Agathis dammara Extract and its Monomer Araucarone Attenuate Abdominal Aortic Aneurysm in Mice.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a chronic vascular disease wherein the inflammation of vascular smooth muscle cells (VSMCs) plays a pivotal role in its development. Effectively mitigating AAA involves inhibiting VSMC inflammation. Agathis dammara (Lamb.) Rich, recognized for its robust anti-inflammatory and antioxidant attributes, has been employed as a traditional medicinal resource. Nonetheless, there is a dearth of information regarding the potential of Agathis dammara extract (AD) in attenuating AAA, specifically by diminishing vascular inflammation, notably VSMC inflammation. Furthermore, the active constituents of AD necessitate identification. AIM OF THE STUDY: This study sought to ascertain the efficacy of AD in reducing AAA, evaluate its impact on VSMC inflammation, and elucidate whether the monomer araucarone (AO) in AD acts as an active component against AAA. MATERIALS AND METHODS: The extraction of AD was conducted and subjected to analysis through High-Performance Liquid Chromatography (HPLC) and mass spectrometry. The isolation of the AO monomer followed, involving the determination of its content and purity. Subsequently, the effects of AD and AO on VSMC inflammation were assessed in vitro, encompassing an examination of inflammatory factors such as IL-6 and IL-18, as well as the activation of matrix metalloproteinase 9 (MMP9) in tumor necrosis factor-alpha (TNF-α)-stimulated VSMCs. To explore the inhibitory effects of AD/AO on AAA, C57BL/6J male mice were subjected to oral gavage (100 mg/kg) or intraperitoneal injection (50 mg/kg) of AD and AO in a porcine pancreatic elastase (PPE)-induced AAA model (14 days). This facilitated the observation of abdominal aorta dilatation, remodeling, elastic fiber disruption, and macrophage infiltration. Additionally, a three-day PPE mouse model was utilized to assess the effects of AD and AO (administered at 100 mg/kg via gavage) on acute inflammation and MMP9 expression in blood vessels. The mechanism by which AD/AO suppresses the inflammatory response was probed through the examination of NF-κB/NLRP3 pathway activation in VSMCs and aortas. RESULTS: Liquid Chromatography-Mass Spectrometry (LC-MS) revealed that AO constituted 15.36% of AD's content, with a purity of 96%. Subsequent pharmacological investigations of AO were conducted in parallel with AD. Both AD and AO exhibited the ability to inhibit TNF-α-induced VSMC inflammation and MMP production in vitro. Furthermore, both substances effectively prevented PPE-induced AAA in mice, whether administered through gavage or intraperitoneal injection, evidenced by decreased vascular diameter dilation, disruption of elastin fiber layers, and infiltration of inflammatory cells. In the three-day PPE mouse model, AD and AO mitigated the heightened expression of inflammatory factors and the elevated expression of MMP9 induced by PPE. The activation of the NF-κB/NLRP3 pathway in both VSMCs and aortas was significantly suppressed by treatment with AD or AO. CONCLUSIONS: Through suppressing NF-κB/NLRP3 pathway activation, AD effectively mitigates the inflammatory response in VSMCs, mitigates inflammation in aortas, prevents extracellular matrix degradation, and consequently impedes the progression of AAA. AO emerges as one of the active compounds in AD responsible for inhibiting VSMC inflammation and inhibiting AAA development.

Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma.

Nur77 modulators have emerged as a promising therapeutic approach for hepatocellular carcinoma. In this study, a structure-based rational drug design approach was used to design and synthesise a series of 4-((8-hydroxy-2-methylquinolin-4-yl)amino)benzoylhydrazone derivatives based on the binding characteristics of our previously reported 10g and the native ligand 3NB at the binding Site C of Nur77. Cell-based cytotoxicity assays revealed that compound TMHA37 demonstrated the highest cytotoxicity against all tested cancer cells. The induced fit docking and binding pose metadynamics simulation suggested that TMHA37 was the most promising Nur77 binder at Site C. Molecular dynamics simulation validated the stable binding of TMHA37 to Nur77's Site C but not to Sites A or B. Specifically, TMHA37 bound strongly to Nur77-LBD (KD = 445.3 nM) and could activate Nur77's transcriptional activity. Furthermore, TMHA37 exhibited antitumor effects by blocking the cell cycle at G2/M phase and inducing cell apoptosis in a Nur77-dependent manner.

Resistance traits and molecular characterization of multidrug-resistant Acinetobacter baumannii isolates from an intensive care unit of a tertiary hospital in Guangdong, southern China.

PURPOSE: This study aims to characterize antimicrobial resistance (AMR) of all the non-duplicated Acinetobacter baumannii strains isolated from an intensive care unit in a tertiary hospital during the period of January 1 to December 31, 2015. METHODS: A. baumannii (n = 95 strains) isolated from patients was subjected to antimicrobial susceptibility test (AST) by Vitek 2 Compact system to determine minimum inhibitory concentrations, followed by genotyping by enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR). Resistance genes of interest were PCR amplified and sequenced. RESULTS: All isolates were qualified as MDR, with a resistance rate of > 80% to 8 antimicrobials tested. In terms of beta-lactamase detection, the blaOXA23, blaTEM-1, and armA genes were detected frequently at 92.63%, 9 1.58%, and 88.42%, respectively. The metallo-ß-lactamase genes blaIMP and blaVIM were undetected. Aph (3')-I was detected in 82 isolates (86.32%), making it the most prevalent aminoglycoside-modifying enzyme (AMEs) encoding gene. In addition, ant (3″)-I was detected at 30.53%, while 26.32% of the strains harbored an aac (6')-Ib gene. ERIC-PCR typing suggested moderate genetic diversity among the isolates, which might be organized into 10 distinct clusters, with cluster A (n = 86 isolates or 90.53%) being the dominant cluster. CONCLUSIONS: All of the A. baumannii strains detected in the ICU were MDR clones exhibiting extremely high resistance to carbapenems and aminoglycosides as monitored throughout the study period. They principally belonged to a single cluster of isolates carrying blaOXA23 and armA co-producing different AMEs genes.

Design and synthesis of N-(1-(6-(substituted phenyl)-pyridazin-3-yl)-piperidine-3-yl)-amine derivatives as JMJD6 inhibitors.

JMJD6 is a member of the JmjC domain-containing family and has been identified as a promising therapeutic target for treating estrogen-induced and triple-negative breast cancer. To develop novel anti-breast cancer agents, we synthesized a class of N-(1-(6-(substituted phenyl)-pyridazine-3-yl)-piperidine-3-yl)-amine derivatives as potential JMJD6 inhibitors. Among them, the anti-cancer compound A29 was an excellent JMJD6 binder (KD = 0.75 ± 0.08 µM). It could upregulate the mRNA and protein levels of p53 and its downstream effectors p21 and PUMA by inhibiting JMJD6. Besides, A29 displayed potent anti-proliferative activities against tested breast cancer cells by the induction of cell apoptosis and cell cycle arrest. Significantly, A29 also promoted a remarkable reduction in tumor growth, with a TGI value of 66.6% (50 mg/kg, i.p.). Taken together, our findings suggest that A29 is a potent JMJD6 inhibitor bearing a new scaffold acting as a promising drug candidate for the treatment of breast cancer.

Design and synthesis of adamantyl-substituted flavonoid derivatives as anti-inflammatory Nur77 modulators: Compound B7 targets Nur77 and improves LPS-induced inflammation in vitro and in vivo.

In continuing our study on discovering new Nur77-targeting anti-inflammatory agents with natural skeletons, we combined adamantyl group and hydroxamic acid moiety with flavonoid nucleus, synthesized three series of flavonoid derivatives with a similar structure like CD437, and evaluated their activities against LPS-induced inflammation. Compound B7 was found to be an excellent Nur77 binder (Kd = 3.55 × 10-7 M) and a potent inhibitor of inflammation, which significantly decreased the production of cytokines in vitro, such as NO, IL-6, IL-1ß, and TNF-α, at concentrations of 1.25, 2.5, and 5 µM. Mechanistically, B7 modulated the colocalization of Nur77 at mitochondria and inhibited the lipopolysaccharides (LPS)-induced inflammation via the blockade of NF-κB activation in a Nur77-dependent manner. Additionally, B7 showed in vivo anti-inflammatory activity in the LPS-induced mice model of acute lung injury (ALI). These data suggest that the Nur77-targeting flavonoid derivatives can be particularly useful for further pharmaceutical development for the treatment of inflammatory diseases such as ALI.

Discovery of a Nur77-mediated cytoplasmic vacuolation and paraptosis inducer (4-PQBH) for the treatment of hepatocellular carcinoma.

Nur77, an orphan nuclear receptor, has antitumor activity in hepatocellular carcinoma (HCC). However, its antitumor mechanisms of action in HCC are complicated and rarely reported. Our recent work demonstrated that certain quinoline-Schiff-base derivatives were good Nur77 mediators that exerted excellent anti-HCC activities in vitro and in vivo. Interestingly, these compounds shared similar chemical structures, but they displayed different Nur77-targeted anticancer mechanisms of action. As a continuous work, we synthesized a series of 4-(quinoline-4-amino) benzoylhydrazide derivatives and evaluated their anti-HCC activity and binding affinity to Nur77 in vitro. Compound 4-PQBH emerged as the best Nur77 binder (KD = 1.17 µM) and has potentially selective cytotoxicity to HCC cells. Mechanistically, 4-PQBH extensively induced caspase-independent cytoplasmic vacuolization and paraptosis through Nur77-mediated ER stress and autophagy. Moreover, 4-PQBH exhibited an effective xenograft tumor inhibition by modulating Nur77-dependent cytoplasmic vacuolation and paraptosis. This paper is the first to disclose that chemotherapeutic agents targeting Nur77-mediated cytoplasmic vacuolization and paraptosis may provide a promising strategy to combat HCC that frequently evade the apoptosis program.

New Sorbicillinoids with Tea Pathogenic Fungus Inhibitory Effect from Marine-Derived Fungus Hypocrea jecorina H8.

Four new dimeric sorbicillinoids (1-3 and 5) and a new monomeric sorbicillinoid (4) as well as six known analogs (6-11) were purified from the fungal strain Hypocrea jecorina H8, which was obtained from mangrove sediment, and showed potent inhibitory activity against the tea pathogenic fungus Pestalotiopsis theae (P. theae). The planar structures of 1-5 were assigned by analyses of their UV, IR, HR-ESI-MS, and NMR spectroscopic data. All the compounds were evaluated for growth inhibition of tea pathogenic fungus P. theae. Compounds 5, 6, 8, 9, and 10 exhibited more potent inhibitory activities compared with the positive control hexaconazole with an ED50 of 24.25 ± 1.57 µg/mL. The ED50 values of compounds 5, 6, 8, 9, and 10 were 9.13 ± 1.25, 2.04 ± 1.24, 18.22 ± 1.29, 1.83 ± 1.37, and 4.68 ± 1.44 µg/mL, respectively. Additionally, the effects of these compounds on zebrafish embryo development were also evaluated. Except for compounds 5 and 8, which imparted toxic effects on zebrafish even at 0.625 µM, the other isolated compounds did not exhibit significant toxicity to zebrafish eggs, embryos, or larvae. Taken together, sorbicillinoid derivatives (6, 9, and 10) from H. jecorina H8 displayed low toxicity and high anti-tea pathogenic fungus potential.

Discovery of new chalone adamantyl arotinoids having RXRα-modulating and anticancer activities.

In the present study, a new series of chalcone adamantly arotinoids (chalcone AdArs) derived from RAR antagonist MX781, are synthesized, characterized, and evaluated for the biological activities in vitro. The studies of antiproliferative activity and RXRα-binding affinity of target compounds result in the discovery of a lead candidate (WA15), which is a good RXRα binder (Kd = 2.89 × 10-6 M) with potent antiproliferative activity against human cancer cell lines (IC50 ≈ 10 µM) and low toxic to normal LO2 and MRC-5 cells (IC50 > 50 µM). Different from MX781, WA15 eliminates RARα antagonist activity but inhibits 9-cis-RA-induced RXRα transactivation activity in a dose-dependent manner. Compound WA15 is found to be a good apoptosis inducer in various cancer cells and promotes cell apoptosis in an RXRα-independent manner. Besides, WA15 shows the induction of proteasome-dependent RXRα degradation which might enhance the WA15-induced apoptosis. Finally, the immunoblotting indicates that WA15 can inhibit the TNFα-induced IKK activation and IκBα degradation, suggesting that the anticancer activity of WA15 might be related to the inhibition of IKK/NF-κB signal pathway.

Glycine metabolomic changes induced by anticancer agents in A549 cells.

Glycine plays a key role in rapidly proliferating cancer cells such as A549 cells. Targeting glycine metabolism is considered as a potential means for cancer treatment. However, the drug-induced alterations in glycine metabolism have not yet been investigated. Herein, a total of 34 glycine metabolites were examined in A549 cells with or without anticancer drug treatment. This work showed all tested anticancer agents could alter glycine metabolism in A549 cells including inhibition of pyruvate metabolism and down-regulation of betaine aldehyde and 5'-phosphoribosylglycinamide. Principal component analysis and orthogonal partial least-squares discrimination analysis exhibited the difference between control and each drug-treated group. In general, cisplatin, camptothecin, and SAHA could induce the significant down-regulation of more metabolites, compared with afatinib, gefitinib, and targretin. Both glycine, serine and threonine metabolism, and purine metabolism were significantly disturbed by the treatment with afatinib, gefitinib, and targretin. However, the treatment using cisplatin, camptothecin, and SAHA was considered to be highly responsible for the perturbation of glycine, serine and threonine metabolism, and cysteine and methionine metabolism. Finally, multivariate analysis for control and all drug-treated groups revealed 11 altered metabolites with a significant difference. It implies anti-cancer agents with different mechanisms of action might induce different comprehensive changes of glycine metabolomics. The current study provides fundamental insights into the acquisition of the role of anti-cancer agents in glycine metabolism while suppressing cancer cell proliferation, and may aid the development of cancer treatment targeting glycine metabolism.

Synthesis and biological evaluations of N'-substituted methylene-4-(quinoline-4-amino) benzoylhydrazides as potential anti-hepatoma agents.

In the effort to develop novel quinoline derivatives for the treatment of liver cancer, we synthesized a series of N'-Substituted methylene-4-(quinoline-4-amino) benzoylhydrazides and evaluated their biological activities as anticancer agents. Compounds 5h and 5j were found to be the potent antiproliferative agents against HepG2 cell line with an IC50 value of 12.6 ± 0.1 µM and 27.3 ± 1.7 µM, respectively. The most effective compound 5h also exhibited potent cytotoxicity against SMMC-7721 and Huh7 cells with IC50 values of 9.6 ± 0.7 µM and 6.3 ± 0.2 µM, respectively. Inspiringly, both 5h and 5j exhibited lower cytotoxic property in normal cells than hepatic carcinoma cells. Compounds 5h and 5j could down-regulate mRNA level of c-Myc and expression level of c-Myc. Meanwhile, they decreased expression level of anti-apoptotic protein Bcl-2 and increased expression levels of pro-apoptotic protein Bax and cleaved PARP with reference to tubulin. So various assays including cell colony formation, cell cycle distribution, as well as cell apoptosis and migration were performed to understand their antitumor role. It was confirmed that 5h and 5j inhibited the growth of HepG2 cells due to their anti-survival effect, induction of cell cycle arrest and cell apoptosis, and inhibition of cell migration. These results demonstrated that 5h might be as potential lead compounds to develop anticancer agents for the treatment of hepatocellular carcinoma.

Two New Cytotoxic Compounds from a Deep-Sea Penicillum citreonigrum XT20-134.

Penicillum citreonigrum XT20-134 (MCCC 3A00956) is a fungus with cytotoxic activity, derived from deep-sea sediment. Five new compounds, adeninylpyrenocine (1), 2-hydroxyl-3-pyrenocine-thio propanoic acid (2), ozazino-cyclo-(2,3-dihydroxyl-trp-tyr) (3), 5,5-dichloro-1-(3,5-dimethoxyphenyl)-1,4-dihydroxypentan-2-one (4), and 2,3,4-trihydroxybutyl cinnamate (5), together with 19 known compounds (6-24), were isolated from an ethyl acetate (EtOAc) extract of its fermentation. The structures of the new compounds were comprehensively characterized by high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR). All isolates were evaluated for their cytotoxic activities. The heteroatom-containing new compounds 2 and 4 showed potent cytotoxicity to the human hepatoma tumor cell Bel7402 with IC50 values of 7.63 ± 1.46, 13.14 ± 1.41 µM and the human fibrosarcoma tumor cell HT1080 with IC50 values of 10.22 ± 1.32, 16.53 ± 1.67 µM, respectively.

New Bis-Alkenoic Acid Derivatives from a Marine-Derived Fungus Fusarium solani H915.

Fusarium solani H915 is a fungus derived from mangrove sediments. From its ethyl acetate extract, a new alkenoic acid, fusaridioic acid A (1), three new bis-alkenoic acid esters, namely, fusariumester A1 (2), A2 (3) and B (4), together with three known compounds (5⁻7), were isolated. The structures of the new compounds were comprehensively characterized by high resolution electrospray ionization-mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR). Additionally, the antifungal activities against tea pathogenic fungi Pestalotiopsis theae and Colletotrichum gloeosporioides were studied. The new compound, 4, containing a ß-lactone ring, exhibited moderate inhibitory activity against P. theae, with an MIC of 50 µg/disc. Hymeglusin (6), a typical ß-lactone antibiotic and a terpenoid alkaloid, equisetin (7), exhibited potent inhibitory activities against both fungal species. The isolated compounds were evaluated for their effects on zebrafish embryo development. Equisetin clearly imparted toxic effect on zebrafish even at low concentrations. However, none of the alkenoic acid derivatives exhibited significant toxicity to zebrafish eggs, embryos, or larvae. Thus, the ß-lactone containing alkenoic acid derivatives from F. solani H915 are low in toxicity and are potent antifungal agents against tea pathogenic fungi.

Open-Ring Butenolides from a Marine-Derived Anti-Neuroinflammatory Fungus Aspergillus terreus Y10.

To investigate structurally novel and anti-neuroinflammatory natural compounds from marine-derived microorganisms, the secondary metabolites of Aspergillus terreus Y10, a fungus separated from the sediment of the coast in the South China Sea, were studied. Three new compounds (2⁻4), with novel open-ring butenolide skeletons, were isolated from the ethyl acetate extract of the culture medium. In addition, a typical new butenolide, asperteretal F (1), was found to dose-dependently inhibit tumor necrosis factor (TNF-α) generation with an IC50 of 7.6 µg/mL. The present study shows the existence of open-ring butenolides, and suggests that butenolides such as asperteretal F (1) are a promising new anti-neuroinflammatroy candidate for neurodegenerative diseases.

Biosynthetic Functional Gene Analysis of Bis-Indole Metabolites from 25D7, a Clone Derived from a Deep-Sea Sediment Metagenomic Library.

This work investigated the metabolites and their biosynthetic functional hydroxylase genes of the deep-sea sediment metagenomic clone 25D7. 5-Bromoindole was added to the 25D7 clone derived Escherichia coli fermentation broth. The new-generated metabolites and their biosynthetic byproducts were located through LC-MS, in which the isotope peaks of brominated products emerged. Two new brominated bis-indole metabolites, 5-bromometagenediindole B (1), and 5-bromometagenediindole C (2) were separated under the guidance of LC-MS. Their structures were elucidated on the basis of 1D and 2D NMR spectra (COSY, HSQC, and HMBC). The biosynthetic functional genes of the two new compounds were revealed through LC-MS and transposon mutagenesis analysis. 5-Bromometagenediindole B (1) also demonstrated moderately cytotoxic activity against MCF7, B16, CNE2, Bel7402, and HT1080 tumor cell lines in vitro.

Macrolactins from Marine-Derived Bacillus subtilis B5 Bacteria as Inhibitors of Inducible Nitric Oxide and Cytokines Expression.

In order to find new natural products with anti-inflammatory activity, chemical investigation of a 3000-meter deep-sea sediment derived bacteria Bacillus subtilis B5 was carried out. A new macrolactin derivative was isolated and identified as 7,13-epoxyl-macrolactin A (1). Owing to the existence of the epoxy ring, 1 exhibited a significant inhibitory effect on the expression of inducible nitric oxide and cytokines, compared with previously isolated known macrolactins (2-5). Real-time Polymerase Chain Reaction (PCR) analysis showed that the new compound significantly inhibited the mRNA expressions of inducible nitric oxide synthase (iNOS), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Reverse transcription-PCR analysis demonstrated that the new compound reduced the mRNA expression level of IL-1ß in a concentration-dependent manner.

Novel N-Substituted 2-(2-(Adamantan-1-yl)-1H-Indol-3-yl)-2-Oxoacetamide Derivatives: Synthesis and Biological Evaluation.

In this study, a series of novel N-substituted 2-(2-(adamantan-1-yl)-1H-indol-3-yl)-2-oxoacetamide derivatives were synthesized, and evaluated for their cytotoxicity in human cell lines including Hela (cervical cancer), MCF7 (breast cancer ) and HepG2 (liver cancer). Several compounds were found to have potent anti-proliferative activity against those human cancer cell lines and compound 5r showed the most potent biological activity against HepG2 cells with an IC50 value of 10.56 ± 1.14 µΜ. In addition, bioassays showed that compound 5r induced time-dependent and dose-dependent cleavage of poly ADP-ribose polymerase (PARP), and also induced a dose-dependent increase in caspase-3 and caspase-8 activity, but had little effect on caspase-9 protease activity in HepG2 cells. These results provide evidence that 5r-induced apoptosis in HepG2 cell is caspase-8-dependent.

Two new cytotoxic indole alkaloids from a deep-sea sediment derived metagenomic clone.

Two new indole alkaloids, metagenetriindole A (1) and metagenebiindole A (2), were identified from deep-sea sediment metagenomic clone derived Escherichia coli fermentation broth. The structures of new compounds were elucidated by spectroscopic methods. The two new indole alkaloids demonstrated moderately cytotoxic activity against CNE2, Bel7402 and HT1080 cancer cell lines in vitro.

Overexpression of SLC35F2 is a potential prognostic biomarker for lung adenocarcinoma.

Objective: To explore the potential clinical and prognostic significance of Homo sapiens solute carrier family 35 member F2 (SLC35F2) in the context of lung adenocarcinoma (LUAD). Methods: The expression pattern of SLC35F2 in LUAD tissues and normal tissues was analyzed in The Cancer Genome Atlas (TCGA) datasets and validated in 12 pairs of fresh clinical LUAD tissues and their corresponding adjacent normal tissues using quantitative real-time PCR (qRT-PCR) and western blotting. Immunohistochemistry (IHC) was used to assess the protein expression of SLC35F2 in 60 paraffin-embedded LUAD tissues, and its associations with clinicopathological parameters were further examined. The prognostic significance of SLC35F2 mRNA expression was also evaluated using the Kaplan-Meier method, and Cox regression models in LUAD patients from the TCGA database. The potential utility of SLC35F2 as an indicator of recurrence or metastasis was explored through the follow-up of selected clinical LUAD cases. Lastly, gene set enrichment analysis (GSEA) was conducted to investigate the underlying biological mechanisms and signaling pathways. Results: Bioinformatics analysis utilizing the TCGA database indicated that SLC35F2 mRNA exhibited heightened expression in LUAD tissues when compared to normal tissues. These findings were further substantiated through the examination of 12 pairs of clinical LUAD tissues and their corresponding adjacent normal tissues, employing qRT-PCR and western blotting techniques. IHC results from a cohort of 60 LUAD patients demonstrated an up-regulation of SLC35F2 in 38 out of 60 individuals (63.3 %), which exhibited a significant correlation with tumor size, lymph node metastasis, and clinical stage (all P < 0.05). Both the Kaplan-Meier curve and the Cox proportional hazard analyses indicated a strong association between the up-regulation of SLC35F2 mRNA expression and unfavorable overall survival (OS) in patients with LUAD, as observed in the TCGA datasets (P < 0.05). The follow-up findings from select clinical LUAD cases provided evidence that the expression of SLC35F2 could serve as a dependable biomarker for monitoring the recurrence or metastasis. Additionally, the GSEA highlighted the enrichment of apoptosis, adhesion, small cell lung cancer (SCLC), and p53 signaling pathways in the subgroup of LUAD patients with elevated SLC35F2 expression. Conclusion: SLC35F2 exhibited an up-regulated in both mRNA and protein expression, rendering it a valuable independent prognostic indicator for patients diagnosed with LUAD.

Hinokione: an abietene diterpene with pancreatic ß cells regeneration and hypoglycemic activity, and other derivatives with novel structures from the woods of Agathis dammara.

In this study, 14 abietene and pimarene diterpenoids were isolated from the woods of Agathis dammara. Among them, 4 new compounds, dammarone A-C and dammaric acid A (1-4), were firstly reported, respectively. The structure of the new compounds was determined by HR ESI-MS and 1D/2D NMR spectroscopy, and their absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. The hypoglycemic effect of all compounds was evaluated by transgenic zebrafish model, and the structure-activity relationship was discussed. Hinokione (7, HO) has low toxicity and significant hypoglycemic effects on zebrafish, the mechanism is mainly by promoting the differentiation of zebrafish pancreatic endocrine precursor cells (PEP cells) into ß cells, thereby promoting the regeneration of pancreatic ß cells.

Compounds from Agathis dammara exert hypoglycaemic activity by enhancing glucose uptake: lignans, terpenes and others.

In this study, two new kaurane diterpenes (16, 17), together with 12 lignans (1-12), a triterpene (15), and two other compounds (13, 14) were isolated from the woods of Agathis dammara. The structure of the new compound was determined by HR ESIMS and 1D/2D NMR spectroscopy, and its absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. Compounds 5, 11, 14 exhibit significant hypoglycaemic activity in zebrafish, and their mechanism of action is to enhance glucose uptake in zebrafish.