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Chemical & Pharmaceutical Bulletin 2020Six new sesquiterpenes, tsukiyols A-C, neoilludin C, and 4-O-methylneoilludins A and B, were isolated from the fruiting body of Omphalotus japonicus (Kawam.) Kirchm. &...
Six new sesquiterpenes, tsukiyols A-C, neoilludin C, and 4-O-methylneoilludins A and B, were isolated from the fruiting body of Omphalotus japonicus (Kawam.) Kirchm. & O. K. Mill. Additionally, six known compounds, illudin S, neoilludins A-B, 5-hydroxydichomitol, ergosterolperoxide, and 3β,5α,9α-trihydroxyergosta-7,22-diene-6-one, were also obtained. Their chemical structures were determined with MS, IR, and NMR spectra and the absolute configurations of neoilludins A-C, 4-O-methylneoilludins A, and B were determined with electronic circular dichroism (ECD). Illudin S and 3β,5α,9α-trihydroxyergosta-7,22-diene-6-one showed cytotoxicity against human acute promyelocytic leukemia HL60 cells. Illudin S, 4-O-methylneoilludin A, B, and tsukiyol C showed growth-restoring activity against mutant yeast via Ca-signal transduction.
Topics: Agaricales; Antifungal Agents; Antineoplastic Agents; Calcium Signaling; Cell Proliferation; Density Functional Theory; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fruiting Bodies, Fungal; HL-60 Cells; Humans; Microbial Sensitivity Tests; Molecular Conformation; Mutation; Saccharomyces cerevisiae; Sesquiterpenes; Structure-Activity Relationship
PubMed: 32378541
DOI: 10.1248/cpb.c19-01009 -
Bioorganic & Medicinal Chemistry Letters Nov 2022Quinones are widespread in plants, animals, insects, and microorganisms. Several anticancer agents contain quinone structures as critical parts to show remarkable...
Quinones are widespread in plants, animals, insects, and microorganisms. Several anticancer agents contain quinone structures as critical parts to show remarkable potential and distinctive modes of actions. The purpose of this study was to investigate the structure-activity relationships of microbial quinones and their derivatives as anticancer agents. A series of p-terphenylquinone and seriniquinone derivatives were therefore prepared. Treatment of the synthesized quinones possessed antiproliferative activity on human leukemia HL-60 cells in a dose-dependent fashion. In addition, seriniquinone derivatives elevated cellular reactive oxygen species (ROS) levels, thereby triggering the ensuing apoptotic events. Our findings emphasize the excellent potential of seriniquinone derivatives as redox cycling-induced ROS-modulating anticancer agents.
Topics: Animals; Humans; Antineoplastic Agents; HL-60 Cells; Oxidation-Reduction; Quinones; Reactive Oxygen Species
PubMed: 36126897
DOI: 10.1016/j.bmcl.2022.128992 -
Proceedings (Baylor University. Medical... Jul 2020On rare occasions, a promonocyte may be difficult to morphologically distinguish from a promyelocyte, giving rise to the diagnosis of acute promyelocytic leukemia,...
On rare occasions, a promonocyte may be difficult to morphologically distinguish from a promyelocyte, giving rise to the diagnosis of acute promyelocytic leukemia, particularly the microgranular variant. It is necessary to correctly diagnose these two types of leukemia, as treatment is different for each. Flow cytometry and cytogenetic/molecular studies are useful in distinguishing the two when morphology alone is equivocal. We report a case of acute monocytic leukemia in which the promonocytes morphologically masqueraded as promyelocytes.
PubMed: 33100557
DOI: 10.1080/08998280.2020.1792752 -
Journal of Cellular and Molecular... Mar 2022Acetylshikonin (ASK) is a natural naphthoquinone derivative of traditional Chinese medicine Lithospermum erythrorhyzon. It has been reported that ASK has bactericidal,...
Acetylshikonin (ASK) is a natural naphthoquinone derivative of traditional Chinese medicine Lithospermum erythrorhyzon. It has been reported that ASK has bactericidal, anti-inflammatory and antitumour effects. However, whether ASK induces apoptosis and autophagy in acute myeloid leukaemia (AML) cells and the underlying mechanism are still unclear. Here, we explored the roles of apoptosis and autophagy in ASK-induced cell death and the potential molecular mechanisms in human AML HL-60 cells. The results demonstrated that ASK remarkably inhibited the cell proliferation, viability and induced apoptosis in HL-60 cells through the mitochondrial pathway, and ASK promoted cell cycle arrest in the S-phase. In addition, the increased formation of autophagosomes, the turnover from light chain 3B (LC3B) I to LC3B II and decrease of P62 suggested the induction of autophagy by ASK. Furthermore, ASK significantly decreased PI3K, phospho-Akt and p-p70S6K expression, while enhanced phospho-AMP-activated protein kinase (AMPK) and phospho-liver kinase B1(LKB1) expression. The suppression of ASK-induced the conversion from LC3B I to LC3B II caused by the application of inhibitors of AMPK (compound C) demonstrated that ASK-induced autophagy depends on the LKB1/AMPK pathway. These data suggested that the autophagy induced by ASK were dependent on the activation of LKB1/AMPK signalling and suppression of PI3K/Akt/mTOR pathways. The cleavage of the apoptosis-related markers caspase-3 and caspase-9 and the activity of caspase-3 induced by ASK were markedly reduced by inhibitor of AMPK (compound C), an autophagy inhibitor 3-methyladenine (3-MA) and another autophagy inhibitor chloroquine (CQ). Taken together, our data reveal that ASK-induced HL-60 cell apoptosis is dependent on the activation of autophagy via the LKB1/AMPK and PI3K/Akt-regulated mTOR signalling pathways.
Topics: AMP-Activated Protein Kinases; Anthraquinones; Apoptosis; Autophagy; Caspase 3; Cell Proliferation; HL-60 Cells; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases
PubMed: 35106915
DOI: 10.1111/jcmm.17202 -
Quercetin induces autophagy-associated death in HL-60 cells through CaMKKβ/AMPK/mTOR signal pathway.Acta Biochimica Et Biophysica Sinica Sep 2022Acute myeloid leukemia (AML) is one of the most common malignancies of the hematopoietic progenitor cell in adults. Quercetin has gained recognition over the years...
Acute myeloid leukemia (AML) is one of the most common malignancies of the hematopoietic progenitor cell in adults. Quercetin has gained recognition over the years because of its anti-cancer effect with minimal toxicity. Herein, we aim to investigate the anti-leukemia mechanism of quercetin and to decipher the signaling pathway of quercetin in HL-60 leukemic cells. We observed that quercetin induces apoptosis and autophagic cell death, in which both pathways play an important role in suppressing the viability of leukemia cells. Phosphorylated AMPK (p-AMPK) protein expressions are lower in primary AML cells, HL-60 cells, KG-1 and THP-1 cells than in peripheral blood monocular cells. After quercetin treatment, the expression of p-AMPK is increased while the expression of p-mTOR is decreased in a dose-dependent manner. Mechanistically, compound C, an AMPK phosphorylation inhibitor, upregulates the phosphorylation of mTOR and inhibits autophagy and apoptosis in quercetin-induced HL-60 cells, while silencing of CaMKKβ inhibits the quercetin-induced phosphorylation of AMPK, resulting in increased mTOR phosphorylation. Furthermore, silencing of CaMKKβ inhibits the autophagy in HL-60 cells. Taken together, our data delineate that quercetin plays its anti-leukemia role by inhibiting cell viability and inducing apoptosis and autophagy in leukemia cells. Quercetin inhibits the phosphorylation of mTOR by regulating the activity of AMPK, thus playing a role in the regulation of autophagy and apoptosis. CaMKKβ is a potential upstream molecule for AMPK/mTOR signaling pathway, through which quercetin induces autophagy in HL-60 cells.
Topics: Humans; HL-60 Cells; Autophagic Cell Death; Quercetin; Calcium-Calmodulin-Dependent Protein Kinase Kinase; AMP-Activated Protein Kinases; Phosphorylation; Signal Transduction; TOR Serine-Threonine Kinases; Apoptosis; Autophagy
PubMed: 36148953
DOI: 10.3724/abbs.2022117 -
Biomolecules Jan 2022The active form of vitamin D (D), 1a,25-dihydroxyvitamn D (1,25D), plays a central role in calcium and bone metabolism. Many structure-activity relationship (SAR)...
The active form of vitamin D (D), 1a,25-dihydroxyvitamn D (1,25D), plays a central role in calcium and bone metabolism. Many structure-activity relationship (SAR) studies of D have been conducted, with the aim of separating the biological activities of 1,25D or reducing its side effects, such as hypercalcemia, and SAR studies have shown that the hypercalcemic activity of C2-substituted derivatives and 19-nor type derivatives is significantly suppressed. In the present paper, we describe the synthesis of 19-nor type 1,25D derivatives with alkoxy groups at C2, by means of the Julia-Kocienski type coupling reaction between a C2 symmetrical A ring ketone and a CD ring synthon. The effect of C2 substituents on the stereoselectivity of the coupling reaction was evaluated. The biological activities of the synthesized derivatives were evaluated in an HL-60 cell-based assay. The a-methoxy-substituted was found to show potent cell-differentiating activity, with an ED value of 0.38 nM, being 26-fold more potent than 1,25D.
Topics: Cell Differentiation; Cholecalciferol; HL-60 Cells; Humans; Structure-Activity Relationship
PubMed: 35053217
DOI: 10.3390/biom12010069 -
Journal of Immunology (Baltimore, Md. :... Mar 2022Protein tyrosine phosphatase (PTPase) is critically involved in the regulation of hematopoietic stem cell development and differentiation. Roles of novel isolated...
Protein tyrosine phosphatase (PTPase) is critically involved in the regulation of hematopoietic stem cell development and differentiation. Roles of novel isolated receptor PTPase PTPRO from bone marrow hematopoietic stem cells in granulopoiesis have not been investigated. PTPRO expression is correlated with granulocytic differentiation, and mice developed neutrophilia, with an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors under steady-state and potentiated innate immune responses against infection. Mechanistically, mTOR and HIF1α signaling engaged glucose metabolism and initiated a transcriptional program involving the lineage decision factor C/EBPα, which is critically required for the PTPRO deficiency-directed granulopoiesis. Genetic ablation of mTOR or HIF1α or perturbation of glucose metabolism suppresses progenitor expansion, neutrophilia, and higher glycolytic activities by In addition, upregulated HIF1α regulates the lineage decision factor α promoter activities. Thus, our findings identify a previously unrecognized interplay between receptor PTPase PTPRO signaling and mTOR-HIF1α metabolic reprogramming in progenitor cells of granulocytes that underlies granulopoiesis.
Topics: Animals; Glucose; Granulocyte Precursor Cells; Granulocytes; Mice; Protein Tyrosine Phosphatases; Receptor-Like Protein Tyrosine Phosphatases, Class 3; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 35246496
DOI: 10.4049/jimmunol.2100878 -
Bioorganic & Medicinal Chemistry Dec 2019Neomacrophorins I-III (1-3) and X have previously been isolated from Trichoderma sp. 1212-03. Their mode of action against cancer cells and the mechanism of biosynthesis...
Neomacrophorins I-III (1-3) and X have previously been isolated from Trichoderma sp. 1212-03. Their mode of action against cancer cells and the mechanism of biosynthesis of the characteristic [4.4.3] propellane framework in neomacrophorin X have not been reported. The isolation and characterization of neomacrophorins IV (4), V (5), and VI (6) is reported. Epoxyquinones 1, 4, and 6 potently induced apoptotic cell death in human acute promyelocytic leukemia HL60 cells, while epoxysemiquinols 2, 3, and 5 showed weak activity. This indicates that the epoxyquinone moiety is crucial for apoptosis-inducing activities of neomacrophorins. We also found that neomacrophorins inhibit proteasome in vitro, and 1, 4, and 6 induced significant accumulation of ubiquitinated proteins in HL60 cells. These activities were completely suppressed by a nucleophile, N-acetyl-l-cysteine (NAC). The analysis of reaction mechanisms using LC-MS suggested that C2' and C7' of neomacrophorins could be Michael acceptors in the reaction with NAC methyl ester (NACM). These findings indicated that the electrophilic properties of neomacrophorins are responsible for both their potent biological effects and the biosynthesis of unique [4.4.3] propellane framework in neomacrophorin X.
Topics: Antineoplastic Agents; Cell Survival; Dose-Response Relationship, Drug; HL-60 Cells; Humans; Molecular Structure; Terpenes; Trichoderma
PubMed: 31732281
DOI: 10.1016/j.bmc.2019.115161 -
Journal of Bronchology & Interventional... Oct 2020
Topics: Aged; Bone Marrow; Bronchi; Bronchoscopy; Cough; Disease Progression; Fatal Outcome; Female; Granulocyte Precursor Cells; Humans; Neoplasm Recurrence, Local; Palliative Care; Sarcoma, Myeloid; Tomography, X-Ray Computed; Trachea
PubMed: 32604321
DOI: 10.1097/LBR.0000000000000693 -
Veterinary Clinical Pathology Mar 2021Routine blood smear findings in two of four 11-day-old mixed-breed dog littermates were suggestive of a lysosomal storage disease (LSD) that was documented to be...
Routine blood smear findings in two of four 11-day-old mixed-breed dog littermates were suggestive of a lysosomal storage disease (LSD) that was documented to be mucopolysaccharidosis type VII (MPS VII) by molecular testing. In this condition, a functional β-glucuronidase deficiency results in the accumulation of glycosaminoglycans (GAGs) in cells and tissues where β-glucuronidase is important in GAG degradation. Most neutrophils and a moderate number of lymphocytes within the blood had atypical cytoplasmic magenta inclusions. The bone marrow assessment from one of the two affected pups at 24 days of age revealed similar magenta granulation in myeloid precursor cells that was most prominent in promyelocytes and myelocytes. Moreover, atypical magenta material was present within vacuoles as well as extracellularly in some osteoblasts and macrophages. Histologic bone marrow sections revealed prominent vacuolation of osteoblasts, and some osteoclasts appeared separated from the bone by layers of osteoblasts or hematopoietic cells. At 2 months of age, the second affected dog showed moderate growth retardation and had similar but more prominent hematologic findings that extended to monocytes, eosinophils, and eosinophil precursors. It had an increased number of bone marrow macrophages with many vacuoles that could be seen cytologically to contain magenta material, and there was mild nonselective phagocytosis of hemic cells. Of the hematologic cells, inclusions were most prominent in promyelocytes, myelocytes, and macrophages, cells with relatively high β-glucuronidase activity, and GAG exposure within lysosomes or lysosome-like primary granules of granulocyte precursors.
Topics: Animals; Bone Marrow; Dog Diseases; Dogs; Glucuronidase; Macrophages; Monocytes; Mucopolysaccharidosis VII
PubMed: 33719080
DOI: 10.1111/vcp.12963