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High-performance fluorescent probes stand as indispensable tools in fluorescence-guided imaging, and are crucial for precise delineation of focal tissue while minimizing unnecessary removal of healthy tissue. Herein, machine-learning-assisted strategy to investigate the current available xanthene dyes is first proposed, and a quantitative prediction model to guide the rational synthesis of novel fluorescent molecules with the desired pH responsivity is constructed. Two novel Siârhodamine derivatives are successfully achieved and the cathepsin/pH sequentially activated probe Siârhodamineâcathepsin-pH (SiRâCTS-pH) is constructed. The results reveal that SiRâCTS-pH exhibits higher signal-to-noise ratio of fluorescence imaging, compared to single pH or cathepsin-activated probe. Moreover, SiRâCTS-pH shows strong differentiation abilities for tumor cells and tissues and accurately discriminates the complex hepatocellular carcinoma tissues from normal ones, indicating its significant application potential in clinical practice. Therefore, the continuous development of xanthene dyes and the rational design of superior fluorescent molecules through machine-learning-assisted model broaden the path and provide more advanced methods to researchers.
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Catepsinas , Colorantes Fluorescentes , Aprendizaje Automático , Rodaminas , Rodaminas/química , Colorantes Fluorescentes/química , Humanos , Concentración de Iones de Hidrógeno , Catepsinas/metabolismo , Silicio/química , Imagen Óptica/métodos , Carcinoma Hepatocelular/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagenRESUMEN
Herein, we constructed a novel aminofluorene-based fluorescence probe (FEN-CE) for the detection of carboxylesterase (CE) in living cells by a ratiometric near-infrared (NIR) fluorescence signal. FEN-CE with NIR emission (650 nm) could be hydrolyzed specifically by CE and transformed to FENH with the release of the self-immolative group, which exhibited a red-shifted emission peak of 680 nm. In addition, FEN-CE showed high selectivity for CE and was successfully used in the detection of CE activity in living cells through its ratiometric NIR fluorescence signals.
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Carboxilesterasa , Fluorenos , Colorantes Fluorescentes , Colorantes Fluorescentes/química , Carboxilesterasa/metabolismo , Carboxilesterasa/análisis , Humanos , Fluorenos/química , Espectroscopía Infrarroja Corta/métodos , Espectrometría de Fluorescencia/métodos , Células HeLaRESUMEN
Background: Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Tumor marker (TM) detection can indicate the existence and growth of a tumor and has therefore been used extensively for diagnosing LC. Here, we conducted a bibliometric analysis to examine TM-related publications for LC diagnosis to illustrate the current state and future trends of this field, as well as to identify additional promising TMs with high sensitivity. Methods: Publications regarding TMs in LC diagnosis were downloaded from the Web of Science Core Collection. CiteSpace was applied to perform a bibliometric analysis of journals, cocitation authors, keywords, and references related to this field. VOSviewer was used to generate concise diagrams about countries, institutions, authors, and keywords. Changes in the TM research frontier were analyzed through citation burst detection. Results: A total of 990 studies were analyzed in this work. The collaboration network analysis revealed that the People's Republic of China, Yonsei University, and Molina R were the most productive country, institution, and scholar, respectively. Additionally, Molina R was the author with the most citations. The National Natural Science Foundation of China was the largest funding source. "Carcinoembryonic antigen (CEA) as tumor marker in lung cancer" was the top reference with the most citations, Lung Cancer was the core journal, and "serum tumor marker" experienced a citation burst over the past 5 years. Conclusion: This bibliometric analysis of TMs in LC diagnosis presents the current trends and frontiers in this field. We summarized the research status of this field and the methods to improve the diagnostic efficacy of traditional serum TMs, as well as provided new directions and ideas for improving the LC clinical detection rate. Priority should be given to the transformation of computer-assisted diagnostic technology for clinical applications. In addition, circulating tumor cells, exosomes, and microRNAs were the current most cutting-edge TMs.
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Enriching the palette of high-performance fluorescent dyes is vital to support the frontier of biomedical imaging. Although various rhodamine skeletons remain the premier type of small-molecule fluorophores due to the apparent high brightness and flexible modifiability, they still suffer from the inherent defect of small Stokes shift due to the nonideal fluorescence imaging signal-to-background ratio. Especially, the rising class of fluorescent dyes, sulfone-substituted xanthone, exhibits great potential, but low chemical stability is also pointed out as the problem. Molecular engineering of sulfone-xanthone to obtain a large Stokes shift and high stability is highly desired, but it is still scarce. Herein, we present the combination modification method for optimizing the performance of sulfone-xanthone. These redesigned fluorescent skeletons owned greatly improved stability and Stokes shift compared with the parent sulfone-rhodamine. To the proof of bioimaging capacity, annexin protein-targeted peptide LS301 was introduced to the most promising dyes, J-S-ARh, to form the tumor-targeted fluorescent probe, J-S-LS301. The resulting probe, J-S-LS301, can be an outstanding fluorescence tool for the orthotopic transplantation tumor model of hepatocellular carcinoma imaging and on-site pathological analysis. In summary, the combination method could serve as a basis for rational optimization of sulfone-xanthone. Overall, the chemistry reported here broadens the scope of accessible sulfone-xanthone functionality and, in turn, enables to facilitate the translation of biomedical research toward the clinical domain.
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Accurate detection of target analytes and generation of high-fidelity fluorescence signals are particularly critical in life sciences and clinical diagnostics. However, the majority of current NIR-I fluorescent probes are vulnerable to pH effects resulting in signal distortion. In this work, a series of fluorescence-tunable and pH-independent probes are reported by combining optically tunable groups of unsymmetric Si-rhodamines and introducing the methoxy instead of the spiro ring on the benzene ring at position 9. To validate the concept, the leucine aminopeptidase response site was introduced into Si-2,6OMe-NH2 with the best optical properties to synthesize Si-LAP for monitoring the intrahepatic LAP in vivo. Therefore, the design approach may provide a new and practical strategy for designing innovative functional fluorescent probes and generating high-stability and high-fidelity fluorescent signals.
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Colorantes Fluorescentes , Leucil Aminopeptidasa , Colorantes Fluorescentes/química , Rodaminas/química , Fluorescencia , Concentración de Iones de HidrógenoRESUMEN
Aberrant lysosomal alkalization is associated with various biological processes, such as oxidative stress, cell apoptosis, ferroptosis, etc. Herein, we developed a novel aminofluorene-based fluorescence probe named FAN to monitor the lysosomal alkalization-related biological processes by its migration from lysosome to nucleus. FAN possessed NIR emission, large Stokes shift, high pH stability, and high photostability, making it suitable for real-time and long-term bioimaging. As a lysosomotropic molecule, FAN can accumulate in lysosomes first and then migrate to the nucleus by right of its binding capability to DNA after lysosomal alkalization. In this manner, FAN was successfully used to monitor these physiological processes which triggered lysosomal alkalization in living cells, including oxidative stress, cell apoptosis, and ferroptosis. More importantly, at higher concentrations, FAN could also serve as a stable nucleus dye for the fluorescence imaging of the nucleus in living cells and tissues. This novel multifunctional fluorescence probe shows great promise for application in lysosomal alkalization-related visual research and nucleus imaging.
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Ferroptosis , Colorantes Fluorescentes , Colorantes Fluorescentes/química , Imagen Óptica , Lisosomas/química , Apoptosis/fisiología , Concentración de Iones de HidrógenoRESUMEN
An "AND" logic gate-based NIR fluorescent probe Si-NH2-Glu was developed based on novel meso-amine Si-Rhodamine, which combined γ-glutamyl transpeptidase and pH dual-responsive sites. The features of Si-NH2-Glu enable it to be applied in orthotopic tumor imaging and fluorescence-guided surgery.
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Neoplasias de la Mama , Colorantes Fluorescentes , Humanos , Femenino , gamma-Glutamiltransferasa , Imagen Óptica/métodos , Concentración de Iones de HidrógenoRESUMEN
Phototheranostics have emerged and flourished as a promising pattern for cancer theranostics owing to their precise photoinduced diagnosis and therapeutic to meet the demands of precision medicine. The diagnosis information and therapeutic effect are directly determined by the fluorescence imaging ability and photothermal conversion efficiency (PCE) of phototheranostic agents. Hence, how to balance the competitive radiative and nonradiative processes of phototheranostic agents is the key factor to evaluate the phototheranostic effect. Herein, molecules named ICRs with high photostaibility are rationally designed, exhibiting fluorescence emission in the second near-infrared window (NIR-II, 1000-1700 nm) and high PCE, which are related to the strong donor-acceptor (D-A) interaction and high reorganization energy Noteworthily, ICR-Qu with stronger D-A interaction and a large-sized conjugated unit encapsulated in nanoparticles exhibits high PCE (81.1%). In addition, ICR-QuNPs are used for fluorescence imaging (FLI), photoacoustic imaging (PAI), and photothermal imaging (PTI) to guide deep-tissue photonic hyperthermia, achieving precise removal and inhibition of breast cancer. Furthermore, combined with α-PD-1, ICR-QuNPs show huge potential to be a facile and efficient tool for photo-immunotherapy. More importantly, this study not only reports an "all-in-one" polymethine-based phototheranostic agent, but also sheds light on the exploration of versatile organic molecules for future practical applications.
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Neoplasias de la Mama , Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Humanos , Femenino , Fototerapia/métodos , Nanomedicina Teranóstica/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Colorantes , Nanopartículas/uso terapéutico , Inmunoterapia , Técnicas Fotoacústicas/métodosRESUMEN
Non-invasive dynamic tracking of lysosomes and their interactions with other organelles is important for the study of lysosomal function and related diseases. However, many fluorescent dyes developed so far to target lysosomes cannot be used to monitor these processes due to the high concentrations required for imaging, long cell penetration times, and non-ideal photostability. In this regard, we synthesized three lysosomal targeting probes with large Stokes shifts, good stability, and high brightness. The Q-P-ARh dye, developed by us for the first time, can stain lysosomes at ultra-low concentrations (1.0â nM) without affecting the physiological functions of the lysosomes. More importantly, its excellent anti-interference ability and ultrafast lysosomal staining ability (within 1.0â min) clearly monitored the entire dynamic process of lipophagy. Ultimately, this method can greatly contribute to the study of autophagy pathways. This novel fluorescence platform shows great promise for the development of biological probes for application in pathological environments.
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Autofagia , Fluorescencia , Colorantes Fluorescentes/química , Imagen Óptica , Colorantes Fluorescentes/síntesis química , Células Hep G2 , Humanos , Lisosomas/químicaRESUMEN
MicroRNA (miRNA/mir)4903p has been defined as a tumor suppressor in different types of cancer, including breast cancer. However, miR4903p has been shown to function as a tumor suppressor and promoter in a contextdependent manner in hepatocellular and lung cancer. Contrary to previous studies, the present study revealed that miR4903p expression was significantly higher in invasive ductal carcinoma (IDC) tissue specimens, the most common form of breast cancer, compared to tumoradjacent normal tissue specimens (n=20). Its expression was also higher in the more metastatic breast cancer cell line, MDAMB231, compared to the nonmetastatic breast cancer cell line, MCF7, and the moderately metastatic breast cancer cell line, MDAMB468. The expression of miR4903p was induced following transforming growth factor (TGF)ßinduced epithelialtomesenchymal transition (EMT) in MCF10A cells. Gainand lossoffunction assays revealed that the expression of miR4903p regulated the proliferation, colony formation, EMT, migration and invasion in vitro, but not the apoptosis of MDAMB468 and MDAMB231 cells. The knockdown of miR4903p expression in MDAMB231 cells inhibited experimental metastasis in a tumor xenograft assay. As in lung cancer, miR4903p was found to target and downregulate the expression of the tumor suppressor RNA binding protein poly r(C) binding protein 1 (PCBP1). PCBP1 protein and miR4903p expression inversely correlated in patients with ductal carcinoma in situ (DCIS; n=10; no nodal involvement) and IDC (n=10; different stages of metastatic progression) with a significantly higher miR4903p expression in patients with IDC compared to those with DCIS. The expression of miR4903p was negatively associated with both overall and diseasefree survival in the patients with breast cancer included in the present study. On the whole, the results confirm a prometastatic role of miR4903p in IDC, establishing it as a biomarker for disease progression in these patients.
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Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Proteínas de Unión al ADN/genética , MicroARNs/metabolismo , Recurrencia Local de Neoplasia/epidemiología , Proteínas de Unión al ARN/genética , Animales , Mama/patología , Mama/cirugía , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/secundario , Carcinoma Ductal de Mama/cirugía , Línea Celular Tumoral , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Transición Epitelial-Mesenquimal/genética , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Mastectomía , Ratones , MicroARNs/genética , Recurrencia Local de Neoplasia/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Insulin-induced gene 2 (INSIG2) functions as a blocker of cholesterol biosynthesis and has been shown to be involved in colon and pancreatic cancer pathogenesis. Cholesterol is a risk factor for breast cancer pathophysiology; however, the underlying mechanisms are not well-defined. Hence, our goal was to determine the role of INISG2 in breast cancer. INSIG2 mRNA and protein expression was correlated to metastatic potential of breast cancer cell lines. Knockdown of INSIG2 inhibited epithelial-to-mesenchymal transition. Conversely, overexpression of INSIG2 induced epithelial-to-mesenchymal transition. Knockdown of INSIG2 did not affect cell proliferation but resulted in altered metabolism in vitro and attenuated experimental metastasis in vivo. Analysis of breast cancer tissue microarrays revealed significantly higher INSIG2 protein expression in breast cancer tissues. INSIG2 protein expression was correlated to hormone receptor status, with significantly higher expression in patients with triple-negative and human epidermal growth factor receptor 2 molecular subtypes of invasive breast cancer. Analysis of The Cancer Genome Atlas, however, revealed significantly lower INSIG2 mRNA expression in triple-negative breast cancer patients. Higher INSIG2 mRNA expression was correlated to poor survival probability. Asian patients with high INSIG2 mRNA expression had significantly lower survival probability compared with Asian patients with low/medium INSIG2 mRNA expression. These results reveal a yet undefined role of INSIG2 in breast cancer, potentially more relevant for breast cancer patients in Asia.
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Neoplasias de la Mama/patología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Metástasis de la Neoplasia/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Transición Epitelial-Mesenquimal/genética , Femenino , Xenoinjertos , Humanos , Ratones , Ratones Desnudos , Metástasis de la Neoplasia/patologíaRESUMEN
In the title compound, C(9)H(9)BrO(3), the dihedral angle between the ethanone group and the aromatic ring is 3.6â (2)°. The mol-ecular conformation is consolidated by an intra-molecular O-Hâ¯O hydrogen bond. The crystal structure is stabilized by π-π inter-actions between the benzene rings [centroid-centroid distance = 3.588â (2)â Å].