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1.
Angew Chem Int Ed Engl ; 63(24): e202405525, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38607969

RESUMO

Cancer stem cells are pivotal players in tumors initiation, growth, and metastasis. While several markers have been identified, there remain challenges particularly in heterogeneous malignancies like adult soft tissue sarcomas, where conventional markers are inherently overexpressed. Here, we designed BODIPY scaffold fluorescence probes (BD-IMC-1, BD-IMC-2) that activate via disaggregation targeting for cyclooxygenase (COX), a potential marker for CSCs in sarcoma in clinical pathology. Based on their structures, BD-IMC-1 showcased higher susceptibility to disaggregation compared to BD-IMC-2, consistent with their selective interaction with COX. Notably, the BD-IMC-1 revealed positive cooperativity binding to COX-2 at sub-micromolar ranges. Both probes showed significant fluorescence turn-on upon LPS or PMA triggered COX-2 upregulation in live RAW264.7, HeLa, and human sarcoma cell line (Saos-LM2) up to 2-fold increase with negligible toxicity. More importantly, the BD-IMC-1 demonstrated their practical imaging for COX-2 positive cells in paraffin-fixed human sarcoma tissue. Considering the fixed tissues are most practiced pathological sample, our finding suggests a potential of disaggregation activated chemosensor for clinical applications.


Assuntos
Ciclo-Oxigenase 2 , Corantes Fluorescentes , Sarcoma , Humanos , Sarcoma/diagnóstico por imagem , Sarcoma/patologia , Sarcoma/metabolismo , Ciclo-Oxigenase 2/metabolismo , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Imagem Óptica , Compostos de Boro/química , Animais , Camundongos , Linhagem Celular Tumoral , Estrutura Molecular
2.
Chemistry ; 30(5): e202302916, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-37902438

RESUMO

Blood continually contributes to the maintenance of homeostasis of the body and contains information regarding the health state of an individual. However, current hematological analyses predominantly rely on a limited number of CD markers and morphological analysis. In this work, differentially sensitive fluorescent compounds based on TCF scaffolds are introduced that are designed for fluorescent phenotyping of blood. Depending on their structures, TCF compounds displayed varied responses to reactive oxygen species, biothiols, redox-related biomolecules, and hemoglobin, which are the primary influential factors within blood. Contrary to conventional CD marker-based analysis, this unbiased fluorescent phenotyping method produces diverse fingerprints of the health state. Precise discrimination of blood samples from 37 mice was demonstrated based on their developmental stages, ranging from 10 to 19 weeks of age. Additionally, this fluorescent phenotyping method enabled the differentiation between drugs with distinct targets, serving as a simple yet potent tool for pharmacological analysis to understand the mode of action of various drugs.


Assuntos
Envelhecimento , Corantes Fluorescentes , Camundongos , Animais , Corantes Fluorescentes/química , Espécies Reativas de Oxigênio/análise , Oxirredução , Células Sanguíneas/química
3.
Hepatology ; 54(6): 2208-17, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21898498

RESUMO

UNLABELLED: Overdose of acetaminophen (APAP), the active ingredient of Tylenol, is the leading cause of drug-induced acute liver failure in the United States. As such, it is necessary to develop novel strategies to prevent or manage APAP toxicity. In this report, we reveal a novel function of the liver X receptor (LXR) in preventing APAP-induced hepatotoxicity. Activation of LXR in transgenic (Tg) mice or by an LXR agonist conferred resistance to the hepatotoxicity of APAP, whereas the effect of LXR agonist on APAP toxicity was abolished in LXR-deficient mice. The increased APAP resistance in LXR Tg mice was associated with increased APAP clearance, increased APAP sulfation, and decreased formation of toxic APAP metabolites. The hepatoprotective effect of LXR may have resulted from the induction of antitoxic phase II conjugating enzymes, such as Gst and Sult2a1, as well as the suppression of protoxic phase I P450 enzymes, such as Cyp3a11 and Cyp2e1. Promoter analysis suggested the mouse Gst isoforms as novel transcriptional targets of LXR. The suppression of Cyp3a11 may be accounted for by the inhibitory effect of LXR on the PXR-responsive transactivation of Cyp3a11. The protective effect of LXR in preventing APAP toxicity is opposite to the sensitizing effect of pregnane X receptor, constitutive androstane receptor, and retinoid X receptor alpha. CONCLUSION: We conclude that LXR represents a potential therapeutic target for the prevention and treatment of Tylenol toxicity.


Assuntos
Acetaminofen/toxicidade , Receptores Nucleares Órfãos/metabolismo , Acetaminofen/metabolismo , Animais , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/biossíntese , Sistema Enzimático do Citocromo P-450/metabolismo , Glutationa S-Transferase pi/biossíntese , Glutationa S-Transferase pi/genética , Fígado/efeitos dos fármacos , Falência Hepática Aguda/induzido quimicamente , Receptores X do Fígado , Proteínas de Membrana/biossíntese , Camundongos , Camundongos Transgênicos , Receptores Nucleares Órfãos/agonistas , Receptor de Pregnano X , Regiões Promotoras Genéticas/efeitos dos fármacos , Receptores de Esteroides/efeitos dos fármacos , Sulfotransferases/metabolismo
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