Mutagenetic analysis of the biosynthetic pathway of tetramate bripiodionen bearing 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione skeleton.

BACKGROUND: Natural tetramates are a family of hybrid polyketides bearing tetramic acid (pyrrolidine-2,4-dione) moiety exhibiting a broad range of bioactivities. Biosynthesis of tetramates in microorganisms is normally directed by hybrid polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) machineries, which form the tetramic acid ring by recruiting trans- or cis-acting thioesterase-like Dieckmann cyclase in bacteria. There are a group of tetramates with unique skeleton of 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione, which remain to be investigated for their biosynthetic logics. RESULTS: Herein, the tetramate type compounds bripiodionen (BPD) and its new analog, featuring the rare skeleton of 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione, were discovered from the sponge symbiotic bacterial Streptomyces reniochalinae LHW50302. Gene deletion and mutant complementation revealed the production of BPDs being correlated with a PKS-NRPS biosynthetic gene cluster (BGC), in which a Dieckmann cyclase gene bpdE was identified by sit-directed mutations. According to bioinformatic analysis, the tetramic acid moiety of BPDs should be formed on an atypical NRPS module constituted by two discrete proteins, including the C (condensation)-A (adenylation)-T (thiolation) domains of BpdC and the A-T domains of BpdD. Further site-directed mutagenetic analysis confirmed the natural silence of the A domain in BpdC and the functional necessities of the two T domains, therefore suggesting that an unusual aminoacyl transthiolation should occur between the T domains of two NRPS subunits. Additionally, characterization of a LuxR type regulator gene led to seven- to eight-fold increasement of BPDs production. The study presents the first biosynthesis case of the natural molecule with 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione skeleton. Genomic mining using BpdD as probe reveals that the aminoacyl transthiolation between separate NRPS subunits should occur in a certain population of NRPSs in nature.

Meroterpenoids from Marine Sponge Hyrtios sp. and Their Anticancer Activity against Human Colorectal Cancer Cells.

Two new meroterpenoids, hyrtamide A (1) and hyrfarnediol A (2), along with two known ones, 3-farnesyl-4-hydroxybenzoic acid methyl ester (3) and dictyoceratin C (4), were isolated from a South China Sea sponge Hyrtios sp. Their structures were elucidated by NMR and MS data. Compounds 2-4 exhibited weak cytotoxicity against human colorectal cancer cells (HCT-116), showing IC50 values of 41.6, 45.0, and 37.3 µM, respectively. Furthermore, compounds 3 and 4 significantly suppressed the invasion of HCT-116 cells while also downregulating the expression of vascular endothelial growth factor receptor 1 (VEGFR-1) and vimentin proteins, which are key markers associated with angiogenesis and epithelial-mesenchymal transition (EMT). Our findings suggest that compounds 3 and 4 may exert their anti-invasive effects on tumor cells by inhibiting the expression of VEGFR-1 and impeding the process of EMT.

Marcytoglobosins A and B, Cytochalasans From a Marine Sponge Associated Chaetomium globosum 162105 Fungus.

Two new cytochalasans, marcytoglobosins A (1) and B (2) were isolated from the marine sponge associated fungus Chaetomium globosum 162105, along with six known compounds (3-8). The complete structures of two new compounds were determined based on 1D/2D NMR and HR-MS spectroscopic analyses coupled with ECD calculations. All eight isolates were evaluated for their antibacterial activity. Among them, compounds 3-8 displayed antibacterial effects against Staphylococcus epidermidis, Bacillus thuringiensis, Pseudomonas syringae pv. Actinidiae, Vibrio alginolyticus, and Edwardsiella piscicida with minimum inhibitory concentration (MIC) values ranging from 10 to 25 µg/mL.

Natural sesquiterpene quinone/quinols: chemistry, biological activity, and synthesis.

Covering: 2010 to 2021Sesquiterpene quinone/quinols (SQs) are characterized by a C15-sesquiterpenoid unit incorporating a C6-benzoquinone/quinol moiety. Numerous unprecedented carbon skeletons have been constructed with various connection patterns between the two parts. The potent anti-cancer, anti-inflammatory, anti-microbial, anti-viral, and fibrinolytic activities of SQs are associated with their diverse structures. The representative avarol has even entered the stage of clinical phase II research as an anti-HIV agent, and was developed as paramedic medicine against psoriasis. This review provides an overall summary of 558 new natural SQs discovered between 2010 and 2021, including seven groups and sixteen structure-type subgroups, which comprehensively recapitulates their chemical structures, spectral characteristics, source organisms, biological activities, synthesis, and biosynthesis, aiming to expand the application scope of this unique natural product resource.

LC-MS-Guided Isolation of Cyanogripeptides A-C, Cyclolipopeptides with ß-Methyl-Leucine Residues, from an Actinoalloteichus cyanogriseus LHW52806.

Cyanogripeptides A-C (1-3), three new cyclolipopeptides with unusual ß-methyl-leucine residues, were identified from an Actinoalloteichus cyanogriseus LHW52806 using an LC-MS-guided strategy. The structures of compounds 1-3 were elucidated by 1D/2D NMR, HR-MS/MS, and the advanced Marfey's method. The absolute configuration of the ß-methyl-leucine residue was determined by a combination of stereoselective biosynthesis of (2S,3R)-ß-methyl-leucine, racemization to its epimer (2R,3R)-ß-methyl-leucine, and the advanced Marfey's method. The biosynthetic pathway of cyanogripeptides was deduced by analyzing the genome of A. cyanogriseus LHW52806. Compound 3 exhibited antibacterial activity against Helicobacter pylori G27, Helicobacter pylori 26695, and Mycolicibacterium smegmatis ATCC607 with MIC values of 32 µg/mL.

Dysiscalarones A-E, scalarane sesterterpenoids with nitric oxide production inhibitory activity from marine sponge Dysidea granulosa.

Dysiscalarones A-E (1-5), five new scalarane-type bishomoscalarane sesterterpenoids, were isolated from marine sponge Dysidea granulosa collected from the South China Sea, together with two known ones, honulactone A (6) and phyllofolactone I (7). The new structures were determined by extensive spectroscopic analysis including HR-ESI-MS and 1D and 2D NMR data, and their absolute configurations were assigned by single crystal X-ray diffraction analyses. The inhibitory activity of all the seven isolates on the production of nitric oxide (NO) stimulated by lipopolysaccharide (LPS) in mouse RAW 264.7 macrophages was evaluated. Of these metabolites, dysiscalarones A-B (1-2), honulactone A (6), and phyllofolactone I (7) showed inhibitory activities with respective IC50 values of 16.4, 18.5, 2.6, and 3.7 µM, which suggested that the γ-methylated α,ß-unsaturated γ-lactone might be the functional group. In addition, all the seven metabolites showed no significant cytotoxicity against lung cancer PC9 cell line at the concentration of 20 µM.

Identification of chemical constituents in vitro and in vivo of Er Shen Zhenwu Decoction by utilizing ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry.

Er Shen Zhenwu Decoction is a prescription for treating chronic heart failure of heart and kidney yang deficiency, while its active ingredients remain unclear and difficult to identify. This paper aims to apply a rapid assay strategy of ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry to collect the mass spectrometry data of Er Shen Zhenwu Decoction and its decomposed recipes (monarch, minister, and assist). By comparing with retention time and MSE fragmentation patterns, 67 and 34 components in vitro and in vivo were identified, respectively, the main ingredients include saponins, terpenes, alkaloids, phenolic acids, tanshinone, urea, steroids, aromatics, organic acids, carbohydrates, and so forth, of which the monarch medicine > minister medicine > assist medicine. By comparison with reference standards, paeoniflorin, rosmarinic acid, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1 and atractylenolide III were identified in vitro and paeoniflorin, ginsenoside Rg1, ginsenoside Re and ginsenoside Rb1 were identified in vivo. In this study, the chemical ingredients of Er Shen Zhenwu Decoction were analyzed by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry technology and each compound was grouped into the decomposed recipes. The identified substances can be used as references for Er Shen Zhenwu Decoction quality control and potential medicinal substances in chronic heart failure of heart and kidney yang deficiency treatment.

Midecamycin Is Inactivated by Several Different Sugar Moieties at Its Inactivation Site.

Glycosylation inactivation is one of the important macrolide resistance mechanisms. The accumulated evidences attributed glycosylation inactivation to a glucosylation modification at the inactivation sites of macrolides. Whether other glycosylation modifications lead to macrolides inactivation is unclear. Herein, we demonstrated that varied glycosylation modifications could cause inactivation of midecamycin, a 16-membered macrolide antibiotic used clinically and agriculturally. Specifically, an actinomycetic glycosyltransferase (GT) OleD was selected for its glycodiversification capacity towards midecamycin. OleD was demonstrated to recognize UDP-D-glucose, UDP-D-xylose, UDP-galactose, UDP-rhamnose and UDP-N-acetylglucosamine to yield corresponding midecamycin 2'-O-glycosides, most of which displayed low yields. Protein engineering of OleD was thus performed to improve its conversions towards sugar donors. Q327F was the most favorable variant with seven times the conversion enhancement towards UDP-N-acetylglucosamine. Likewise, Q327A exhibited 30% conversion enhancement towards UDP-D-xylose. Potent biocatalysts for midecamycin glycosylation were thus obtained through protein engineering. Wild OleD, Q327F and Q327A were used as biocatalysts for scale-up preparation of midecamycin 2'-O-glucopyranoside, midecamycin 2'-O-GlcNAc and midecamycin 2'-O-xylopyranoside. In contrast to midecamycin, these midecamycin 2'-O-glycosides displayed no antimicrobial activities. These evidences suggested that besides glucosylation, other glycosylation patterns also could inactivate midecamycin, providing a new inactivation mechanism for midecamycin resistance. Cumulatively, glycosylation inactivation of midecamycin was independent of the type of attached sugar moieties at its inactivation site.

[Progress in pharmacodynamic basis, mechanism, and prediction of Q-markers of Zhenwu Decoction in treatment of chronic heart failure].

Zhenwu Decoction(ZWD) has a history of more than 1 800 years in traditional Chinese medicine(TCM), which is used to treat various diseases characterized by Yangqi deficiency and exuberant water and dampness. It is currently the classic prescription for the treatment of chronic heart failure(CHF). This study provides a basis for the treatment of CHF with ZWD by elaborating the traditional efficacy, theoretical basis, and underlying mechanism of the prescription. Based on the research methods and judgment basis of quality markers(Q-markers) of Chinese medicine, the Q-markers of ZWD in the treatment of CHF were predicted from the aspects of transfer and traceability, specificity, effectiveness, compatibility environment, measurability, and processing. Demethyl-coclaurine,benzoylaconine, atractylenolide Ⅲ, paeoniflorin, 6-gingerol, 8-gingerol, pachymic acid, and dehydrotumulosic acid can be used as Q-markers of ZWD for treating CHF. The result provides a reference for exploring the pharmacodynamic substances of ZWD in the treatment of CHF.

Meroterpenoids with Protein Tyrosine Phosphatase 1B Inhibitory Activity from a Hyrtios sp. Marine Sponge.

Three new meroterpenoids, hyrtiolacton A (1), nakijinol F (2), and nakijinol G (3), along with three known ones, nakijinol B (4), nakijinol E (5), and dactyloquinone A (6), were isolated and characterized from a Hyrtios sp. marine sponge collected from the South China Sea. The new structures were determined based on extensive analysis of HRESIMS and NMR data, and their absolute configurations were assigned by a combination of single-crystal X-ray diffraction and electronic circular dichroism analyses. Hyrtiolacton A (1) represents an unprecedented meroterpenoid featuring an unusual 2-pyrone attached to the sesquiterpene core, which is the first example of a pyrone-containing 4,9-friedodrimane-type sesquiterpene. These compounds were evaluated for their protein tyrosine phosphatase (PTP1B) inhibitory and cytotoxic activities. Nakijinol G (3) showed PTP1B inhibitory activity with an IC50 value of 4.8 µM but no cytotoxicity against four human cancer cell lines.

[Efficacy and safety of low-dose high intensity focused ultrasound combined with S-1 and oxaliplatin in metastatic colorectal patients with pelvic masses].

OBJECTIVE: To evaluate the efficacy and safety of the regimen of low-dose high intensity focused ultra-sound (HIFU) plus S-1 and oxaliplatin (SOX) in the treatment of metastatic colorectal cancer patients with pelvic masses. METHODS: A total of 46 patients with metastatic colorectal cancer were recruited and divided into 2 groups: Twenty patients received concurrent HIFU plus S-1 and oxaliplatin (SOX) while another 26 patients SOX alone. The baseline characteristics, progressive-free survival, overall survival time and adverse events were retrospectively analyzed. RESULTS: The median PFS was 11.2 months (95% CI 9.8-12.7) in the HIFU+SOX group and 7.1 months (95% CI 5.8-8.4) in the SOX group (P = 0.003). And the overall survival time in two groups were 21.9 months (95% CI 18.0-25.9) and 16.9 months (95%CI 14.1-19.6) (P = 0.072) respectively. Major toxic effects included grade 3/4 neutropenia (15%), anemia (10%), thrombocytopenia (10%), diarrhea (15%) and hand-foot syndrome (10%) in the HIFU+SOX group. And it showed no statistically significant differences with the SOX group. CONCLUSION: The combined regimen of HIFU and SOX is effective and well-tolerated in patients of late-stage colorectal cancer with pelvic masses.

Exploring 3-O-glycosylations of 20(R)-dammarane ginsenosides and the catalytic mechanism underlying the stereoselectivity with the combined assistance of AlphaFold 2 and molecular docking.

Glycosylation at C3-OH is the favorable modification for pharmaceutical activities and diversity expansion of 20(R)-dammarane ginsenosides. The 3-O-glycosylation, exclusively occurring in 20(R)-PPD ginsenosides, has never been achieved in 20(R)-PPT ginsenosides. Herein, 3-O-glycosylation of 20(R)-PPT enabled by a glycosyltransferase (GT) OsSGT2 was achieved with the combined assistance of AlphaFold 2 and molecular docking. Firstly, we combined AlphaFold2 algorithm and molecular docking to predict interactions between 20(R)-PPT and candidate GTs. A catalytically favorable binding geometry was thus identified in the OsSGT2-20(R)-PPT complex, suggesting OsSGT2 might act on 20(R)-PPT. The enzymatic assays demonstrated that OsSGT2 reacted with varied sugar donors to form 20(R)-PPT 3-O-glycosides, exhibiting donor promiscuity. Additionally, OsSGT2 displayed acceptor promiscuity, catalyzing 3-O-glucosylation of 20(R/S)-PPT, 20(R/S)-PPD and 20(R/S)-Rh1, respectively. Protein engineering on OsSGT2 was thus performed to probe its catalytic mechanism underlying its stereoselectivity. The W207A mutant preferred 20(S)-dammarane aglycons, while F395Q/A396G(QG) displayed a conversion enhancement towards both 20(R/S)-dammarane aglycons. The QG mutant was then used to synthesize 20(R)-PPT 3-O-glucoside, which displayed a moderate angiotensin-converting enzyme inhibitory effect with an IC50 of 27.5 ± 4.7 µM, superior to that of its 20(S)-epimer, with the combined assistance of target fishing and reverse docking. The water solubility of 20(R)-PPT 3-O-glucoside increased as well.

The novel HLA-B*40:555 allele identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-B*40:555 differs from HLA-B*40:01:02:01 by one nucleotide in exon 3.

m5 C regulator-mediated methylation modification patterns and tumor microenvironment infiltration characteristics in acute myeloid leukemia.

BACKGROUND: Recently, many studies have been conducted to examine immune response modification at epigenetic level, but the candidate effect of RNA 5-methylcytosine (m5 C) modification on tumor microenvironment (TME) of acute myeloid leukemia (AML) is still unknown at present. METHODS: We assessed the patterns of m5 C modification among 417 AML cases by using nine m5 C regulators. Thereafter, we associated those identified modification patterns with TME cell infiltration features. Additionally, stepwise regression and LASSO Cox regression analyses were conducted for quantifying patterns of m5 C modification among AML cases to establish the m5 C-score. Meanwhile, we validated the expression of genes in the m5C-score model by qRT-PCR. Finally, the present work analyzed the association between m5 C-score and AML clinical characteristics and prognostic outcomes. RESULTS: In total, three different patterns of m5 C modification (m5 C-clusters) were identified, and highly differentiated TME cell infiltration features were also identified. On this basis, evaluating patterns of m5 C modification in single cancer samples was important for evaluating the immune/stromal activities in TME and for predicting prognosis. In addition, the m5 C-score was established, which showed a close relation with the overall survival (OS) of test and training set samples. Moreover, multivariate Cox analysis suggested that our constructed m5 C-score served as the independent predicting factor for the prognosis of AML (hazard ratio = 1.57, 95% confidence interval = 1.38-1.79, p < 1e-5 ). CONCLUSIONS: This study shows that m5 C modification may be one of the key roles in the formation of diversity and complexity of TME. Meanwhile, assessing the patterns of m5 C modification among individual cancer samples is of great importance, which provides insights into cell infiltration features within TME, thereby helping to develop relevant immunotherapy and predict patient prognostic outcomes.

Marchaetoglobins A-D: Four Cytochalasans with Proangiogenic Activity from the Marine-Sponge-Associated Fungus Chaetomium globosum 162105.

Four new cytochalasans, marchaetoglobins A-D (1-4), along with five known compounds (5-9), were isolated from the marine-sponge-associated fungus Chaetomium globosum 162105. Compounds 1-4 represent examples of 19,20-seco-chaetoglobosins, of which compound 1 is the first furan-containing cytochalasan. Their structures and absolute configurations were elucidated by extensive spectroscopic analyses and electronic circular dichroism calculations. Compounds 5, 8, and 9 displayed weak to moderate antibacterial activities against Bacillus thuringiensis, Edwardsiella piscicida, Vibrio alginolyticus, and Pseudomonas syringae pv. actinidiae with minimum inhibitory concentration values ranging from 5 to 25 µg/mL. In addition, compounds 2, 3, and 5 showed potent in vivo proangiogenic activity in transgenic zebrafish, comparable to the positive control.

Cardiovascular adverse events associated with immune checkpoint inhibitors: A retrospective multicenter cohort study.

BACKGROUND: Over the past decade, immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, ICIs inevitably may cause a spectrum of immune-related adverse events, among which cardiovascular toxicity, particularly myocarditis, while infrequent, has garnered increasing attention due to its high fatality rate. METHODS: We conducted a multicenter retrospective study to characterize ICI-associated cardiovascular adverse events. Logistic regression was performed to explore the risk factors for the development of myocarditis and severe myocarditis. Receiver operating characteristic curves were conducted to assess the diagnostic abilities of cardiac biomarkers to distinguish different cardiovascular toxicities, and the performance and calibration were evaluated using Hosmer-Lemeshow test. RESULTS: Forty-four patients were identified, including thirty-five myocarditis, five heart failure, three arrhythmias, and one myocardial infarction. Compared with other patients, myocarditis patients had higher cardiac troponin-I (cTnI) levels (p < 0.001), higher creatine kinase levels (p = 0.003), higher creatine kinase isoenzyme-MB (CK-MB) levels (p = 0.013), and shorter time to the incidence of adverse cardiovascular events (p = 0.022) after ICI treatment. Twenty-one patients (60%) were classified as severe myocarditis, and they presented higher cardiac troponin I (cTnI) levels (p = 0.013), higher N-terminal pro-B-type natriuretic peptide levels (p = 0.031), higher creatine kinase levels (p = 0.018), higher CK-MB levels (p = 0.026), and higher neutrophil to lymphocyte ratio (NLR) levels (p = 0.016) compared to non-severe myocarditis patients after ICI treatment. Multivariate logistic regression showed that CK-MB (adjusted odds ratio [OR]: 1.775, 95% confidence interval [CI]: 1.055-2.984, p = 0.031) was the independent risk factor of the development of ICI-associated myocarditis, and cTnI (adjusted OR: 1.021, 95% CI: 1.002-1.039, p = 0.03) and NLR (adjusted OR: 1.890, 95% CI: 1.026-3.483, p = 0.041) were the independent risk factors of ICI-associated severe myocarditis. The receiver operating characteristic curve showed an area under curve of 0.785 (95% CI: 0.642 to 0.928, p = 0.013) for CK-MB, 0.765 (95% CI: 0.601 to 0.929, p = 0.013) for cTnI, and 0.773 for NLR (95% CI: 0.597 to 0.948, p = 0.016). CONCLUSIONS: Elevated CK-MB after ICI treatment is the independent risk factor for the incidence of ICI-associated myocarditis, and elevated cTnI and NLR after ICI treatment are the independent risk factors for the development of ICI-associated severe myocarditis. CK-MB, cTnI, and NLR demonstrated a promising predictive utility for the identification of ICI-associated myocarditis and severe myocarditis.

Isolation and absolute configuration of alkylpyridine alkaloids from the marine sponge Hippospongia lachne.

Marine sponges are well known as prolific producers of structurally diverse molecules with valuable pharmacological potential. As part of our ongoing program to discover bioactive compounds from marine sponges collected from the Xisha Islands in the South China Sea, a chemical study on the specimens of Hippospongia lachne was conducted. As a result, eight undescribed compounds, including four zwitterionic alkylpyridinium salts, hippospondines A-D (1-4), and four 3-alkylpyridine alkaloids, hippospondines E (5), F (6), and (±)-hippospondine G (7), were isolated from the marine sponge H. lachne, together with one known 3-alkylpyridine alkaloid (8). The undescribed structures were elucidated by HRESIMS, NMR, DP4+ and CP3 probability analysis, and the Snatzke's method. Hippospondines A-D (1-4) represent the rare example of inner salt type alkylpyridinium alkaloid with a farnesyl moiety. Compounds 1-3 and 8 were subjected to cytotoxic and lymphocyte proliferation assays. Compound 3 exhibited a weak promotion effect on the ConA-induced T lymphocyte proliferation.

Low-dose hypomethylating agents cooperate with ferroptosis inducers to enhance ferroptosis by regulating the DNA methylation-mediated MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway in acute myeloid leukemia.

BACKGROUND: Ferroptosis is a new form of nonapoptotic and iron-dependent type of cell death. Glutathione peroxidase-4 (GPX4) plays an essential role in anti-ferroptosis by reducing lipid peroxidation. Although acute myeloid leukemia (AML) cells, especially relapsed and refractory (R/R)-AML, present high GPX4 levels and enzyme activities, pharmacological inhibition of GPX4 alone has limited application in AML. Thus, whether inhibition of GPX4 combined with other therapeutic reagents has effective application in AML is largely unknown. METHODS: Lipid reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) assays were used to assess ferroptosis in AML cells treated with the hypomethylating agent (HMA) decitabine (DAC), ferroptosis-inducer (FIN) RAS-selective lethal 3 (RSL3), or their combination. Combination index (CI) analysis was used to assess the synergistic activity of DAC + RSL3 against AML cells. Finally, we evaluated the synergistic activity of DAC + RSL3 in murine AML and a human R/R-AML-xenografted NSG model in vivo. RESULTS: We first assessed GPX4 expression and found that GPX4 levels were higher in AML cells, especially those with MLL rearrangements, than in NCs. Knockdown of GPX4 by shRNA and indirect inhibition of GPX4 enzyme activity by RSL3 robustly induced ferroptosis in AML cells. To reduce the dose of RSL3 and avoid side effects, low doses of DAC (0.5 µM) and RSL3 (0.05 µM) synergistically facilitate ferroptosis by inhibiting the AMP-activated protein kinase (AMPK)-SLC7A11-GPX4 axis. Knockdown of AMPK by shRNA enhanced ferroptosis, and overexpression of SLC7A11 and GPX4 rescued DAC + RSL3-induced anti-leukemogenesis. Mechanistically, DAC increased the expression of MAGEA6 by reducing MAGEA6 promoter hypermethylation. Overexpression of MAGEA6 induced the degradation of AMPK, suggesting that DAC inhibits the AMPK-SLC7A11-GPX4 axis by increasing MAGEA6 expression. In addition, DAC + RSL3 synergistically reduced leukemic burden and extended overall survival compared with either DAC or RSL3 treatment in the MLL-AF9-transformed murine model. Finally, DAC + RSL3 synergistically reduced viability in untreated and R/R-AML cells and extended overall survival in two R/R-AML-xenografted NSG mouse models. CONCLUSIONS: Our study first identify vulnerability to ferroptosis by regulating MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway. Combined treatment with HMAs and FINs provides a potential therapeutic choice for AML patients, especially for R/R-AML.

Daphnane-type diterpenes with inhibitory activities against human cancer cell lines from Daphne genkwa.

Four new daphnane-type diterpenes, genkwadanes A-D (1-4), together with 19 known ones, were isolated from ethanol extract of the flower buds of Daphne genkwa. Their structures were determined on the basis of extensive spectroscopic data. Among them, daphnane-type diterpene with a 1,10-double bond (1) was isolated from this plant for the first time. The cytotoxicity of all compounds 1-23 against the 10 selected human cancer cell lines was assayed. A number of compounds exhibited significant activities against the 10 cancer cell lines (IC50<9.56 µM). and most interestingly, all the compounds revealed preferred cytotoxicities on the HT-1080 cell line and displayed much stronger inhibitory activities (IC50<29.94 µM) compared with positive control 5-fluorouracil (IC50=35.62 µM), particularly, compounds 9-11, 13, 16 and 19 exhibited the strongest cytotoxicity activities against the HT-1080 cell line (IC50<0.1 µM).

Hipposponols A and B, two new 9, 11-secosterols from the marine sponge Hippospongia lachne de Laubenfels.

Two new 9,11-secosterols, hipposponols A (1) and B (2), together with five known analogues, aplidiasterol B (3), (3ß,5α,6ß)-3,5,6-triol-cholest-7-ene (4), (3ß,5α,6ß,22E)-3,5,6-triol-ergosta-7,22-diene (5), and one pair of inseparable C-24 epimers of (3ß,5α,6ß,22E)-3,5,6-triol-stigmasta-7,22-diene (6/7), were isolated from the marine sponge Hippospongia lachne de Laubenfels. The structures of isolated compounds were extensively elucidated based on HRESIMS and NMR data. Compounds 2 - 5 showed cytotoxicity against PC9 cells with IC50 values ranging from 34.1 ± 0.9 to 38.9 ± 1.0 µM and compound 4 displayed cytotoxicity against MCF-7 cells with IC50 value of 39.0 ± 0.4 µM.