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The Journal of Antibiotics Feb 2021Two new naphthyl-products calinaphthyltriol A (1) and calinaphthalenone A (2) were isolated from Aspergillus californicus IBT 16748 together with one known compound...
Two new naphthyl-products calinaphthyltriol A (1) and calinaphthalenone A (2) were isolated from Aspergillus californicus IBT 16748 together with one known compound ophiobolin X (3). Their structures were elucidated by extensive spectroscopic analyses. The absolute configuration of 2 was solved by comparing its optical rotation with data for the known compounds 4, 5, and 6 as well as theoretical calculations. The antibacterial and cytotoxic activities of 1 and 3 were evaluated. Both compounds did not show antibacterial activity (MIC > 96 µg·ml) against a few selected clinically relevant Gram positive and Gram negative bacterial strains. However, they showed moderate cytotoxicity against HL-60 cell line with IC values of 18 and 24 µg·ml, respectively.
Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Aspergillus; Fermentation; Gram-Negative Bacteria; Gram-Positive Bacteria; HL-60 Cells; Humans; Microbial Sensitivity Tests; Molecular Conformation; Molecular Structure
PubMed: 32999431
DOI: 10.1038/s41429-020-00372-4 -
Journal of Toxicology and Environmental... Feb 2021Oncocalyxone A, a 1,4-benzoquinone derived from , exhibits anti-inflammatory, antimicrobial and antidiabetic properties. The aim of this study was to (1) examine the...
Oncocalyxone A, a 1,4-benzoquinone derived from , exhibits anti-inflammatory, antimicrobial and antidiabetic properties. The aim of this study was to (1) examine the cytotoxic actions of oncocalyxone A on human normal and tumor cell lines and (2) determine mechanistic actions underlying effects upon leukemia cells using cellular and molecular techniques. Antiproliferative studies on cancer cell lines, peripheral blood mononuclear cells, and human erythrocytes were performed using colorimetric assays. To understand cytotoxicity, assessments were performed with HL-60 leukemia cells (8, 16.5, or 33 µM) after 24 hr incubation using light and fluorescence microscopy, trypan blue, flow cytometry, Comet assay, western blot of caspases and poly-ADP-ribose polymerase (PARP), and effects on topoisomerase I and II. Oncocalyxone A exhibited cytotoxic action upon HL-60 cells and dividing leukocytes, but minimal hemolytic action on erythrocytes. Mechanistic investigations demonstrated reduction of cell viability, loss of membrane integrity, cell shrinking, chromatin condensation, blebbings, externalization of phosphatidylserine, caspase activation, PARP cleavage, mitochondrial depolarization, and DNA damage. Pre-treatment with N-acetylcysteine 4 mM significantly reduced DNA damage and prevented membrane integrity loss. Oncocalyxone A displayed free radical dependent antileukemic activity via apoptotic pathways and induced DNA damage in HL-60 cells. Oncocalyxone A possesses structural chemical simplicity enabling it to be a cost-effective alternative. These properties justify further improvements to enhance activity and selectivity and the development of pharmaceutical formulations. Abbreviations Acridine orange, AO; ANOVA, analysis of variance; BSA, bovine serum albumin; DI, Damage Index; DMSO, dimethylsulfoxide; EC, effective concentration 50%; EDTA, ethylenediamine tetraacetic acid; EB, ethidium bromide; HCT-116, colon carcinoma line; HL-60, promyelocytic leukemia line; IC, inhibitory concentration 50%; MTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; OVCAR-8, ovarian carcinoma line; NAC, N-acetylcysteine, PBMC, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; PI, propidium iodide; PARP, poly-ADP-ribose polymerase; RPMI-1640, Roswell Park Memorial Institute medium; SF-295, glioblastoma line; ROS, reactive oxygen species; 7-AAD, 7-amino-actinomycin D; H-DCF-DA, 7'-dichlorodihydrofluorescein diacetate.
Topics: Anthraquinones; Antineoplastic Agents; HL-60 Cells; Humans
PubMed: 33092495
DOI: 10.1080/15287394.2020.1835763 -
Chemical & Pharmaceutical Bulletin 2022Two novel triterpene glycosides (1 and 2), 17 known triterpene glycosides (3-19), two known flavonoid glycosides (20 and 21), and two known norsesquiterpene glucosides...
Two novel triterpene glycosides (1 and 2), 17 known triterpene glycosides (3-19), two known flavonoid glycosides (20 and 21), and two known norsesquiterpene glucosides (22 and 23) were isolated from Hedera rhombea (Araliaceae) leaves. The structures of 1 and 2 were determined by spectroscopic analysis, including two-dimensional NMR spectroscopy, and chromatographic analysis of the hydrolyzed products. The cytotoxicity of the isolated triterpene glycosides (1-19) against HL-60 human promyelocytic leukemia cells was evaluated. Compounds 9, 10, and 11 were cytotoxic to HL-60 cells with IC values of 7.2, 21.9, and 32.8 µM, respectively. Other compounds isolated from the leaves were not cytotoxic at sample concentrations of 50 μM.
Topics: Antineoplastic Agents, Phytogenic; Araliaceae; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Glycosides; HL-60 Cells; Humans; Molecular Structure; Plant Leaves; Structure-Activity Relationship; Triterpenes
PubMed: 35110439
DOI: 10.1248/cpb.c21-00907 -
Frontiers in Public Health 2020subverts neutrophil function permitting intracellular survival, propagation and transmission. Sustained pro-inflammatory response, recruitment of new host cells for...
subverts neutrophil function permitting intracellular survival, propagation and transmission. Sustained pro-inflammatory response, recruitment of new host cells for population expansion, and delayed apoptosis are associated with prolonged nuclear presence of NF-κB. We investigated NF-κB signaling and transcriptional activity with infection using inhibitors of NF-κB signaling pathways, and through silencing of signaling pathway genes. How inhibitors or silencing affected growth, inflammatory response (transcription of the κB-enhanced genes and ), and NF-κB signaling pathway gene expression were tested. Among -infected HL-60 cells, nuclear NF-κB p50, p65, and p52 were detected by immunoblots or iTRAQ proteomics. growth was affected most by the IKKαβ inhibitor wedelolactone (reductions of 96 to 99%) as compared with SC-514 that selectively inhibits IKKβ, illustrating a role for the non-canonical pathway. Wedelolactone inhibited transcription of both ( = 0.001) and ( = 0.002) in infected cells. Compared to uninfected THP-1 cells, infection led to >2-fold down regulation of 64 of 92 NF-κB signaling pathway genes, and >2-fold increased expression in only 4. Wedelolactone and SC-514 reversed downregulation in all 64 and 45, respectively, of the genes down-regulated by infection, but decreased expression in 1 gene with SC-514 only. Silencing of 20 NF-κB signal pathway genes increased bacterial growth in 12 (, and ). Most findings support canonical pathway activation; however, the presence of NFKB2 in infected cell nuclei, selective non-canonical pathway inhibitors that dampen and transcription with infection, upregulation of non-canonical pathway target genes and , enhanced bacterial growth with and silencing provide evidence for non-canonical pathway signaling. Whether this impacts distinct inflammatory processes that underlie disease, and whether and how subverts NF-κB signaling via these pathways, need to be investigated.
Topics: Anaplasma phagocytophilum; Ehrlichiosis; HL-60 Cells; Humans; I-kappa B Kinase; NF-kappa B; Signal Transduction; TNF Receptor-Associated Factor 3
PubMed: 33194960
DOI: 10.3389/fpubh.2020.558283 -
PloS One 2023In myelodysplastic syndromes (MDS), neoplastic myeloblast (CD34+CD13+CD33+ cells) numbers often increase over time, leading to secondary acute myeloid leukemia (AML). In...
OBJECTIVES
In myelodysplastic syndromes (MDS), neoplastic myeloblast (CD34+CD13+CD33+ cells) numbers often increase over time, leading to secondary acute myeloid leukemia (AML). In recent studies, blasts in some MDS patients have been found to express a megakaryocyte-lineage molecule, CD41, and such patients show extremely poor prognosis. This is the first study to evaluate whether myeloblasts transition to CD41+ blasts over time and to investigate the detailed immunophenotypic features of CD41+ blasts in MDS.
METHODS
We performed a retrospective cohort study, in which time-dependent changes in blast immunophenotypes were analyzed using multidimensional flow cytometry (MDF) in 74 patients with MDS and AML (which progressed from MDS).
RESULTS
CD41+ blasts (at least 20% of CD34+ blasts expressing CD41) were detected in 12 patients. In five of these 12 patients, blasts were CD41+ from the first MDF analysis. In the other seven patients, myeloblasts (CD34+CD33+CD41- cells) transitioned to megakaryoblasts (CD34+CD41+ cells) over time, which was often accompanied by disease progression (including leukemic transformation). These CD41+ patients were more frequently observed among patients with monosomal and complex karyotypes. CD41+ blasts were negative for the erythroid antigen, CD235a, and positive for CD33 in all cases, but CD33 expression levels were lower in three cases when compared with CD34+CD41- blasts. Among the five CD41+ patients who underwent extensive immunophenotyping, CD41+ blasts all expressed CD61, but two cases had reduced CD42b expression, three had reduced/absent CD13 expression, and three also expressed CD7.
CONCLUSIONS
Myeloblasts become megakaryoblastic over time in some MDS patients, and examining the megakaryocyte lineage (not only as a diagnostic work-up but also as follow-up) is needed to detect CD41+ MDS. The immunophenotypic features revealed in this study may have diagnostic relevance for CD41+ MDS patients.
Topics: Humans; Granulocyte Precursor Cells; Immunophenotyping; Megakaryocyte Progenitor Cells; Retrospective Studies; Antigens, CD34; Myelodysplastic Syndromes
PubMed: 37729123
DOI: 10.1371/journal.pone.0291662 -
Yakugaku Zasshi : Journal of the... 2021I here present the results of our studies on the synthesis and functional analysis of tautomeric dihydropyrimidines (DPs) and related compounds in two sections. In the... (Review)
Review
I here present the results of our studies on the synthesis and functional analysis of tautomeric dihydropyrimidines (DPs) and related compounds in two sections. In the first section, we describe our experimental and theoretical studies on the thermodynamics and properties of 2-substituted 1,4- and 1,6-dihydropyrimidine-5-carboxylates by H NMR measurements and density functional theory (DFT) calculations, respectively. The concentration ratios of tautomers a/b of DPs 1, 2, and 3 were determined under various conditions to determine the effects of temperature, solvent, and concentration on thermodynamics data. The obtained free energy differences (ΔG), enthalpy differences (ΔH), and entropy differences (ΔS) are discussed in terms of the molecular structures, dipole moments (DM), and electrostatic potential maps obtained by DFT calculations to clarify the nature of DPs 4-8. In the second section, an efficient synthetic method developed for 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-thiones 9 and 2-ones 10 is described. The novelties of the synthesis protocol are as follows: 1) the use of Lewis acid-mediated reaction, 2) good to high yields, and 3) its broad scope of applicability to aldehydes and ureas. Hitherto unavailable 6-unsubstituted 2-amino DP 11 and 2-aryl DP 12 were obtained from 9 by a substitution reaction with the amine and the Liebeskind-Srogl reaction, respectively. The compounds 9, 10, and related 6-methyl derivatives 19-21 were assessed for their antiproliferative effect on the human promyelocytic leukemia cell line HL-60. 4,4-Dipropyl derivative 20 showed relatively strong activity with an IC value of 341 nM.
Topics: Cell Proliferation; Dose-Response Relationship, Drug; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Molecular Structure; Pyrimidines; Solvents; Static Electricity; Structure-Activity Relationship; Temperature; Thermodynamics
PubMed: 33518632
DOI: 10.1248/yakushi.20-00182 -
General Physiology and Biophysics Sep 2021The present study was conducted to explore the anti-acute myeloid leukaemia (AML) effects of leonurine. HL-60 and U-937 cells were used to assess the antileukaemia...
The present study was conducted to explore the anti-acute myeloid leukaemia (AML) effects of leonurine. HL-60 and U-937 cells were used to assess the antileukaemia effect of leonurine in vitro, and HL-60 and U-937 xenograft nude mice were used to evaluate its antitumour effect in vivo. Leonurine inhibited the proliferation of HL-60 and U-937 cells in a time- and dose-dependent manner. Moreover, leonurine therapy prevented the growth of tumours in both xenograft animal models. Leonurine could induce apoptosis in HL-60 and U-937 cells. The cytotoxic effects of leonurine on HL-60 and U-937 cells were associated with an increased ratio of Bax/Bcl-2, activation of caspase-3, caspase-8 and caspase-9, and increased expression of cytochrome c in the cytoplasm. Leonurine inhibited activation of the PI3K/Akt pathway in HL-60 and U-937 cells by lowering the phosphorylation levels of PI3K and Akt. Our results indicate that leonurine is a potential anti-AML agent, and this activity may be associated with its repression of the phosphorylation of PI3K and Akt.
Topics: Animals; Gallic Acid; HL-60 Cells; Humans; Leukemia; Mice; Mice, Nude; Phosphatidylinositol 3-Kinases
PubMed: 34602453
DOI: 10.4149/gpb_2021018 -
Genes Mar 2023Acute promyelocytic leukemia (APL) pathogenesis is based on gene translocations, which are of high importance in the diagnosis of and proper therapy selection for APL....
Acute promyelocytic leukemia (APL) pathogenesis is based on gene translocations, which are of high importance in the diagnosis of and proper therapy selection for APL. However, in some cases acute myeloid leukemia (AML) demonstrates APL-like morphological features such as atypical promyelocytes accumulation. This type of AML is characterized by the involvement of other family members or completely different genes. In the present study, we used conventional karyotyping, FISH and high-throughput sequencing in a group of 271 de novo AML with atypical promyelocytes accumulation. Of those, 255 cases were shown to carry a typical chromosomal translocation t(15;17)(q24;q21) with chimeric gene formation (94.1%). Other -positive cases exhibited cryptic fusion without t(15;17)(q24;q21) (1.8%, = 5) and variant t(5;17)(q35;q21) translocation with chimeric gene formation (1.5%, = 4). However, 7 -negative AMLs with atypical promyelocytes accumulation were also discovered. These cases exhibited and fusions as well as mutations, e.g., insertion and non-recurrent chromosomal aberrations. Our findings demonstrate the genetic diversity of AML with APL-like morphological features, which is of high importance for successful therapy implementation.
Topics: Humans; Granulocyte Precursor Cells; Leukemia, Promyelocytic, Acute; Leukemia, Myeloid, Acute; Translocation, Genetic; Nuclear Proteins
PubMed: 36980947
DOI: 10.3390/genes14030675 -
Bioorganic & Medicinal Chemistry Letters Dec 2021The FDA approved drug Dronabinol was identified in a previous study applying virtual screening using the haemozoin crystal as a target against malaria parasites. The...
The FDA approved drug Dronabinol was identified in a previous study applying virtual screening using the haemozoin crystal as a target against malaria parasites. The active ingredient of dronabinol is synthetic tetrahydrocannabinol (THC), which is one of the major cannabinoids from Cannabis sativa. Traditional use of cannabis for malaria fever was reported in the world's oldest pharmacopoeia, dating to around 5000 years ago. In this research we report that THC inhibits β-haematin (synthetic haemozoin) and malaria parasite growth. Due the psychoactivity of THC, CBD, the other major naturally occurring cannabinoid that lacks the off-target psychoactive effects of THC, was also tested and inhibited β-haematin but showed only a mild antimalarial activity. To evaluate whether THC inhibit haemozoin formation, we performed a cellular haem fractionation assay that indicated that is not the likely mechanism of action. For the first time, the cannabinoid chemical structure is raised as a new chemical class to be further studied for malaria treatment, aiming to overcome the undesirable psychoactive effects of THC and optimize the antimalarial effects.
Topics: Antimalarials; Cannabis; Dose-Response Relationship, Drug; Dronabinol; HL-60 Cells; Hemeproteins; Humans; Malaria; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum; Structure-Activity Relationship
PubMed: 34763083
DOI: 10.1016/j.bmcl.2021.128442 -
Fitoterapia Jul 2020Two unusual dendrobine-type alkaloids, findlayines E and F (1, 2), along with five known dendrobine-type alkaloids (3-7), were isolated from the stems of Dendrobium...
Two unusual dendrobine-type alkaloids, findlayines E and F (1, 2), along with five known dendrobine-type alkaloids (3-7), were isolated from the stems of Dendrobium findlayanum Par. et Rchb. f. Compound 1 is the first example of dendrobine-type alkaloids with a 2-ethoxy-2-oxoethyl group attaching to the C-2, and compound 2 is a nor-dendrobine-type alkaloid, featuring a 5-decarboxylated structure. The structures of compounds 1 and 2 were elucidated by means of extensive spectroscopic analyses, and their absolute configuration were confirmed by electronic circular dichroism (ECD) calculations. All isolates were evaluated for their cytotoxicity against HL-60, SMMC-7721, A-549 and MCF-7 human cancer cells.
Topics: A549 Cells; Alkaloids; China; Dendrobium; HL-60 Cells; Humans; MCF-7 Cells; Molecular Structure; Phytochemicals; Plant Stems
PubMed: 32387373
DOI: 10.1016/j.fitote.2020.104607