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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 -
Nature Chemistry Aug 2022Phosphorus mononitride (PN) only has a fleeting existence on Earth, and molecular precursors for the release of this molecule under mild conditions in solution have...
Phosphorus mononitride (PN) only has a fleeting existence on Earth, and molecular precursors for the release of this molecule under mild conditions in solution have remained elusive. Here we report the synthesis of an anthracene-based precursor-an anthracene moiety featuring an azidophosphine bridge across its central ring-that dissociates into dinitrogen, anthracene and P≡N in solution with a first-order half-life of roughly 30 min at room temperature. Heated under reduced pressure, this azidophosphine-anthracene precursor decomposes in an explosive fashion at around 42 °C, as demonstrated in a molecular-beam mass spectrometry study. The precursor is also shown to serve as a PN transfer reagent in the synthesis of an Fe-NP coordination complex, through ligand exchange with its Fe-N counterpart. The terminal N-bonded complex was found to be energetically preferred, compared to its P-bonded linkage isomer, owing to a significant covalent Fe-pnictogen bond character and an associated less unfavourable Pauli repulsion in the metal-ligand interaction.
Topics: Anthracenes; Ligands; Metals; Models, Molecular; Phosphorus
PubMed: 35697930
DOI: 10.1038/s41557-022-00958-5 -
Photodiagnosis and Photodynamic Therapy Sep 2021Hypericin is considered a potent photosensitizer for use in antitumor and antimicrobial photodynamic therapy (PDT). This review presents the primary biological results... (Review)
Review
Hypericin is considered a potent photosensitizer for use in antitumor and antimicrobial photodynamic therapy (PDT). This review presents the primary biological results obtained with hypericin in photodynamic therapy applications, such as photodynamic cancer treatment, photoinactivation of microorganisms (PDI), tissue scarring, and photo diagnosis. We present a compilation of in vitro results that have been published thus far; for these studies, we highlight the hypericin concentration, light dose, and other experimental conditions to evaluate the efficiency of photodynamic treatment like cell death, cell viability, or cell proliferation. The results indicate that different hypericin phototoxicity levels can be observed according to the specific light dose and concentration. Furthermore, it was shown that cellular localization and cell death mechanisms (apoptosis and necrosis) are dependent on the cell type.
Topics: Anthracenes; Apoptosis; Cell Survival; Perylene; Photochemotherapy; Photosensitizing Agents
PubMed: 34038765
DOI: 10.1016/j.pdpdt.2021.102343 -
Phytomedicine : International Journal... Mar 2023Hypericin is a prominent secondary metabolite mainly existing in genus Hypericum. It has become a research focus for a quiet long time owing to its extensively... (Review)
Review
BACKGROUND
Hypericin is a prominent secondary metabolite mainly existing in genus Hypericum. It has become a research focus for a quiet long time owing to its extensively pharmacological activities especially the anti-cancer, anti-bacterial, anti-viral and neuroprotective effects. This review concentrated on summarizing and analyzing the existing studies of hypericin in a comprehensive perspective.
METHODS
The literature with desired information about hypericin published after 2010 was gained from electronic databases including PubMed, SciFinder, Science Direct, Web of Science, China National Knowledge Infrastructure databases and Wan Fang DATA.
RESULTS
According to extensive preclinical and clinical studies conducted on the hypericin, an organized and comprehensive summary of the natural and artificial sources, strategies for improving the bioactivities, pharmacological activities, drug combination of hypericin was presented to explore the future therapeutic potential of this active compound.
CONCLUSIONS
Overall, this review offered a theoretical guidance for the follow-up research of hypericin. However, the pharmacological mechanisms, pharmacokinetics and structure activity relationship of hypericin should be further studied in future research.
Topics: Humans; Anthraquinones; Anthracenes; Neoplasms; Photochemotherapy
PubMed: 36689857
DOI: 10.1016/j.phymed.2023.154654 -
The Science of the Total Environment Dec 2023Polycyclic aromatic hydrocarbons (PAHs) and Chlorinated PAHs (Cl-PAHs) are ubiquitous environmental contaminants. The toxicological information of anthracene (Ant) and...
Polycyclic aromatic hydrocarbons (PAHs) and Chlorinated PAHs (Cl-PAHs) are ubiquitous environmental contaminants. The toxicological information of anthracene (Ant) and its chlorinated derivatives is quite limited. In this study, an integrated metabolomic and transcriptomic analysis approach was adopted to assess the toxic effects triggered by Ant and its chlorinated derivatives, 2-chloroanthracene (2-ClAnt) and 9,10-dichloroanthracen (9,10-ClAnt), at human-relevant levels on human normal hepatocyte L02 cells. The cell viability test showed no significant effects on the viability of L02 cells exposed to Ant, 2-ClAnt and 9,10-ClAnt at doses of 5-500 nM for 24 h. However, based on transcriptomic analysis, Ant, 2-ClAnt and 9,10-ClAnt exposure at human-relevant levels obviously perturbed global gene expression in L02 cells and induced the differential expression of several genes related to cancer development. As the number of genes related to cancer development altered by 9,10-ClAnt is the largest, 9,10-ClAnt posed greater risks of tumor development than Ant and 2-ClAnt did. Metabolomics analysis demonstrated that Ant, 2-ClAnt and 9,10-ClAnt caused significant metabolic perturbation in L02 cells. Pathway enrichment analysis indicated that Ant, 2-ClAnt and 9,10-ClAnt mainly perturbed the lipid metabolism and nucleotide metabolism pathway. However, 9,10-ClAnt caused a wider perturbation to metabolic pathways than Ant and 2-ClAnt did. In addition, dysregulation of nucleotide metabolism perturbed by Ant, 2-ClAnt and 9,10-ClAnt may be associated with the genomic instability and further carcinogenesis.
Topics: Humans; Transcriptome; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hepatocytes; Metabolomics; Neoplasms; Nucleotides
PubMed: 37678537
DOI: 10.1016/j.scitotenv.2023.166886 -
Environmental Science and Pollution... Nov 2020At present, research progress of anthracene's toxicity lags far behind the pollution caused on its application fields such as petroleum and minerals. In this paper,...
At present, research progress of anthracene's toxicity lags far behind the pollution caused on its application fields such as petroleum and minerals. In this paper, anthracene-induced oxidative stress effects and genetic toxicity were investigated at both the molecular and cellular levels. The intracellular oxidative stress effect of anthracene on earthworm primary coelomocyte was confirmed by the detection of reactive oxygen species, antioxidant enzymes activity, and malondialdehyde content. Moreover, after anthracene exposure, the decrease in the mitochondrial membrane potential and cell viability also indicated the adverse effects of anthracene on earthworm coelomocyte. The comet assay proved the break in DNA strand, revealing the anthracene-induced DNA damage. On the molecular level, we revealed that anthracene caused the shrinkage of the catalase skeleton and altered the microenvironment of chromophores of catalase by multi-spectral methods. Molecular simulation results indicated that anthracene interacted with His74 by "arene-arene" force and the dominant binding site between anthracene and catalase was close to the active site of catalase. In addition, anthracene was shown to bind to the DNA molecule by groove binding mode. This study proposed a new combined analysis method for the toxicity evaluation of anthracene at the cellular and molecular levels. Graphical abstract This study creatively proposed a new combined analysis for the toxicity evaluation of ANT at the cellular and molecular levels.
Topics: Animals; Anthracenes; Catalase; Comet Assay; DNA Damage; Oxidative Stress; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 32683626
DOI: 10.1007/s11356-020-10049-y -
Methods in Cell Biology 2021Every year, over 2 million women are diagnosed with breast cancer. Although considerable progress was made within the last years in cancer prevention, diagnosis and...
Every year, over 2 million women are diagnosed with breast cancer. Although considerable progress was made within the last years in cancer prevention, diagnosis and treatment, breast cancer is still responsible for over 600,000 of deaths per year. Over the years, numerous mouse models have been developed to understand breast cancer etiology and progression. Among those, mammary carcinomas induced by carcinogen, such as 7,12-dimethylbenz[a]anthracene (DMBA), has been widely used. Generally, 30-70% of mice exposed to 4-6 weekly doses of 1mg of DMBA during the peripubertal period (4-10 weeks of age) will develop mammary tumors within 150-200 days after the first exposure, that sometime metastasize to the lungs. As a result, DMBA-induced tumorigenesis is thought to be an accurate and relevant model to study breast cancer as it closely mimics this multistep process. This chapter presents the typical protocol used in mice to induce mammary gland tumors using DMBA. The influence of the number of doses and the total burden of DMBA given, as well as of the age and strain of the mice on mammary gland incident and on tumor onset are discussed. The current knowledge regarding mechanisms involved in DMBA-induced tumorigenesis is also presented.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anthracenes; Carcinogenesis; Carcinogens; Mammary Neoplasms, Experimental; Mice
PubMed: 33785167
DOI: 10.1016/bs.mcb.2020.09.003 -
Nature Communications Jun 2023Natural proteins exhibit rich structural diversity based on the folds of an invariably linear chain. Macromolecular catenanes that cooperatively fold into a single...
Natural proteins exhibit rich structural diversity based on the folds of an invariably linear chain. Macromolecular catenanes that cooperatively fold into a single domain do not belong to the current protein universe, and their design and synthesis open new territories in chemistry. Here, we report the design, synthesis, and properties of a single-domain green fluorescent protein catenane via rewiring the connectivity of GFP's secondary motifs. The synthesis could be achieved in two steps via a pseudorotaxane intermediate or directly via expression in cellulo. Various proteins-of-interest may be inserted at the loop regions to give fusion protein catenanes where the two subunits exhibit enhanced thermal resilience, thermal stability, and mechanical stability due to strong conformational coupling. The strategy can be applied to other proteins with similar fold, giving rise to a family of single-domain fluorescent proteins. The results imply that there may be multiple protein topological variants with desirable functional traits beyond their corresponding linear protein counterparts, which are now made accessible and fully open for exploration.
Topics: Green Fluorescent Proteins; Anthracenes; Catenanes; Coloring Agents; Mutant Proteins
PubMed: 37311944
DOI: 10.1038/s41467-023-39233-7 -
Scientific Reports Apr 2021In order to analyze whether the marine macroalga Ulva lactuca can absorb and metabolize anthracene (ANT), the alga was cultivated with 5 µM ANT for 0-72 h, and the...
In order to analyze whether the marine macroalga Ulva lactuca can absorb and metabolize anthracene (ANT), the alga was cultivated with 5 µM ANT for 0-72 h, and the level of ANT was detected in the culture medium, and in the alga. The level of ANT rapidly decreased in the culture medium reaching a minimal level at 6 h, and rapidly increased in the alga reaching a maximal level at 12 h and then decreased to reach a minimal level at 48 h of culture. In addition, ANT induced an increase in hydrogen peroxide that remained until 72 h and a higher increase in superoxide anions that reach a maximal level at 24 h and remained unchanged until 72 h, indicating that ANT induced an oxidative stress condition. ANT induced an increase in lipoperoxides that reached a maximal level at 24 h and decreased at 48 h indicating that oxidative stress caused membrane damage. The activity of antioxidant enzymes SOD, CAT, AP, GR and GP increased in the alga treated with ANT whereas DHAR remained unchanged. The level of transcripts encoding these antioxidant enzymes increased and those encoding DHAR did not change. Inhibitors of monooxygenases, dioxygenases, polyphenol oxidases, glutathione-S-transferases and sulfotransferases induced an increase in the level of ANT in the alga cultivated for 24 h. These results strongly suggest that ANT is rapidly absorbed and metabolized in U. lactuca and the latter involves Phase I and II metabolizing enzymes.
Topics: Anthracenes; Antioxidants; Enzyme Activation; Enzymes; Hydrogen Peroxide; Oxidative Stress; Ulva
PubMed: 33833321
DOI: 10.1038/s41598-021-87147-5 -
Molecules (Basel, Switzerland) Aug 2019Metastatic melanoma (MM) has a poor prognosis and is attributed to late diagnoses only when metastases has already occurred. Thus, early diagnosis is crucial to improve... (Review)
Review
Metastatic melanoma (MM) has a poor prognosis and is attributed to late diagnoses only when metastases has already occurred. Thus, early diagnosis is crucial to improve its overall treatment efficacy. The standard diagnostic tools for MM are incisional biopsies and/or fine needle aspiration biopsies, while standard treatments involve surgery, chemotherapy, or irradiation therapy. The combination of photodynamic diagnosis (PDD) and therapy (PDT) utilizes a photosensitizer (PS) that, when excited by light of a low wavelength, can be used for fluorescent non-destructive diagnosis. However, when the same PS is activated at a higher wavelength of light, it can be cytotoxic and induce tumor destruction. This paper focuses on PS drugs that have been used for PDD as well as PDT treatment of MM. Furthermore, it emphasizes the need for continued investigation into enhanced PS delivery via active biomarkers and passive nanoparticle systems. This should improve PS drug absorption in MM cells and increase effectiveness of combinative photodynamic methods for the enhanced diagnosis and treatment of MM can become a reality.
Topics: Aminolevulinic Acid; Anthracenes; Biopsy, Fine-Needle; Drug Carriers; Early Diagnosis; Humans; Indoles; Isoindoles; Light; Lymphatic Metastasis; Melanoma; Molecular Imaging; Nanoparticles; Perylene; Photochemotherapy; Photosensitizing Agents; Skin Neoplasms
PubMed: 31470637
DOI: 10.3390/molecules24173153