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FASEB Journal : Official Publication of... Jan 2023The G protein-coupled receptors, GPR43 (free fatty acid receptor 2, FFA2) and GPR41 (free fatty acid receptor 3, FFA3), are activated by short-chain fatty acids produced...
The G protein-coupled receptors, GPR43 (free fatty acid receptor 2, FFA2) and GPR41 (free fatty acid receptor 3, FFA3), are activated by short-chain fatty acids produced under various conditions, including microbial fermentation of carbohydrates. Previous studies have implicated this receptor energy homeostasis and immune responses as well as in cell growth arrest and apoptosis. Here, we observed the expression of both receptors in human blood cells and a remarkable enhancement in leukemia cell lines (HL-60, U937, and THP-1 cells) during differentiation. A reporter assay revealed that GPR43 is coupled with Gα and Gα and is constitutively active without any stimuli. Specific blockers of GPR43, GLPG0974 and CATPB function as inverse agonists because treatment with these compounds significantly reduces constitutive activity. In HL-60 cells, enhanced expression of GPR43 led to growth arrest through Gα . In addition, the blockage of GPR43 activity in these cells significantly impaired their adherent properties due to the reduction of adhesion molecules. We further revealed that enhanced GPR43 activity induces F-actin formation. However, the activity of GPR43 did not contribute to butyrate-induced apoptosis in differentiated HL-60 cells because of the ineffectiveness of the inverse agonist on cell death. Collectively, these results suggest that GPR43, which possesses constitutive activity, is crucial for growth arrest, followed by the proper differentiation of leukocytes.
Topics: Humans; Fatty Acids, Volatile; Leukocytes; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Cell Differentiation; HL-60 Cells
PubMed: 36468834
DOI: 10.1096/fj.202201591R -
Natural Product Research May 2024Bioassay-guided isolation of the stems of led to one new adamantane-type polycyclic polyprenylated acylphloroglucinols (PPAPs), (-)-garpauvinin A (), and four known...
Bioassay-guided isolation of the stems of led to one new adamantane-type polycyclic polyprenylated acylphloroglucinols (PPAPs), (-)-garpauvinin A (), and four known analogues (). The structure and absolute configuration of was established spectroscopic techniques and ECD method. All the isolates displayed moderate antiproliferative activity against HL-60, PC-3 and Caco-2 human cancer cell lines with IC values ranging from 0.81 to 19.92 μM, and exhibited low toxicity on WPMY-1 normal human cells, showing selectivity between normal and malignant prostate cells. The biosynthetic pathways of the isolated PPAPs were proposed.
Topics: Humans; Molecular Structure; Caco-2 Cells; Garcinia; HL-60 Cells; Phloroglucinol; Hypericum
PubMed: 37234037
DOI: 10.1080/14786419.2023.2217469 -
Chinese Journal of Natural Medicines Feb 2024This study reports the isolation of four new β-carboline alkaloids (1-4) and six previously identified alkaloids (5-10) from the roots of Peganum harmala L. Among these...
This study reports the isolation of four new β-carboline alkaloids (1-4) and six previously identified alkaloids (5-10) from the roots of Peganum harmala L. Among these compounds, 1 and 2 were characterized as rare β-carboline-quinazoline dimers exhibiting axial chirality. Compound 3 possessed a unique 6/5/6/7 tetracyclic ring system with an azepine ring, and compound 4 was a novel annomontine β-carboline. The structures of these compounds were elucidated by spectroscopic data and quantum mechanical calculations. The biosynthetic pathways of 1-3 were proposed. Additionally, the cytotoxicity of some isolates against four cancer cell lines (HL-60, A549, MDA-MB-231, and DU145) was evaluated. Notably, compound 4 exhibited significant cytotoxicity against HL-60, A549, and DU145 cells with IC values of 12.39, 12.80, and 30.65 μmol·L, respectively. Furthermore, compound 2 demonstrated selective cytotoxicity against HL-60 cells with an IC value of 17.32 μmol·L.
Topics: Humans; Peganum; Alkaloids; Carbolines; HL-60 Cells
PubMed: 38342569
DOI: 10.1016/S1875-5364(24)60583-2 -
PLoS Computational Biology Aug 2021Navigation of fast migrating cells such as amoeba Dictyostelium and immune cells are tightly associated with their morphologies that range from steady polarized forms... (Comparative Study)
Comparative Study
Navigation of fast migrating cells such as amoeba Dictyostelium and immune cells are tightly associated with their morphologies that range from steady polarized forms that support high directionality to those more complex and variable when making frequent turns. Model simulations are essential for quantitative understanding of these features and their origins, however systematic comparisons with real data are underdeveloped. Here, by employing deep-learning-based feature extraction combined with phase-field modeling framework, we show that a low dimensional feature space for 2D migrating cell morphologies obtained from the shape stereotype of keratocytes, Dictyostelium and neutrophils can be fully mapped by an interlinked signaling network of cell-polarization and protrusion dynamics. Our analysis links the data-driven shape analysis to the underlying causalities by identifying key parameters critical for migratory morphologies both normal and aberrant under genetic and pharmacological perturbations. The results underscore the importance of deciphering self-organizing states and their interplay when characterizing morphological phenotypes.
Topics: Animals; Cell Movement; Cell Polarity; Cell Shape; Cell Surface Extensions; Cells, Cultured; Cichlids; Computational Biology; Computer Simulation; Deep Learning; Dictyostelium; Fibroblasts; HL-60 Cells; Humans; Models, Biological
PubMed: 34383753
DOI: 10.1371/journal.pcbi.1009237 -
Chemical & Pharmaceutical Bulletin 2022Five podophyllotoxin derivatives (1-5), two diterpenoids (6 and 7), three diterpenoid xylosides (8-10), a flavanonol glycoside (11), flavonol (12), and biflavonoid (13)...
Five podophyllotoxin derivatives (1-5), two diterpenoids (6 and 7), three diterpenoid xylosides (8-10), a flavanonol glycoside (11), flavonol (12), and biflavonoid (13) were isolated from the leaves of Thujopsis dolabrata (Cupressaceae). Compounds 1, 6, and 8 were named (-)-β-isopeltatin, epi-nootkastatin 2, and acetoxyanticopalol 15-O-β-D-xylopyranoside, respectively. The structures of the isolated compounds were determined based on a detailed analysis of NMR spectroscopic data and through chromatographic and spectroscopic analyses following specific chemical transformations. The isolated compounds (1-5 and 7-11) were evaluated for their cytotoxicity toward HL-60 human promyelocytic leukemia cells and Caki-1 human kidney carcinoma cells. The podophyllotoxin derivatives (1-5) exhibited cytotoxicity against both HL-60 and Caki-1 cells with IC values ranging from 0.00069 to 5.4 µM, and the diterpenoid derivatives (7-10) demonstrated cytotoxicity against HL-60 cells with IC values ranging from 4.5 to 11 µM. HL-60 cells treated with 8 exhibited apoptosis characteristics, such as accumulation of sub-G cells and nuclear chromatin condensation.
Topics: Antineoplastic Agents, Phytogenic; Biflavonoids; Chromatin; Cupressaceae; Diterpenes; Flavonols; Glycosides; HL-60 Cells; Humans; Plant Leaves; Podophyllotoxin
PubMed: 36184455
DOI: 10.1248/cpb.c22-00286 -
Bioorganic & Medicinal Chemistry Letters Feb 2023A series of 1-O-acyl- and 1-oxo-kamebanin analogues were prepared from kamebanin, isolated from Rabdosia excisa and their cytotoxicity was assayed on HL60 promyelocytic...
A series of 1-O-acyl- and 1-oxo-kamebanin analogues were prepared from kamebanin, isolated from Rabdosia excisa and their cytotoxicity was assayed on HL60 promyelocytic leukemia cells and HCT116 human colon cancer cells. The structure-activity relationship study showed that the presence of 1-O-acyl groups of a C-C carbon chain increased the cytotoxic activity.
Topics: Humans; Antineoplastic Agents; Structure-Activity Relationship; Isodon; HL-60 Cells; HCT116 Cells
PubMed: 36690039
DOI: 10.1016/j.bmcl.2023.129149 -
Laboratory Investigation; a Journal of... Oct 2021Acute myeloid leukemia (AML) is a common subtype of leukemia, and a large proportion of patients with AML eventually develop drug resistance. Curcumin exerts cancer...
Acute myeloid leukemia (AML) is a common subtype of leukemia, and a large proportion of patients with AML eventually develop drug resistance. Curcumin exerts cancer suppressive effects and increases sensitivity to chemotherapy in several diseases. This study aimed to investigate the mechanism by which curcumin affects the resistance of AML to Adriamycin by regulating HOX transcript antisense RNA (HOTAIR) expression. Cell viability, colony-formation, flow cytometry, and Transwell assays were used to assess cell proliferation, apoptosis, and migration. A dual-luciferase reporter assay was used to verify the interaction between microRNA (miR)-20a-5p and HOTAIR or Wilms' tumor 1 (WT1). RT-qPCR and Western blotting assays were performed to detect gene and protein expression. The results showed that curcumin suppressed the resistance to Adriamycin, inhibited the expression of HOTAIR and WT1, and promoted the expression of miR-20a-5p in human acute leukemia cells (HL-60) or Adriamycin-resistant HL-60 cells (HL-60/ADR). Furthermore, curcumin suppressed proliferation and promoted apoptosis of HL-60/ADR cells. Overexpression of HOTAIR reversed the regulatory effect of curcumin on apoptosis and migration and restored the effect of curcumin on inducing the expression of cleaved caspase3, Bax, and P27. In addition, HOTAIR upregulated WT1 expression by targeting miR-20a-5p, and inhibition of miR-20a-5p reversed the regulation of Adriamycin resistance by curcumin in AML cells. Finally, curcumin inhibited Adriamycin resistance by suppressing the HOTAIR/miR-20a-5p/WT1 pathway in vivo. In short, curcumin suppressed the proliferation and migration, blocked the cell cycle progression of AML cells, and sensitized AML cells to Adriamycin by regulating the HOTAIR/miR-20a-5p/WT1 axis. These findings suggest a potential role of curcumin and HOTAIR in AML treatment.
Topics: Cell Line, Tumor; Cell Survival; Curcumin; Doxorubicin; Drug Resistance, Neoplasm; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; MicroRNAs; RNA, Long Noncoding; Signal Transduction; WT1 Proteins
PubMed: 34282279
DOI: 10.1038/s41374-021-00640-3 -
International Journal of Laboratory... Oct 2021Drug resistance and relapse of acute myeloid leukemia (AML) is still an important problem in the treatment of leukemia. Leukemia outbreak causes severe hypoxia in bone...
INTRODUCTION
Drug resistance and relapse of acute myeloid leukemia (AML) is still an important problem in the treatment of leukemia. Leukemia outbreak causes severe hypoxia in bone marrow (BM), remolding BM microenvironment (niche), and transforming hematopoietic stem cell (HSC) niche into leukemia stem cell (LSC) niche. AML cells and the microenvironment usually conduct "cross-talk" through cytokines to anchor resistant AML cells into LSC niche, thus supporting their survival. Therefore, this study was aimed to investigate the role of CXCL2 in the hypoxic AML niche.
METHODS
AML hypoxic niche was simulated by hypoxic culture of THP-1 and HL-60 cells in vitro, thus to study the effects of CXCL2 on the proliferation and migration of AML cells. The expression of hypoxia-inducible factor-1α (HIF-1α) and the activation of survival-related kinases such as PIM2 and mTOR under CoCl -simulated hypoxic conditions were detected. The correlation between CXCL2 and the prognosis of AML with big data was verified.
RESULTS
(a) CXCL2 promoted the proliferation and migration of AML cells. (b) CXCL2 up-regulated the expression of PIM2 by enhancing the transcriptional activity of HIF-1α. (c) CXCL2 activated mTOR in AML cells. (d) CXCL2 was associated with poor prognosis in AML.
CONCLUSION
CXCL2 promotes survival, migration, and drug resistance pathway of AML cells in hypoxia and is associated with poor prognosis in AML. Therefore, CXCL2 can be considered as an important factor in promoting the development of AML cells in hypoxia.
Topics: Cell Movement; Cell Proliferation; Chemokine CXCL2; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Prognosis; THP-1 Cells; Tumor Hypoxia
PubMed: 33793061
DOI: 10.1111/ijlh.13512 -
Journal of Natural Products Sep 2019Eight new limonoids, toononoids A-H (-), eight new B--29-norlimonoids, toonanoronoids A-H (-), and seven known analogues were obtained from the EtOAc extract of the...
Eight new limonoids, toononoids A-H (-), eight new B--29-norlimonoids, toonanoronoids A-H (-), and seven known analogues were obtained from the EtOAc extract of the twigs and leaves of . Compounds , , , and are rare lactam-bearing limonoids. Compounds , , and possess an unusual γ-methoxybutenolide moiety at C-17, while compounds , , and have a rare 3β-hydroxy group. Their 2D structure and relative configurations were identified using spectroscopic data. The absolute configurations of , , , and were established via X-ray diffraction crystallography or comparison of experimental and calculated ECD data. The cytotoxicity of the compounds was assessed toward five human tumor cell lines, and their anti-inflammatory activity was assessed based on NO production using LPS-stimulated RAW264.7 macrophages. Compounds and exerted inhibition toward two tumor cell lines (MCF-7, SW-480) with IC values between 2.1 and 3.7 μM, while - inhibited the proliferation of HL-60, MCF-7, and SW-480 cells (IC 0.6-4.0 μM). Only compound exhibited weak anti-inflammatory activity with an IC value of 28.3 μM.
Topics: Antineoplastic Agents, Phytogenic; HL-60 Cells; Humans; Limonins; Meliaceae; Plant Leaves; Plant Stems
PubMed: 31503490
DOI: 10.1021/acs.jnatprod.8b00954 -
Life Science Alliance Jan 2021Chromosomal rearrangements of the mixed-lineage leukemia gene are the hallmark of infant acute leukemia. The granulocyte-macrophage progenitor state forms the...
Chromosomal rearrangements of the mixed-lineage leukemia gene are the hallmark of infant acute leukemia. The granulocyte-macrophage progenitor state forms the epigenetic basis for myelomonocytic leukemia stemness and transformation by MLL-type oncoproteins. Previously, it was shown that the establishment of murine myelomonocytic - transformation, but not its maintenance, depends on the transcription factor C/EBPα, suggesting an epigenetic hit-and-run mechanism of MLL-driven oncogenesis. Here, we demonstrate that compound deletion of / almost entirely abrogated the growth and survival of --transformed cells. Rare, slow-growing, and apoptosis-prone --transformed escapees were recovered from compound / deletions. The escapees were uniformly characterized by high expression of the resident gene, suggesting inferior functional compensation of C/EBPα/C/EBPβ deficiency by C/EBPε. Complementation was augmented by ectopic C/EBPβ expression and downstream activation of IGF1 that enhanced growth. gene inactivation was accomplished only in the presence of complementing C/EBPβ, but not in its absence, confirming the dependency of the / double knockouts. Our data show that -transformed myeloid cells are dependent on C/EBPs during the initiation and maintenance of transformation.
Topics: Animals; Apoptosis; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Protein-beta; CCAAT-Enhancer-Binding Proteins; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Gene Knockout Techniques; Granulocyte Precursor Cells; HEK293 Cells; Humans; Leukemia, Myeloid, Acute; Mice; Myeloid-Lymphoid Leukemia Protein; Oncogene Proteins, Fusion; Signal Transduction; Transfection
PubMed: 33144337
DOI: 10.26508/lsa.202000709