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Cancer Cell Jul 2020Fat mass and obesity-associated protein (FTO), an RNA N-methyladenosine (mA) demethylase, plays oncogenic roles in various cancers, presenting an opportunity for the...
Fat mass and obesity-associated protein (FTO), an RNA N-methyladenosine (mA) demethylase, plays oncogenic roles in various cancers, presenting an opportunity for the development of effective targeted therapeutics. Here, we report two potent small-molecule FTO inhibitors that exhibit strong anti-tumor effects in multiple types of cancers. We show that genetic depletion and pharmacological inhibition of FTO dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially LILRB4. FTO inhibition sensitizes leukemia cells to T cell cytotoxicity and overcomes hypomethylating agent-induced immune evasion. Our study demonstrates that FTO plays critical roles in cancer stem cell self-renewal and immune evasion and highlights the broad potential of targeting FTO for cancer therapy.
Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Anthracenes; Biphenyl Compounds; Cell Line, Tumor; Cell Self Renewal; Cell Survival; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Immune Evasion; Leukemia; Membrane Glycoproteins; Molecular Structure; Protein Binding; Protein Domains; Receptors, Immunologic; U937 Cells
PubMed: 32531268
DOI: 10.1016/j.ccell.2020.04.017 -
Drug Design, Development and Therapy 2022This study was designed to evaluate the pharmacological mechanisms of Aloin against gastric cancer (GC) via network pharmacology analysis combined with experimental...
PURPOSE
This study was designed to evaluate the pharmacological mechanisms of Aloin against gastric cancer (GC) via network pharmacology analysis combined with experimental verification.
METHODS
Using network pharmacology methods, the potential targets of Aloin and targets related to GC were screened from public databases. The protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to predict the core targets and pathways of Aloin against GC. The expressions of major targets predicted by network pharmacology in normal stomach tissues and GC tissues and their relationships with overall survival of GC were searched in GEPIA, HPA and DriverDBv3 database. The results of network pharmacology analysis were verified by in vitro experiments.
RESULTS
A total of 129 potential targets were retrieved by searching the intersection of Aloin and GC targets. PPI network analysis indicated that 10 targets, including AKT1 and CASP3, were hub genes. GO enrichment analysis involved 93 biological processes, 19 cellular components, and 37 molecular functions. KEGG enrichment analysis indicated that the anti-cancer effect of Aloin was mediated through multiple pathways, such as PI3K-AKT, FoxO and Ras signaling pathway. Among them, the PI3K-AKT signaling pathway, which contained the largest number of enriched genes, may play a greater role in the treatment of GC. The validation of key targets in GEPIA, HPA and DriverDBv3 database showed that the verification results for most core genes were consistent with this study. Then, the results of in vitro experiment indicated that Aloin could inhibit proliferation of NCI-N87 cells and induce cell apoptosis. The results also showed that Aloin could decrease the mRNA and protein expressions of PI3K and AKT, suggesting that Aloin can treat GC by inducing cell apoptosis and regulating the PI3K-AKT signaling pathway.
CONCLUSION
This study identified the potential targets of Aloin against GC using network pharmacology and in vitro verification, which provided a new understanding of the pharmacological mechanisms of Aloin in treatment of GC.
Topics: Emodin; Humans; Molecular Docking Simulation; Network Pharmacology; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Stomach Neoplasms
PubMed: 35757520
DOI: 10.2147/DDDT.S360790 -
Cell Metabolism Dec 2019Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like...
Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like α-smooth muscle actin (ACTA2). Allosteric regulation is considered to be an innovative strategy to discover a highly selective and potent inhibitor targeting PGAM1. Here, we identified a novel PGAM1 allosteric inhibitor, HKB99, via structure-based optimization. HKB99 acted to allosterically block conformational change of PGAM1 during catalytic process and PGAM1-ACTA2 interaction. HKB99 suppressed tumor growth and metastasis and overcame erlotinib resistance in non-small-cell lung cancer (NSCLC). Mechanistically, HKB99 enhanced the oxidative stress and altered multiple signaling pathways including the activation of JNK/c-Jun and suppression of AKT and ERK. Collectively, the study highlights the potential of PGAM1 as a therapeutic target in NSCLC and reveals a distinct mechanism by which HKB99 inhibits both metabolic activity and nonmetabolic function of PGAM1 by allosteric regulation.
Topics: Actins; Animals; Anthracenes; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Enzyme Inhibitors; Female; Humans; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Phosphoglycerate Mutase; Sulfonamides
PubMed: 31607564
DOI: 10.1016/j.cmet.2019.09.014 -
Bioengineered Dec 2021The role of autophagic mechanisms in the protective effect of berberine (BBR) on lipopolysaccharide (LPS)-induced injury in the endothelial cells human umbilical vein...
The role of autophagic mechanisms in the protective effect of berberine (BBR) on lipopolysaccharide (LPS)-induced injury in the endothelial cells human umbilical vein endothelial cells (HUVECs) and human pulmonary microvascular endothelial cells (HPMECs) was investigated. Cell viability, proliferation, and apoptosis were detected by the CCK-8 assay, the EdU kit, and flow cytometry, respectively, and autophagy-related protein expression, the number of autophagic vacuoles, and LC3 double-fluorescence were examined using western blot analysis, transmission electron microscopy, and confocal microscopy, respectively. LPS resulted in a decrease in the cell viability and proliferation of HUVECs and HPMECs and an increase in the number of apoptotic cells, while BBR treatment resulted in an increase in cell viability and proliferation, as well as a decrease in cell apoptosis. Furthermore, BBR could inhibit LPS-induced autophagy, as demonstrated by its inhibitory effects on the LC3-II/LC3-I ratio and Beclin-1 levels and its promotive effect on p62 expression. Addition of the autophagy inducer rapamycin (RAPA) aggravated LPS-induced injury, while treatment with the autophagy blocker 3-methyladenine (3-MA) attenuated the injury. Further, the protective effect of BBR was inhibited by rapamycin. JNK inhibition by SP600125 inhibited LPS-induced autophagy, and BBR could not alter the LPS-induced autophagy in HUVECs and HPMECs that were pretreated with SP600125. The present data indicate that BBR attenuated LPS-induced cell apoptosis by blocking JNK-mediated autophagy in HUVECs and HPMECs. Therefore, the JNK-mediated autophagy pathway could be a potential target for the prevention and treatment of cardiovascular disease.
Topics: Adenine; Anthracenes; Autophagy; Berberine; Cell Proliferation; Cell Survival; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Lipopolysaccharides; MAP Kinase Signaling System; Protective Agents; Sirolimus
PubMed: 33896366
DOI: 10.1080/21655979.2021.1915671 -
Toxins Nov 2020This review, covering the literature from 1966 to the present (2020), describes naturally occurring fungal bioactive anthraquinones and analogues biosynthesized by the... (Review)
Review
This review, covering the literature from 1966 to the present (2020), describes naturally occurring fungal bioactive anthraquinones and analogues biosynthesized by the acetate route and concerning several different functionalized carbon skeletons. Hydrocarbons, lipids, sterols, esters, fatty acids, derivatives of amino acids, and aromatic compounds are metabolites belonging to other different classes of natural compounds and are generated by the same biosynthetic route. All of them are produced by plant, microorganisms, and marine organisms. The biological activities of anthraquinones and analogues comprise phytotoxic, antibacterial, antiviral, anticancer, antitumor, algicide, antifungal, enzyme inhibiting, immunostimulant, antiplatelet aggregation, cytotoxic, and antiplasmodium activities. The review also covers some practical industrial applications of anthraquinones.
Topics: Animals; Anthraquinones; Fungi; Humans
PubMed: 33198270
DOI: 10.3390/toxins12110714 -
Inflammation Apr 2022Emodin, the effective component of the traditional Chinese medicine Dahuang, has anti-inflammatory effects. However, the protective effects and potential mechanisms of...
Emodin, the effective component of the traditional Chinese medicine Dahuang, has anti-inflammatory effects. However, the protective effects and potential mechanisms of emodin are not clear. This study investigated the protective effects and potential mechanisms of emodin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in vitro and in vivo. In vivo, we designed an LPS-induced ALI rat model. In vitro, we chose the J774A.1 cell line to establish an inflammatory cellular model, and knocked down NOD-like receptor family pyrin domain containing 3 (NLRP3) using small interfering RNA. The mRNA and protein expression of NLRP3, a C-terminal caspase recruitment domain (ASC), caspase 1 (CASP1), and gasdermin D (GSDMD) in cells and lung tissues were detected by western blot and real-time quantitative polymerase chain reaction (PCR). The expression levels of interleukin 1 beta (IL-1β) and IL-18 in the serum and supernatant were determined by the enzyme-linked immunosorbent assay. The degree of pathological injury in lung tissue was evaluated by hematoxylin and eosin (H&E) staining. In vitro, we demonstrated that emodin could inhibit NLRP3 and then inhibit the expression of ASC, CASP1, GSDMD, IL-1β, and IL-18. In vivo, we confirmed that emodin had protective effects on LPS-induced ALI and inhibitory effects on NLRP3 inflammasome -dependent pyroptosis. Emodin showed excellent protective effects against LPS-induced ALI by regulating the NLRP3 inflammasome-dependent pyroptosis signaling pathway.
Topics: Acute Lung Injury; Animals; Emodin; Inflammasomes; Lipopolysaccharides; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Rats; Signal Transduction
PubMed: 34787801
DOI: 10.1007/s10753-021-01581-1 -
Marine Drugs May 2021The marine ecosystem, populated by a myriad of animals, plants, and microorganisms, is an inexhaustible reservoir of pharmacologically active molecules. Among the... (Review)
Review
The marine ecosystem, populated by a myriad of animals, plants, and microorganisms, is an inexhaustible reservoir of pharmacologically active molecules. Among the multiple secondary metabolites produced by marine sources, there are anthraquinones and their derivatives. Besides being mainly known to be produced by terrestrial species, even marine organisms and the uncountable kingdom of marine microorganisms biosynthesize anthraquinones. Anthraquinones possess many different biological activities, including a remarkable antitumor activity. However, due to their peculiar chemical structures, anthraquinones are often associated with toxicological issues, even relevant, such as genotoxicity and mutagenicity. The aim of this review is to critically describe the anticancer potential of anthraquinones derived from marine sources and their genotoxic and mutagenic potential. Marine-derived anthraquinones show a promising anticancer potential, although clinical studies are missing. Additionally, an in-depth investigation of their toxicological profile is needed before advocating anthraquinones as a therapeutic armamentarium in the oncological area.
Topics: Animals; Anthraquinones; Antineoplastic Agents; Aquatic Organisms; Cell Line, Tumor; Humans; Mutagens; Neoplasms
PubMed: 34068184
DOI: 10.3390/md19050272 -
Nature Communications Jan 2022Enteroendocrine (EE) cells are the most abundant hormone-producing cells in humans and are critical regulators of energy homeostasis and gastrointestinal function....
Enteroendocrine (EE) cells are the most abundant hormone-producing cells in humans and are critical regulators of energy homeostasis and gastrointestinal function. Challenges in converting human intestinal stem cells (ISCs) into functional EE cells, ex vivo, have limited progress in elucidating their role in disease pathogenesis and in harnessing their therapeutic potential. To address this, we employed small molecule targeting of the endocannabinoid receptor signaling pathway, JNK, and FOXO1, known to mediate endodermal development and/or hormone production, together with directed differentiation of human ISCs from the duodenum and rectum. We observed marked induction of EE cell differentiation and gut-derived expression and secretion of SST, 5HT, GIP, CCK, GLP-1 and PYY upon treatment with various combinations of three small molecules: rimonabant, SP600125 and AS1842856. Robust differentiation strategies capable of driving human EE cell differentiation is a critical step towards understanding these essential cells and the development of cell-based therapeutics.
Topics: Anthracenes; Cell Differentiation; Chromogranin A; Endocannabinoids; Enteroendocrine Cells; Glucagon-Like Peptide 1; Humans; Intestinal Mucosa; Peptide YY; Quinolones; Rimonabant; Signal Transduction; Somatostatin; Stem Cells; Transcription Factors
PubMed: 35017529
DOI: 10.1038/s41467-021-27901-5 -
Molecules (Basel, Switzerland) Nov 2022The present review summarizes the work carried out mostly in the last decade on iridium and ruthenium complexes bearing various perylene ligands, of particular interest... (Review)
Review
The present review summarizes the work carried out mostly in the last decade on iridium and ruthenium complexes bearing various perylene ligands, of particular interest for bioimaging, photodynamic therapy, and solar energy conversion. In these complexes, the absorption spectra and the electrochemical properties are those of the perylene subunit plus those of the metal moiety. In contrast, the emissions are completely changed with respect to perylenes considered alone. Thus, fully organic perylenes are characterized by a strong fluorescence in the visible region, lifetimes of a few nanoseconds, and luminescence quantum yields approaching 100%, whereas perylene Ir and Ru complexes usually do not emit; however, in few cases, weak phosphorescent emissions, with lifetimes in the range of microseconds and relatively low quantum yields, are reported. This is due to a strong interaction between the perylene core and the heavy metal center, taking place after the excitation. Nevertheless, an important advantage deriving from the presence of the heavy metal center is represented by the ability to generate large amounts of singlet oxygen, which plays a key role in photodynamic therapy.
Topics: Iridium; Ruthenium; Perylene; Ligands; Luminescence
PubMed: 36432028
DOI: 10.3390/molecules27227928 -
Theranostics 2023Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology with no cure. A better understanding of the disease processes and...
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology with no cure. A better understanding of the disease processes and identification of druggable targets will benefit the development of effective therapies for IPF. We previously reported that MDM4 promoted lung fibrosis through the MDM4-p53-dependent pathway. However, it remained unclear whether targeting this pathway would have any therapeutic potential. In this study, we evaluated the efficacy of XI-011, a small molecular inhibitor of MDM4, for treating lung fibrosis. We found that XI-011 significantly reduced MDM4 expression and increased the expression of total and acetylated p53 in primary human myofibroblasts and a murine fibrotic model. XI-011 treatment resulted in the resolution of lung fibrosis in mice with no notable impact on normal fibroblast death or the morphology of healthy lungs. Based on these findings, we propose that XI-011 might be a promising therapeutic drug candidate for treating pulmonary fibrosis.
Topics: Humans; Mice; Animals; Tumor Suppressor Protein p53; Idiopathic Pulmonary Fibrosis; Anthracenes; Lung; Fibroblasts; Proto-Oncogene Proteins; Cell Cycle Proteins
PubMed: 37284444
DOI: 10.7150/thno.81993