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Rationale: Myocardial infarction (MI) is a severe global clinical condition with widespread prevalence. The adult mammalian heart's limited capacity to generate new cardiomyocytes (CMs) in response to injury remains a primary obstacle in developing effective therapies. Current approaches focus on inducing the proliferation of existing CMs through cell-cycle reentry. However, this method primarily elevates cyclin dependent kinase 6 (CDK6) and DNA content, lacking proper cytokinesis and resulting in the formation of dysfunctional binucleated CMs. Cytokinesis is dependent on ribosome biogenesis (Ribo-bio), a crucial process modulated by nucleolin (Ncl). Our objective was to identify a novel approach that promotes both DNA synthesis and cytokinesis. Methods: Various techniques, including RNA/protein-sequencing analysis, Ribo-Halo, Ribo-disome, flow cytometry, and cardiac-specific tumor-suppressor retinoblastoma-1 (Rb1) knockout mice, were employed to assess the series signaling of proliferation/cell-cycle reentry and Ribo-bio/cytokinesis. Echocardiography, confocal imaging, and histology were utilized to evaluate cardiac function. Results: Analysis revealed significantly elevated levels of Rb1, bur decreased levels of circASXL1 in the hearts of MI mice compared to control mice. Deletion of Rb1 induces solely cell-cycle reentry, while augmenting the Ribo-bio modulator Ncl leads to cytokinesis. Mechanically, bioinformatics and the loss/gain studies uncovered that circASXL1/CDK6/Rb1 regulates cell-cycle reentry. Moreover, Ribo-Halo, Ribo-disome and circRNA pull-down assays demonstrated that circASXL1 promotes cytokinesis through Ncl/Ribo-bio. Importantly, exosomes derived from umbilical cord mesenchymal stem cells (UMSC-Exo) had the ability to enhance cardiac function by facilitating the coordinated signaling of cell-cycle reentry and Ribo-bio/cytokinesis. These effects were attenuated by silencing circASXL1 in UMSC-Exo. Conclusion: The series signaling of circASXL1/CDK6/Rb1/cell-cycle reentry and circASXL1/Ncl/Ribo-bio/cytokinesis plays a crucial role in cardiac repair. UMSC-Exo effectively repairs infarcted myocardium by stimulating CM cell-cycle reentry and cytokinesis in a circASXL1-dependent manner. This study provides innovative therapeutic strategies targeting the circASXL1 signaling network for MI and offering potential avenues for enhanced cardiac repair.
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Ciclo Celular , Citocinese , Camundongos Knockout , Infarto do Miocárdio , Miócitos Cardíacos , Ribossomos , Animais , Camundongos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Ribossomos/metabolismo , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Nucleolina , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteína do Retinoblastoma/metabolismo , Proteína do Retinoblastoma/genética , Proliferação de Células , Masculino , HumanosRESUMO
Photosensitizer-based phototherapies, including photodynamic therapy (PDT) and photothermal therapy (PTT), offer safe treatment modalities for tumor ablation with spatiotemporal precision. After photons are absorbed, PDT creates localized chemical damage by generating reactive oxygen species (ROS), while PTT induces localized thermal damage. However, PDT still faces hypoxic tumor challenges, while PTT encounters issues related to heat resistance and potential overheating. The combination of PDT and PTT shows great potential as an effective anticancer strategy. By targeting lysosomes with carefully designed phototherapeutic reagents for combined phototherapy, rapid dysfunction and cell death in cancer cells can be induced, showing promise for cancer treatment. Herein, two α-α-linked bisBODIPYs with tetraphenylethene (TPE) moieties are designed and synthesized. These TPE-substituted bisBODIPYs expand the absorption into NIR range (λmaxabs/λmaxem â¼ 740/810 nm) and confer aggregation-induced emission (AIE) activity (λmaxem â¼ 912 nm). Moreover, these bisBODIPYs self-assemble with surfactant F-127 into nanoparticles (NPs), which efficiently generate ROS (1O2 and â¢OH) in both solution and cellular environments and demonstrate superior photothermal conversion efficiencies (η â¼ 68.3%) along with exceptional photothermal stability. More importantly, these NPs showed lysosomal targeting and remarkable tumor ablation in cellular and murine models, indicating their potential in precision tumor therapy.
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Lisossomos , Nanopartículas , Fármacos Fotossensibilizantes , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Humanos , Animais , Camundongos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Nanopartículas/química , Raios Infravermelhos , Fotoquimioterapia , Estilbenos/química , Estilbenos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fototerapia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Neoplasias/patologia , Camundongos NusRESUMO
Photocages, also known as photoactivated protective groups (PPGs), have been utilized to achieve controlled release of target molecules in a non-invasive and spatiotemporal manner. In the past decade, BODIPY fluorophores, a well-established class of fluorescent dyes, have emerged as a novel type of photoactivated protective group capable of efficiently releasing cargo species upon irradiation. This is due to their exceptional properties, including high molar absorption coefficients, resistance to photochemical and thermal degradation, multiple modification sites, favorable uncaging quantum yields, and highly adjustable spectral properties. Compared to traditional photocages that mainly absorb UV light, BODIPY-based photocages that absorb visible/near-infrared (Vis/NIR) light offer advantages such as deeper tissue penetration and reduced bio-autofluorescence, making them highly suitable for various biomedical applications. Consequently, different types of photoactivated protective groups based on the BODIPY skeleton have been established. This highlight provides a comprehensive overview of the strategies employed to construct BODIPY photocages by substituting leaving groups at different positions within the BODIPY fluorophore, including the meso-methyl position, boron position, 2,6-position, and 3,5-position. Furthermore, the application of these BODIPY photocages in biomedical fields, such as fluorescence imaging and controlled release of active species, is discussed.
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Compostos de Boro , Corantes Fluorescentes , Compostos de Boro/química , Corantes Fluorescentes/química , Humanos , Imagem Óptica , Processos Fotoquímicos , Estrutura Molecular , AnimaisRESUMO
Three new distinct NIR α,α-NH-bridged BODIPY dimers were prepared by a direct nucleophilic substitution reaction. The synergistic effects of the nitrogen bridges and strong excitonic coupling between each BODIPY unit play major roles in enhancing the delocalization of an electron spin over the entire BODIPY dimers. The in situ formed aminyl radical dimer showed an absorption maximum at 1040 nm.
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A series of nitrogen-bridged BODIPY oligomers were synthesized via nucleophilic aromatic substitution (SNAr) as a convenient approach. Further transformations achieved novel α,α-aryl BODIPY dimers as well as a BODIPY hexamer efficiently. These BODIPY oligomers showed good photophysical properties, such as apparent absorption and emission both in visible and near-infrared regions. Interestingly, the high air and photothermal stability, strong NIR absorption, and high photothermal conversion rates of hexamer B6 suggest potential applications in photothermal therapy.
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A series of solid-state emissive meso-aryl/alkyl-substituted and heteroatom-mixed bisBF2-anchoring fluorophore incorporating pyrrolyl-pyridylhydrazone (BOPPY) dyes have been developed by a one-pot condensation of ketonized or formylated pyrroles and 2-heterocyclohydrazine as well as the subsequent borylation coordination. Interestingly, the BOPPY dyes with meso-alkyl-substituted groups or oxygen-substituted pyridine moieties exhibit high fluorescence quantum yields (QYs) of up to 79%, the highest solid QY of 74%, and long lifetimes independent of polarity in the available BOPPYs. On the other hand, the BOPPYs with meso-aryl or N-substituted moieties display a high solution QY of up to 93% and slight emission wavelength maxima. However, the S-substituted BOPPY dye exhibited weak fluorescence in all studied solvents, which was attributed to the structural flexibility of the N-C-S bond and different from those BOPPYs with O or N substitution, indicated by quantum calculations. And the significant excited-state structural rearrangement in a polar solvent is further confirmed by femtosecond time-resolved transient absorption spectroscopy. More importantly, those novel and barely fluorescent BOPPYs in acetonitrile show advantageous aggregation-induced enhanced emission and viscosity-dependent activities. These advancements in the photophysical and electrochemical properties of BOPPY dyes offer valuable insights into their further development and potential applications.
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A series of novel N,N-carbonyl-bridged dipyrrinone fluorophores have been directly constructed from α-halogenated dipyrrinones, which are conveniently obtained from the acid-catalyzed hydrolysis of readily available α,α'-dihalodipyrrins. This novel methodology affords efficient modulation of the functional groups at both the meso- and α-positions of this fluorophore. These resultant dyes show tunable absorption and emission wavelengths, good molar absorption coefficients, relatively large Stokes shifts, and excellent fluorescence quantum yields up to 0.99, and have been successfully applied in both one- and two-photon fluorescence microscopy imaging in living cells.
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An efficient synthesis of 3-pyrrolylBODIPY dyes has been developed from a rational mixture of various aromatic aldehydes and pyrrole in a straightforward condensation reaction, followed by in situ successively oxidative nucleophilic substitution using a one-pot strategy. These resultant 3-pyrrolylBODIPYs without blocking substituents not only exhibit the finely tunable photophysical properties induced by the flexible meso-aryl substituents but also serve as a valuable synthetic framework for further selective functionalization. As a proof of such potential, one 3-pyrrolylBODIPY dye (581/603 nm) through the installation of the morpholine group is applicable for lysosome-targeting imaging. Furthermore, an ethene-bridged 3,3'-dipyrrolylBODIPY dimer was constructed, which displayed a near-infrared (NIR) emission extended to 1200 nm with a large fluorescence brightness (2840 M-1 cm-1). The corresponding dimer nanoparticles (NPs) afforded a high photothermal conversion efficiency (PCE) value of 72.5%, eventually resulting in favorable photocytotoxicity (IC50 = 9.4 µM) and efficient in vitro eradication of HeLa cells under 808 nm laser irradiation, highlighting their potential application for photothermal therapy in the NIR window.
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Corantes , Nanopartículas , Humanos , Células HeLa , Compostos de Boro/farmacologia , Imagem Óptica , PolímerosRESUMO
Achieving photothermal therapy (PTT) at ultralow laser power density is crucial for minimizing photo-damage and allowing for higher maximum permissible skin exposure. However, this requires photothermal agents to possess not just superior photothermal conversion efficiency (PCE), but also exceptional near-infrared (NIR) absorptivity. J-aggregates, exhibit a significant redshift and narrower absorption peak with a higher extinction coefficient. Nevertheless, achieving predictable J-aggregates through molecular design remains a challenge. In this study, we successfully induced desirable J-aggregation (λabs max : 968â nm, ϵ: 2.96×105 â M-1 cm-1 , λem max : 972â nm, ΦFL : 6.2 %) by tuning electrostatic interactions between π-conjugated molecular planes through manipulating molecular surface electrostatic potential of aromatic ring-fused aza-BODIPY dyes. Notably, by controlling the preparation method for encapsulating dyes into F-127 polymer, we were able to selectively generate H-/J-aggregates, respectively. Furthermore, the J-aggregates exhibited two controllable morphologies: nanospheres and nanowires. Importantly, the shortwave-infrared J-aggregated nanoparticles with impressive PCE of 72.9 % effectively destroyed cancer cells and mice-tumors at an ultralow power density of 0.27â W cm-2 (915â nm). This phototherapeutic nano-platform, which generates predictable J-aggregation behavior, and can controllably form J-/H-aggregates and selectable J-aggregate morphology, is a valuable paradigm for developing photothermal agents for tumor-treatment at ultralow laser power density.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Animais , Camundongos , Compostos de Boro/uso terapêutico , Neoplasias/tratamento farmacológico , Corantes , Lasers , Fototerapia/métodos , Linhagem Celular TumoralRESUMO
A Rh-catalyzed two-fold, regioselective and enantioselective C-H activation via chiral transient directing group strategy has been demonstrated in moderate to good yields with commendable enantioselectivities. The newly synthesized chiral fluorophores exhibit favorable photophysical properties, including large Stokes shifts, good fluorescence quantum yields, aggregation-induced emission in aqueous solution, and intense emission and circularly polarized luminescence in the solid state, indicating great potential applications as chiral fluorescent probes or optoelectronic materials.
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New and dynamical chiral co-assembled systems bearing BOPPY were successfully developed with amplified CPL signals. Remarkably, these stable chiral co-assemblies prepared at high concentrations retain uniform microrods and exceptional chiroptical performance (glum = 0.028, ΦF = 14%) after 48 h.
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Through a strong oxidant Pb(OAc)4 promoted oxidative nucleophilic hydrogen substitution, site-selective direct and stepwise cyanation of BODIPYs using tetrabutylammonium cyanide was developed to give α-cyanated BODIPY derivatives. Characterization of optical and electrochemical properties of these dyes provides substantial enhancement of the electron affinity, with a reduction potential and LUMO level as low as -0.04 V and -4.43 eV, respectively. Radical anions of these electron-deficient 3,5-dicyanated BODIPYs were characterized by absorption and EPR spectroscopy.
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By taking advantage of their strong absorption ability, visible-light-induced direct photoamination of BODIPY dyes with aqueous ammonia was developed to give structurally diverse α-amino BODIPYs. The excited state of BODIPYs possessed higher electron affinity than the ground state and thus showed largely enhanced reactivity toward weak nucleophile of ammonia. Those α-amino BODIPYs are valuable synthetic intermediates and have been successfully demonstrated in several post-transformation reactions. The work indicates that photoreaction is an excellent alternative to conventional functionalization of this popular fluorophore.
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A novel family of bisbenzothieno[b]-fused BODIPYs containing seven fused aromatic rings has been developed from readily available benzothieo[3,2-b]pyrroles through an efficient two-step synthetic route, exhibiting planar skeletons with excellent photostabilities, deep-red absorptions, and near-infrared emissions (up to 753 nm). Importantly, the thin-film transistors based on BTB with a meso-dimethylamino-phenyl group exhibit unipolar n-type charge transporting characteristics with a high electron mobility of 0.013 cm2 V-1 s-1.
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Singly and doubly quinoline-fused BODIPYs were effectively synthesized through a reaction sequence consisting of the reduction of nitrophenyl-substituted BODIPYs and subsequent Pictet-Spengler cyclization. The combination of the BODIPY core and fused quinoline rings imposed significantly twisted conformations in the quinoline-fused BODIPYs (around 20.0° deviation from coplanarity obtained from X-ray crystal structure analysis). These twisted BODIPYs showed significantly reduced LUMO, redshifted absorption/emission bands, high molar extinction coefficients and satisfactory reactive oxygen species generation efficiency up to 0.56, indicating potential use as heavy-atom-free photosensitizers.
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Bodipy is one of the most versatile and studied functional dyes due to its myriad applications and tunable spectral properties. One of the strategies to adjust their properties is the formation of Bodipy dimers and oligomers whose properties differ significantly from the corresponding monomer. Recently, we have developed a novel strategy for synthesizing α,α-ethylene-bridged Bodipy dimers; however, their excited-state dynamics was heretofore unknown. This work presents the ultrafast excited-state dynamics of a novel α,α-ethylene-bridge Bodipy dimer and its monomeric parent. The dimer's steady-state absorption and fluorescence suggest a Coulombic interaction between the monomeric units' transition dipole moments (TDMs), forming what is often termed a "J-dimer". The excited-state properties of the dimer were studied using molecular excitonic theory and time-dependent density functional theory (TD-DFT). We chose the M06 exchange-correlation functional (XCF) based on its ability to reproduce the experimental oscillator strength and resonance Raman spectra. Ultrafast laser spectroscopy reveals symmetry-breaking charge separation (SB-CS) in the dimer in polar solvents and the subsequent population of the charge-separated ion-pair state. The charge separation rate falls into the normal regime, while the charge recombination is in the inverted regime. Conversely, in nonpolar solvents, the charge separation is thermodynamically not feasible. In contrast, the monomer's excited-state dynamics shows no dependence on the solvent polarity. Furthermore, we found no evidence of significant structural rearrangement upon photoexcitation, regardless of the deactivation pathway. After an extensive analysis of the electronic transitions, we concluded that the solvent fluctuations in the local environment around the dimer create an asymmetry that drives and stabilizes the charge separation. This work sheds light on the charge-transfer process in this new set of molecular systems and how excited-state dynamics can be modeled by combining the experiment and theory.
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A family of directly ß,ß-linked BODIPY dimers with amino groups at α-positions were regioselectively prepared by the oxidative coupling reaction of α-amino-substituted BODIPYs. The structure of one representative dimer was elucidated by X-ray diffraction analysis, showing its twisted orientation of two BODIPY units with a dihedral angle of 49°. Comparing with the corresponding monomers, these dimers showed red-shifted absorptions and emissions along with efficient intersystem crossing, giving ΦΔ of 43% for dimer 4b in toluene, indicating potential use as heavy-atom-free photosensitizers.
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Compostos de Boro , Estrutura Molecular , Acoplamento Oxidativo , Cristalografia por Raios X , Compostos de Boro/químicaRESUMO
Linear π-conjugated oligopyrroles are attractive precursors for the synthesis of expanded porphyrinoids, chemosensors, and supramolecular motifs. We demonstrate a new method for the synthesis of a set of linear pyrrolyltripyrrins and dipyrrolyltripyrrins through a regioselective SNAr reaction on α,α'-dibromotripyrrins using various pyrroles or indoles. A representative calixsmaragdyrin was prepared via the 2-fold SNAr reaction between α,α'-dibromotripyrrin and dipyrromethene through a convergent [3 + 2] strategy. These oligopyrroles showed intense deep red absorptions with an interesting pH response.
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Indóis , Pirróis , Pirróis/química , Indóis/química , Estrutura MolecularRESUMO
Aromatic ring fusion on BODIPY core can effectively tune its electronic property, and red-shift its absorption and emission wavelength. In this work, we report that a one-pot Pd(II) catalyzed multiple C-H activation to access acenaphtho[b]-fused BODIPYs though the reaction of α,ß-unsubstituted-BODIPYs and 1,8-dibromonaphthalenes. These newly synthesized acenaphtho[b]-fused BODIPYs revealed intensified deep red absorptions (639-669â nm) and emissions (643-683â nm), with high fluorescence quantum yields (0.53-0.84) in dichloromethane. Notably, these acenaphtho[b]-fused BODIPYs exhibited well-defined self-aggregation behavior in water/THF mixture, and for instance, the absorption of 3 a was red-shifted by 53â nm to 693â nm after forming aggregates.
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Corantes Fluorescentes , Paládio , Paládio/química , Corantes Fluorescentes/química , Compostos de Boro/química , CatáliseRESUMO
Rhodomonas salina, Cryptophyta, Rhodomonas genus, is a valuable source for live feed in aquaculture and for the production of phycoerythrin (PE). In this study, PE was extracted from Rhodomonas salina and characterized as having a molecular weight of approximately 24 kDa, an absorbance at 545 nm, and a purity of up to 6.61 (which meets reagent grade requirements with an OD545/OD280 ratio >4). The effects of PE on anticancer activity and its underlying mechanisms were evaluated to assess the immunomodulatory potential on the human lung cancer A549 cell line. Biochemical assays and western blot analysis were applied to confirm the immune mechanisms. The results showed that after 24 h of exposure to PE, the proliferation of A549 cells was significantly and dose-dependently decreased. PE also caused the generation of reactive oxygen species (ROS) and a decrease in mitochondrial membrane potential (MMP). The further results showed that PE can remarkably enhance the protein levels of cleaved caspase-3 and p53. Simultaneously, the BCL-2 family was also affected and had some changes, such as the dramatically enhance of Bim and Bak and the decrease of Bcl-2 level. However, it is interesting to note that there was no apparent alteration in Bax expression during the experiment. Furthermore, the biological mechanism for the potential of PE to induce apoptosis showed that the ERK/Bak and the JNK/caspase-3 signaling pathway were activated. This study provides evidence that the anticancer activity of PE in Rhodomonas salina may have potential for preventing cancer and serving as a novel immunostimulant in the pharmaceutical industry.