RESUMEN
N-linked glycosylation is a ubiquitous protein post-translational modification in which aberrant glycan biosynthesis has been linked to severe conditions like cancer. Accurate qualitative and quantitative analysis of N-glycans are crucial for investigating their physiological functions. Owing to the intrinsic absence of chromophores and high polarity of the glycans, current detection methods are restricted to liquid chromatography and mass spectrometry. Herein, we describe three new imidazolium-based glycan tags: 2'GITag, 3'GITag, and 4'GITag, that significantly improve both the limit of detection and limit of quantification of derivatized oligosaccharides, in terms of fluorescence intensity and ionisation efficiency. Our top-performing derivatisation agent, 4'GITag, shifted the detection sensitivity range from high femtomole to sub-femtomole levels in ESI-MS compared to traditional glycan label, 2AB, enabling the identification of 24 N-glycans in mouse serum, including those bearing sialic acids. Additionally, 4'GITag stabilized Na-salt forms of sialic acids, simplifying the simultaneous analysis of neutral and negative charged N-glycans significantly, avoiding the need for complex derivatisation procedures typically required for the detection of sialylated species. Overall, the favorable performance of imidazolium tags in the derivatisation and sensitive profiling of glycans has the potential for labeling tissue or live cells to explore disease biomarkers and for developing new targeted therapeutic strategies.
Asunto(s)
Imidazoles , Polisacáridos , Espectrometría de Masa por Ionización de Electrospray , Animales , Polisacáridos/química , Polisacáridos/sangre , Ratones , Imidazoles/química , Espectrometría de Masa por Ionización de Electrospray/métodos , Colorantes Fluorescentes/química , Límite de Detección , GlicosilaciónRESUMEN
Background: A successful immune response against tumors depends on various cellular processes. Hence, there is an urgent need to construct a proficient nanoplatform for immunotherapy that can concurrently regulate the activities of various cells participating in the immune process. We have developed zeolitic imidazolate framework-8 (ZIF-8) formula, with good pH sensitivity, which is conducive to the release of drugs in the tumor site (acidic environment) and significantly improves immunotherapy. This is achieved through the coordinated action of different therapeutic agents, such as the photothermal agent polydopamine (PDA), the chemodrug camptothecin (CPT), and the immunomodulator 1-methyl-D-tryptophan (1-MT). Materials and Methods: In this study, we evaluated the antitumor effect of PDA/(CPT + 1-MT) @ZIF-8 (PCMZ) nanoparticles (NPs) in vitro and in vivo and investigated the molecular mechanism of PCMZ NPs in tumor suppression via photothermal-chemo-immunotherapy. Results: MTT and Annexin V-FITC/PI double staining apoptosis test showed that PCMZ NPs could induce apoptosis of 4T1 cell, and PCMZ NPs could cause 4T1 cell necrosis under 808 nm laser irradiation. The objective is to establish a unilateral breast cancer model in mice and investigate the effect of PCMZ NPs on tumor growth and tumor suppression in tumor bearing mice. The results showed that PCMZ NPs showed good heating effect in vivo and effectively inhibited tumor growth under 808 nm laser irradiation. In addition, PCMZ NPs could induce the immunogenic death of tumor cells, promote the maturation of DCs, inhibit IDO pathway, and finally differentiate T cells into cytotoxic T cells and helper T cells, so as to effectively activate the anti-tumor immune response. Conclusion: The PCMZ NPs, possessing good photothermal conversion capabilities due to join of PDA, effectively overcome two main challenges in immunotherapy: insufficient stimulation of the immune response and evasion of the immune system. This provides a robust platform against invasive cancer and recurrent tumors.
Asunto(s)
Camptotecina , Inmunoterapia , Indoles , Ratones Endogámicos BALB C , Polímeros , Triptófano , Zeolitas , Animales , Indoles/química , Indoles/farmacología , Zeolitas/química , Zeolitas/farmacología , Inmunoterapia/métodos , Triptófano/química , Triptófano/farmacología , Triptófano/análogos & derivados , Ratones , Concentración de Iones de Hidrógeno , Línea Celular Tumoral , Femenino , Polímeros/química , Polímeros/farmacología , Camptotecina/química , Camptotecina/farmacología , Nanopartículas/química , Apoptosis/efectos de los fármacos , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Humanos , Terapia Fototérmica/métodos , Imidazoles/química , Imidazoles/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Terapia CombinadaRESUMEN
We have prepared a novel assembly with copper nanoclusters (CuNCs) and imidazolium-based gemini surfactants (different chain lengths). These novel mimic enzymes formed through the assembly of nanocluster-gemini surfactants have been utilized in creating colorimetric sensors to detect biomolecules. Yet, understanding the method for detecting glutathione (GSH) and its sensing mechanism using this specific assembly-based colorimetric sensor poses a significant challenge. Because of the role of surface ligands, the complexes of cysteine-capped CuNCs (Cys-CuNCs) and gemini surfactants exhibit strong amphiphilicity, enabling them to self-assemble like a molecular amphiphile. We have investigated the kinetics and catalytic capabilities of this Cys-CuNCs@gemini surfactant assembly through peroxidase-like activity. Additionally, a sensitive and simple-to-use colorimetric sensing approach for glutathione (GSH) is also disclosed here, demonstrating a low limit of detection, by using this peroxidase-like activity of Cys-CuNCs@gemini surfactant assemblies. Thus, the remarkable advantages of the Cys-CuNCs@gemini surfactant nanozyme make it suitable for the precise colorimetric detection of GSH, demonstrating excellent sensitivity and reliable selectivity. Additionally, it performs well in detecting GSH in various soft drinks.
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Colorimetría , Cobre , Cisteína , Glutatión , Nanopartículas del Metal , Tensoactivos , Cobre/química , Glutatión/análisis , Glutatión/química , Colorimetría/métodos , Tensoactivos/química , Cisteína/análisis , Cisteína/química , Nanopartículas del Metal/química , Imidazoles/química , Peroxidasa/química , Peroxidasa/metabolismoRESUMEN
Human tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are two important targets in cancer immunotherapy. Extensive research has led to a large number of potent IDO inhibitors; in addition, 52 structures of IDO in complex with inhibitors with a wide array of chemical scaffolds have been documented. In contrast, progress in the development of TDO inhibitors has been limited. Only four structures of TDO in complex with competitive inhibitors that compete with the substrate L-tryptophan for binding to the active site have been reported to date. Here we systematically evaluated the structures of TDO in complex with competitive inhibitors with three types of pharmacophores, imidazo-isoindole, indole-tetrazole, and indole-benzotriazole. The comparative assessment of the protein-inhibitor interactions sheds new light into the structure-based design of enzyme-selective inhibitors.
Asunto(s)
Inhibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenasa , Triptófano Oxigenasa , Humanos , Triptófano Oxigenasa/antagonistas & inhibidores , Triptófano Oxigenasa/metabolismo , Triptófano Oxigenasa/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Relación Estructura-Actividad , Indoles/química , Indoles/farmacología , Indoles/metabolismo , Modelos Moleculares , Tetrazoles/química , Tetrazoles/farmacología , Tetrazoles/metabolismo , Triptófano/química , Triptófano/metabolismo , Imidazoles/química , Imidazoles/farmacología , Imidazoles/metabolismo , Unión ProteicaRESUMEN
A new imidazolium ionic liquid (IL) halide conjugated with dimethylcardamonin (DMC, 1), namely [Bbim]Br-DMC (3), was synthesised to improve the biological activity of the natural chalcone. DMC was isolated from seeds of Syzygium nervosum A. Cunn. ex DC. which was an effective anti-breast cancer agent. The compound 1 and 3 showed anticancer activity in MDA-MB-231 cells with IC50 values of 14.54 ± 0.99 µM and 7.40 ± 0.15 µM, respectively. MTT assay showed that compound 3 had cytotoxic effect at least two-fold greater than compound 1 but was low toxic to normal cells of Hs 578Bst. After 48â¯h, compound 3 at concentration of IC50 value inhibited the proliferation and induced morphological changes of MDA-MB-231 cells in a time-dependent manner. The cell cycle profile also showed that compound 3 exerted anti-proliferation activity with the cell cycle arrest at G0/G1 phase and compound 3 also induced apoptosis and reduced mitochondrial membrane potential in MDA-MB-231 cells in a dose-dependent manner. In gene expression assay, compound 3 up-regulated pro-apoptotic genes such as Bax and p53 and suppressed anti-apoptotic Bcl-2 whereas there was no effect on DNA repair gene such as PARP1. The Bax/Bcl-2 ratio was significantly increased after treated with compound 3. In the molecular docking study, the interactions between compound 3 and B-DNA structure in the minor groove region via hydrogen bonds was reported. In conclusion, [Bbim]Br-DMC or compound 3 is a potential candidate to induce apoptosis and inhibits proliferation via cell cycle arrest and decreases mitochondrial membrane of triple-negative breast cancer MDA-MB-231 cells.
Asunto(s)
Apoptosis , Proliferación Celular , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Imidazoles/farmacología , Imidazoles/síntesis química , Imidazoles/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Simulación del Acoplamiento Molecular , Femenino , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/químicaRESUMEN
Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.
Asunto(s)
Cardiotónicos , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas , Piridinas , Humanos , Animales , Piridinas/farmacología , Piridinas/química , Piridinas/síntesis química , Piridinas/uso terapéutico , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/metabolismo , Relación Estructura-Actividad , Cardiotónicos/farmacología , Cardiotónicos/química , Cardiotónicos/síntesis química , Cardiotónicos/uso terapéutico , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Masculino , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Imidazoles/uso terapéutico , Ratones Desnudos , Descubrimiento de DrogasRESUMEN
The development of targeted drug delivery systems has been a pivotal area in nanomedicine, addressing challenges like low drug loading capacity, uncontrolled release, and systemic toxicity. This study aims to develop and evaluate dual-functionalized mesoporous silica nanoparticles (MSN) for targeted delivery of celecoxib, enhancing drug loading, achieving controlled release, and reducing systemic toxicity through amine grafting and imidazolyl polyethyleneimine (PEI) gatekeepers. MSN were synthesized using the sol-gel method and functionalized with (3-aminopropyl) triethoxysilane (APTES) to create amine-grafted MSN (MSN-NH2). Celecoxib was loaded into MSN-NH2, followed by conjugation of imidazole-functionalized PEI (IP) gatekeepers synthesized via carbodiimide coupling. Characterization was conducted using Fourier-transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (1H-NMR). Drug loading capacity, entrapment efficiency, and in vitro drug release at pH 5.5 and 7.4 were evaluated. Cytotoxicity was assessed using the MTT assay on RAW 264.7 macrophages. The synthesized IP was confirmed by FTIR and 1H-NMR. Amine-grafted MSN demonstrated a celecoxib loading capacity of 12.91 ± 2.02%, 2.1 times higher than non-functionalized MSN. In vitro release studies showed pH-responsive behavior with significantly higher celecoxib release from MSN-NH2-celecoxib-IP at pH 5.5 compared to pH 7.4, achieving a 33% increase in release rate within 2 h. Cytotoxicity tests indicated significantly higher cell viability for IP-treated cells compared to PEI-treated cells, confirming reduced toxicity. The dual-functionalization of MSN with amine grafting and imidazolyl PEI gatekeepers enhances celecoxib loading and provides controlled pH-responsive drug release while reducing systemic toxicity. These findings highlight the potential of this advanced drug delivery system for targeted anti-inflammatory and anticancer therapies.
Asunto(s)
Aminas , Celecoxib , Preparaciones de Acción Retardada , Liberación de Fármacos , Nanopartículas , Polietileneimina , Dióxido de Silicio , Celecoxib/química , Celecoxib/farmacología , Dióxido de Silicio/química , Ratones , Nanopartículas/química , Animales , Polietileneimina/química , Células RAW 264.7 , Aminas/química , Preparaciones de Acción Retardada/farmacología , Preparaciones de Acción Retardada/química , Portadores de Fármacos/química , Porosidad , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Espectroscopía Infrarroja por Transformada de Fourier , Imidazoles/química , Concentración de Iones de HidrógenoRESUMEN
Although hierarchically porous zeolitic imidazolate frameworks (HPZIFs) not only inherit the intrinsic architectural and chemical stabilities of their microporous counterparts but also afford open space for the efficient mass diffusion of the macromolecules involved, their rational design and construction are still challenging. Herein, HPZIFs with tailorable pore sizes ranging from 18 to 54 nm were successfully fabricated by using a newly developed soft-template-directed strategy. Our success rooted in the fact that the screened PS81-PVP44-PEO113 triblock copolymer could effectively coordinate with the metal precursor for the directed crystallization of ZIFs along surfactant assemblies. The advantages of continuous large pores and open structures in such HPZIFs were fully taken into account to serve as a bioreactor for the efficient immunoassay. The expanded large pores provided not only a significantly vast surface area to enhance the density of capture antibodies but also enough space for accommodating multiple conjugated biomolecules in one pore channel. In combination with a cascade enzyme cycle amplification strategy, a model biomarker of prostate-specific antigen (PSA) at the femtomolar level was checked with a limit of detection of 92 fM using the developed immunosensor. Specific screening on patients with prostate cancer or even benign prostatic hyperplasia was exemplified through accurately quantifying small changes of PSA concentration in clinical serum samples, prefiguring the great potential of the developed HPZIF-8 immunosensor platform for the early monitoring and diagnostics of diseases.
Asunto(s)
Imidazoles , Antígeno Prostático Específico , Zeolitas , Zeolitas/química , Inmunoensayo/métodos , Porosidad , Imidazoles/química , Humanos , Antígeno Prostático Específico/sangre , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/síntesis química , Técnicas Biosensibles/métodos , Límite de DetecciónRESUMEN
Osteoarthritis treatment remains a significant clinical challenge. Quercetin, a natural flavonoid with anti-inflammatory and antiapoptotic properties, might be utilized to treat OA. However, poor water solubility and short joint retention duration limit its bioavailability and translation to clinical applications. A one-step self-assembly method was utilized to fabricate quercetin-loaded zeolitic imidazolate framework-8 (Qu@ZIF-8) nanoparticles using zinc ions, 2-methylimidazole, and quercetin. In vitro tests showed that Qu@ZIF-8 nanoparticles released pH-responsive agents into chondrocytes, effectively protecting them from interleukin (IL)-induced inflammation and apoptosis, thereby promoting cartilage anabolic activities. These underlying mechanisms revealed a remarkable increase of autophagy in IL-ß-treated chondrocytes, followed by the inhibition of the Pi3k/Akt signaling pathway, which contributed to the protective effect of Qu @ZIF-8. By the establishment of medial meniscus instability (DMM) in OA mice, Qu@ZIF-8 substantially improved cartilage structural integrity and chondrocyte status, as well as attenuated OA progression. Importantly, Qu@ZIF-8 outperformed quercetin alone in the treatment of OA due to its control release. The combined research findings indicate that Qu@ZIF-8 shields chondrocytes from inflammation and apoptosis by activating autophagy and repressing the Pi3k/Akt pathway. This investigation may provide new insights for clinically extending the therapy of OA.
Asunto(s)
Autofagia , Condrocitos , Nanopartículas , Osteoartritis , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Quercetina , Transducción de Señal , Animales , Quercetina/química , Quercetina/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones , Autofagia/efectos de los fármacos , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , Osteoartritis/metabolismo , Nanopartículas/química , Transducción de Señal/efectos de los fármacos , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Condrocitos/patología , Zeolitas/química , Zeolitas/farmacología , Imidazoles/química , Imidazoles/farmacología , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Apoptosis/efectos de los fármacos , Masculino , Ratones Endogámicos C57BLRESUMEN
The dominant role of non-homologous end-joining in the repair of radiation-induced double-strand breaks identifies DNA-dependent protein kinase (DNA-PK) as an excellent target for the development of radiosensitizers. We report the discovery of a new class of imidazo[4,5-c]pyridine-2-one DNA-PK inhibitors. Structure-activity studies culminated in the identification of 78 as a nM DNA-PK inhibitor with excellent selectivity for DNA-PK compared to related phosphoinositide 3-kinase (PI3K) and PI3K-like kinase (PIKK) families and the broader kinome, and displayed DNA-PK-dependent radiosensitization of HAP1 cells. Compound 78 demonstrated robust radiosensitization of a broad range of cancer cells in vitro, displayed high oral bioavailability, and sensitized colorectal carcinoma (HCT116/54C) and head and neck squamous cell carcinoma (UT-SCC-74B) tumor xenografts to radiation. Compound 78 also provided substantial tumor growth inhibition of HCT116/54C tumor xenografts in combination with radiation. Compound 78 represents a new, potent, and selective class of DNA-PK inhibitors with significant potential as radiosensitizers for cancer treatment.
Asunto(s)
Proteína Quinasa Activada por ADN , Inhibidores de Proteínas Quinasas , Fármacos Sensibilizantes a Radiaciones , Humanos , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Proteína Quinasa Activada por ADN/metabolismo , Animales , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Fármacos Sensibilizantes a Radiaciones/síntesis química , Relación Estructura-Actividad , Ratones , Línea Celular Tumoral , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Imidazoles/farmacocinética , Piridonas/farmacología , Piridonas/química , Piridonas/síntesis química , Piridonas/farmacocinética , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , RatasRESUMEN
Imiqualines are analogues of the immunomodulatory drug imiquimod. EAPB02303, the lead of the second-generation imiqualines, is characterized by significant anti-tumor effects with IC50s in the nanomolar range. We used Caenorhabditis elegans transgenic and mutant strains of two key signaling pathways (PI3K-Akt and Ras-MAPK) disrupted in human cancers to investigate the mode of action of EAPB02303. The ability of this imiqualine to inhibit the insulin/IGF1 signaling (IIS) pathway via the PI3K-Akt kinase cascade was explored through assessing the lifespan of wild-type worms. Micromolar doses of EAPB02303 significantly enhanced longevity of N2 strain and led to the nuclear translocation and subsequent activation of transcription factor DAF-16, the only forkhead box transcription factor class O (Fox O) homolog in C. elegans. Moreover, EAPB02303 significantly reduced the multivulva phenotype in let-60/Ras mutant strains MT2124 and MT4698, indicative of its mode of action through the Ras pathway. In summary, we showed that EAPB02303 potently reduced the activity of IIS and Ras-MAPK signaling in C. elegans. Our results revealed the mechanism of action of EAPB02303 against human cancers associated with hyperactivated IIS pathway and oncogenic Ras mutations.
Asunto(s)
Antineoplásicos , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Factores de Transcripción Forkhead , Quinoxalinas , Transducción de Señal , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Animales , Quinoxalinas/farmacología , Quinoxalinas/química , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Antineoplásicos/farmacología , Antineoplásicos/química , Transducción de Señal/efectos de los fármacos , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Longevidad/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Humanos , Imidazoles/farmacología , Imidazoles/química , Animales Modificados GenéticamenteRESUMEN
Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)-activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-κB and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037's in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses.
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Adyuvantes Inmunológicos , Pirimidinas , Receptor Toll-Like 7 , Receptor Toll-Like 8 , Humanos , Receptor Toll-Like 8/agonistas , Receptor Toll-Like 8/metabolismo , Animales , Ratones , Adyuvantes Inmunológicos/farmacología , Receptor Toll-Like 7/agonistas , Pirimidinas/farmacología , Pirimidinas/química , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Imidazoles/farmacología , Imidazoles/química , Células THP-1 , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , COVID-19/virología , COVID-19/inmunología , FN-kappa B/metabolismo , Femenino , Descubrimiento de Drogas/métodos , Inmunidad Innata/efectos de los fármacosRESUMEN
Designing antibacterial agents with rapid bacterial eradication performance is paramount for the treatment of bacteria-infected wounds. Metal nanoclusters (NCs) with aggregation-induced emission (AIE) have been considered as novel photodynamic antibacterial agents without drug resistance, but they suffer from poor photostability and low charge carrier separation efficiency. Herein, we report the design of a photodynamic antibacterial agent by encapsulating AIE-type AgAu NCs (Ag28Au1 NCs) into a zeolitic Zn(2-methylimidazole)2 framework (ZIF-8). The encapsulation of AIE-type Ag28Au1 NCs into porous ZIF-8 could not only enhance the photostability of Ag28Au1 NCs by inhibiting their aggregation but also promote the separation of photoinduced charge carriers, resulting in the rapid generation of destructive reactive oxygen species (ROS) for bacterial killing under visible-light irradiation. Consequently, the as-designed photodynamic Ag28Au1 NCs@ZIF-8 antibacterial agent could rapidly eliminate 97.7% of Escherichia coli (E. coli) and 91.6% of Staphylococcus aureus (S. aureus) within 5 min in vitro under visible light irradiation. Furthermore, in vivo experimental results have highlighted the synergistic effect created by AIE-type Ag28Au1 NCs and ZIF-8, enabling Ag28Au1 NCs@ZIF-8 to effectively eradicate bacteria in infected areas, reduce inflammation, and promote the generation of blood vessels, epithelial tissue, and collagen. This synergistic effect promoted the healing of S. aureus-infected wound, with nearly 100% of wound recovery within 11 days. This work may be interesting because it sheds light on the design of metal NC-based photodynamic nanomedicine for bacteria-infected disease treatment.
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Antibacterianos , Escherichia coli , Imidazoles , Estructuras Metalorgánicas , Fotoquimioterapia , Staphylococcus aureus , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Antibacterianos/química , Antibacterianos/farmacología , Animales , Staphylococcus aureus/efectos de los fármacos , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Ratones , Imidazoles/química , Imidazoles/farmacología , Zeolitas/química , Zeolitas/farmacología , Plata/química , Plata/farmacología , Especies Reactivas de Oxígeno/metabolismo , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Oro/química , Oro/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , LuzRESUMEN
Cancer vaccines aim at generating cytotoxic CD8+ T cells that kill cancer cells and confer durable tumor regression. Hereto, CD8+ peptide epitopes should be presented by antigen presenting cells to CD8+ T cells in lymphoid tissue. Unfortunately, in unformulated soluble form, peptide antigens are poorly taken up by antigen presenting cells and do not efficiently reach lymph nodes. Hence, the lack of efficient delivery remains a major limitation for successful clinical translation of cancer vaccination using peptide antigens. Here we propose a generic peptide nanoformulation strategy by extending the amino acid sequence of the peptide antigen epitope with 10 glutamic acid residues. The resulting overall anionic charge of the peptide allows encapsulation into lipid nanoparticles (peptide-LNP) by electrostatic interaction with an ionizable cationic lipid. We demonstrate that intravenous injection of peptide-LNP efficiently delivers the peptide to immune cells in the spleen. Peptide-LNP that co-encapsulate an imidazoquinoline TLR7/8 agonist (IMDQ) induce robust innate immune activation in a broad range of immune cell subsets in the spleen. Peptide-LNP containing the minimal CD8+ T cell epitope of the HPV type 16 E7 oncoprotein and IMDQ induces high levels of antigen-specific CD8+ T cells in the blood, and can confer protective immunity against E7-expressing tumors in both prophylactic and therapeutic settings.
Asunto(s)
Ratones Endogámicos C57BL , Nanopartículas , Receptor Toll-Like 7 , Receptor Toll-Like 8 , Animales , Nanopartículas/química , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 8/agonistas , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Ratones , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Lípidos/química , Péptidos/química , Femenino , Proteínas E7 de Papillomavirus/inmunología , Quinolinas/farmacología , Quinolinas/química , Imidazoles/química , Imidazoles/farmacologíaRESUMEN
Objective: Ovarian cancer cells are prone to acquire tolerance to chemotherapeutic agents, which seriously affects clinical outcomes. The development of novel strategies to enhance the targeting of chemotherapeutic agents to overcome drug resistance and minimize side effects is significant for improving the clinical outcomes of ovarian cancer patients. Methods: We employed folic acid (FA)-modified ZIF-90 nanomaterials (FA-ZIF-90) to deliver the chemotherapeutic drug, cisplatin (DDP), via dual targeting to improve its targeting to circumvent cisplatin resistance in ovarian cancer cells, especially by targeting mitochondria. FA-ZIF-90/DDP could rapidly release DDP in response to dual stimulation of acidity and ATP in tumor cells. Results: FA-ZIF-90/DDP showed good blood compatibility. It was efficiently taken up by human ovarian cancer cisplatin-resistant cells A2780/DDP and aggregated in the mitochondrial region. FA-ZIF-90/DDP significantly inhibited the mitochondrial activity and metastatic ability of A2780/DDP cells. In addition, it effectively induced apoptosis in A2780/DDP cells and overcame cisplatin resistance. In vivo experiments showed that FA-ZIF-90/DDP increased the accumulation of DDP in tumor tissues and significantly inhibited tumor growth. Conclusion: FA-modified ZIF-90 nanocarriers can improve the tumor targeting and anti-tumor effects of chemotherapeutic drugs, reduce toxic side effects, and are expected to be a novel therapeutic strategy to reverse drug resistance in ovarian cancer.
Asunto(s)
Antineoplásicos , Apoptosis , Cisplatino , Resistencia a Antineoplásicos , Ácido Fólico , Imidazoles , Neoplasias Ováricas , Zeolitas , Femenino , Cisplatino/farmacología , Cisplatino/química , Cisplatino/farmacocinética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Animales , Zeolitas/química , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Ácido Fólico/química , Ácido Fólico/farmacología , Imidazoles/química , Imidazoles/farmacología , Imidazoles/administración & dosificación , Apoptosis/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Mitocondrias/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Portadores de Fármacos/química , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ponatinib and tofacitinib, established kinase inhibitors and FDA-approved for chronic myeloid leukemia and rheumatoid arthritis, are recently undergoing investigation in diverse clinical trials for potential repurposing. The aryl hydrocarbon receptor (AhR), a transcription factor influencing a spectrum of physiological and pathophysiological activities, stands as a therapeutic target for numerous diseases. This study employs molecular modelling tools and in vitro assays to identify ponatinib and tofacitinib as AhR ligands, elucidating their binding and molecular interactions in the AhR PAS-B domain. Molecular docking analyses revealed that ponatinib and tofacitinib occupy the central pocket within the primary cavity, similar to AhR agonists 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and (benzo[a]pyrene) B[a]P. Our simulations also showed that these compounds exhibit good stability, stabilizing many hot spots within the PAS-B domain, including the Dα-Eα loop, which serves as a regulatory element for the binding pocket. Binding energy calculations highlighted ponatinib's superior predicted affinity, revealing F295 as a crucial residue in maintaining strong interaction with the two compounds. Our in vitro data suggest that ponatinib functions as an AhR antagonist, blocking the downstream signaling of AhR pathway induced by TCDD and B[a]P. Additionally, both tofacitinib and ponatinib cause impairment in AhR-regulated CYP1A1 enzyme activity induced by potent AhR agonists. This study unveils ponatinib and tofacitinib as potential modulators of AhR, providing valuable insights into their therapeutic roles in AhR-associated diseases and enhancing our understanding of the intricate relationship between kinase inhibitors and AhR.
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Imidazoles , Piperidinas , Piridazinas , Pirimidinas , Receptores de Hidrocarburo de Aril , Humanos , Sitios de Unión , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A1/antagonistas & inhibidores , Imidazoles/farmacología , Imidazoles/química , Ligandos , Simulación del Acoplamiento Molecular , Piperidinas/farmacología , Piperidinas/química , Unión Proteica , Piridazinas/farmacología , Piridazinas/química , Pirimidinas/farmacología , Pirimidinas/química , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/química , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , /farmacologíaRESUMEN
Nitrogen-containing steroids are known as prostate cancer therapeutics. In this work, a series of pregnane derivatives bearing an imidazolium moiety were synthesized using Δ16-20-ketones as starting material. An improved approach for the construction of the 20-keto-21-heterocycle-substituted fragment involved the rearrangement of 16,17-epoxides with HCl, followed by reaction of the formed α-chloroketone with 1-substituted imidazoles. Binding affinity analysis of the imidazolium steroids and their synthetic intermediates to human CYP17A1 showed only type I (substrate-like) interactions. The strongest affinity was observed for 16α,17α-epoxy-5α-pregnan-20-on-3ß-ol (Kd = 0.66 ± 0.05 µM). The steroid derivatives have been evaluated for antitumor activity against a range of prostate cancer cells as well as against various other solid tumor and hematologic cancer cell lines. All 21-imidazolium salts were active against the hormone-dependent prostate cancer line LNCaP. The most pronounced cytotoxicity in solid tumor and hematologic cancer cell lines was observed for intermediate product, 21-chloro-5α-pregn-16-en-20-on-3ß-ol. Among the imidazolium salts, the derivatives with a single bond were more cytotoxic than their unsaturated congeners.
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Antineoplásicos , Imidazoles , Humanos , Masculino , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Imidazoles/química , Imidazoles/farmacología , Imidazoles/síntesis química , Sales (Química)/química , Sales (Química)/farmacología , Sales (Química)/síntesis química , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Esteroide 17-alfa-Hidroxilasa/metabolismo , Esteroides/química , Esteroides/farmacología , Esteroides/síntesis química , Relación Estructura-Actividad , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacologíaRESUMEN
We introduce aqueous ionic liquid (IL) mixtures, specifically mixtures of 1-butyl-3-imidazoliumtetrafluoroborate (BMImBF4), with water as a minimal model of lipid bilayer membranes. Imidazolium-based ILs are known to form clustered nanoscale structures in which local inhomogeneities, micellar or lamellar structures, are formed to shield hydrophobic parts of the cation from the polar cosolvent (water). To investigate these nanostructures, dynamic light scattering (DLS) on samples with different mixing ratios of water and BMImBF4 was performed. At mixing ratios of 50% and 45% (v/v), small and homogeneous nanostructures can indeed be detected. To test whether, in particular, these stable nanostructures in aqueous mixtures may mimic the effects of phospholipid bilayer membranes, we further investigated their interaction with myelin basic protein (MBP), a peripheral, intrinsically disordered membrane protein of the myelin sheath. Using dynamic light scattering (DLS), continuous wave (CW) and pulse electron paramagnetic resonance (EPR), and small-angle X-ray scattering (SAXS) on recombinantly produced, "healthy" charge variants rmC1WT and double cysteine variant C1S17CH85C, we find that the size and the shape of the determined nanostructures in an optimum mixture offer model membranes in which the protein exhibits native behavior. SAXS measurements illuminate the size and shape of the nanostructures and indicate IL-rich "beads" clipped together by functional MBP, one of the in vivo roles of the protein in the myelin sheath. All the gathered data combined indicate that the 50% and 45% aqueous IL mixtures can be described as offering minimal models of a lipid mono- or bilayer that allow native processing and potential study of at least peripheral membrane proteins like MBP.
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Líquidos Iónicos , Membrana Dobles de Lípidos , Agua , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Líquidos Iónicos/química , Agua/química , Dispersión del Ángulo Pequeño , Imidazoles/química , Difracción de Rayos XRESUMEN
A class of chemical with a potentially important perceived future contribution to the net zero carbon goal (as "green" solvents) is the methylimidazolium ionic liquids (MILs). These solvents are used in industrial processes such as biofuel production yet little is known about their environmental stability or toxicity in man although one MIL - 1-octyl-3-methylimidazolium (M8OI) - has been shown to activate the human estrogen receptor alpha (ERα). The stabilities of the chloride unsubstituted methylimidazolium (MI) and MILs possessing increasing alkyl chain lengths (2C, 1-ethyl-3-methylimidazolium (EMI); 4C, 1-butyl-3-methylimidazolium (BMI); 6C; 1-hexyl-3-methylimidazolium (HMI), 8C, M8OI; 10C, 1-decyl-3-methylimidazolium (DMI)) were examined in river water and a human liver model system. The MILs were also screened for their abilities to activate the human ERα in vitro and induce uterine growth in pre-pubertal rats in vivo. Short chain MILs (EMI, BMI and HMI) underwent negligible metabolism and mineralisation in river water; were not metabolised in a model of human liver metabolism; activated the human ERα in vitro and were estrogenic in vivo in rats. A structure-based computational approach predicted short chain MIL binding to both the estrogen binding site and an additional site on the human estrogen receptor alpha. Longer chain MILs (M8OI and DMI) were metabolised in river water and partially mineralised. Based on structure-activity considerations, some of these environmentally-derived metabolites may however, remain a hazard to the population. MILs therefore have the potential to become forever chemicals with adverse effects to both man, other animals and the environment in general.
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Disruptores Endocrinos , Receptor alfa de Estrógeno , Imidazoles , Líquidos Iónicos , Líquidos Iónicos/toxicidad , Líquidos Iónicos/química , Imidazoles/toxicidad , Imidazoles/química , Disruptores Endocrinos/toxicidad , Disruptores Endocrinos/química , Humanos , Receptor alfa de Estrógeno/metabolismo , Animales , Ratas , FemeninoRESUMEN
Histidine and arginine are two amino acids that exhibit beneficial properties for gene delivery. In particular, the imidazole group of histidine facilitates endosomal release, while the guanidinium group of arginine promotes cellular entry. Consequently, a dual-charged copolymer library based on these amino acids was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The content of the N-acryloyl-l-histidine (His) monomer was systematically increased, while maintaining consistent levels of methyl N-acryloyl-l-argininate hydrochloride (ArgOMe) or N-(4-guanidinobutyl)acrylamide hydrochloride (GBAm). The resulting polymers formed stable, nanosized polyplexes when complexed with nucleic acids. Remarkably, candidates with increased His content exhibited reduced cytotoxicity profiles and enhanced transfection efficiency, particularly retaining this performance level at lower pDNA concentrations. Furthermore, endosomal release studies revealed that increased His content improved endosomal release, while ArgOMe improved cellular entry. These findings underscore the potential of customized dual-charged copolymers and the synergistic effects of His and ArgOMe/GBAm in enhancing gene delivery.