroxisome proliferator-activated receptor γ (PPAR-γ) transcription factor assays of all compounds were performed. None of the isolated compounds were found to exhibit activity in the PPAR-γ transcription factor assay. The anti-inflammatory assays showed that (+)-7α,8ß-dihydroxydeepoxysarcophine (13) inhibited the production of IL-1ß to 56 ± 1% at a concentration of 30 µM in lipopolysaccharide (LPS)-stimulated J774A.1 macrophage cells. In addition, 1 and 2 were found to exhibit cytotoxicity towards a panel of cancer cell lines.

Clerodane Diterpenoids from Callicarpa hypoleucophylla and Their Anti-Inflammatory Activity.

Plants of the genus Callicarpa are known to possess several medicinal effects. The constituents of the Taiwan endemic plant Callicarpa hypoleucophylla have never been studied. Therefore, C. hypoleucophylla was selected for our phytochemical investigation. Two new clerodane-type diterpenoids, named callihypolins A (1) and B (2), along with seven known compounds were isolated from the leaves and twigs of the Lamiaceae plant C. hypoleucophylla and then characterized. The structures of compounds 1 and 2 were elucidated by spectroscopic data analysis, specifically, two-dimension nuclear magnetic resonance (NMR). The anti-inflammatory activity of compounds 1-9 based on the suppression of superoxide anion generation and elastase release was evaluated. Among the isolates, compounds 2-4 showed anti-inflammatory activity (9.52-32.48% inhibition at the concentration 10 µm) by suppressing superoxide anion generation and elastase release. Our findings not only expand the description of the structural diversity of the compounds present in plants of the genus Callicarpa but also highlight the possibility of developing anti-inflammatory agents from Callicarpa endemic species.

Anti-Lymphangiogenic Alkaloids from the Zoanthid Zoanthus vietnamensis Collected in Taiwan.

Eleven new secondary metabolites [kuroshines H-J (1-3), 27-methyl glycinate zoanthenamine (4), 27-hydroxyzoanthenamine (5), 27-methyl glycinate kuroshine A (6), 27-hydroxykuroshine A (7), 3ß-hydroxy-28-deoxyzoanthenamine (8), 14α-hydroxy-28-deoxyzoanthenamine (9), 27-hydroxy-28-deoxyzoanthenamine (10), and kuroshine K (11)], along with seven known compounds (12-18), were isolated from the zoantharian Zoanthus vietnamensis. The structures of all isolated components were elucidated by spectroscopic data (IR, MS, NMR, and UV), especially 2D NMR analyses. The relative configurations of 1 and 2 were confirmed by using single-crystal X-ray crystallography. Compounds 1-3 were found to have an unprecedented ether linkage between C-15 and C-28, while the unusual substituent methyl glycinate, attached at C-27 in compounds 4 and 6, was found for the first time in zoanthamine-type alkaloids. The anti-lymphangiogenic activities of 17 isolated compounds were evaluated. Compounds 4, 5, and 10 exerted promising anti-lymphangiogenic functions by reducing cell growth and tube formation of human lymphatic endothelial cells (LECs). In addition, the structure-activity relationships of the isolated alkaloids against lymphangiogenesis of LECs are discussed.

Antiproliferation for Breast Cancer Cells by Ethyl Acetate Extract of Nepenthes thorellii x (ventricosa x maxima).

Extracts from the Nepenthes plant have anti-microorganism and anti-inflammation effects. However, the anticancer effect of the Nepenthes plant is rarely reported, especially for breast cancer cells. Here, we evaluate the antitumor effects of the ethyl acetate extract of Nepenthes thorellii x (ventricosa x maxima) (EANT) against breast cancer cells. Cell viability and flow cytometric analyses were used to analyze apoptosis, oxidative stress, and DNA damage. EANT exhibits a higher antiproliferation ability to two breast cancer cell lines (MCF7 and SKBR3) as compared to normal breast cells (M10). A mechanistic study demonstrates that EANT induces apoptosis in breast cancer cells with evidence of subG1 accumulation and annexin V increment. EANT also induces glutathione (GSH) depletion, resulting in dramatic accumulations of reactive oxygen species (ROS) and mitochondrial superoxide (MitoSOX), as well as the depletion of mitochondrial membrane potential (MMP). These oxidative stresses attack DNA, respectively leading to DNA double strand breaks and oxidative DNA damage in γH2AX and 8-oxo-2'deoxyguanosine (8-oxodG) assays. Overall these findings clearly revealed that EANT induced changes were suppressed by the ROS inhibitor. In conclusion, our results have shown that the ROS-modulating natural product (EANT) has antiproliferation activity against breast cancer cells through apoptosis, oxidative stress, and DNA damage.

Anti-Lymphangiogenesis Components from Zoanthid Palythoa tuberculosa.

Three new compounds, tuberazines A-C (1-3), and eleven known compounds (4-14) were obtained from the ethanolic extract of Taiwanese zoanthid Palythoa tuberculosa. Compounds 1-4 are rare marine natural products with a pyrazine moiety, and compound 5 is a tricyclic tryptamine derivative isolated from nature for the first time. The structures of all isolated metabolites were determined by analyzing their IR, Mass, NMR, and UV spectrometric data. The absolute configuration of 1 was confirmed by comparing the trend of experimental electronic circular dichroism (ECD) with calculated ECD spectra. The anti-lymphangiogenic activities of new compounds were evaluated in human lymphatic endothelial cells (LECs). Of these, new compound 3 displayed the most potent anti-lymphangiogenesis property by suppressing cell growth and tube formation of LECs.

Novel 11-norbetaenone isolated from an entomopathogenic fungus Lecanicillium antillanum.

A novel nor-betaenone compound, 11-norbetaenone (1), was isolated from the culture broth of an entomopathogenic fungus Lecanicillium antillanum. The structure was determined on the basis of 1D and 2D NMR spectroscopic data. The absolute stereochemistry of 1 was further confirmed by X-ray single crystallography analysis. It is the first secondary metabolite reported from the species Lecanicillium antillanum. And it is also the first time that a betaenone-type compound was isolated from the genus Lecanicillium. Furthermore, 11-norbetaenone (1) displayed significant anti-angiogenic effect by suppressing tube formation.

Ecdysones from Zoanthus spp. with inhibitory activity against dengue virus 2.

Bioassay-guided fractionation of an ethanolic extract of Zoanthus spp. collected in Taiwan has resulted in the isolation of one new ecdysone, zoanthone A (1), along with thirteen known compounds (2-14). The structures of these compounds were determined by spectroscopic methods, especially 2D NMR analyses. The in vitro antiviral activities of all isolated ecdysones (1-14) against dengue virus type 2 (DENV-2) were evaluated using DENV infectious system. New compound (1) exhibited potent antiviral activity (EC50=19.61 ± 2.46 µM) with a selectivity index (CC50/EC50) value of 36.7. The structure-activity relationships of isolated ecdysones against DENV-2 were concluded. Molecular docking information of 3 and NS5 polymerase was performed either.

Anti-Dengue Virus Constituents from Formosan Zoanthid Palythoa mutuki.

A new marine ecdysteroid with an α-hydroxy group attaching at C-4 instead of attaching at C-2 and C-3, named palythone A (1), together with eight known compounds (2-9) were obtained from the ethanolic extract of the Formosan zoanthid Palythoa mutuki. The structures of those compounds were mainly determined by NMR spectroscopic data analyses. The absolute configuration of 1 was further confirmed by comparing experimental and calculated circular dichroism (CD) spectra. Anti-dengue virus 2 activity and cytotoxicity of five isolated compounds were evaluated using virus infectious system and [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assays, respectively. As a result, peridinin (9) exhibited strong antiviral activity (IC50 = 4.50 ± 0.46 µg/mL), which is better than that of the positive control, 2'CMC. It is the first carotene-like substance possessing anti-dengue virus activity. In addition, the structural diversity and bioactivity of the isolates were compared by using a ChemGPS-NP computational analysis. The ChemGPS-NP data suggested natural products with anti-dengue virus activity locate closely in the chemical space.