Reduction of HIF-1α/PD-L1 by Catalytic Topoisomerase Inhibitor Induces Cell Death Through Caspase Activation in Cancer Cells Under Hypoxia.

Background/aim: Under severe hypoxia, cellular apoptosis is induced through hypoxia-inducible factor 1, alpha subunit (HIF-1α)-dependent P53 accumulation and P53 phosphorylation via ataxia telangiectasia mutated and ataxia telangiectasia and RAD3-related (ATR) activation via replication stress-induced DNA damage response (DDR) activation. We previously demonstrated that the topoisomerase I catalytic inhibitor, 3-O-(2'E,4'Z-decadienoyl)-20-O-acetylingenol (3EZ,20Ac-ingenol), induced apoptosis in Jeko-1 and Panc-1 cells, both of which show cyclin D1 overexpression. After progression to the S phase facilitated by nuclear cyclin D1, an intra S phase checkpoint was induced in the presence of 3EZ,20Ac-ingenol, by ATR activation in response to replication stress-induced DDR.

Ingenol mebutate inhibits the growth of pancreatic cancer cells in vitro via STING with an efficacy comparable to that of clinically used anticancer agents.

Pancreatic cancer is associated with a poor prognosis; thus, there is an urgent need to develop new and effective treatments. Ingenol mebutate (IM), which is isolated from the latex of Euphorbia peplus, was recently shown to be effective against pancreatic cancer cell lines; however, its mechanism of action has not been fully elucidated. In this study, we focused on the less drug-sensitive pancreatic cancer cell line Panc-1 and compared IM to commercially available anticancer drugs using cell survival assays.

3EZ, 20Ac-ingenol-induced Apoptosis in Chemoresistant Cancers With Cyclin D1 Accumulation.

Background/aim: The topoisomerase 1 catalytic inhibitor 3EZ, 20Ac-ingenol specifically induces apoptosis through the activation of ATR and the up-regulation of PTEN by enhancing the DNA damage response (DDR) in human B lymphoma (BALL-1) cells. The accumulation of cyclin D1 in cancer is known to be related to chemoresistance to DNA damage agents and nuclei of BALL-1 cells exhibit high levels of cyclin D1. However, 3EZ, 20Ac-ingenol effectively induced apoptosis of BALL-1 cells.

Identification of Lycopodium Alkaloids Produced by an Ultraviolet-Irradiated Strain of Paraboeremia, an Endophytic Fungus from Lycopodium serratum var. longipetiolatum.

12- epi-Lycopodine (1), a Lycopodium alkaloid, along with lycopodine (2) and huperzine A (3), were discovered in the mycelium of Paraboeremia sp. Lsl3KI076, a UV-irradiated strain of Paraboeremia sp. Lsl3, an endophytic fungus from Lycopodium serratum Thunb.

Identification of Two Phenanthrene Derivatives from Australasian Allied Species in Genus Dendrobium.

Genus Dendrobium (Orchidaceae) contains numerous species. Phylogenetic analyses based on morphological characteristics and DNA sequences indicated that this genus is divided into two major groups: Asian and Australasian clades. On the other hand, little is known about the phytochemical differences and similarities among the species in each clade.

3EZ, 20Ac-ingenol induces cell-specific apoptosis in cyclin D1 over-expression through the activation of ATR and downregulation of p-Akt.

Acute lymphoblastic leukemia (ALL) samples exhibit an activated PI3K/Akt pathway, which suggests a general role of Akt in the development of leukemia. We have previously used western blot analysis to show that the catalytic topoisomerase (topo) inhibitor, 3EZ, 20Ac-ingenol, induced DNA damage response (DDR), which activated ATR, downregulated p-Akt through upregulation of PTEN level, and led to cell cycle arrest or apoptosis. In this study, we used ATR or PTEN siRNA and observed that the specific cell arrest and apoptosis of BALL-1 cells in DDR caused by 3EZ, 20Ac-ingenol was dependant on activation of ATR and downregulation of nuclear p-Akt through upregulation of PTEN.

Stereospecific inhibition of nitric oxide production in macrophage cells by flavanonols: Synthesis and the structure-activity relationship. Part 2.

To explore the structure-activity relationships of flavanonols on the inhibition of nitric oxide (NO) production in RAW 264.7 cells, we have prepared a series of synthetic flavanonols. In our previous study, the 2',3'-dihydroxyphenyl substructure was found to be the most potent B ring substructure among the flavanonols having 3,5,7-trihydroxychroman-4-one as the A/C ring.

Structure-activity relationship of the inhibitory effects of flavonoids on nitric oxide production in RAW264.7 cells.

We isolated flavonoids from herbal specimens from the Tibetan region (Sophora yunnanensis and Rhodiola sacra) that suppress nitric oxide (NO) production in macrophages stimulated by lipopolysaccharide and interferon-γ. The isolated flavonoids carry symmetric substitutions in the B ring (R=R). We analyzed the quantitative structure-activity relationship of the inhibitory activity by comparative molecular field analysis (CoMFA) using this series of flavonoids.

[Chemical Compounds in Natural Medicines That Affect Macropharges and Adipocyte Cells].

Macrophages play major roles in inflammation, immunity and host defense mechanisms. Once activated they produce and release cytokines, oxygen and nitrogen species, and eicosanoids. The best characterized stimuli to induce the transcription of genes encoding pro-inflammatory proteins in macrophages in vitro is bacterial lipopolysaccharide (LPS).

Metabolome Analysis of Oryza sativa (Rice) Using Liquid Chromatography-Mass Spectrometry for Characterizing Organ Specificity of Flavonoids with Anti-inflammatory and Anti-oxidant Activity.

Oryza sativa L. (rice) is an important staple crop across the world. In the previous study, we identified 36 specialized (secondary) metabolites including 28 flavonoids.

Serralongamines B-D, three new Lycopodium alkaloids from Lycopodium serratum var. longipetiolatum, and their inhibitory effects on foam cell formation in macrophages.

Three new Lycopodium alkaloids, serralongamines B-D (1-3), have been isolated from the club moss Lycopodium serratum var. longipetiolatum, and the structures were elucidated on the basis of spectroscopic data and chemical transformation. 1 and 3 significantly exhibited the inhibitory activity against foam cell formation in human macrophages, one of characteristic features of early atherosclerotic lesions.

[Isoflavonoids from Caragana changduensis and their nitric oxideinhibitory activities].

Ten isoflavonoids were isolated from the heartwoods of Caragana changduensis Lion f. by means of various column chromatographic techniques. Based on the detailed spectral data analysis (MS and NMR), as well as comparison with the literatures, their chemical structures were determined as 7,2'-dihydroxy-8,4'-dimethoxyisoflavone (1), 4'-hydroxy-7,3'-dimethoxyisoflavone (2), 5, 7, 4'-trihydroxy-2',5'-dimethoxyisoflavone (3), prunetin (4), afrormosin (5), odoratin (6), genistein (7), texasin (8), pratensein (9), and 6,7,3'-trihydroxy-4'-methoxyisoflavone (10).

Stereospecific inhibition of nitric oxide production in macrophage cells by flavanonols: Synthesis and the structure-activity relationship.

To explore the structure-activity relationships on the inhibitory activity of flavanonols against nitric oxide (NO) production in inflammatory cells, we synthesized 19 flavanonols which shared a common 3,5,7-trihydroxychroman scaffold. A range of substitutions was included in the B ring in order to investigate the structure-activity relationship. We also succeeded in isolating stereoisomers from 16 of the flavanonols using chiral column chromatography.

Mechanism of the inhibition of leukemia cell growth and induction of apoptosis through the activation of ATR and PTEN by the topoisomerase inhibitor 3EZ, 20Ac-ingenol.

The PI3K/Akt signaling pathway is constitutively activated in various leukemias. In the present study, the topoisomerase inhibitor, 3EZ, 20Ac-ingenol, was more effective in inhibiting the growth of BALL-1 cells than that of normal lymphocyte cells. ATM/ATR protein levels were increased, PTEN protein was upregulated, and p-Akt protein was downregulated at early time points after treatment with 3EZ, 20Ac-ingenol.

Chemical constituents isolated from Juncus effusus induce cytotoxicity in HT22 cells.

Effususol A (1), a new 9,10-dihydrophenanthrene, has been isolated from the medullae of Juncus effusus along with ten known compounds, effusol (2), dehydroeffusol (3), juncusol (4), dehydrojuncusol (5), juncuenin B (6), dehydrojuncuenin B (7), juncuenin D (8), luteolin (9), luteolin 5-methyl ether (10), and 4-hydroxy-2,3-dimethyl-2-nonen-4-olide (11). The structure of 1 was elucidated on the basis of spectroscopic data. 2, 4, 6, 7, and 8 have induced caspase-3-mediated cytotoxicity in HT22 cells.

Nortriterpene Saponins from Akebia trifoliate.

Three new nortriterpene saponins, 2α,3β,20α-trihydroxy-30-norolean-12-en-28-oic acid O-β-D-xylopyranosyl-(1-->3)-α-L-rhamnopyranosyl-(1-->4)-β-D- glucopyranosyl-(1-->6)-β-D-glucopyranosyl ester (3), 2α,3β,20α-trihydroxy-30-norolean-12-en-28-oic acid O-α-L-rhamnopyranosyl-(1-->4)-β-D- glucopyranosyl-(1-->6)-β-D-glucopyranosyl ester (4), and 2α,3β,23-trihydroxy-30-noroleana-12,19-dien-28-oic acid O-β-D-xylopyranosyl-(1-->3)-α-L- rhamnopyranosyl-(1-->4)-β-D-glucopyranosyl-(1-->6)-β-D-glucopyranosyl ester (6), were isolated from the methanol extract of the pericarps of Akebia trifoliata Koidzumi (Lardizabalaceae), together with five known nortriterpene saponins and three phenolic glycosides. Their structures were elucidated by spectroscopic analyses and acid hydrolysis.

Molecular phylogenetics and character evolution of morphologically diverse groups, Dendrobium section Dendrobium and allies.

It is always difficult to construct coherent classification systems for plant lineages having diverse morphological characters. The genus Dendrobium, one of the largest genera in the Orchidaceae, includes ∼1100 species, and enormous morphological diversification has hindered the establishment of consistent classification systems covering all major groups of this genus. Given the particular importance of species in Dendrobium section Dendrobium and allied groups as floriculture and crude drug genetic resources, there is an urgent need to establish a stable classification system.

Toward better annotation in plant metabolomics: isolation and structure elucidation of 36 specialized metabolites from (rice) by using MS/MS and NMR analyses.

Metabolomics plays an important role in phytochemical genomics and crop breeding; however, metabolite annotation is a significant bottleneck in metabolomic studies. In particular, in liquid chromatography-mass spectrometry (MS)-based metabolomics, which has become a routine technology for the profiling of plant-specialized metabolites, a substantial number of metabolites detected as MS peaks are still not assigned properly to a single metabolite. (rice) is one of the most important staple crops in the world.

Inhibitory effect of chemical constituents from Artemisia scoparia Waldst. et Kit. on triglyceride accumulation in 3T3-L1 cells and nitric oxide production in RAW 264.7 cells.

We investigated the anti-obesity effect of the aerial part of Artemisia scoparia Waldst. et Kit. (Compositae).

Sesquiterpene coumarins from Ferula fukanensis and their pro-inflammatory cytokine gene expression inhibitory effects.

Six new sesquiterpene coumarin derivatives, fukanefuromarin H-M (1-6), were isolated from an 80% aqueous methanol extract of the roots of Ferula fukanensis. The structures were elucidated on the basis of spectroscopic evidence, particularly heteronuclear multiple-bond connectivity (HMBC) and high-resolution MS. The sesquiterpene coumarin derivatives inhibited nitric oxide (NO) and inducible NO synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) gene expression in a murine macrophage-like cell line (RAW264.

3EZ,20Ac-ingenol, a catalytic inhibitor of topoisomerases, downregulates p-Akt and induces DSBs and apoptosis of DT40 cells.

We have previously reported that many ingenol compounds derived from Euphorbia kansui exhibit topoisomerase (topo) II inhibitory activity. Of these compounds, 3EZ,20Ac-ingenol inhibited topo I activity. Camptothecin, which inhibits the religation activity of topo I without interfering with the binding of topo I to DNA and induces topo I-mediated DNA cleavage, was used as a positive control.

Inhibitory effects of the constituents of Hippophae rhamnoides on 3T3-L1 cell differentiation and nitric oxide production in RAW264.7 cells.

Three new flavonol glycosides, hippophaeosides A-C (1-3), together with 27 known constituents, were isolated from Hippophae rhamnoides L. leaves. Their structures were determined by spectroscopic analyses.

Effects of the herbal medicine composition "Saiko-ka-ryukotsu-borei-To" on the function of endothelial progenitor cells in hypertensive rats.

Endothelial progenitor cells (EPCs) are known to repair vascular injuries. Recent studies suggest that Saiko-ka-ryukotsu-borei-To (SKRBT), a traditional herbal medicine that has been used to treat stress-related neuropsychiatric disorders, has protective effects on cardiovascular diseases such as hypertension and arteriosclerosis. Spontaneously hypertensive rats (SHRs) were fed diets containing lyophilized SKRBT extract for 6 weeks.

Triterpenes from Kadsura coccinea.

In vitro anti-allergic screening of medicinal herbal extracts revealed that the 80% acetone extract of the rhizome of Kadsura coccinea inhibited nitric oxide (NO) production in a lipopolysaccharide (LPS) and recombinant mouse interferon-γ (IFN-γ) activated murine macrophage like cell line, RAW264.7. Further fractionation of the EtOAc extract led to the isolation of one new 3,4-seco-lanostane type triterpene named kadsuracoccin acid A (1) together with two known triterpenes anwuweizonic acid (2) and neokadsuranic acid B (3).

Monoterpene glucosides from Ziziphora clinopodioides (Labiatae).

Three new monoterpene glucosides, ziziphoroside A (1), B (2), and C (3), together with fifteen known compounds were isolated from the whole herb of Z. clinopodioides. The structures of new compounds were determined primarily from 1D-, 2D-NMR and circular dichroism (CD) spectroscopic analyses.