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The chemical screening of an octocoral identifed as Junceella fragilis has led to the isolation of five chlorinated briarane-type diterpenoids, including three known metabolites, gemmacolide X (1), frajunolide I (2), and fragilide F (3), along with two new analogs, 12α-acetoxyfragilide F (4) and 12α-acetoxyjunceellin (5). Single-crystal X-ray diffraction analysis was carried out to determine the absolute configurations of 1 and 2, while the structures of new compounds 4 and 5 were ascertained with 2D NMR experiments. Briaranes 1 and 3-5 were active in enhancing alkaline phosphatase (ALP) activity., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Understanding how to modulate the microenvironment of tumors that are resistant to immune checkpoint inhibitors represents a major challenge in oncology.Here we investigate the ability of USP7 inhibitors to reprogram the tumor microenvironment (TME) by inhibiting secretion of vascular endothelial growth factor (VEGF) from fibroblasts., Methods: To understand the role played by USP7 in the TME, we systematically evaluated the effects of potent, selective USP7 inhibitors on co-cultures comprising components of the TME, using human primary cells. We also evaluated the effects of USP7 inhibition on tumor growth inhibition in syngeneic models when dosed in combination with immune checkpoint inhibitors (ICIs)., Results: Abrogation of VEGF secretion from fibroblasts in response to USP7 inhibition resulted in inhibition of tumor neoangiogenesis and increased tumor recruitment of CD8-positive T-lymphocytes, leading to significantly improved sensitivity to immune checkpoint inhibitors. In syngeneic models, treatment with USP7 inhibitors led to striking tumor responses resulting in significantly improved survival., Conclusions: USP7-mediated reprograming of the TME is not linked to its previously characterized role in modulating MDM2 but does require p53 and UHRF1 in addition to the well-characterized VEGF transcription factor, HIF-1α. This represents a function of USP7 that is unique to fibroblasts, and which is not observed in cancer cells or other components of the TME. Given the potential for USP7 inhibitors to transform "immune desert" tumors into "immune responsive" tumors, this paves the way for a novel therapeutic strategy combining USP7 inhibitors with immune checkpoint inhibitors (ICIs)., (© 2024 Almac Discovery Ltd. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Prodigiosin (PG) is a naturally occurring polypyrrole red pigment produced by numerous microorganisms including some Serratia and Streptomyces strains. PG has exhibited promising anticancer activity; however, the molecular mechanisms of action of PG on malignant cells remain ambiguous. Transforming growth factor- β (TGF- β ) is a multifunctional cytokine that governs a wide array of cellular processes in development and tissue homeostasis. Malfunctions of TGF- β signaling are associated with numerous human cancers. Emerging evidence underscores the significance of internalized TGF- β receptors and their intracellular trafficking in initiating signaling cascades. In this study, we identified PG as a potent inhibitor of the TGF- β pathway. PG blocked TGF- β signaling by targeting multiple sites of this pathway, including facilitating the sequestering of TGF- β receptors in the cytoplasm by impeding the recycling of type II TGF- β receptors to the cell surface. Additionally, PG prompts a reduction in the abundance of receptors on the cell surface through the disruption of the receptor glycosylation. In human Caucasian lung carcinoma cells and human hepatocellular cancer cell line cells, nanomolar concentrations of PG substantially diminish TGF- β -triggered phosphorylation of Smad2 protein. This attenuation is further reflected in the suppression of downstream target gene expression, including those encoding fibronectin, plasminogen activator inhibitor-1, and N-cadherin. SIGNIFICANCE STATEMENT: Prodigiosin (PG) emerges from this study as a potent TGF-β pathway inhibitor, disrupting receptor trafficking and glycosylation and reducing TGF-β signaling and downstream gene expression. These findings not only shed light on PG's potential therapeutic role but also present a captivating avenue towards future anti-TGF-β strategies., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Atopic dermatitis (AD) is a chronic inflammatory skin condition primarily driven by T helper 2 (Th2) cytokines, resulting in skin barrier defects, angiogenesis, and inflammatory responses. The marine natural product excavatolide B (EXCB), isolated from the Formosan Gorgonian coral Briareum stechei, exhibits anti-inflammatory and analgesic properties. To enhance solubility, EXCB is chemically modified into the derivatives EXCB-61 salt and EXCB-79. The study aims to investigate the therapeutic effects of these compounds on dinitrochlorbenzene (DNCB)-induced skin damage and to elucidate the underlying anti-inflammatory and anti-angiogenesis mechanism. In vitro, using lipopolysaccharide (LPS)-induced RAW 264.7 cells, all compounds at 10 μM significantly inhibited expression of inflammatory proteins (inducible nitric oxide synthase and cyclooxygenase-2), vascular endothelial growth factor (VEGF), and cytokines (interleukin (IL)-1β, IL-6, and IL-17A). In vivo, topical application of these compounds on DNCB-induced AD mice alleviated skin symptoms, reduced serum levels of IgE, IL-4, IL-13, IL-17, and interferon-γ, and moderated histological phenomena such as hyperplasia, inflammatory cell infiltration, and angiogenesis. The three compounds restored the expression of skin barrier-related proteins (loricrin, filaggrin, and claudin-1) and reduced the expression of angiogenesis-related proteins (VEGF and platelet endothelial cell adhesion molecule-CD31) in the tissues. This is the first study to indicate that EXCB, EXCB-61 salt, and EXCB-79 can treat AD disease by reducing inflammation and angiogenesis. Hence, they may be considered potential candidates for the development of new drugs for AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Antioral cancer drugs need a greater antiproliferative impact on cancer than on normal cells. Demethoxymurrapanine (DEMU) inhibits proliferation in several cancer cells, but an in-depth investigation was necessary. This study evaluated the proliferation-modulating effects of DEMU, focusing on oral cancer and normal cells. DEMU (0, 2, 3, and 4 μg/mL) at 48 h treatments inhibited the proliferation of oral cancer cells (the cell viability (%) for Ca9-22 cells was 100.0 ± 2.2, 75.4 ± 5.6, 26.0 ± 3.8, and 15.4 ± 1.4, and for CAL 27 cells was 100.0 ± 9.4, 77.2 ± 5.9, 57.4 ± 10.7, and 27.1 ± 1.1) more strongly than that of normal cells (the cell viability (%) for S-G cells was 100.0 ± 6.6, 91.0 ± 4.6, 95.0 ± 2.6, and 95.8 ± 5.5), although this was blocked by the antioxidant N-acetylcysteine. The presence of oxidative stress was evidenced by the increase of reactive oxygen species and mitochondrial superoxide and the downregulation of the cellular antioxidant glutathione in oral cancer cells, but these changes were minor in normal cells. DEMU also caused greater induction of the subG1 phase, extrinsic and intrinsic apoptosis (annexin V and caspases 3, 8, and 9), and DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) in oral cancer than in normal cells. N-acetylcysteine attenuated all these DEMU-induced changes. Together, these data demonstrate the preferential antiproliferative function of DEMU in oral cancer cells, with the preferential induction of oxidative stress, apoptosis, and DNA damage in these cancer cells, and low cytotoxicity toward normal cells., (© 2023 Wiley Periodicals LLC.)

Internal tandem duplication mutations in fms-like tyrosine kinase 3 (FLT3-ITD) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the FLT3-ITD clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3. FLT3-ITD and loss-of-function mutations in EZH2 are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine Flt3-ITD AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of FLT3-ITD leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

To look in-depth into the phytochemical and pharmacological properties of Taiwan juniper, this study investigated the chemical profiles and anti-lymphangiogenic activity of Juniperus chinensis var. tsukusiensis . In this study, four new sesquiterpenes, 12-acetoxywiddrol ( 1 ), cedrol-13-al ( 2 ), α-corocalen-15-oic acid ( 3 ), 1,3,5-bisaoltrien-10-hydroperoxy-11-ol ( 4 ), one new diterpene, 1β,2β-epoxy-9α-hydroxy-8(14),11-totaradiene-3,13-dione ( 5 ), and thirty-three known terpenoids were successfully isolated from the heartwood of J. chinensis var. tsukusiensis . The structures of all isolates were determined through the analysis of physical data (including appearance, UV, IR, and optical rotation) and spectroscopic data (including 1D, 2D NMR, and HRESIMS). Thirty-four compounds were evaluated for their anti-lymphangiogenic effects in human lymphatic endothelial cells (LECs). Among them, totarolone ( 6 ) displayed the most potent anti-lymphangiogenic activity by suppressing cell growth (IC 50 = 6 ± 1 µM) of LECs. Moreover, 3β-hydroxytotarol ( 7 ), 7-oxototarol ( 8 ), and 1-oxo-3β-hydroxytotarol ( 9 ) showed moderate growth-inhibitory effects on LECs with IC 50 values of 29 ± 1, 28 ± 1, and 45 ± 2 µM, respectively. Totarolone ( 6 ) also induced a significant concentration-dependent inhibition of LEC tube formation (IC 50 = 9.3 ± 2.5 µM) without cytotoxicity. The structure-activity relationship discussion of aromatic totarane-type diterpenes against lymphangiogenesis of LECs is also included in this study. Altogether, our findings unveiled the promising potential of J. chinensis var. tsukusiensis in developing therapeutics targeting tumor lymphangiogenesis.

The marine sponge Lendenfeldia sp., collected from the Southern waters of Taiwan, was subjected to chemical composition screening, resulting in the isolation of four new 24-homoscalarane compounds, namely lendenfeldaranes R-U ( 1 - 4 ). The structures and relative stereochemistry of the new metabolites 1 - 4 were assigned based on NMR studies. The absolute configurations of compounds 1 - 4 were determined by comparing the calculated and experimental values of specific optical rotation. The antioxidant and anti-inflammatory activities of the isolated compounds were assayed using superoxide anion generation and elastase release assays. These assays are used to determine neutrophilic inflammatory responses of respiratory burst and degranulation. Compounds 2 and 4 inhibited superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB) with IC 50 : 3.98-4.46 μM. Compounds 2 and 4 inhibited fMLP/CB-induced elastase release, with IC 50 values ranging from 4.73 to 5.24 μM. These findings suggested that these new 24-homoscalarane compounds possess unique structures and potential anti-inflammatory activity.

CEBPA variants are frequently recurring in acute myeloid leukemia (AML). The prognostic significance of CEBPA mutations has recently undergone a major shift in the 5th edition of WHO classification of hematological neoplasms and ELN 2022 classification. Whereas prior iterations did not specify the type of CEBPA mutation, the updated schema specify that only mutations localized to the C-terminal basic zipper (bZIP) domain are considered prognostically favorable. This change is based primarily on three recently published large datasets evaluating the prognostic significance of mutation location in CEBPA mutant AML. Here, we review the evolution of the prognostic classification of CEBPA variants., Competing Interests: The authors declare no competing interests., (© 2023 The Authors. Published by Elsevier Ltd.)

Despite recent therapeutic advances, the 5-year survival rate for adults with acute myeloid leukemia (AML) is poor and standard-of-care chemotherapy is associated with significant toxicity, highlighting the need for new therapeutic approaches. Recent work from our group and others established that the G protein-coupled estrogen receptor (GPER) is tumor suppressive in melanoma and other solid tumors. We performed a preliminary screen of human cancer cell lines from multiple malignancies and found that LNS8801, a synthetic pharmacologic agonist of GPER currently in early phase clinical trials, promoted apoptosis in human AML cells. Using human AML cell lines and primary cells, we show that LNS8801 inhibits human AML in preclinical in vitro models, while not affecting normal mononuclear cells. Although GPER is broadly expressed in normal and malignant myeloid cells, this cancer-specific LNS8801-induced inhibition appeared to be independent of GPER signaling. LNS8801 induced AML cell death primarily through a caspase-dependent apoptosis pathway. This was independent of secreted classical death receptor ligands, and instead required induction of reactive oxygen species (ROS) and activation of endoplasmic reticulum (ER) stress response pathways including IRE1α. These studies demonstrate a novel activity of LNS8801 in AML cells and show that targeting ER stress with LNS8801 may be a useful therapeutic approach for AML., Significance: Previous work demonstrated that LNS8801 inhibits cancer via GPER activation, especially in solid tumors. Here we show that LNS8801 inhibits AML via GPER-independent mechanisms that include ROS induction and ER activation., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background and Purpose: Acute respiratory distress syndrome (ARDS) is a catastrophic pulmonary inflammatory dysfunction with a high mortality rate. An overwhelming immune response by neutrophils is a key feature in infective or sterile ARDS. The formyl peptide receptor 1 (FPR1) is a crucial damage-sensing receptor for inflammatory reactions in the initiation and progression of neutrophil-mediated ARDS. However, effective targets for controlling dysregulated neutrophilic inflammatory injuries in ARDS are limited., Experimental Approach: Human neutrophils were used to explore the anti-inflammatory effects of cyclic lipopeptide anteiso-C13-surfactin (IA-1) from marine Bacillus amyloliquefaciens. The lipopolysaccharide-induced model of ARDS in mice was used to determine the therapeutic potential of IA-1 in ARDS. Lung tissues were harvested for histology analyses., Key Results: The lipopeptide IA-1 inhibited immune responses of neutrophils, including respiratory burst, degranulation, and expression of adhesion molecules. IA-1 inhibited the binding of N-formyl peptides to FPR1 in human neutrophils and in hFPR1-transfected HEK293 cells. We identified IA-1 as a competitive FPR1 antagonist, thus diminishing the downstream signalling pathways involving calcium, mitogen-activated protein kinases and Akt. Furthermore, IA-1 ameliorated the inflammatory damage to lung tissue, by decreasing neutrophil infiltration, reducing elastase release and oxidative stress in endotoxemic mice., Conclusion and Implications: The lipopeptide IA-1 could serve as a therapeutic option for ARDS by inhibiting FPR1-mediated neutrophilic injury., (© 2023 British Pharmacological Society.)

Natural products are important sources of therapeutic agents and useful drug discovery tools. The fused macrocycles and multiple stereocenters of briarane-type diterpenoids pose a major challenge to total synthesis and efforts to characterize their biological activities. Harnessing a scalable source of excavatolide B (excB) from cultured soft coral Briareum stechei, we generated analogs by late-stage diversification and performed structure-activity analysis, which was critical for the development of functional excB probes. We further used these probes in a chemoproteomic strategy to identify Stimulator of Interferon Genes (STING) as a direct target of excB in mammalian cells. We showed that the epoxylactone warhead of excB is required to covalently engage STING at its membrane-proximal Cys91, inhibiting STING palmitoylation and signaling. This study reveals a possible mechanism-of-action of excB, and expands the repertoire of covalent STING inhibitors., (© 2023. The Author(s).)

Acute myeloid leukemias (AMLs) frequently harbor activating mutations in Fms-like tyrosine kinase 3 ( FLT3 ). The use of FLT3 inhibitors (FLT3i) is the standard of care for treatment of newly diagnosed and relapsed patients with AML. Differentiation responses including clinical differentiation syndrome have been previously reported with FLT3i when used as single agents in relapsed disease. We present a case of hypereosinophilia in a patient on FLT3i therapy with persistent FLT3 polymerase chain reaction (PCR) positivity in peripheral blood. We sorted mature leukocytes by lineage to determine if the eosinophils were leukemia-derived. FLT3 PCR and next-generation sequencing analysis demonstrated monocytic differentiation of the FLT3-ITD leukemic clone with reactive hypereosinophilia that was derived from a preleukemic SF3B1 , FLT3 wild-type clone. Our case is the first to definitively demonstrate the emergence of clonal FLT3-ITD monocytes with FLT3i and the first to demonstrate a differentiation response following decitabine, venetoclax, and gilteritinib triplet therapy., (© 2023 Martinez-Gutierrez et al.; Published by Cold Spring Harbor Laboratory Press.)

Chemical composition screening of an octocoral identified as Sinularia species led to the isolation of a novel diterpenoid, sinulariaone A (1), featuring a 13-membered carbocyclic skeleton. The structure of 1 was established by spectroscopic elucidation, computed calculation, and X-ray diffraction analysis. Moreover, a single-crystal X-ray diffraction analysis of chlorofurancembranoid B (2), obtained in our previous study from the same octocoral species, was reported for the first time to demonstrate the absolute configuration. Diterpenoid 1 showed cytotoxicity towards human promyelocytic leukemia HL-60 cells, with an IC 50 value of 38.01 μM., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Parthenogenetic reproduction is a common feature for social Hymenoptera, as males typically develop from unfertilized eggs (arrhenotoky). Production of female offspring without the involvement of sperm (thelytoky) also exists but is rather exceptional as it has been reported for only 16 ant species so far. Three of these belong to the genus Strumigenys: S. hexamera , S. membranifera and S. rogeri . Our observations on the reproductive biology in various Oriental Strumigenys species extends this list of thelytokous ants with three more species: S. emmae , S. liukueiensis and S. solifontis . Of these six thelotykous species, S. emmae , S. membranifera and S. rogeri are known as tramp species. Reproduction without the need to fertilize eggs no doubt offers these species a considerable advantage when establishing colonies in new environments. Published histological data on S. hexamera and S. membranifera already showed that the queens possess a functional spermatheca. We now provide evidence that this is also the case for the four other thelytokous Strumigenys species. Retaining a functional spermatheca and reproductive system may keep the queens ready for the exceptional event of mating and hence increase genetic variability, as males do occur very rarely.

The chemical screening of a cultured soft coral, Briareum violaceum , led to the isolation of eight natural, briarane-related diterpenoids, including three unreported metabolites, briavioids E-G ( 1 - 3 ), and five known briaranes, briacavatolides B ( 4 ) and C ( 5 ), briaexcavatin L ( 6 ), briaexcavatolide U ( 7 ) and briarenol K ( 8 ). The structures of briaranes 1 - 8 were established using spectroscopic methods. The absolute configuration of briavioid A ( 9 ), obtained in a previous study, was reported for the first time in this study by a single-crystal X-ray diffraction analysis using a copper radiation source. The anti-inflammatory activity of briaranes 1 and 2 and briaranes 4 - 8 was evaluated by screening their inhibitory ability against the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins in lipopolysaccharide (LPS)-induced RAW 264.7 macrophage cells.

Aaptamine, a natural marine compound isolated from the sea sponge, has various biological activities, including delta-opioid agonist properties. However, the effects of aaptamine in neuropathic pain remain unclear. In the present study, we used a chronic constriction injury (CCI)-induced peripheral neuropathic rat model to explore the analgesic effects of intrathecal aaptamine administration. We also investigated cellular angiogenesis and lactate dehydrogenase A (LDHA) expression in the ipsilateral lumbar spinal cord after aaptamine administration in CCI rats by immunohistofluorescence. The results showed that aaptamine alleviates CCI-induced nociceptive sensitization, allodynia, and hyperalgesia. Moreover, aaptamine significantly downregulated CCI-induced vascular endothelial growth factor (VEGF), cluster of differentiation 31 (CD31), and LDHA expression in the spinal cord. Double immunofluorescent staining showed that the spinal VEGF and LDHA majorly expressed on astrocytes and neurons, respectively, in CCI rats and inhibited by aaptamine. Collectively, our results indicate aaptamine's potential as an analgesic agent for neuropathic pain. Furthermore, inhibition of astrocyte-derived angiogenesis and neuronal LDHA expression might be beneficial in neuropathy.

A formerly unpublicized briarane diterpenoid, briastecholide M (1), and its established analogue, brianodin B (2), were purified from Briareum stechei, an octocoral collected from Okinawan waters. Using spectroscopic methods, the structure of 1 was established. Functional study showed that 1 can reducing the release of inducible nitric oxide synthase (iNOS) but enhancing cyclooxygenase-2 (COX-2) protein expression.

Three norsesquiterpenoids, pathyspirolactones A (1) and B (2), and napalilactone (3), featuring a γ -spirolactone moiety, were isolated from the cultured octocoral Paralemnalia thyrsoides . The structures of 1-3 were determined by analyzing spectroscopic data, DP4+ computation, specific optical rotation, and X-ray diffraction. In addition, we explored the absolute configurations of pathyspirolactone A (1) and its conformation of the cyclohexane ring to resolve the stereochemical confusion of those of norsesquiterpenoid compounds. Furthermore, we proved that pathyspirolactone B (2) was the first bromine-containing norsesquiterpenoid reported from octocorals., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Dianella ensifolia is a perennial herb with thickened rhizome and is widely distributed in tropical and subtropical regions of Asia, Australia, and the Pacific islands. This plant has the potential to be used as a source of herbal medicine. This study investigated further phytochemistry and tyrosinase inhibitory effect of some constituents isolated from D. ensifolia. Four new flavans, (2S)-4’-hydroxy-6,7-dimethoxyflavan (1), (2S)-3’,4’-dihydroxy-7-methoxy-8-methylflavan (2), (2S)-2’-hydroxy-7-methoxyflavan (3), and (2S,1′S)-4-hydroxy-4-(7-methoxy-8-methylchroman-2-yl)-cyclohex-2-enone (4), together with 67 known compounds, including 10 flavans (5−14), 5 flavanones (15−19), 3 flavone (20−22), 5 chalcones (23−27), 3 chromones (28−30), 15 aromatics (31−45), 7 phenylpropanoids (46−52), one lignan (53), 7 steroids (54−60), one monoterpene (61), one diterpene (62), 4 triterpenes (63−66), a carotenoid (67), 2 alkaloids (68 and 69), and 2 fatty acids (70 and 71) were isolated from D. ensifolia. Their structures were elucidated on the basis of physical and spectroscopic data analyses. Moreover, compounds 1−4, 8, 10−15, 20, 21, and 41 were evaluated for their mushroom tyrosinase inhibitory effect. Compounds 11 and 14 strongly inhibited mushroom tyrosinase activity with IC50 values of 8.6 and 14.5 μM, respectively.

The unmet need for specific anti-leukemic agents for the treatment of acute lymphoblastic leukemia led us to screen a variety of marine-derived bacteria. The fermentation broth extract of Streptomyces sp. LY1209 exhibited the most potent anti-proliferative effect against Molt 4 leukemia cells. A chromatographic anti-proliferative profiling approach was applied to characterize the metabolites with bioactive potential. Among all the metabolites, the major anti-leukemic constituents were staurosporine and a series of diketopiperazines (DKPs), including one novel and two known DKPs identified from nature for the first time. The structures of these compounds were identified using extensive spectroscopic analysis. The anti-proliferative potential of these metabolites against the Molt 4 cancer cell line was also determined. According to the in silico analysis utilizing a chemical global positioning system for natural products (ChemGPS-NP), it was suggested that these DKPs are potential anti-microtubule and alkylating agents, while staurosporine was proposed to be a tyrosine kinase inhibitor. Our findings not only identified a series of anti-proliferative metabolites, but also suggested a strategic workflow for the future discovery of natural product drug leads.

Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML., Significance: AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a "writer-reader" epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML. This article is highlighted in the In This Issue feature, p. 587., (©2021 American Association for Cancer Research.)

Crataegus pinnatifida is used to treat various diseases, including indigestion, congestive heart failure, hypertension, atherosclerosis, and myocardial dysfunction. We evaluated antioxidant and anti-α-glucosidase activities of various solvent extracts and major bioactive components from the fruit of C. pinnatifida . Ethyl acetate extracts showed potent antioxidant activities with IC 50 values of 23.26 ± 1.97 and 50.73 ± 8.03 μg/mL, respectively, in DPPH and ABTS radical scavenging assays. Acetone extract exhibited significant anti-α-glucosidase activity with IC 50 values of 42.35 ± 2.48 μg/mL. HPLC analysis was used to examine and compare the content of active components in various solvent extracts. We isolated four active compounds and evaluated their antioxidant and anti-α-glucosidase properties. Among the isolated compounds, chlorogenic acid and hyperoside showed potential antioxidant activities in ABTS and superoxide radical scavenging assays. Moreover, hyperoside also displayed stronger anti-α-glucosidase activity than other isolates. The molecular docking model and the hydrophilic interactive mode of anti-α-glucosidase assay revealed that hyperoside might have a higher antagonistic effect than positive control acarbose. The present study suggests that C. pinnatifida and its active extracts and components are worth further investigation and might be expectantly developed as the candidates for the treatment or prevention of oxidative stress-related diseases and hyperglycemia.

A known polyoxygenated briarane, briaexcavatolide P ( 1 ), was isolated from a Formosan octocoral Briareum stechei . Moreover, the same species B. stechei , collected from Okinawan waters, yielded three chlorine-containing briaranes, including two new compounds, briastecholides B ( 2 ) and C ( 3 ) as well as a known analogue, briarenol R ( 4 ). The structures of 1 - 4 were established using spectroscopic methods. In addition, briarane 1 demonstrated anti-inflammatory activity in lipo-polysaccharide-induced RAW 264.7 mouse macrophage cells by suppressing the expression of inducible nitric oxide synthase (iNOS) protein.

Sponge-derived scalaranes are remarkable sesterterpenoids previously found to exhibit profound inhibitory effects against neutrophilic inflammation. In our current work, we constructed the metabolomic profile of marine sponge Lendenfeldia sp. for the first time using a tandem mass spectrometry (MS/MS) molecular networking approach. The results highlighted the rich chemical diversity of these scalaranes, motivating us to conduct further research to discover novel scalaranes targeting neutrophilic inflammation. MS- and NMR-assisted isolation and elucidation led to the discovery of seven new homoscalaranes, lendenfeldaranes K-Q ( 1 - 7 ), characterized by methylation at C-24, together with five known derivatives, lendenfeldarane B ( 8 ), 25-nor-24-methyl-12,24-dioxoscalar-16-en-22-oic acid ( 9 ), 24-methyl-12,24,25-trioxoscalar-16-en-22-oic acid ( 10 ), felixin B ( 11 ), and 23-hydroxy-20-methyldeoxoscalarin ( 12 ). Scalaranes 1 - 4 and 6 - 12 were assayed against superoxide anion generation and elastase release, which represented the neutrophilic inflammatory responses of respiratory burst and degranulation, respectively. The results indicated that 1 - 3 and 6 - 12 exhibited potential anti-inflammatory activities (IC 50 for superoxide anion scavenging: 0.87~6.57 μM; IC 50 for elastase release: 1.12~6.97 μM).

One new naturally occurring quinone, 3',4'-dihydroxy-1,2,6-trimethoxy-[1,1'-biphenyl]-4(1 H )-one ( 1 ), one new diarylpropane, emarginone A ( 2 ), and one new neolignan, emarginone B ( 3 ), along with eighteen known compounds have been isolated from the chemical investigation of the EtOAc-soluble fraction of the Vaccinium emarginatum whole plant methanolic extract. The new structures were elucidated by combined analysis of spectroscopic analytical methods and comparison with the literature data obtained from known analogues. In addition, the cytotoxicity of compounds 2 , 4 , and 14-20 against Du145 and PC-3 prostate cancer cell lines using MTT cell proliferation assay was evaluated. Compounds 2 and 19 showed most potent cytotoxicity against Du145 with IC 50 values of 7.53 and 6.63 μg/mL, respectively. Furthermore, compounds 2 , 17 , and 19 also exhibited significant cytotoxicity against PC-3 with IC 50 values ranging from 3.44-6.64 μg/mL.

Chemical investigation of the octocoral Briareum stechei , collected in the Ie Island, Okinawa, Japan, resulted in the isolation of a new briarane-type diterpenoid, briastecholide A ( 1 ), as well as the previously reported metabolites, solenolide C ( 2 ) and briarenolide S ( 3 ). The structures of briaranes 1 - 3 were characterized through spectroscopic analysis, and the absolute configuration of 2 was corroborated by a single-crystal X-ray diffraction analysis. Briarane 3 exhibited bioactivity against the protein expression of inducible nitric oxide synthase (iNOS).

Two cembranoids, including a new compound, lobocrassin I ( 1 ), as well as a known analogue, lobohedleolide ( 2 ), were obtained by solvent extraction from octocoral Lobophytum crassum . This study employed a spectroscopic approach to establish the structures of these two cembranoids, and utilized single-crystal X-ray diffraction analysis to determine their absolute configurations. The results of biological activity assays demonstrated that cembranoid 2 exhibited bioactivity against the protein expressions of inducible nitric oxide synthase (iNOS) lipopolysaccharide (LPS)-treated RAW 264.7 mouse macrophage cells.

Briareum stechei is proven to be a rich source of 3,8-cyclized cembranoids (briarane) with a bicyclo[8.4.0] carbon core. In the present study, four previously unreported briaranes, briarenols W-Z ( 1 - 4 ), along with solenolide A ( 5 ), briarenolide M ( 6 ), briaexcavatolide F ( 7 ), and brianolide ( 8 ), were isolated and characterized through spectroscopic analysis, and the absolute configuration of 8 was corroborated by a single-crystal x-ray diffraction analysis. Briaranes 2 and 5 were found to induce significant inflammatory activity in lipopolysaccharide (LPS)-induced RAW 264.7 mouse macrophage cells by enhancing the expression of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins.

In this review, 170 natural substances, including steroid, diterpenoid, sesquiterpenoid, peptide, prostaglandin, base, chlorolipid, bicyclolactone, amide, piperazine, polyketide, glycerol, benzoic acid, glycyrrhetyl amino acid, hexitol, pentanoic acid, aminoethyl ester, octadecanone, alkaloid, and a 53-kD allergenic component from octocorals belonging to genus Dendronephthya , were listed. Some of these compounds displayed potential bioactivities.

Qin Pi ( Fraxinus chinensis Roxb.) is commercially used in healthcare products for the improvement of intestinal function and gouty arthritis in many countries. Three new secoiridoid glucosides, (8 E )-4''- O -methylligstroside ( 1 ), (8 E )-4''- O -methyldemethylligstroside ( 2 ), and 3'',4''-di- O -methyl-demethyloleuropein ( 3 ), have been isolated from the stem bark of Fraxinus chinensis , together with 23 known compounds ( 4 - 26 ). The structures of the new compounds were established by spectroscopic analyses (1D, 2D NMR, IR, UV, and HRESIMS). Among the isolated compounds, (8 E )-4''- O -methylligstroside ( 1 ), (8 E )-4''- O -methyldemethylligstroside ( 2 ), 3'',4''-di- O -methyldemethyloleuropein ( 3 ), oleuropein ( 6 ), aesculetin ( 9 ), isoscopoletin ( 11 ), aesculetin dimethyl ester ( 12 ), fraxetin ( 14 ), tyrosol ( 21 ), 4-hydroxyphenethyl acetate ( 22 ), and (+)-pinoresinol ( 24 ) exhibited inhibition (IC 50 ≤ 7.65 μg/mL) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leuckyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds 1 , 9 , 11 , 14 , 21 , and 22 inhibited fMLP/CB-induced elastase release with IC 50 ≤ 3.23 μg/mL. In addition, compounds 2 , 9 , 11 , 14 , and 21 showed potent inhibition with IC 50 values ≤ 27.11 μM, against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation. The well-known proinflammatory cytokines , tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), were also inhibited by compounds 1 , 9 , and 14 . Compounds 1 , 9 , and 14 displayed an anti-inflammatory effect against NO, TNF-α, and IL-6 through the inhibition of activation of MAPKs and IκBα in LPS-activated macrophages. In addition, compounds 1 , 9 , and 14 stimulated anti-inflammatory M2 phenotype by elevating the expression of arginase 1 and Krüppel-like factor 4 (KLF4). The above results suggested that compounds 1 , 9 , and 14 could be considered as potential compounds for further development of NO production-targeted anti-inflammatory agents.

Two previously undescribed caryophyllane-related sesquiterpenoids, antipacids A ( 1 ) and B ( 2 ), with a novel bicyclo[5.2.0] core skeleton, and known compound clovane-2β,9α-diol ( 3 ), along with rumphellolide L ( 4 ), an esterified product of 1 and 3 , were isolated from the organic extract of octocoral Rumphella antipathes . Their structures, including the absolute configurations were elucidated by spectroscopic and chemical experiments. In vivo anti-inflammatory activity analysis indicated that antipacid B ( 2 ) inhibited the generation of superoxide anions and the release of elastase by human neutrophils, with IC 50 values of 11.22 and 23.53 μM, respectively, while rumphellolide L ( 4 ) suppressed the release of elastase with an IC 50 value of 7.63 μM.

Two new Δ 12 ursene-type triterpenoid coumaroyl esters (1: and 2: ), one new Δ 7,15 isopimarane-type diterpenoid glycoside (20: ), and two new irido- δ -lactone-type iridoids (21: and 22: ), together with 17 known pentacyclic triterpenoids (3:  - 19: ), were isolated during the phytochemical investigation of a methanol extract of the whole plant of Vaccinium emarginatum . Their structures were determined by detailed analysis of standard spectroscopic data (MS, IR, 1D, and 2D NMR) and comparison with data of known analogs. The isolates were evaluated for their cytotoxicity against the PC-3 and Du145 prostate cancer cell lines (as assessed by an MTT cell proliferation assay), as well as for their anti-inflammatory activity via the inhibition of nitric oxide production in lipopolysaccharide-induced murine macrophage RAW 264.7 cells. Among the isolates, the triterpenoid coumaroyl and feruloyl esters (1, 3: , and 4: ) exhibited strong cytotoxicity against PC-3 prostate cancer cells, with 85.6 - 90.2% inhibition at 10.0 µg/mL. The pomolic acid coumaroyl and feruloyl esters (1: and 3: ) also showed moderate anti-inflammatory activity against nitric oxide production in lipopolysaccharide-induced RAW 264.7 cells, with 59.2 (± 1.0) and 47.1% (± 0.2) inhibition at 12.5 µg/mL, respectively., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Chemical examination from the cultured soft coral Sarcophyton digitatum resulted in the isolation and structural identification of four new biscembranoidal metabolites, sardigitolides A-D ( 1 - 4 ), along with three previously isolated biscembranoids, sarcophytolide L ( 5 ), glaucumolide A ( 6 ), glaucumolide B ( 7 ), and two known cembranoids ( 8 and 9 ). The chemical structures of all isolates were elucidated on the basis of 1D and 2D NMR spectroscopic analyses. Additionally, in order to discover bioactivity of marine natural products, 1 - 8 were examined in terms of their inhibitory potential against the upregulation of inflammatory factor production in lipopolysaccharide (LPS)-stimulated murine macrophage J774A.1 cells and their cytotoxicities against a limited panel of cancer cells. The anti-inflammatory results showed that at a concentration of 10 µg/mL, 6 and 8 inhibited the production of IL-1 β to 68 ± 1 and 56 ± 1%, respectively, in LPS-stimulated murine macrophages J774A.1. Furthermore, sardigitolide B ( 2 ) displayed cytotoxicities toward MCF-7 and MDA-MB-231 cancer cell lines with the IC 50 values of 9.6 ± 3.0 and 14.8 ± 4.0 µg/mL, respectively.

Scalarane-type sesterterpenoids are known for their therapeutic potential in cancer treatments. However, the anti-inflammatory properties of this class of metabolites remain elusive. Our current work aimed to investigate the anti-inflammatory scalaranes from marine sponge Lendenfeldia sp., resulting in the isolation of six new 24-homoscalaranes, lendenfeldaranes E-J ( 1 - 6 ). The structures of the new metabolites were determined by extensive spectroscopic analyses, and the absolute configuration of 1 was established by electronic circular dichroism (ECD) calculations. Compounds 2 and 3 were discovered to individually reduce the generation of superoxide anions, and compound 1 displayed an inhibitor effect on the release of elastase. These three compounds were proven to be the first anti-neutrophilic scalaranes.