RESUMO
Small molecule chaperones have been exploited as therapeutics for the hundreds of diseases caused by protein misfolding. The most successful examples are the CFTR correctors, which transformed cystic fibrosis therapy. These molecules revert folding defects of the ΔF508 mutant and are widely used to treat patients. To investigate the molecular mechanism of their action, we determined cryo-electron microscopy structures of CFTR in complex with the FDA-approved correctors lumacaftor or tezacaftor. Both drugs insert into a hydrophobic pocket in the first transmembrane domain (TMD1), linking together four helices that are thermodynamically unstable. Mutating residues at the binding site rendered ΔF508-CFTR insensitive to lumacaftor and tezacaftor, underscoring the functional significance of the structural discovery. These results support a mechanism in which the correctors stabilize TMD1 at an early stage of biogenesis, prevent its premature degradation, and thereby allosterically rescuing many disease-causing mutations.
Assuntos
Aminopiridinas/metabolismo , Benzodioxóis/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Indóis/metabolismo , Dobramento de Proteína , Aminopiridinas/química , Aminopiridinas/uso terapêutico , Animais , Benzodioxóis/química , Benzodioxóis/uso terapêutico , Sítios de Ligação , Células CHO , Membrana Celular/química , Membrana Celular/metabolismo , Cricetulus , Microscopia Crioeletrônica , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/química , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Células HEK293 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indóis/química , Indóis/uso terapêutico , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/uso terapêutico , Mutação , Domínios Proteicos/genética , Células Sf9 , TransfecçãoRESUMO
All cellular proteins are synthesized by ribosomes, whose biogenesis in eukaryotes is a complex multi-step process completed within minutes. Several chemical inhibitors of ribosome function are available and used as tools or drugs. By contrast, we lack potent validated chemical probes to analyze the dynamics of eukaryotic ribosome assembly. Here, we combine chemical and genetic approaches to discover ribozinoindoles (or Rbins), potent and reversible triazinoindole-based inhibitors of eukaryotic ribosome biogenesis. Analyses of Rbin sensitivity and resistance conferring mutations in fission yeast, along with biochemical assays with recombinant proteins, provide evidence that Rbins' physiological target is Midasin, an essential â¼540-kDa AAA+ (ATPases associated with diverse cellular activities) protein. Using Rbins to acutely inhibit or activate Midasin function, in parallel experiments with inhibitor-sensitive or inhibitor-resistant cells, we uncover Midasin's role in assembling Nsa1 particles, nucleolar precursors of the 60S subunit. Together, our findings demonstrate that Rbins are powerful probes for eukaryotic ribosome assembly.
Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Subunidades Ribossômicas Maiores de Eucariotos/efeitos dos fármacos , Subunidades Ribossômicas Maiores de Eucariotos/metabolismo , Proteínas de Schizosaccharomyces pombe/antagonistas & inibidores , Triazinas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Indóis/química , Indóis/isolamento & purificação , Schizosaccharomyces/efeitos dos fármacos , Schizosaccharomyces/metabolismo , Relação Estrutura-Atividade , Triazinas/química , Triazinas/isolamento & purificaçãoRESUMO
Naturally evolved enzymes, despite their astonishingly large variety and functional diversity, operate predominantly through thermochemical activation. Integrating prominent photocatalysis modes into proteins, such as triplet energy transfer, could create artificial photoenzymes that expand the scope of natural biocatalysis1-3. Here, we exploit genetically reprogrammed, chemically evolved photoenzymes embedded with a synthetic triplet photosensitizer that are capable of excited-state enantio-induction4-6. Structural optimization through four rounds of directed evolution afforded proficient variants for the enantioselective intramolecular [2+2]-photocycloaddition of indole derivatives with good substrate generality and excellent enantioselectivities (up to 99% enantiomeric excess). A crystal structure of the photoenzyme-substrate complex elucidated the non-covalent interactions that mediate the reaction stereochemistry. This study expands the energy transfer reactivity7-10 of artificial triplet photoenzymes in a supramolecular protein cavity and unlocks an integrated approach to valuable enantioselective photochemical synthesis that is not accessible with either the synthetic or the biological world alone.
Assuntos
Biocatálise , Reação de Cicloadição , Enzimas , Processos Fotoquímicos , Biocatálise/efeitos da radiação , Transferência de Energia , Estereoisomerismo , Enzimas/genética , Enzimas/metabolismo , Enzimas/efeitos da radiação , Indóis/química , Especificidade por Substrato , Cristalização , Evolução Molecular Direcionada/métodosRESUMO
Electrochemical carbon dioxide (CO2) reduction can in principle convert carbon emissions to fuels and value-added chemicals, such as hydrocarbons and alcohols, using renewable energy, but the efficiency of the process is limited by its sluggish kinetics1,2. Molecular catalysts have well defined active sites and accurately tailorable structures that allow mechanism-based performance optimization, and transition-metal complexes have been extensively explored in this regard. However, these catalysts generally lack the ability to promote CO2 reduction beyond the two-electron process to generate more valuable products1,3. Here we show that when immobilized on carbon nanotubes, cobalt phthalocyanine-used previously to reduce CO2 to primarily CO-catalyses the six-electron reduction of CO2 to methanol with appreciable activity and selectivity. We find that the conversion, which proceeds via a distinct domino process with CO as an intermediate, generates methanol with a Faradaic efficiency higher than 40 per cent and a partial current density greater than 10 milliamperes per square centimetre at -0.94 volts with respect to the reversible hydrogen electrode in a near-neutral electrolyte. The catalytic activity decreases over time owing to the detrimental reduction of the phthalocyanine ligand, which can be suppressed by appending electron-donating amino substituents to the phthalocyanine ring. The improved molecule-based electrocatalyst converts CO2 to methanol with considerable activity and selectivity and with stable performance over at least 12 hours.
Assuntos
Dióxido de Carbono , Eletroquímica , Dióxido de Carbono/química , Catálise , Indóis/química , Metanol/síntese química , Nanotubos de Carbono/química , Compostos Organometálicos/químicaRESUMO
Organoboron reagents are important synthetic intermediates that have a key role in the construction of natural products, pharmaceuticals and organic materials1. The discovery of simpler, milder and more efficient approaches to organoborons can open additional routes to diverse substances2-5. Here we show a general method for the directed C-H borylation of arenes and heteroarenes without the use of metal catalysts. C7- and C4-borylated indoles are produced by a mild approach that is compatible with a broad range of functional groups. The mechanism, which is established by density functional theory calculations, involves BBr3 acting as both a reagent and a catalyst. The potential utility of this strategy is highlighted by the downstream transformation of the formed boron species into natural products and drug scaffolds.
Assuntos
Compostos de Boro/química , Compostos de Boro/síntese química , Boro/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Teoria da Densidade Funcional , Descoberta de Drogas , Indóis/química , Compostos Organometálicos/química , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/químicaRESUMO
Single-atom nanozymes (SANs) are considered to be ideal substitutes for natural enzymes due to their high atom utilization. This work reported a strategy to manipulate the second coordination shell of the Ce atom and reshape the carbon carrier to improve the oxidase-like activity of SANs. Internally, S atoms were symmetrically embedded into the second coordination layer to form a Ce-N4S2-C structure, which reduced the energy barrier for O2 reduction, promoted the electron transfer from the Ce atom to O atoms, and enhanced the interaction between the d orbital of the Ce atom and p orbital of O atoms. Externally, in situ polymerization of mussel-inspired polydopamine on the precursor helps capture metal sources and protects the 3D structure of the carrier during pyrolysis. On the other hand, polyethylene glycol (PEG) modulated the interface of the material to enhance water dispersion and mass transfer efficiency. As a proof of concept, the constructed PEG@P@Ce-N/S-C was applied to the multimodal assay of butyrylcholinesterase activity.
Assuntos
Cério , Cério/química , Polietilenoglicóis/química , Oxirredutases/química , Oxirredutases/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Polímeros/química , Indóis/química , Oxigênio/química , OxirreduçãoRESUMO
Polydopamine (PDA)-derived melanin-like materials exhibit significant photothermal conversion owing to their broad-spectrum light absorption. However, their low near-infrared (NIR) absorption and inadequate hydrophilicity compromise their utilization of solar energy. Herein, we developed metal-loaded poly(norepinephrine) nanoparticles (PNE NPs) by predoping metal ions (Fe3+, Mn3+, Co2+, Ca2+, Ga3+, and Mg2+) with norepinephrine, a neuron-derived biomimetic molecule, to address the limitations of PDA. The chelation between catechol and metal ions induces a ligand-to-metal charge transfer (LMCT) through the formation of donor-acceptor pairs, modulating the light absorption behavior and reducing the band gap. Under 1 sun illumination, the Fe-loaded PNE coated wood evaporator achieved a high seawater evaporation rate and efficiency of 1.75 kg m-2 h-1 and 92.4%, respectively, owing to the superior hydrophilicity and photothermal performance of PNE. Therefore, this study offers a comprehensive exploration of the role of metal ions in enhancing the photothermal properties of synthetic melanins.
Assuntos
Melaninas , Norepinefrina , Melaninas/química , Norepinefrina/química , Polimerização/efeitos da radiação , Polímeros/química , Neurotransmissores/química , Indóis/química , Oxirredução , Metais/química , Nanopartículas/químicaRESUMO
Bimetallic hollow structures have attracted much attention due to their unique properties, but they still face the problems of nonuniform alloys and excessive etching leading to structural collapse. Here, uniform bimetallic hollow nanospheres are constructed by pore engineering and then highly loaded with hemin (Hemin@MOF). Interestingly, in the presence of polydopamine (PDA), the competitive coordination between anionic polymer (γ-PGA) and dimethylimidazole does not lead to the collapse of the external framework but self-assembly into a hollow structure. By constructing the Hemin@MOF immune platform and using E. coli O157:H7 as the detection object, we find that the visual detection limits can reach 10, 3, and 3 CFU/mL in colorimetric, photothermal, and catalytic modes, which is 4 orders of magnitude lower than the traditional gold standard. This study provides a new idea for the morphological modification of the metal-organic skeleton and multifunctional immunochromatography detection.
Assuntos
Hemina , Indóis , Imunoensaio/métodos , Imunoensaio/instrumentação , Hemina/química , Indóis/química , Polímeros/química , Escherichia coli O157 , Estruturas Metalorgânicas/química , Nanosferas/química , Limite de DetecçãoRESUMO
Various applications related to glucose catalysis have led to the development of functional nanozymes with glucose oxidase (GOX)-like activity. However, the unsatisfactory catalytic activity of nanozymes is a major challenge for their practical applications due to their inefficient hydrogen and electron transfer. Herein, we present the synthesis of AuFe/polydopamine (PDA) superparticles that exhibit photothermal-enhanced GOX-like activity. Experimental investigations and theoretical calculations reveal that the glucose oxidation process catalyzed by AuFe/PDA follows an artificial-cofactor-mediated hydrogen atom transfer mechanism, which facilitates the generation of carbon-centered radical intermediates. Rather than depending on charged Au surfaces for thermodynamically unstable hydride transfer, Fe(III)-coordinated PDA with abundant amino and phenolic hydroxyl groups serves as cofactor mimics, facilitating both hydrogen atom and electron transfer in the catalytic process. Finally, leveraging the photothermal-enhanced GOX-like and catalase-like activities of AuFe/PDA, we establish a highly sensitive and accurate point-of-care testing blood glucose determination with exceptional anti-jamming capabilities.
Assuntos
Glucose Oxidase , Ouro , Hidrogênio , Indóis , Polímeros , Glucose Oxidase/química , Glucose Oxidase/metabolismo , Ouro/química , Hidrogênio/química , Transporte de Elétrons , Indóis/química , Polímeros/química , Glucose/química , Catálise , Oxirredução , Glicemia/análise , Ferro/química , HumanosRESUMO
Herein, a multifunctional nanohybrid (PL@HPFTM nanoparticles) was fabricated to perform the integration of chemodynamic therapy, photothermal therapy, and biological therapy over the long term at a designed location for continuous antibacterial applications. The PL@HPFTM nanoparticles consisted of a polydopamine/hemoglobin/Fe2+ nanocomplex with comodification of tetrazole/alkene groups on the surface as well as coloading of antimicrobial peptides and luminol in the core. During therapy, the PL@HPFTM nanoparticles would selectively cross-link to surrounding bacteria via tetrazole/alkene cycloaddition under chemiluminescence produced by the reaction between luminol and overexpressed H2O2 at the infected area. The resulting PL@HPFTM network not only significantly damaged bacteria by Fe2+-catalyzed ROS production, effective photothermal conversion, and sustained release of antimicrobial peptides but dramatically enhanced the retention time of these therapeutic agents for prolonged antibacterial therapy. Both in vitro and in vivo results have shown that our PL@HPFTM nanoparticles have much higher bactericidal efficiency and remarkably longer periods of validity than free antibacterial nanoparticles.
Assuntos
Antibacterianos , Nanopartículas , Antibacterianos/farmacologia , Antibacterianos/química , Animais , Nanopartículas/química , Camundongos , Escherichia coli/efeitos dos fármacos , Polímeros/química , Indóis/química , Indóis/farmacologia , Terapia Fototérmica , Humanos , Staphylococcus aureus/efeitos dos fármacos , Peptídeos Antimicrobianos/química , Peptídeos Antimicrobianos/farmacologia , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologiaRESUMO
Accumulated reactive oxygen species (ROS) and their resultant vascular dysfunction in androgenic alopecia (AGA) hinder hair follicle survival and cause permanent hair loss. However, safe and effective strategies to rescue hair follicle viability to enhance AGA therapeutic efficiency remain challenging. Herein, we fabricated a quercetin-encapsulated (Que) and polydopamine-integrated (PDA@QLipo) nanosystem that can reshape the perifollicular microenvironment to initial hair follicle regeneration for AGA treatment. Both the ROS scavenging and angiogenesis promotion abilities of PDA@QLipo were demonstrated. In vivo assays revealed that PDA@QLipo administrated with roller-microneedles successfully rejuvenated the "poor" perifollicular microenvironment, thereby promoting cell proliferation, accelerating hair follicle renewal, and facilitating hair follicle recovery. Moreover, PDA@QLipo achieved a higher hair regeneration coverage of 92.5% in the AGA mouse model than minoxidil (87.8%), even when dosed less frequently. The nanosystem creates a regenerative microenvironment by scavenging ROS and augmenting neovascularity for hair regrowth, presenting a promising approach for AGA clinical treatment.
Assuntos
Alopecia , Folículo Piloso , Indóis , Polímeros , Quercetina , Espécies Reativas de Oxigênio , Alopecia/tratamento farmacológico , Alopecia/patologia , Quercetina/farmacologia , Quercetina/administração & dosagem , Quercetina/química , Animais , Indóis/química , Indóis/farmacologia , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/crescimento & desenvolvimento , Polímeros/química , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Regeneração/efeitos dos fármacos , Humanos , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Proliferação de Células/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Modelos Animais de Doenças , MasculinoRESUMO
Artificial photoenzymes with novel catalytic modes not found in nature are in high demand; yet, they also present significant challenges in the field of biocatalysis. In this study, a chemogenetic modification strategy is developed to facilitate the rapid diversification of photoenzymes. This strategy integrates site-specific chemical conjugation of various artificial photosensitizers into natural protein cavities and the iterative mutagenesis in cell lysates. Through rounds of directed evolution, prominent visible-light-activatable photoenzyme variants were developed, featuring a thioxanthone chromophore. They successfully enabled the enantioselective [2 + 2] photocycloaddition of 2-carboxamide indoles, a class of UV-sensitive substrates that are traditionally challenging for known photoenzymes. Furthermore, the versatility of this photoenzyme is demonstrated in enantioselective whole-cell photobiocatalysis, enabling the efficient synthesis of enantioenriched cyclobutane-fused indoline tetracycles. These findings significantly expand the photophysical properties of artificial photoenzymes, a critical factor in enhancing their potential for harnessing excited-state reactivity in stereoselective transformations.
Assuntos
Reação de Cicloadição , Estereoisomerismo , Indóis/química , Indóis/síntese química , Indóis/metabolismo , Processos Fotoquímicos , Biocatálise , Evolução Molecular Direcionada , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Luz , Escherichia coli/enzimologia , Estrutura MolecularRESUMO
It is well-known in biochemistry that structure confers function, meaning that chemical structural elucidation is critical to truly understanding the function of a given metabolite. Indole-3-pyruvate (IPyA) exists in an equilibrium between the keto and enol tautomeric forms. IPyA is suggested to play a role in immune function; however, determining whether the tautomeric forms function differently can only be studied if an analytical method is capable of distinguishing between the two forms. Herein, we describe the use of UHPLC-HRMS to gain insight into the physical variables that govern IPyA tautomer equilibrium, reactivity, and detection limit. We use hydrogen-deuterium exchange (HDX) to identify enol and keto peaks, and we show that tautomers exhibit a valley of fronting followed by a tailing peak shape (though separation is still attainable) and identical MS/MS spectra. We observed drastically different ratios of keto and enol forms in different solvents, which is an important consideration for in vitro studies. IPyA was found to be highly unstable with accelerated reactivity in peroxides. Through in vitro reactivity studies, IPyA produced a myriad of known and unknown metabolites via nonenzymatic processes, many of which were mapped in vivo via the analysis of human plasma. Finally, we show that vitamin C (ascorbic acid) can slow this reactivity and enable sensitive detection in whole blood.
Assuntos
Indóis , Indóis/química , Cromatografia Líquida de Alta Pressão , Humanos , Espectrometria de Massas em Tandem , IsomerismoRESUMO
Single-molecule localization microscopy (SMLM) requires high-intensity laser irradiation, typically exceeding kW/cm2, to yield a sufficient photon count. However, this intense visible light exposure incurs substantial cellular toxicity, hindering its use in living cells. Here, we developed a class of near-infrared (NIR) spontaneously blinking fluorophores for SMLM. These NIR fluorophores are a combination of rhodamine spirolactams and merocyanine derivatives, where the rhodamine spirolactam component converts between a bright and dark state based on pH-dependent spirocyclization and merocyanine derivatives shift the excitation wavelength into the infrared. Single-molecule characterizations demonstrated their potential for SMLM. At a moderate power density of 3.93 kW/cm2, these probes exhibit duty cycle as low as 0.18% and an emission rate as high as 26,700 photons/s. Phototoxicity assessment under single-molecule imaging conditions reveals that NIR illumination (721 nm) minimizes harm to living cells. Employing these NIR fluorophores, we successfully captured time-lapse super-resolution tracking of mitochondria at a Fourier ring correlation (FRC) resolution of 69.4 nm and reconstructed the ultrastructures of endoplasmic reticulum (ER) in living cells.
Assuntos
Corantes Fluorescentes , Raios Infravermelhos , Corantes Fluorescentes/química , Humanos , Células HeLa , Indóis/química , Rodaminas/química , Microscopia de Fluorescência , Sobrevivência Celular/efeitos dos fármacos , Mitocôndrias , BenzopiranosRESUMO
Dental adhesives are widely used in daily practice for minimally invasive restorative dentistry but suffer from bond degradation and biofilm attack. Bio-inspired by marine mussels having excellent surface-adhesion capability and high chemical affinity of polydopamine (PDA) to metal ions, herein, experimental zinc (Zn)-containing polydopamine-based adhesive formulation, further being referred to as "Zn-PDA@SiO2"-incorporated adhesive is proposed as a novel dental adhesive. Different Zn contents (5 and 10 mm) of Zn-PDA@SiO2 are prepared. Considering the synergistic effect of Zn and PDA, Zn-PDA@SiO2 not only presents excellent antibacterial potential and notably inhibits enzymatic activity (soluble and matrix-bound proteases), but also exhibits superior biocompatibility and biosafety in vitro/vivo. The long-term bond stability is substantially improved by adding 5 wt% 5 mm Zn-PDA@SiO2 to the primer. The aged bond strength of the experimentally formulated dental adhesives applied in self-etch (SE) bonding mode is 1.9 times higher than that of the SE gold-standard adhesive. Molecular dynamics calculations indicate the stable formation of covalent bonds, Zn-assisted coordinative bonds, and hydrogen bonds between PDA and collagen. Overall, this bioinspired dental adhesive provides an avenue technology for innovative biomedical applications and has already revealed promising perspectives for dental restorative dentistry.
Assuntos
Microesferas , Dióxido de Silício , Animais , Dióxido de Silício/química , Indóis/química , Zinco/química , Polímeros/química , Cimentos Dentários/química , Antibacterianos/química , Antibacterianos/farmacologia , Simulação de Dinâmica MolecularRESUMO
Triple-negative breast cancer (TNBC) is a highly heterogeneous subtype of breast cancer, characterized by aggressiveness and high recurrence rate. As monotherapy provides limited benefit to TNBC patients, combination therapy emerges as a promising treatment approach. Gambogic acid (GA) is an exceedingly promising anticancer agent. Nonetheless, its application potential is hampered by low drug loading efficiency and associated toxic side effects. To overcome these limitations, using mesoporous polydopamine (MPDA) endowed with photothermal conversion capabilities is considered as a delivery vehicle for GA. Meanwhile, GA can inhibit the activity of heat shock protein 90 (HSP90) to enhance the photothermal effect. Herein, GA-loaded MPDA nanoparticles (GA@MPDA NPs) are developed with a high drug loading rate of 75.96% and remarkable photothermal conversion performance. GA@MPDA NPs combined with photothermal treatment (PTT) significantly inhibit the tumor growth, and effectively trigger the immunogenic cell death (ICD), which thereby increase the number of activated effector T cells (CD8+ T cells and CD4+ T cells) in the tumor, and hoist the level of immune-inflammatory cytokines (IFN-γ, IL-6, and TNF-α). The above results suggest that the combination of GA@MPDA NPs with PTT expected to activate the antitumor immune response, thus potentially enhancing the clinical therapeutic effect on TNBC.
Assuntos
Indóis , Polímeros , Neoplasias de Mama Triplo Negativas , Xantonas , Xantonas/química , Xantonas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Indóis/química , Indóis/farmacologia , Polímeros/química , Humanos , Animais , Linhagem Celular Tumoral , Feminino , Porosidade , Camundongos , Nanopartículas/químicaRESUMO
Bacterial cellulose/oxidized bacterial cellulose nanofibrils (BC/oxBCNFs) macro-fibers are developed as a novel scaffold for vascular tissue engineering. Utilizing a low-speed rotary coagulation spinning technique and precise solvent control, macro-fibers with a unique heterogeneous structure with dense surface and porous core are created. Enhanced by a polydopamine (PDA) coating, these macro-fibers offer robust mechanical integrity, high biocompatibility, and excellent cell adhesion. When cultured with endothelial cells (ECs) and smooth muscle cells (SMCs), the macro-fibers support healthy cell proliferation and exhibit a unique spiral SMC alignment, demonstrating their vascular suitability. This innovative strategy opens new avenues for advances in tissue engineering.
Assuntos
Celulose , Nanofibras , Engenharia Tecidual , Alicerces Teciduais , Engenharia Tecidual/métodos , Nanofibras/química , Alicerces Teciduais/química , Celulose/química , Humanos , Miócitos de Músculo Liso/citologia , Proliferação de Células/efeitos dos fármacos , Adesão Celular , Células Endoteliais/citologia , Células Endoteliais da Veia Umbilical Humana , Indóis/química , PolímerosRESUMO
Cuproptosis is an emerging programmed cell death, displaying great potential in cancer treatment. However, intracellular copper content to induce cuproptosis is unmet, which mainly ascribes to the intracellular pumping out equilibrium mechanism by copper exporter ATP7A and ATP7B. Therefore, it is necessary to break such export balance mechanisms for desired cuproptosis. Mediated by diethyldithiocarbamate (DTC) coordination, herein a strategy to efficiently assemble copper ions into polydopamine nanostructure (PDA-DTC/Cu) for reprogramming copper metabolism of tumor is developed. The deposited Cu2+ can effectively trigger the aggregation of lipoylated proteins to induce cuproptosis of tumor cells. Beyond elevating intracellular copper accumulation, PDA-DTC/Cu enables to break the balance of copper metabolism by disrupting mitochondrial function and restricting the adenosine triphosphate (ATP) energy supply, thus catalytically inhibiting the expressions of ATP7A and ATP7B of tumor cells to enhance cuproptosis. Meanwhile, the killed tumor cells can induce immunogenic cell death (ICD) to stimulate the immune response. Besides, PDA-DTC/Cu NPs can promote the repolarization of tumor-associated macrophages (TAMs ) to relieve the tumor immunosuppressive microenvironment (TIME). Collectively, PDA-DTC/Cu presented a promising "one stone two birds" strategy to realize copper accumulation and inhibit copper export simultaneously to enhance cuproptosis for 4T1 murine breast cancer immunotherapy.
Assuntos
Cobre , Imunoterapia , Indóis , Nanoestruturas , Polímeros , Cobre/química , Polímeros/química , Animais , Imunoterapia/métodos , Indóis/química , Indóis/farmacologia , Camundongos , Nanoestruturas/química , Linhagem Celular Tumoral , Humanos , Catálise , Feminino , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Inspired by the timely emergence of silkworm pupae from their cocoons, silkworm chrysalis-like probiotic composites (SCPCs) are developed for the comprehensive therapy of inflammatory bowel disease (IBD), in which probiotics are enveloped as the "pupa" in a sequential layering of silk sericin (SS), tannic acid (TA), and polydopamine, akin to the protective "cocoon". Compared to unwrapped probiotics, these composites not only demonstrate exceptional resistance to the harsh gastrointestinal environment and exhibit over 200 times greater intestinal colonization but also safeguard probiotics from the damage of IBD environment while enabling probiotics sustained release. The probiotics, in synergy with SS and TA, provide a multi-crossed comprehensive therapy for IBD that simultaneously addresses various pathological features of IBD, including intestinal barrier disruption, elevated pro-inflammatory cytokines, heightened oxidative stress, and disturbances in the intestinal microbiota. SCPCs exhibit remarkable outcomes, including a 9.7-fold reduction in intestinal permeability, an 8.9-fold decrease in IL-6 levels, and a 2.9-fold reduction in TNF-α levels compared to uncoated probiotics. Furthermore, SCPCs demonstrate an impressive 92.25% reactive oxygen species clearance rate, significantly enhance the richness of beneficial intestinal probiotics, and effectively diminish the abundance of pathogenic bacteria, indicating a substantial improvement in the overall therapeutic effect of IBD.
Assuntos
Bombyx , Doenças Inflamatórias Intestinais , Probióticos , Animais , Bombyx/química , Doenças Inflamatórias Intestinais/terapia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Intestinos , Polímeros/química , Microbioma Gastrointestinal/efeitos dos fármacos , Sericinas/química , Sericinas/farmacologia , Indóis/química , Taninos/química , Taninos/farmacologia , CamundongosRESUMO
Ferroptosis therapy, which uses ferroptosis inducers to produce lethal lipid peroxides and induce tumor cell death, is considered a promising cancer treatment strategy. However, challenges remain regarding how to increase the accumulation of reactive oxygen species (ROS) in the tumor microenvironment (TME) to enhance antitumor efficacy. In this study, a hyaluronic acid (HA) encapsulated hollow mesoporous manganese dioxide (H-MnO2) with double-shell nanostructure is designed to contain iron coordinated cyanine near-infrared dye IR783 (IR783-Fe) for synergistic ferroptosis photodynamic therapy against tumors. The nano photosensitizer IR783-Fe@MnO2-HA, in which HA actively targets the CD44 receptor, subsequently dissociates and releases Fe3+ and IR783 in acidic TME. First, Fe3+ consumes glutathione to produce Fe2+, which promotes the Fenton reaction in cells to produce hydroxyl free radicals (·OH) and induce ferroptosis of tumor cells. In addition, MnO2 catalyzes the production of O2 from H2O2 and enhances the production of singlet oxygen (1O2) by IR783 under laser irradiation, thus increasing the production and accumulation of ROS to provide photodynamic therapy. The highly biocompatible IR783-Fe@MnO2-HA nano-photosensitizers have exhibited tumor-targeting ability and efficient tumor inhibition in vivo due to the synergistic effect of photodynamic and ferroptosis antitumor therapies.