Pyrenosetins A–C, New Decalinoylspirotetramic Acid Derivatives Isolated by Bioactivity-Based Molecular Networking from the Seaweed-Derived Fungus Pyrenochaetopsis sp. FVE-001

Marine algae represent a prolific source of filamentous fungi for bioprospecting. In continuation of our search for new anticancer leads from fungi derived from the brown alga Fucus vesiculosus, an endophytic Pyrenochaetopsis sp. FVE-001 was selected for an in-depth chemical analysis. The crude fungal extract inhibited several cancer cell lines in vitro, and the highest anticancer activity was tracked to its CHCl3–soluble portion. A bioactivity-based molecular networking approach was applied to C18-SPE fractions of the CHCl3 subextract to predict the bioactivity scores of metabolites in the fractions and to aid targeted purification of anticancer metabolites. This approach led to a rapid isolation of three new decalinoylspirotetramic acid derivatives, pyrenosetins A–C (1–3) and the known decalin tetramic acid phomasetin (4). The structures of the compounds were elucidated by extensive NMR, HR-ESIMS, FT-IR spectroscopy, [α]D and Mosher’s ester method. Compounds 1 and 2 showed high anticancer activity against malignant melanoma cell line A-375 (IC50 values 2.8 and 6.3 μM, respectively), in line with the bioactivity predictions. This is the first study focusing on secondary metabolites of a marine-derived Pyrenochaetopsis sp. and the second investigation performed on the member of the genus Pyrenochaetopsis

Angiotensin II mediates the high-glucose-induced endothelial-to-mesenchymal transition in human aortic endothelial cells

<p>Abstract</p> <p>Background</p> <p>Substantial evidence suggests that high glucose (HG) causes endothelial cell damage; however, the potential mechanism therein has yet to be clarified. The aim of this study was to investigate the influence of HG on the endothelial-to-mesenchymal transition (EndMT) and its relevance to the activation of the renin-angiotensin system.</p> <p>Methods</p> <p>Primary human aortic endothelial cells (HAECs) were divided into three groups: a normal glucose (NG) group, HG group, and irbesartan (1 μM)-treated (HG+irbesartan) group. The concentration of angiotensin II in the supernatant was detected by radioimmunoassay. Pathological changes were investigated using fluorescence microscopy and electron microscopy. Immunofluorescence staining was performed to detect the co-expression of CD31 and fibroblast markers, such as fibroblast-specific protein 1 (FSP1). The expressions of FSP1 and α-SMA were detected by RT-PCR and Western blot.</p> <p>Results</p> <p>The treatment of HAECs in the HG group resulted in significant increases in the expressions of FSP1 and angiotensin II in dose-and time-dependent manners. The incubation of HAECs exposure to HG resulted in a fibroblast-like phenotype, wherein increased microfilamentation and a roughened endoplasmic reticulum structure were observed in the cytoplasm. The expressions of FSP1 and α-SMA were significantly increased in the HG group, and these changes were inhibited by irbesartan treatment (<it>P </it>< 0.05). Double staining of the HAECs indicated a co-localization of CD31 and FSP1 and that some cells acquired spindle-shaped morphologies and a loss of CD31 staining; however, treatment with irbesartan attenuated the expression of EndMT (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>These findings suggest a novel mechanism in HG-induced endothelial damage via the mediation of the EndMT by angiotensin II, which was inhibited by Irbesartan.</p

Pyrenosetin D, a New Pentacyclic Decalinoyltetramic Acid Derivative from the Algicolous Fungus Pyrenochaetopsis sp. FVE-087

The fungal genus Pyrenochaetopsis is commonly found in soil, terrestrial, and marine environments, however, has received little attention as a source of bioactive secondary metabolites so far. In a recent work, we reported the isolation and characterization of three new anticancer decalinoyltetramic acid derivatives, pyrenosetins A-C, from the Baltic Fucus vesiculosus-derived endophytic fungus Pyrenochaetopsis sp. FVE-001. Herein we report a new pentacyclic decalinoylspirotetramic acid derivative, pyrenosetin D (1), along with two known decalin derivatives wakodecalines A (2) and B (3) from another endophytic strain Pyrenochaetopsis FVE-087 isolated from the same seaweed and showed anticancer activity in initial screenings. The chemical structures of the purified compounds were elucidated by comprehensive analysis of HR-ESIMS, FT-IR, [a]D, 1D and 2D NMR data coupled with DFT calculations of NMR parameters and optical rotation. Compounds 1-3 were evaluated for their anticancer and toxic potentials against the human malignant melanoma cell line (A-375) and the non-cancerous keratinocyte cell line (HaCaT). Pyrenosetin D (1) showed toxicity towards both A-375 and HaCaT cells with IC50 values of 77.5 and 39.3 μM, respectively, while 2 and 3 were inactive. This is the third chemical study performed on the fungal genus Pyrenochaetopsis and the first report of a pentacyclic decalin ring system from the fungal genus Pyrenochaetopsis

A novel artificial intelligence network to assess the prognosis of gastrointestinal cancer to immunotherapy based on genetic mutation features

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized gastrointestinal cancer treatment, yet the absence of reliable biomarkers hampers precise patient response prediction.MethodsWe developed and validated a genomic mutation signature (GMS) employing a novel artificial intelligence network to forecast the prognosis of gastrointestinal cancer patients undergoing ICIs therapy. Subsequently, we explored the underlying immune landscapes across different subtypes using multiomics data. Finally, UMI-77 was pinpointed through the analysis of drug sensitization data from the Genomics of Drug Sensitivity in Cancer (GDSC) database. The sensitivity of UMI-77 to the AGS and MKN45 cell lines was evaluated using the cell counting kit-8 (CCK8) assay and the plate clone formation assay.ResultsUsing the artificial intelligence network, we developed the GMS that independently predicts the prognosis of gastrointestinal cancer patients. The GMS demonstrated consistent performance across three public cohorts and exhibited high sensitivity and specificity for 6, 12, and 24-month overall survival (OS) in receiver operating characteristic (ROC) curve analysis. It outperformed conventional clinical and molecular features. Low-risk samples showed a higher presence of cytolytic immune cells and enhanced immunogenic potential compared to high-risk samples. Additionally, we identified the small molecule compound UMI-77. The half-maximal inhibitory concentration (IC50) of UMI-77 was inversely related to the GMS. Notably, the AGS cell line, classified as high-risk, displayed greater sensitivity to UMI-77, whereas the MKN45 cell line, classified as low-risk, showed less sensitivity.ConclusionThe GMS developed here can reliably predict survival benefit for gastrointestinal cancer patients on ICIs therapy

Application of Feature-Based Molecular Networking for Comparative Metabolomics and Targeted Isolation of Stereoisomers from Algicolous Fungi

Seaweed endophytic (algicolous) fungi are talented producers of bioactive natural products. We have previously isolated two strains of the endophytic fungus, Pyrenochaetopsis sp. FVE-001 and FVE-087, from the thalli of the brown alga Fucus vesiculosus. Initial chemical studies yielded four new decalinoylspirotetramic acid derivatives with antimelanoma activity, namely pyrenosetins A–C (1–3) from Pyrenochaetopsis sp. strain FVE-001, and pyrenosetin D (4) from strain FVE-087. In this study, we applied a comparative metabolomics study employing HRMS/MS based feature-based molecular networking (FB MN) on both Pyrenochaetopsis strains. A higher chemical capacity in production of decalin derivatives was observed in Pyrenochaetopsis sp. FVE-087. Notably, several decalins showed different retention times despite the same MS data and MS/MS fragmentation pattern with the previously isolated pyrenosetins, indicating they may be their stereoisomers. FB MN-based targeted isolation studies coupled with antimelanoma activity testing on the strain FVE-087 afforded two new stereoisomers, pyrenosetins E (5) and F (6). Extensive NMR spectroscopy including DFT computational studies, HR-ESIMS, and Mosher’s ester method were used in the structure elucidation of compounds 5 and 6. The 3′R,5′R stereochemistry determined for compound 6 was identical to that previously reported for pyrenosetin C (3), whose stereochemistry was revised as 3′S,5′R in this study. Pyrenosetin E (5) inhibited the growth of human malignant melanoma cells (A-375) with an IC50 value of 40.9 μM, while 6 was inactive. This study points out significant variations in the chemical repertoire of two closely related fungal strains and the versatility of FB MN in identification and targeted isolation of stereoisomers. It also confirms that the little-known fungal genus Pyrenochaetopsis is a prolific source of complex decalinoylspirotetramic acid derivatives

Metabolomic and transcriptomic responses of Adiantum (Adiantum nelumboides) leaves under drought, half-waterlogging, and rewater conditions

Introduction:Adiantum nelumboides (Adiantum) is an endangered fern with a narrow distribution along the Yangtze River in China. Due to its cliff-dwelling habit, it experiences water stress conditions, which further endangers its survival. However, no information is available about its molecular responses to drought and half-waterlogging conditions.Methods: Here, we applied five and ten days of half-waterlogging stress, five days of drought stress, and rewatering after five days of drought stress, and studied the resulting metabolome profiles and transcriptome signatures of Adiantum leaves.Results and Discussion: The metabolome profiling detected 864 metabolites. The drought and half-waterlogging stress induced up-accumulation of primary and secondary metabolites including amino acids and derivatives, nucleotides and derivatives, flavonoids, alkaloids, and phenolic acid accumulation in Adiantum leaves. Whereas, rewatering the drought-stressed seedlings reversed most of these metabolic changes. Transcriptome sequencing confirmed the differential metabolite profiles, where the genes enriched in pathways associated with these metabolites showed similar expression patterns. Overall, the half-waterlogging stress for 10 days induced large-scale metabolic and transcriptomic changes compared to half-waterlogging stress for 05 days, drought stress for 05 days or rewatering for 05 days.Conclusion: This pioneering attempt provides a detailed understanding of molecular responses of Adiantum leaves to drought and half-waterlogging stresses and rewater conditions. This study also provides useful clues for the genetic improvement of Adiantum for drought/half-waterlogging stress tolerance

Analysis of chromosomal structural variations in patients with recurrent spontaneous abortion using optical genome mapping

Background and aims: Certain chromosomal structural variations (SVs) in biological parents can lead to recurrent spontaneous abortions (RSAs). Unequal crossing over during meiosis can result in the unbalanced rearrangement of gamete chromosomes such as duplication or deletion. Unfortunately, routine techniques such as karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and copy number variation sequencing (CNV-seq) cannot detect all types of SVs. In this study, we show that optical genome mapping (OGM) quickly and accurately detects SVs for RSA patients with a high resolution and provides more information about the breakpoint regions at gene level.Methods: Seven couples who had suffered RSA with unbalanced chromosomal rearrangements of aborted embryos were recruited, and ultra-high molecular weight (UHMW) DNA was isolated from their peripheral blood. The consensus genome map was created by de novo assembly on the Bionano Solve data analysis software. SVs and breakpoints were identified via alignments of the reference genome GRCh38/hg38. The exact breakpoint sequences were verified using either Oxford Nanopore sequencing or Sanger sequencing.Results: Various SVs in the recruited couples were successfully detected by OGM. Also, additional complex chromosomal rearrangement (CCRs) and four cryptic balanced reciprocal translocations (BRTs) were revealed, further refining the underlying genetic causes of RSA. Two of the disrupted genes identified in this study, FOXK2 [46,XY,t(7; 17)(q31.3; q25)] and PLXDC2 [46,XX,t(10; 16)(p12.31; q23.1)], had been previously shown to be associated with male fertility and embryo transit.Conclusion: OGM accurately detects chromosomal SVs, especially cryptic BRTs and CCRs. It is a useful complement to routine human genetic diagnostics, such as karyotyping, and detects cryptic BRTs and CCRs more accurately than routine genetic diagnostics

Exercise improves mental health status of young adults via attenuating inflammation factors but modalities matter

IntroductionThe mental health of young adults is a global public health challenge. Numerous studies have demonstrated that exercise benefits mental health. However, it is still unclear which exercise mode is optimal for protecting mental health and its association with the immune system. This study aimed to compare the intervention effect of high-intensity interval training (HIIT) and moderate-to-vigorous intensity continuous training (MVCT) on mental health and assess the underlying mechanism of exercise interventions to improve the immune system, which facilitated the mental health status.MethodsThis is a double-blinded RCT study conducted from October 13, 2020 to January 25, 2021 (ClinicalTrials.gov identifier: NCT04830059). Ninety-three participants who met the inclusion criteria were randomized into the HIIT (N = 33), MVCT (N = 32), and control groups (N = 28) with a mean age of 25.26 (SD = 2.21), and 43% of males enrolled in the study. Professional coaches guided participants in HIIT and MVCT groups to perform 40 min of exercise training three times a week for 12-week while those in the control group received 1 h of health education twice a week. Questionnaires related to mental health status and blood samples of inflammatory factors, including immunoglobulin A (IgA), immunoglobulin M (IgM), albumin (Alb), globulin (GLO), lymphocytes (LYM), and lymphocyte percentage (LYM) were assessed before and after the intervention.ResultsWe found that blood inflammation factors increased significantly in the control group during 12 weeks (ΔIgA = 0.16 g/L, ΔIgM = 0.092 g/L, ΔAlb = 2.59 g/L, ΔGlo = 3.08 g/L, ΔLYM = 0.36, and ΔLYM% = 3.72%, p &lt; 0.05), and both MVCT and HIIT intervention could effectively defend the increased inflammatory response compared with the control group (IgA: MVCT β = −0.14, p &lt; 0.001, HIIT β = −0.096, p &lt; 0.05; IgM: MVCT β = −0.12, p &lt; 0.001; HIIT β = −0.068, p &lt; 0.05; Alb: MVCT β = −1.64, p &lt; 0.05, HIIT β = −1.14, p &gt; 0.05; Glo: MVCT β = −3.17, p &lt; 0.001, HIIT β = −2.07, p &lt; 0.01; LYM: MVCT β = −0.34, p &lt; 0.05, HIIT β = −0.35, p &lt; 0.05). However, the MVCT intervention modality was more conducive to enhancing positive affect (β = 0.52, p = 0.018) and well-being (β = 1.08, p = 0.035) than HIIT. Furthermore, decreased IgA, Alb, and Glo were associated with improved mental health.ConclusionBoth 12-week HIIT and MVCT are beneficial to the immune system. The MVCT intervention mode is recommended to prevent mental health problems and attenuate immune inflammation, and the immune system is a potential mechanism that exercises improving mental health.Clinical trial registration[ClinicalTrials.gov], identifier [NCT04830059]