Smyd3 negatively regulates the anti-viral pathway by promoting TAK1 degradation in teleost fish.

IMPORTANCE: In this study, we have found that the existence of Smyd3 promoted the replication of SCRV. Additionally, we report that Smyd3 negatively regulates the NF-κB and IRF3 signaling pathway by facilitating the degradation of TAK1 in fish. Our findings suggest that Smyd3 interacts with TAK1. Further investigations have revealed that Smyd3 specifically mediates K48-linked ubiquitination of TAK1 and enhances TAK1 degradation, resulting in a significant inhibition of the NF-κB and IRF3 signaling pathway. These results not only contribute to the advancement of fish anti-viral immunity but also provide new evidence for understanding the mechanism of TAK1 in mammals.

Proton Collective Quantum Tunneling Induces Anomalous Thermal Conductivity of Ice under Pressure.

Proton tunneling is believed to be nonlocal in ice, but its range has been shown to be limited to only a few molecules. Here, we measured the thermal conductivity of ice under pressure up to 50 GPa and found it increases with pressure until 20 GPa but decreases at higher pressures. We attribute this nonmonotonic thermal conductivity to the collective tunneling of protons at high pressures, supported by large-scale quantum molecular dynamics simulations. The collective tunneling loops span several picoseconds in time and are as large as nanometers in space, which match the phonon periods and wavelengths, leading to strong phonon scattering at high pressures. Our results show direct evidence of global quantum motion existing in high-pressure ice and provide a new perspective to understanding the coupling between phonon propagation and atomic tunneling.

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.

Exoproteome analysis of Pseudomonas aeruginosa response to high alkane stress.

Microbial biodegradation serves as an effective approach to treat oil pollution. However, the application of such methods for the degrading long-chain alkanes still encounters significant challenges. Comparative proteomics has extensively studied the intracellular proteins of bacteria that degrade short- and medium-chain alkanes, but the role and mechanism of extracellular proteins in many microorganism remain unclear. To enhance our understanding of the roles of extracellular proteins in the adaptation to long-chain alkanes, a label-free LC-MS/MS strategy was applied for the relative quantification of extracellular proteins of Pseudomonas aeruginosa SJTD-1-M (ProteomeXchange identifier PXD014638). 444 alkane-sentitive proteins were acquired and their cell localization analysis was performed using the Pseudomonas Genome Database. Among them, 111 proteins were found to be located in extracellular or Outer Membrane Vesicles (OMVs). The alkane-induced abundance of 11 extracellular or OMV target proteins was confirmed by parallel reaction monitoring (PRM). Furthermore, we observed that the expression levels of three proteins (Pra, PA2815, and FliC) were associated with the carbon chain length of the added alkane in the culture medium. The roles of these proteins in cell mobility, alkane emulsification, assimilation, and degradation were further discussed. OMVs were found to contain a number of enzymes involved in alkane metabolism, fatty acid beta-oxidation, and the TCA cycle, suggesting their potential as sites for facilitated alkane degradation. In this sense, this exoproteome analysis contributes to a better understanding of the role of extracellular proteins in the hydrocarbon treatment process.

Metabolomics unveil key pathways underlying the synergistic activities of aztreonam and avibactam against multidrug-resistant Escherichia coli.

PURPOSE: Aztreonam/avibactam is effective against serious infections caused by Gram-negative bacteria including Enterobacterales harboring metallo-ß-lactamases. While the utility of this combination has been established in vitro and in clinical trials, the purpose of this study is to enhance our understanding of the underlying mechanism responsible for their activities through metabolomic profiling of a multidrug-resistant Escherichia coli clinical isolate. METHODS: Metabolomic analyses of time-dependent changes in endogenous bacterial metabolites in a clinical isolate of a multidrug-resistant E. coli treated with aztreonam and avibactam were performed. E. coli metabolomes were compared at 15 min, 1 h and 24 h following treatments with either avibactam (4 mg/L), aztreonam (4 mg/L), or aztreonam (4 mg/L) + avibactam (4 mg/L). RESULTS: Drug treatment affected 326 metabolites with magnitude changes of at least 2-fold, most of which are involved primarily in peptidoglycan biosynthesis, nucleotide metabolism, and lipid metabolism. The feedstocks for peptidoglycan synthesis were depleted by aztreonam/avibactam combination; a significant downstream increase in nucleotide metabolites and a release of lipids were observed at the three timepoints. CONCLUSION: The findings indicate that the aztreonam/avibactam combination accelerates structural damage to the bacterial membrane structure and their actions were immediate and sustained compared to aztreonam or avibactam alone. By inhibiting the production of crucial cell wall precursors, the combination may have inflicted damages on bacterial DNA.

Serum Autotaxin Level Positively Associates with Metabolic Associated Fatty Liver Disease and Hyperuricemia in Postmenopausal Women.

INTRODUCTION: Autotaxin is an adipokine known to affect energy metabolism and lipid homeostasis. We aimed to evaluate serum autotaxin levels in metabolic associated fatty liver disease (MAFLD) and other metabolic disorders in postmenopausal women. METHODS: Postmenopausal women who received an annual health examination were included. The metabolic and demographic characteristics of the subjects were collected, including age, gender, weight, height, blood pressure, and biochemical parameters. Serum autotaxin level was determined by ELISA. RESULTS: This cross-sectional includes 20 postmenopausal women and 20 age-paired healthy controls. MAFLD patients showed significant metabolic disturbance presented with increased BMI, blood pressure (P＜0.001) and decreased HDL-C (P＜0.05), as well as liver injury companied by elevated ALT (P＜0.05). Serum autotaxin levels were statistically higher in MAFLD (253.1±52.1 vs. 202.2±53.2 ng/mL; P < 0.01) and positively correlated with ALT (P＜0.001), GGT and BMI (P＜0.01), SBP and TG (P＜0.05). Higher autotaxin group demonstrated worsen metabolic states with greater proportion of MAFLD, higher BMI (P＜0.01) and ALT (P＜0.05). Logistic regression analysis revealed that serum autotaxin levels would positively independently predicted MAFLD (OR 1.049, 95% CI 1.001-1.098, P＜0.05) with AUC of 0.763. Serum level of autotaxin is significantly elevated in hyperuricemia group (257.3±60.9 vs. 214.5±49.4 ng/mL; P < 0.05), and positively correlated with uric acid level (P＜0.01). Serum autotaxin would also act as diagnosing parameter of hyperuricemia with AUC of 0.706. CONCLUSIONS: Among postmenopausal women, serum autotaxin level is significantly elevated in MAFLD and related to multiple metabolic characteristics, especially hyperuricemia, which would thus serve as a potential non-invasive biomarker as well as a therapeutic target.

Peniditerpenoids A and B: Oxidized Indole Diterpenoids with Osteoclast Differentiation Inhibitory Activity from a Mangrove-Sediment-Derived Penicillium sp.

An unprecedented di-seco-indole diterpenoid, peniditerpenoid A (1), and a rare N-oxide-containing indole diterpenoid derivative, peniditerpenoid B (2), together with three known ones (3-5), were obtained from the mangrove-sediment-derived fungus Penicillium sp. SCSIO 41411. Their structures were determined by the analysis of spectroscopic data, quantum chemical calculations, and X-ray diffraction analyses. Peniditerpenoid A (1) inhibited lipopolysaccharide-induced NF-κB with an IC50 value of 11 µM and further effectively prevented RANKL-induced osteoclast differentiation in bone marrow macrophages. In vitro studies demonstrated that 1 exerted significant inhibition of NF-κB activation in the classical pathway by preventing TAK1 activation, IκBα phosphorylation, and p65 translocation. Furthermore, 1 effectively reduced the level of NFATc1 activation, resulting in the attenuation of osteoclast differentiation. Our findings suggest that 1 holds promise as an inhibitor with significant potential for the treatment of diseases related to osteoporosis.

Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products.

A strategy integrating in silico molecular docking with LXRα and phenotypic assays was adopted to discover anti-hypercholesterolemia agents in a small library containing 205 marine microorganism-derived natural products, collected by our group in recent years. Two fumitremorgin derivatives, 12R,13S-dihydroxyfumitremorgin C (1) and tryprostatin A (3), were identified as potential LXRα agonists, by real-time qPCR and Western blot (WB) analysis, together with a surface plasmon resonance (SPR) assay. The anti-hypercholesterolemic effects of 1 and 3, together with their mechanisms, were investigated in depth using different cell and mouse models, among which the study of LXRα is of crucial importance. Compound 1 or 3 exhibited the capacity to effectively reverse excessive lipid accumulation in a hepatic steatosis cell model and significantly reduce liver damage and blood cholesterol levels in high cholesterol diet (HCD)-fed wild-type mice, whereas those beneficial effects were completely nullified in HCD-fed LXRα-knockout mice. Furthermore, 1 and 3 outperformed common LXRα agonists by suppressing the expression of sterol regulatory element-binding protein 1 (SREBP1) in HCD-fed mice, mitigating lipotoxicity. Thus, this study highlights the discovery of two marine microorganism-derived anti-hypercholesterolemia agents targeting LXRα.

Discovery of Oxidized p-Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi.

Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40-16 µM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-ß1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 µM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.

New Sesquiterpenoids from the Mangrove-Derived Fungus Talaromyces sp. as Modulators of Nuclear Receptors.

Four new sesquiterpenoids, talaroterpenes A-D (1-4), were isolated from the mangrove-derived fungus Talaromyces sp. SCSIO 41412. The structures of compounds 1-4 were elucidated through comprehensive NMR and MS spectroscopic analyses. The absolute configurations of 1-4 were assigned based on single-crystal X-ray diffraction and calculated electronic circular dichroism analysis. Talaroterpenes A-D (1-4) were evaluated with their regulatory activities on nuclear receptors in HepG2 cells. Under the concentrations of 200 µM, 1, 3 and 4 exhibited varying degrees of activation on ABCA1 and PPARα, while 4 showed the strongest activities. Furthermore, 4 induced significant alterations in the expression of downstream target genes CLOCK and BMAL1 of RORα, and the in silico molecular docking analysis supported the direct binding interactions of 4 with RORα protein. This study revealed that talaroterpene D (4) was a new potential non-toxic modulator of nuclear receptors.

New Bioactive Polyketides from the Mangrove-Derived Fungus Penicillium sp. SCSIO 41411.

Three new polyketides, including three ester derivatives (1, 3, and 5) and a new natural product, which was a benzoquinone derivative, embelin A (4), together with nine known ones (2 and 6-13), were isolated from the mangrove-derived fungus Penicillium sp. SCSIO 41411. Their structures were determined by detailed NMR and MS spectroscopic analyses. The X-ray single-crystal diffraction analysis of 4 was described for the first time. Compound 9 displayed obvious inhibition against PDE4 with an inhibitory ratio of 40.78% at 10 µM. Compound 12 showed DPPH radical scavenging activity, with an EC50 of 16.21 µg/mL, compared to the positive control (ascorbic acid, EC50, 11.22 µg/mL). Furthermore, compound 4 exhibited cytotoxicity against PC-3 and LNCaP with IC50 values of 18.69 and 31.62 µM, respectively.

Two C23-Steroids and a New Isocoumarin Metabolite from Mangrove Sediment-Derived Fungus Penicillium sp. SCSIO 41429.

Two new C23-steroids derivatives, cyclocitrinoic acid A (1) and cyclocitrinoic acid B (2), and a new isocoumarin metabolite, (3R,4S)-6,8-dihydroxy-3,4,5-trimethyl-7-carboxamidelisocoumarin (10), together with 12 known compounds (3-9, 11-15) were isolated from the mangrove-sediment fungus Penicillium sp. SCSIO 41429. The structures of the new compounds were comprehensively characterized by 1D and 2D NMR, HRESIMS and ECD calculation. All isolates were evaluated for pancreatic lipase (PL) inhibitory and antioxidant activities. The biological evaluation results revealed that compounds 2, 14 and 15 displayed weak or moderate inhibition against PL, with IC50 values of 32.77, 5.15 and 2.42 µM, respectively. In addition, compounds 7, 12 and 13 showed radical scavenging activities against DPPH, with IC50 values of 64.70, 48.13, and 75.54 µM, respectively. In addition, molecular docking results indicated that these compounds had potential for PL inhibitory and antioxidant activities, which provided screening candidates for antioxidants and a reduction in obesity.

Two New Sesquiterpenoids and a New Shikimic Acid Metabolite from Mangrove Sediment-Derived Fungus Roussoella sp. SCSIO 41427.

Two new sesquiterpenoid derivatives, elgonenes M (1) and N (2), and a new shikimic acid metabolite, methyl 5-O-acetyl-5-epi-shikimate (3), were isolated from the mangrove sediment-derived fungus Roussoella sp. SCSIO 41427 together with fourteen known compounds (4-17). The planar structures were elucidated through nuclear magnetic resonance (NMR) and mass spectroscopic (MS) analyses. The relative configurations of 1-3 were ascertained by NOESY experiments, while their absolute configurations were determined by electronic circular dichroism (ECD) calculation. Elgonene M (1) exhibited inhibition of interleukin-1ß (IL-1ß) mRNA, a pro-inflammatory cytokine, at a concentration of 5 µM, with an inhibitory ratio of 31.14%. On the other hand, elgonene N (2) demonstrated inhibition at a concentration of 20 µM, with inhibitory ratios of 27.57%.

Novel Metabolites from the Marine-Derived Fungus Peniophora sp. SCSIO41203 Show Promising In Vitro Antitumor Activity as Methuosis Inducers in PC-3 Cells.

Two new cytochalasin derivatives, peniotrinins A (1) and B (2), three new citrinin derivatives, peniotrinins C-E (4, 5, 7), and one new tetramic acid derivative, peniotrinin F (12), along with nine structurally related known compounds, were isolated from the solid culture of Peniophora sp. SCSIO41203. Their structures, including the absolute configurations of their stereogenic carbons, were fully elucidated based on spectroscopic analysis, quantum chemical calculations, and the calculated ECD. Interestingly, 1 is the first example of a rare 6/5/5/5/6/13 hexacyclic cytochalasin. We screened the above compounds for their anti-prostate cancer activity and found that compound 3 had a significant anti-prostate cancer cell proliferation effect, while compounds 1 and 2 showed weak activity at 10 µM. We then confirmed that compound 3 exerts its anti-prostate cancer effect by inducing methuosis through transmission electron microscopy and cellular immunostaining, which suggested that compound 3 might be first reported as a potential anti-prostate methuosis inducer.

Discovery and Bioactivity Evaluation of Citrinin Derivatives from the Mangrove Sediment-Derived Fungus Talaromyces sp. SCSIO 41428.

A dimeric citrinin derivative with a unique spiro[chroman-2,3'-isochroman] skeleton, xerucitrinic acid C (1), and a new citrinin derivative, cladosporin E (6), along with ten known polyketides (2-5 and 7-12), were isolated from the mangrove sediment-derived fungus Talaromyces sp. SCSIO 41428. Their structures were elucidated through comprehensive spectral data analysis. The absolute configurations of 1 and 6 were determined by quantum chemical calculations. Compound 1 exhibited significant inhibitory effects on Staphylococcus aureus and Streptococcus suis, with the MIC of 25 µg/mL for both bacterial strains. Xerucitrinin C (3) exhibited significant radical scavenging activity against DPPH, with an IC50 value of 25.4 µM, and also demonstrated inhibitory activity against phosphodiesterase-4 (PDE4). Moreover, cladosporin C (7) notably inhibited prostate cancer cells PC-3 and 22Rv1, with IC50 values of 6.10 and 9.25 µM, respectively.

One New Quinazoline-Containing Diketopiperazine Isolated from the Marine-Sponge-Derived Fungus Penicillium sp. SCSIO41043.

One new quinazoline-containing diketopiperazine (1), along with 24 known compounds including nine alkaloids (2-9, and 25), thirteen lactones (10-22), aspterric acid (23), and catechol (24), were isolated from the marine sponge-derived Penicillium sp. SCSIO41043. Their planar structures were unequivocally elucidated by spectroscopic analysis. The absolute configuration of 1 was determined by a comparison of reported and experimental electronic circular dichroism (ECD) spectra. Compound 16 was found to notably inhibit the growth of five pathogenic bacteria and fungi with MIC values ranging from 0.5-16.0 µg/mL. Compounds 7, 17, 20, and 22 demonstrated moderate activity against Micrococcus luteus with MIC values ranging from 35.6 to 71.1 µg/mL. Moreover, 1-3 displayed different degrees of antioxidant activity with EC50 values of 0.98, 0.60, 0.46 mg/mL, respectively.

Two New Isocoumarins Isolated from the Marine-Sponge-Derived Fungus Setosphaeria sp. SCSIO41009.

Two new dihydroisocoumarins, exserolides L and M (1 and 2), along with six known compounds (3-8) were isolated from the extract of the marine-sponge-derived fungus Setosphaeria sp. SCSIO41009. Their structures were established by spectroscopic analyses. The absolute configurations of two new compounds were determined by modified Mosher's method and ECD data. Compounds 1 and 4 showed significant antiviral activities against A/Puerto Rico/8/34 H274Y (H1 N1) with IC50 values of 4.07±0.76 µM and 20.06±4.85 µM, respectively.

Antimicrobial Isochroman-Derived Atropo-diastereomeric Dimers from Penicillium steckii SCISO 41228.

A pair of unidentified atropisomeric dimers, penicisteckins G (1) and H (2), and twelve known compounds (3-16) were isolated from the marine coral-derived fungus Penicillium steckii SCISO41228. Their structures including the absolute configuration were determined by HR-ESI-MS, ECD, 1D-, and 2D-NMR spectra. Compounds 1 and 2 exhibited potent antibacterial activity against most pathogenic strains, especially for MASA and Micrococcus luteus, with MIC values of 4.0 µg·mL-1. In addition, compounds 2 and 3 exhibit potent antioxidant activity with IC50 values of 10.76 and 8.66 µg·mL-1, respectively.

Discovery of Enzyme Inhibitors from Mangrove Sediment Derived Fungus Trichoderma harzianum SCSIO 41051.

One new fatty acid derivative, (2E,4E)-6,7-dihydroxy-2-methylocta-2,4-dienoic acid (1), and 16 known compounds (2-17) were isolated from the mangrove sediment derived fungus Trichoderma harzianum SCSIO 41051. Their structures were established by spectroscopic methods, computational ECD, and Mo2(OAc)4-induced ECD experiment. All the compounds were evaluated for their acetylcholinesterase (AChE) and pancreatic lipase (PL) inhibition. Compounds 9 and 14 exhibited moderate AChE inhibitory activities with IC50 values of 2.49 and 2.92 µM, respectively, which compounds 8 and 9 displayed moderate inhibition on PL with IC50 value of 2.30 and 2.34 µM, respectively.

A New Brominated Isocoumarin from the Marine Starfish-Associated Fungus Aspergillus sp. WXF1904.

Based on the one strain many compounds strategy, a new brominated isocoumarin, 5-bromo-6,8-dihydroxy-3,7-dimethylisocoumarin (1), along with four new natural products, methyl 3-bromo-2,4-dihydroxy-6-methylbenzoate (2), methyl 2-bromo-4,6-dihydroxybenzoate (3), (E)-3-(3-bromo-4-hydroxyphenyl) acrylic acid (4) and 4-hydroxy-3-methyl-6-phenyl-2H-pyran-2-one (5), and four known compounds, methyl orsellinate (6), 4-hydroxy-3-methyl-6-(1-methyl-1-propenyl)-2H-pyran-2-one (7), pilobolusate (8) and cis-ferulic acid (9), were isolated from the ethyl acetate extract of the fungus Aspergillus sp. WXF1904 under the condition of adding bromine salt to the production medium. The structures of the new compounds were established by analysis of NMR and MS data. Compounds (1-9) were evaluated for inhibitory activity of acetylcholinesterase and pancreatic lipase, the new compound 1, known compounds 6 and 7 displayed weak inhibitory activity against acetylcholinesterase, compounds 2, 5, 7 and 8 showed weak inhibitory activity against pancreatic lipase.