Diagnostic value of urine cyclic RNA-0071196 for bladder urothelial carcinoma.

OBJECTIVE: To investigate the diagnostic value of urine cyclic RNA-0071196 (circRNA-0071196) in the patients with bladder urothelial carcinoma (BUC). METHOD: The expression of circRNA-0071196 was detected in the urine samples using qRT-PCR from 40 BUC patients and 30 non-UBC patients at our department from December 2018 to September 2021. The expression difference of circRNA-0071196 was compared between the two groups, and the relationship between the expression of circRNA-0071196 in the urine of UBC patients and the clinical pathological characteristics was analyzed. RESULTS: (1) The expression of circRNA-0071196 in the urine of BUC group was significantly higher than that in the non-BUC group (P < 0.05). (2) The expression of circRNA-0071196 in the urine of BUC group was not related to age, sex, or lymph node metastasis (P > 0.05). (3) The expression of circRNA-0071196 in the urine of BUC group was related to tumor T stage, tumor grade and muscle invasion. (4) The urine circRNA-0071196 expression effectively distinguished BUC patients from non-BUC patients. CONCLUSION: The elevated expression of urine circRNA-0071196 in BUC patients indicates that circRNA-0071196 has promising potential as a non-invasive urinary biomarker for detecting BUC.

Antioxidative Indenone and Benzophenone Derivatives from the Mangrove-Derived Fungus Cytospora heveae NSHSJ-2.

Seven new polyketides, including four indenone derivatives, cytoindenones A-C (1, 3-4), 3'-methoxycytoindenone A (2), a benzophenone derivative, cytorhizophin J (6), and a pair of tetralone enantiomers, (±)-4,6-dihydroxy-5-methoxy-α-tetralone (7), together with a known compound (5) were obtained from the endophytic fungus Cytospora heveae NSHSJ-2 isolated from the fresh stem of the mangrove plant Sonneratia caseolaris. Compound 3 represented the first natural indenone monomer substituted by two benzene moieties at C-2 and C-3. Their structures were determined by the analysis of 1D and 2D NMR, as well as mass spectroscopic data, and the absolute configurations of (±)-7 were determined on the basis of the observed specific rotation value compared with those of the tetralone derivatives previously reported. In bioactivity assays, compounds 1, 4-6 showed potent DPPH· scavenging activities, with EC50 values ranging from 9.5 to 16.6 µM, better than the positive control ascorbic acid (21.9 µM); compounds 2-3 also exhibited DPPH· scavenging activities comparable to ascorbic acid.

Cytotoxic Bromine- and Iodine-Containing Cytochalasins Produced by the Mangrove Endophytic Fungus Phomopsis sp. QYM-13 Using the OSMAC Approach.

Twelve new cytochalasins, phomopchalasins D-O (1-3, 5-12, and 14), including one brominated (2) and two iodinated cytochalasins (3 and 6), together with six known analogues (4, 13, and 15-18) were isolated from the mangrove-derived fungus Phomopsis sp. QYM-13 treated with 3% NaBr or 3% KI in potato liquid medium. Their structures and absolute configurations were established by extensive spectroscopic analysis (1D and 2D NMR, HRESIMS), electronic circular dichroism calculations, and a single-crystal X-ray diffraction experiment. Compounds 3 and 6 represent the first iodinated cytochalasins. Compounds 2, 15, 17, and 18 exhibited significant cytotoxicity against human cancer cell line MDA-MB-435 with IC50 values ranging from 0.2 to 8.2 µM.

Two Antimicrobial Heterodimeric Tetrahydroxanthones with a 7,7'-Linkage from Mangrove Endophytic Fungus Aspergillus flavus QQYZ.

Mangrove endophytic fungi represent significant and sustainable sources of novel metabolites with unique structures and excellent biological activities, attracting extensive chemical investigations. In this research, two novel heterodimeric tetrahydroxanthones, aflaxanthones A (1) and B (2), dimerized via an unprecedented 7,7'-linkage, a sp3-sp3 dimeric manner, were isolated from the mangrove endophytic fungus Aspergillus flavus QQYZ. Their structures were elucidated through high resolution electrospray ionization mass spectroscopy (HRESIMS) and nuclear magnetic resonance (NMR) spectroscopy, the absolute configurations of them were determined by a single-crystal X-ray diffraction combined with calculated electronic circular dichroism (ECD) spectra and a 1D potential energy scan. These compounds were evaluated for antifungal activities in vitro and exhibited broad-spectrum and potential antifungal activities against several pathogenic fungi with minimum inhibitory concentration (MIC) values in the range of 3.13-50 µM. They also performed moderate antibacterial activities against several bacteria with MIC values in the range of 12.5-25 µM. This research enriched the resources of lead compounds and templates for marine-derived antimicrobial drugs.

Small molecule approaches to treat autoimmune and inflammatory diseases (Part I): Kinase inhibitors.

Autoimmune and inflammatory diseases place a huge burden on the healthcare system. Small molecule (SM) therapeutics provide much needed complementary treatment options for these diseases. This digest series highlights the latest progress in the discovery and development of safe and efficacious SMs to treat autoimmune and inflammatory diseases with each part representing a class of SMs, namely: 1) protein kinases; 2) nucleic acid-sensing pathways; and 3) soluble ligands and receptors on cell surfaces. In this first part of the series, the focus is on kinase inhibitors that emerged between 2018 and 2020, and which exhibit increased target and tissue selectivity with the aim of increasing their therapeutic index.

Small molecule approaches to treat autoimmune and inflammatory diseases (Part II): Nucleic acid sensing antagonists and inhibitors.

Nucleic acid sensing pathways play an important role in the innate immune system, protecting hosts against infections. However, a large body of evidence supports a close association between aberrant activation of those pathways and autoimmune and inflammatory diseases. Part II of the digest series on small molecule approaches to autoimmune and inflammatory diseases concentrates on recent advances with respect to small molecule antagonists or inhibitors of the nucleic acid sensing pathways, including endosomal TLRs, NLRP3 inflammasome and cGAS-STING.

Bioactive sesquiterpene derivatives from mangrove endophytic fungus Phomopsis sp. SYSU-QYP-23: Structures and nitric oxide inhibitory activities.

Eight new sesquiterpene derivatives (2, 4-6 and 10-13), along with five known analogues were isolated from the mangrove endophytic fungus Phomopsis sp. SYSU-QYP-23. Their structures of new compounds were established by spectroscopic methods, and the absolute configurations were confirmed by single-crystal X-ray diffraction analysis and comparison of the experimental ECD spectra. The absolute configuration of the side chain in 1 was first defined by modified Mosher's method. Compounds 1-7 showed potent inhibitory activities against nitric oxide (NO) production in lipopolysaccharides (LPS) induced RAW 264.7 cells with IC50 values ranging from 8.6 to 14.5 µM. The molecular docking results implied that the bioactive sesquiterpenes may directly bind with targeting residues in the active cavity of iNOS protein.

Mediator kinase inhibition further activates super-enhancer-associated genes in AML.

Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.

Furobenzotropolones A, B and 3-Hydroxyepicoccone B with Antioxidative Activity from Mangrove Endophytic Fungus Epicoccum nigrum MLY-3.

Three new metabolites, furobenzotropolones A, B (1-2) with unusual benzene and dihydrofuran moieties and 3-hydroxyepicoccone B (3), together with seven known compounds (4-10) were obtained from the endophytic fungus Epicoccum nigrum MLY-3 isolated from the fresh leaf of mangrove plant Bruguiear gymnorrhiza collected from Zhuhai. Their structures were assigned by the analysis of UV, IR, NMR, and mass spectroscopic data. Compound 1 was further confirmed by single-crystal X-ray diffraction experiment using Cu Kα radiation. In antioxidant activities in vitro, compounds 2, 3, 5, and 8 showed promising DPPH· scavenging activity with IC50 values ranging from 14.7 to 29.3 µM. Compounds 2, 3, 5, 7, and 8 exhibited promising potent activity in scavenging ABTS· with IC50 values in the range of 18-29.2 µM, which was stronger than that of the positive control ascorbic acid (IC50 = 33.6 ± 0.8 µM).

Metabolites with Anti-Inflammatory Activity from the Mangrove Endophytic Fungus Diaporthe sp. QYM12.

One new diterpenoid, diaporpenoid A (1), two new sesquiterpenoids, diaporpenoids B-C (2,3) and three new α-pyrone derivatives, diaporpyrones A-C (4-6) were isolated from an MeOH extract obtained from cultures of the mangrove endophytic fungus Diaporthe sp. QYM12. Their structures were elucidated by extensive analysis of spectroscopic data. The absolute configurations were determined by electronic circular dichroism (ECD) calculations and a comparison of the specific rotation. Compound 1 had an unusual 5/10/5-fused tricyclic ring system. Compounds 1 and 4 showed potent anti-inflammatory activities by inhibiting the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 cells with IC50 values of 21.5 and 12.5 µM, respectively.

Anti-inflammatory activities of alkaloids from the mangrove endophytic fungus Phomopsis sp. SYSUQYP-23.

Five new maleimide derivatives, (+)- and (-)- farinomalein F (1), (+)- and (-)- farinomalein G (2), farinomalein H (3) and one new linearly fused prenylated indole alkaloid phomoamide (8), along with five known compounds 4-7 and 9 were isolated from the mangrove endophytic fungus Phomopsis sp. SYSUQYP-23. Their structures and absolute configurations were determined by HRESIMS, spectroscopic and electronic circular dichroism (ECD) calculations. Bioassay results showed that compounds 3-9 exhibited significant inhibitory activities against nitric oxide (NO) production in lipopolysaccharides (LPS) induced RAW 264.7 cells, with IC50 values ranging from 4.5 to 25 µM. Moreover, the molecular docking study implied the probable binding interaction of compounds 4 and 5 with nitric oxide synthase.

Benzopyran Derivatives and an Aliphatic Compound from a Mangrove Endophytic Fungus Penicillium citrinum QJF-22.

Two new benzopyran derivatives, (2R,4S)-5-methoxy-2-methyl-3,4-dihydro-2H-1-benzopyran-4-ol and (2S,4R,2'S,4'R)-4,4'-oxybis(5-methoxy-2-methyl-3,4-dihydro-2H-1-benzopyran), and a new aliphatic compound, (3E,5Z,8S,10E)-8-hydroxytrideca-3,5,10,12-tetraen-2-one, together with three known benzopyran derivatives, were obtained from a mangrove endophytic fungus Penicillium citrinum QJF-22 collected in Hainan island. Their structures were determined by analysis of spectroscopic data and the relative configuration of (2R,4S)-5-methoxy-2-methyl-3,4-dihydro-2H-1-benzopyran-4-ol was also confirmed by single-crystal X-ray diffraction. The absolute configurations of four compounds were established by comparison of ECD spectra to calculations. The configuration of (3E,5Z,8S,10E)-8-hydroxytrideca-3,5,10,12-tetraen-2-one was confirmed by comparison of optical value to the similar compound. The configurations of the compounds (2S,4S)-5-methoxy-2-methyl-3,4-dihydro-2H-1-benzopyran-4-ol and (2R,4R)-5-methoxy-2-methyl-3,4-dihydro-2H-1-benzopyran-4-ol were first determined. (3R,4S)-3,4,8-Trihydroxy-3,4-dihydronaphthalen-1(2H)-one exhibited moderate inhibitory effects on LPS-induced NO production in RAW264.7 cells with IC50 of 44.7 µM, and without cytotoxicity to RAW264.7 cells within 50 µM.

Sinulaspirolactam A, a novel aza-spirocyclic valerenane sesquiterpenoid from soft coral Sinularia sp.

A novel valerenane sesquiterpenoid sinulaspirolactam A (1), together with five known compounds, was isolated from the soft coral Sinularia sp. Their structures were determined by spectroscopic analyses. The absolute configuration of 1 was established by ECD calculation. Compound 1 was the first example of valerenane sesquiterpenoid bearing an aza-spiro[4.5] ring moiety, the plausible biogenetic pathway of which was proposed. Cytotoxic activities of these compounds were also evaluated.

A new α-pyrone from the deep-sea actinomycete Nocardiopsis dassonvillei subsp. dassonvillei DSM 43111(T).

A new α-pyrone, nocapyrone S (1), together with five known compounds (2-6), were isolated from the deep-sea actinomycete Nocardiopsis dassonvillei subsp. dassonvillei DSM 43111(T). Their structures were determined by spectroscopic analyses. The absolute configuration of 1 was established by quantum approaches. Cytotoxic activity of 1 was evaluated against K562, MCF-7, SGC7901, A375, Hela, and HepG2 cell lines.

Comprehensive analysis and prognostic assessment of senescence-associated genes in bladder cancer.

BACKGROUND: The prevalence and mortality of bladder cancer (BLCA) present a significant medical challenge. While the function of senescence-related genes in tumor development is recognized, their prognostic significance in BLCA has not been thoroughly explored. METHODS: BLCA transcriptome datasets were sourced from the TCGA and GEO repositories. Gene groupings were determined through differential gene expression and non-negative matrix factorization (NMF) methodologies. Key senescence-linked genes were isolated using singular and multivariate Cox regression analyses, combined with lasso regression. Validation was undertaken with GEO database information. Predictive models, or nomograms, were developed by merging risk metrics with clinical records, and their efficacy was gauged using ROC curve methodologies. The immune response's dependency on the risk metric was assessed through the immune phenomenon score (IPS). Additionally, we estimated IC50 metrics for potential chemotherapeutic agents. RESULTS: Reviewing 406 neoplastic and 19 standard tissue specimens from the TCGA repository facilitated the bifurcation of subjects into two unique clusters (C1 and C2) according to senescence-related gene expression. After a stringent statistical evaluation, a set of ten pivotal genes was discerned and applied for risk stratification. Validity tests for the devised nomograms in forecasting 1, 3, and 5-year survival probabilities for BLCA patients were executed via ROC and calibration plots. IC50 estimations highlighted a heightened responsiveness in the low-risk category to agents like cisplatin, cyclopamine, and sorafenib. CONCLUSIONS: In summation, our research emphasizes the prospective utility of risk assessments rooted in senescence-related gene signatures for enhancing BLCA clinical oversight.

Griseofulvin enantiomers and bromine-containing griseofulvin derivatives with antifungal activity produced by the mangrove endophytic fungus Nigrospora sp. QQYB1.

Marine microorganisms have long been recognized as potential sources for drug discovery. Griseofulvin was one of the first antifungal natural products and has been used as an antifungal agent for decades. In this study, 12 new griseofulvin derivatives [(±)-1-2, (+)-3, (±)-4, 10-12, and 14-15] and two new griseofulvin natural products (9 and 16) together with six known analogues [(-)-3, 5-8, and 13] were isolated from the mangrove-derived fungus Nigrospora sp. QQYB1 treated with 0.3% NaCl or 2% NaBr in rice solid medium. Their 2D structures and absolute configurations were established by extensive spectroscopic analysis (1D and 2D NMR, HRESIMS), ECD spectra, computational calculation, DP4 + analysis, and X-ray single-crystal diffraction. Compounds 1-4 represent the first griseofulvin enantiomers with four absolute configurations (2S, 6'S; 2R, 6'R; 2S, 6'R; 2R, 6'S), and compounds 9-12 represent the first successful production of brominated griseofulvin derivatives from fungi via the addition of NaBr to the culture medium. In the antifungal assays, compounds 6 and 9 demonstrated significant inhibitory activities against the fungi Colletotrichum truncatum, Microsporum gypseum, and Trichophyton mentagrophyte with inhibition zones varying between 28 and 41 mm (10 µg/disc). The structure-activity relationship (SAR) was analyzed, which showed that substituents at C-6, C-7, C-6' and the positions of the carbonyl and double bond of griseofulvin derivatives significantly affected the antifungal activity. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00210-0.

4-Hydroxy-2-pyridone derivatives with antitumor activity produced by mangrove endophytic fungus Talaromyces sp. CY-3.

OSMAC strategy is a useful tool for discovering series of metabolites from microorganism. Five new sambutoxin derivatives (1-2, 4, 8-9), together with seven known compounds (3, 5-7, 10-12), were isolated from Talaromyces sp. CY-3 under OSMAC strategy and guidance of molecular networking. Their planar structures and absolute configurations were determined by NMR, HRESIMS, ECD spectra and common biosynthetic pathway. In bioassay, compounds 1-12 showed cytotoxicity to tumor cell lines with IC50 values in the range of 1.76-49.13 µM. The antitumor molecular mechanism of 10 was also explored. In vitro compound 10 significantly inhibited the growth and proliferation of two lung cancer cell lines (A549 and H1703). Furthermore, colony formation, EdU analysis, flow cytometry and Western blot analysis showed that 10 could induce cell cycle arrest in G0/G1 phase by promoting the expression of p53 and p21. The molecular mechanism of its antitumor effects in vitro is that 10 arrests the cell cycle by activating the p21/CyclinD1/Rb signaling pathway and the p53 pathway. Our results identified a lead small molecule compound with efficient antitumor growth and proliferation activity.

Diels-Alder reactions of 12-hydroxy-9(10®20)-5aH-abeo-abieta-1(10),8(9),12(13)-triene-11,14-dione.

12-Hydroxy-9(10-->20)-5aH-abeo-abieta-1(10),8(9),12(13)-triene-11,14-dione (quinone 2) served as the dienophile in numerous intermolecular Diels-Alder reactions. These cycloadditions were conducted either thermally (including microwave heating) or with Lewis acid activation. While most dienes reacted with quinone 2 in good chemical yield, others were incompatible under the experimental conditions used.

Cytosporones W and X: Two Mutually Converting Epimers from a Mangrove Endophytic Fungus Diaporthe sp. ZJHJYZ-1.

Two new octaketides, cytosporones W (1) and X (2), along with eight known cytosporone derivatives [(±)-3-9], were isolated from mangrove endophytic fungus Diaporthe sp. ZJHJYZ-1. Compounds 1 and 2 were a pair of epimers, whose configuration of C-1 could mutually convert, causing racemization of the lactone ring. The planar structures of compounds were elucidated through detailed 1D, 2D NMR, and HR-ESI-MS analysis. ECD spectra comparison and modified Mosher ester method were applied to determine the absolute configuration of 1 and 2. In bioassays, (±)-3 exhibited promising inhibitory activities against Bacillus subtilis, Pseudomonas aeruginosa, and Penicillium italicum with MIC, respectively, for 12.5, 12.5, and 3.13 µM.

Metabolites With Cytotoxic Activities From the Mangrove Endophytic Fungus Fusarium sp. 2ST2.

Two new 3-decalinoyltetramic acid derivatives with peroxide bridge fusarisetins E (1) and F (2), one new chromone fusarimone A (5), two new benzofurans fusarifurans A (9) and B (10), three new isocoumarins fusarimarins A-C (11-13), as well as five known analogues 3, 4, 6-8 and 14 were isolated from mangrove endophytic fungus Fusarium sp. 2ST2. Their structures and absolute configurations were established by spectroscopic analysis, density functional theory-gauge invariant atomic orbital NMR calculation with DP4+ statistical analysis, and electronic circular dichroism calculation. Compounds 1 and 2 showed significant cytotoxicity against human A549 cell lines with IC50 values of 8.7 and 4.3 µM, respectively.