Ferroptosis crosstalk in anti-tumor immunotherapy: molecular mechanisms, tumor microenvironment, application prospects.

Immunotherapies for cancer, specifically immune checkpoint inhibition (ICI), have shown potential in reactivating the body's immune response against tumors. However, there are challenges to overcome in addressing drug resistance and improving the effectiveness of these treatments. Recent research has highlighted the relationship between ferroptosis and the immune system within immune cells and the tumor microenvironment (TME), suggesting that combining targeted ferroptosis with immunotherapy could enhance anti-tumor effects. This review explores the potential of using immunotherapy to target ferroptosis either alone or in conjunction with other therapies like immune checkpoint blockade (ICB) therapy, radiotherapy, and nanomedicine synergistic treatments. It also delves into the roles of different immune cell types in promoting anti-tumor immune responses through ferroptosis. Together, these findings provide a comprehensive understanding of synergistic immunotherapy focused on ferroptosis and offer innovative strategies for cancer treatment.

Identification of RRM2 as a key ferroptosis-related gene in sepsis.

OBJECTIVE: Sepsis and sepsis-associated organ failure are devastating conditions for which there are no effective therapeutic agent. Several studies have demonstrated the significance of ferroptosis in sepsis. The study aimed to identify ferroptosis-related genes (FRGs) in sepsis, providing potential therapeutic targets. METHODS: The weighted gene co-expression network analysis (WGCNA) was utilized to screen sepsis-associated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to explore gene functions. Three machine learning methods were employed to identify sepsis-related hub genes. Survival and multivariate Cox regression analysis allowed further screening for the key gene RRM2 associated with prognosis. The immune infiltration analysis of the screened sepsis key genes was performed. Additionally, a cecum ligation and puncture (CLP)-induced mouse sepsis model was constructed to validate the expression of key gene in the sepsis. RESULTS: Six sepsis-associated differentially expressed FRGs (RRM2, RPL7A, HNRNPA1, PEBP1, MYL8B and TXNIP) were screened by WGCNA and three machine learning methods analysis. Survival analysis and multivariate Cox regression analysis showed that RRM2 was a key gene in sepsis and an independent prognostic factor associated with clinicopathological and molecular features of sepsis. Immune cell infiltration analysis demonstrated that RRM2 had a connection to various immune cells, such as CD4 T cells and neutrophils. Furthermore, animal experiment demonstrated that RRM2 was highly expressed in CLP-induced septic mice, and the use of Fer-1 significantly inhibited RRM2 expression, inhibited serum inflammatory factor TNF-α, IL-6 and IL-1ß expression, ameliorated intestinal injury and improved survival in septic mice. CONCLUSION: RRM2 plays an important role in sepsis and may contribute to sepsis through the ferroptosis pathway. This study provides potential therapeutic targets for sepsis.

HPPO-Derived Meroterpenoids from the Marine-Derived Fungus Penicillium sp. SCSIO 41691.

Seven new 4-hydroxy-6-phenyl-2H-pyran-2-one (HPPO) derived meroterpenoids, 1-methyl-12a,12b-epoxyarisugacin M (1), 1-methyl-4a,12b-epoxyarisugacin M (2), 2,3-dihydroxy-3,4a-epoxy-12a-dehydroxyisoterreulactone A (3), 2-hydroxy-12a-dehydroxyisoterreulactone A (4), 3'-demethoxyterritrems B' (5), 4a-hydroxyarisugacin P (6), and 1-epi-arisugacin H (7), together with two known analogues (8 and 9), were isolated from the marine-derived fungal strain Penicillium sp. SCSIO 41691. Their structures were elucidated by spectroscopic methods, and the absolute configurations of compounds 1 and 3 were determined by single-crystal X-ray diffraction. Among them, 1 and 2 had a unique methyl migration in the basic meroterpenoid skeleton with a 12a,12b-epoxy or 4a,12b-epoxy group, and 3 was a highly oxygenated HPPO-derived meroterpenoid featuring a rare 6/5/6/6/6/6 hexacyclic system with a 3,4a-epoxy group. Biologically, 5 exhibited inhibitory activity against lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells with an IC50 value of 21 µM, more potent than the positive control indomethacin.

Development of novel ALOX15 inhibitors combining dual machine learning filtering and fragment substitution optimisation approaches, molecular docking and dynamic simulation methods.

The oxidation of unsaturated lipids, facilitated by the enzyme Arachidonic acid 15-lipoxygenase (ALOX15), is an essential element in the development of ferroptosis. This study combined a dual-score exclusion strategy with high-throughput virtual screening, naive Bayesian and recursive partitioning machine learning models, the already established ALOX15 inhibitor i472, and a docking-based fragment substitution optimisation approach to identify potential ALOX15 inhibitors, ultimately leading to the discovery of three FDA-approved drugs that demonstrate optimal inhibitory potential against ALOX15. Through fragment substitution-based optimisation, seven new inhibitor structures have been developed. To evaluate their practicality, ADMET predictions and molecular dynamics simulations were performed. In conclusion, the compounds found in this study provide a novel approach to combat conditions related to ferroptosis-related injury by inhibiting ALOX15.

Identification of PLK1-PBD Inhibitors from the Library of Marine Natural Products: 3D QSAR Pharmacophore, ADMET, Scaffold Hopping, Molecular Docking, and Molecular Dynamics Study.

PLK1 is found to be highly expressed in various types of cancers, but the development of inhibitors for it has been slow. Most inhibitors are still in clinical stages, and many lack the necessary selectivity and anti-tumor effects. This study aimed to create new inhibitors for the PLK1-PBD by focusing on the PBD binding domain, which has the potential for greater selectivity. A 3D QSAR model was developed using a dataset of 112 compounds to evaluate 500 molecules. ADMET prediction was then used to select three molecules with strong drug-like characteristics. Scaffold hopping was employed to reconstruct 98 new compounds with improved drug-like properties and increased activity. Molecular docking was used to compare the efficient compound abbapolin, confirming the high-activity status of [(14S)-14-hydroxy-14-(pyridin-2-yl)tetradecyl]ammonium,[(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium. Molecular dynamics simulations and MMPBSA were conducted to evaluate the stability of the compounds in the presence of proteins. An in-depth analysis of [(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium identified them as potential candidates for PLK1 inhibitors.

Identification of Marine-Derived SLC7A11 Inhibitors: Molecular Docking, Structure-Based Virtual Screening, Cytotoxicity Prediction, and Molecular Dynamics Simulation.

The search for anticancer drugs that target ferroptosis is a promising avenue of research. SLC7A11, a key protein involved in ferroptosis, has been identified as a potential target for drug development. Through screening efforts, novel inhibitors of SLC7A11 have been designed with the aim of promoting ferroptosis and ultimately eliminating cancer cells. We initially screened 563 small molecules using pharmacophore and 2D-QSAR models. Molecular docking and ADMET toxicity predictions, with Erastin as a positive control, identified the small molecules 42711 and 27363 as lead compounds with strong inhibitory activity against SLC7A11. Further optimization resulted in the development of a new inhibitor structure (42711_11). Molecular docking and ADMET re-screening demonstrated successful fragment substitution for this small molecule. Final molecular dynamics simulations also confirmed its stable interaction with the protein. These findings represent a significant step towards the development of new therapeutic strategies for ferroptosis-related diseases.

TRAF6 Inhibitors from Marine Compound Library: Pharmacophore, Virtual Screening, Fragment Replacement, ADMET, and Molecular Dynamics.

TRAF6 is an E3 ubiquitin ligase that plays a crucial role in cell signaling. It is known that MMP is involved in tumor metastasis, and TRAF6 induces MMP-9 expression by binding to BSG. However, inhibiting TRAF6's ubiquitinase activity without disrupting the RING domain is a challenge that requires further research. To address this, we conducted computer-based drug screening to identify potential TRAF6 inhibitors. Using a ligand-receptor complex pharmacophore based on the inhibitor EGCG, known for its anti-tumor properties, we screened 52,765 marine compounds. After the molecular docking of 405 molecules with TRAF6, six compounds were selected for further analysis. By replacing fragments of non-binding compounds and conducting second docking, we identified two promising molecules, CMNPD9212-16 and CMNPD12791-8, with strong binding activity and favorable pharmacological properties. ADME and toxicity predictions confirmed their potential as TRAF6 inhibitors. Molecular dynamics simulations showed that CMNPD12791-8 maintained a stable structure with the target protein, comparable to EGCG. Therefore, CMNPD12791-8 holds promise as a potential inhibitor of TRAF6 for inhibiting tumor growth and metastasis.

New Alkaloids and Steroids from Hydranth of Goniopora columna Corals and Their Inhibiting Lung Cancer Cell Activities.

A new alkaloids, aplysingoniopora A (1), and new configuration pregnane type steroid compound, 9,17-α-pregn-1,4,20-en-3-one (2), and two known pregnane type steroid compounds (3 and 4) were isolated from hydranth of Goniopora columna corals. The compounds structures and absolute configurations were determined by extensive spectroscopic analysis, MS data, single-crystal X-ray diffraction analysis and quantum chemical calculation. The anticancer effect of the compounds were explored in human non-small-cell lung cancer (NSCLC) A549 cell lines. As the results, the compound 3 and 4 induces toxicity and has proliferation inhibitory effects on A549 cells (IC50=58.99 µM and 58.77 µM, respectively) in vitro.

Administration of Gracilariopsis lemaneiformis polysaccharide attenuates cisplatin-induced inflammation and intestinal mucosal damage in colon-26 carcinoma tumor-bearing mice.

BACKGROUND: Our preliminary research revealed that the polysaccharide GP90 from Gracilariopsis lemaneiformis enhanced the antitumor effect of cisplatin, indicating that GP90 may increase the chemotherapeutic sensitivity. However, it is still necessary to fully understand whether GP90 can also improve the intestinal barrier dysfunction and systemic inflammation induced by cisplatin. RESULTS: GP90 has been demonstrated to inhibit the excessive release of nitirc oxide, interleukin (IL)-6, IL-1ß and tumor necrosis factor (TNF)-α induced by lipopolysaccharide in RAW264.7 cells. In vivo, GP90 effectively ameliorated the decrease in the serum CD4+ /CD8+ T-cell ratio induced by cisplatin and significantly reduced the increase in the inflammatory cytokines, CD4+ Foxp3+ , CD4+ granzyme B+ and CD4+ TNF-α induced by cisplatin. Furthermore, when combined with cisplatin, GP90 increases the protein expression levels of mucin-2 and zonula occludens-1 in the mouse small intestine. Additionally, GP90 combined with cisplatin has a modulatory effect on the intestinal microbiota by elevating the Firmicutes-to-Bacteroidetes ratio and the relative abundance of beneficial microorganisms (Lachnospiraceae bacterium), at the same time as reducing the abundance of cisplatin specific Bacteroides acidifaciens and elevating the content of butyric acid and isobutyric acid. CONCLUSION: Collectively, these findings indicate that GP90 potentially mitigates inflammation and protects the intestinal barrier in tumor-bearing organisms undergoing chemotherapy. © 2024 Society of Chemical Industry.

Molecular mechanisms of ferroptosis and relevance to inflammation.

INTRODUCTION: Inflammation is a defensive response of the organism to irritation which is manifested by redness, swelling, heat, pain and dysfunction. The inflammatory response underlies the role of various diseases. Ferroptosis, a unique modality of cell death, driven by iron-dependent lipid peroxidation, is regulated by multifarious cellular metabolic pathways, including redox homeostasis, iron processing and metabolism of lipids, as well as various signaling pathways associated with diseases. A growing body of evidence suggests that ferroptosis is involved in inflammatory response, and targeting ferroptosis has great prospects in preventing and treating inflammatory diseases. MATERIALS AND METHODS: Relevant literatures on ferroptosis, inflammation, inflammatory factors and inflammatory diseases published from January 1, 2010 to now were searched in PubMed database. CONCLUSION: In this review, we summarize the regulatory mechanisms associated with ferroptosis, discuss the interaction between ferroptosis and inflammation, the role of mitochondria in inflammatory ferroptosis, and the role of targeting ferroptosis in inflammatory diseases. As more and more studies have confirmed the relationship between ferroptosis and inflammation in a wide range of organ damage and degeneration, drug induction and inhibition of ferroptosis has great potential in the treatment of immune and inflammatory diseases.

The combination of machine learning and untargeted metabolomics identifies the lipid metabolism -related gene CH25H as a potential biomarker in asthma.

BACKGROUND: Lipids, significant signaling molecules, regulate a multitude of cellular responses and biological pathways in asthma which are closely associated with disease onset and progression. However, the characteristic lipid genes and metabolites in asthma remain to be explored. It is also necessary to further investigate the role of lipid molecules in asthma based on high-throughput data. OBJECTIVE: To explore the biomarkers and molecular mechanisms associated with lipid metabolism in asthma. METHODS: In this study, we selected three mouse-derived datasets and one human dataset (GSE41665, GSE41667, GSE3184 and GSE67472) from the GEO database. Five machine learning algorithms, LASSO, SVM-RFE, Boruta, XGBoost and RF, were used to identify core gene. Additionally, we used non-negative matrix breakdown (NMF) clustering to identify two lipid molecular subgroups and constructed a lipid metabolism score by principal component analysis (PCA) to differentiate the subtypes. Finally, Western blot confirmed the altered expression levels of core genes in OVA (ovalbumin) and HDM+LPS (house dust mite+lipopolysaccharide) stimulated and challenged BALB/c mice, respectively. Results of non-targeted metabolomics revealed multiple differentially expressed metabolites in the plasma of OVA-induced asthmatic mice. RESULTS: Cholesterol 25-hydroxylase (CH25H) was finally localized as a core lipid metabolism gene in asthma and was verified to be highly expressed in two mouse models of asthma. Five-gene lipid metabolism constructed from CYP2E1, CH25H, PTGES, ALOX15 and ME1 was able to distinguish the subtypes effectively. The results of non-targeted metabolomics showed that most of the aberrantly expressed metabolites in the plasma of asthmatic mice were lipids, such as LPC 16:0, LPC 18:1 and LPA 18:1. CONCLUSION: Our findings imply that the lipid-related gene CH25H may be a useful biomarker in the diagnosis of asthma.

In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries.

USP7 is highly expressed in a variety of tumors and is thought to play a major role in cancer development. However, there are no drugs available to target USP7, so there is a need to develop new USP7 inhibitors. In this study, AutoQSAR, multiple linear regression, and Naive Bayesian models were constructed using 543 compounds and used to analyze marine compounds. After selecting 240 small molecules for molecular docking with Maestro, MOE, and GOLD, better small molecules than the positive compound P217564 were screened. The molecular structure of "1, 2-dibromobenzene" was optimized to improve the binding effect of the protein, and 10 optimized compounds in ADMET performed well during the screening process. To study the dynamic combination of protein-ligand effect consistency with static molecular docking, 100ns molecular dynamics simulations of candidate compound 1008-1, reference compound P217564, and negative-positive GNE2917 were conducted. The results of molecular docking and molecular dynamics simulation analysis showed that compound 1008-1 maintained a stable conformation with the target protein. Thus, the comprehensive analysis suggests that compound 1008-1 could provide new possibilities for USP7 covalent inhibitor candidates.

Lecanicilliums A-F, Thiodiketopiperazine-Class Alkaloids from a Mangrove Sediment-Derived Fungus Lecanicillium kalimantanense.

Six new thiodiketopiperazine-class alkaloids lecanicilliums A-F were isolated from the mangrove sediment-derived fungus Lecanicillium kalimantanense SCSIO41702, together with thirteen known analogues. Their structures were determined by spectroscopic analysis. The absolute configurations were determined by quantum chemical calculations. Electronic circular dichroism (ECD) spectra and the structure of Lecanicillium C were further confirmed by a single-crystal X-ray diffraction analysis. Lecanicillium A contained an unprecedented 6/5/6/5/7/6 cyclic system with a spirocyclic center at C-2'. Biologically, lecanicillium E, emethacin B, and versicolor A displayed significant cytotoxicity against human lung adenocarcinoma cell line H1975, with IC50 values of 7.2~16.9 µM, and lecanicillium E also showed antibacterial activity against four pathogens with MIC values of 10~40 µg/mL. Their structure-activity relationship is also discussed.

mPGES-1 Inhibitor Discovery Based on Computer-Aided Screening: Pharmacophore Models, Molecular Docking, ADMET, and MD Simulations.

mPGES-1 is an enzyme, which, when activated by inflammatory factors, can cause prostaglandin E synthesis. Traditional non-steroidal anti-inflammatory drugs are capable of inhibiting prostaglandin production, yet they can also cause gastrointestinal reactions and coagulation disorders. mPGES-1, the enzyme at the conclusion of prostaglandin production, does not cause any adverse reactions when inhibited. Numerous studies have demonstrated that mPGES-1 is more abundant in cancerous cells than in healthy cells, indicating that decreasing the expression of mPGES-1 could be a potential therapeutic strategy for cancer. Consequently, the invention of mPGES-1 inhibitors presents a fresh avenue for the treatment of inflammation and cancer. Incorporating a database of TCM compounds, we collected a batch of compounds that had an inhibitory effect on mPGES-1 and possessed IC50 value. Firstly, a pharmacophore model was constructed, and the TCM database was screened, and the compounds with score cut-off values of more than 1 were retained. Then, the compounds retained after being screened via the pharmacodynamic model were screened for docking at the mPGES-1 binding site, followed by high-throughput virtual screening [HTVS] and standard precision [SP] and super-precision [XP] docking, and the compounds in the top 20% of the XP docking score were selected to calculate the total free binding energy of MM-GBSA. The best ten compounds were chosen by comparing their score against the reference ligand 4U9 and the MM-GBSA_dG_Bind score. ADMET analysis resulted in the selection of ten compounds, three of which had desirable medicinal properties. Finally, the binding energy of the target protein mPGES-1 and the candidate ligand compound was analyzed using a 100 ns molecular dynamics simulation of the reference ligand 4U9 and three selected compounds. After a gradual screening study and analysis, we identified a structure that is superior to the reference ligand 4U9 in all aspects, namely compound 15643. Taken together, the results of this study reveal a structure that can be used to inhibit mPGES-1 compound 15643, thereby providing a new option for anti-inflammatory and anti-tumor drugs.

Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy.

OBJECTIVE: Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and Panax ginseng has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota. DESIGN: Syngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed. RESULTS: We found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of Teff cells after combination treatment. Besides, the microbial analysis indicated that the abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders. CONCLUSION: Our results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.

Identification and validation of a ferroptosis-related gene to predict survival outcomes and the immune microenvironment in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is a leading cause of cancer-related death worldwide. Ferroptosis, a form of cell death characterized by iron-dependent lipid peroxidation. However, the involvement of ferroptosis in the regulation of immune cell infiltration and its immunotherapeutic efficacy in LUAD remain unclear. METHODS: The Cancer Genome Atlas (TCGA) LUAD cohort was used to assess the survival prognosis of FRGs and construct a seven-gene risk signature. Correlation tests, difference tests, and a cluster analysis were performed to explore the role of FRGs in the immune microenvironment and their immunotherapeutic efficacy in LUAD. The effects of FRGs on LUAD cells were assessed by Western blot, iron assay, and lipid peroxidation assay. RESULTS: The seven-gene risk signatures of patients with LUAD were established and validated. FRG clustering based on 70 differentially expressed FRGs was associated with the immune microenvironment and indicated potential immune subtypes of LUAD. The seven-gene risk signature was an independent prognostic factor for LUAD and was used to divide the LUAD cohort into a high-risk and a low-risk group. Immunocyte infiltration levels, immune checkpoints, and immunotherapy response rates were significantly different between the two groups. Patients with high risk scores had lower overall levels of immunocyte infiltration but higher immunotherapy response rates. The key gene ribonucleotide reductase subunit M2 (RRM2) was associated with LUAD prognosis, which may be related to its ability to regulate the infiltration levels of activated mast cells and activated CD4 memory T cells. In addition, RRM2 was involved in ferroptosis, and its expression was up regulated in lung cancer tissues and the LUAD cell lines. Silencing RRM2 can inhibit the proliferation and induce ferroptosis of H1975 cells suggesting that silencing RRM2 could promote ferroptosis in H1975 cells. CONCLUSION: Our results revealed RRM2 as a promising biomarker and therapeutic target associated with tumor immune infiltration in patients with LUAD.

Pyrrospirones K-Q, Decahydrofluorene-Class Alkaloids from the Marine-Derived Fungus Penicillium sp. SCSIO 41512.

Seven new decahydrofluorene-class alkaloids, pyrrospirones K-Q (1-7), together with six known analogues (8-13) were isolated from the marine-derived fungal strain Penicillium sp. SCSIO 41512. Their structures were determined by extensive spectroscopic analysis, and their absolute configurations were established by single-crystal X-ray diffraction analysis and quantum chemical calculations of electronic circular dichroism spectra. Compounds 1 and 3 possess a novel decahydrofluorene-class alkaloid skeleton with a 6/5/6/8/5/6/13 and a 6/5/6/5/6/13 polycyclic system, respectively. Biologically, 13 displayed significant inhibitory activity against protein tyrosine phosphatases CD45, TCPTP, SHP1, and PTP1B with IC50 values of 8.1-17.8 µM, and 1, 2, 5, 8-10, 12, and 13 showed antibacterial activity against six pathogens. Their structure-activity relationship is also discussed.

The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and Molecular Dynamics Study.

BACKGROUND: CDK4/6 (Cyclin-dependent kinases 4/6) are the key promoters of cell cycle transition from G1 phase to S phase. Thus, selective inhibition of CDK4/6 is a promising cancer treatment. METHODS: A total of 52,765 marine natural products were screened for CDK4/6. To screen out better natural compounds, pharmacophore models were first generated, then the absorption, distribution, metabolism, elimination, and toxicity (ADMET) were tested, followed by molecular docking. Finally, molecular dynamics simulation was carried out to verify the binding characteristics of the selected compounds. RESULTS: Eighty-seven marine small molecules were screened based on the pharmacophore model. Then, compounds 41369 and 50843 were selected according to the ADMET and molecular docking score for further kinetic simulation evaluation. Finally, through molecular dynamics analysis, it was confirmed that compound 50843 maintained a stable conformation with the target protein, so it has the opportunity to become an inhibitor of CDK4/6. CONCLUSION: Through structure-based pharmacophore modeling, ADMET, the molecular docking method and molecular dynamics (MD) simulation, marine natural compound 50843 was proposed as a promising marine inhibitor of CDK4/6.

Isoquinoline Alkaloids as Protein Tyrosine Phosphatase Inhibitors from a Deep-Sea-Derived Fungus Aspergillus puniceus.

Puniceusines A-N (1-14), 14 new isoquinoline alkaloids, were isolated from the extracts of a deep-sea-derived fungus, Aspergillus puniceus SCSIO z021. Their structures were elucidated by spectroscopic analyses. The absolute configuration of 9 was determined by ECD calculations, and the structures of 6 and 12 were further confirmed by a single-crystal X-ray diffraction analysis. Compounds 3-5 and 8-13 unprecedentedly contained an isoquinolinyl, a polysubstituted benzyl or a pyronyl at position C-7 of isoquinoline nucleus. Compounds 3 and 4 showed selective inhibitory activity against protein tyrosine phosphatase CD45 with IC50 values of 8.4 and 5.6 µM, respectively, 4 also had a moderate cytotoxicity towards human lung adenocarcinoma cell line H1975 with an IC50 value of 11.0 µM, and 14, which contained an active center, -C=N+, exhibited antibacterial activity. An analysis of the relationship between the structures, enzyme inhibitory activity and cytotoxicity of 1-14 revealed that the substituents at C-7 of the isoquinoline nucleus could greatly affect their bioactivity.

Ferroptosis Related Immunomodulatory Effect of a Novel Extracellular Polysaccharides from Marine Fungus Aureobasidium melanogenum.

Marine fungi represent an important and sustainable resource, from which the search for novel biological substances for application in the pharmacy or food industry offers great potential. In our research, novel polysaccharide (AUM-1) was obtained from marine Aureobasidium melanogenum SCAU-266 were obtained and the molecular weight of AUM-1 was determined to be 8000 Da with 97.30% of glucose, 1.9% of mannose, and 0.08% galactose, owing to a potential backbone of α-D-Glcp-(1→2)-α-D-Manp-(1→4)-α-D-Glcp-(1→6)-(SO3-)-4-α-D-Glcp-(1→6)-1-ß-D-Glcp-1→2)-α-D-Glcp-(1→6)-ß-D-Glcp-1→6)-α-D-Glcp-1→4)-α-D-Glcp-6→1)-[α-D-Glcp-4]26→1)-α-D-Glcp and two side chains that consisted of α-D-Glcp-1 and α-D-Glcp-(1→6)-α-D-Glcp residues. The immunomodulatory effect of AUM-1 was identified. Then, the potential molecular mechanism by which AUM-1 may be connected to ferroptosis was indicated by metabonomics, and the expression of COX2, SLC7A11, GPX4, ACSL4, FTH1, and ROS were further verified. Thus, we first speculated that AUM-1 has a potential effect on the ferroptosis-related immunomodulatory property in RAW 264.7 cells by adjusting the expression of GPX4, regulated glutathione (oxidative), directly causing lipid peroxidation owing to the higher ROS level through the glutamate metabolism and TCA cycle. Thus, the ferroptosis related immunomodulatory effect of AUM-1 was obtained.