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Cationic polymers have great potential for cancer therapy due to their unique interactions with cancer cells. However, their clinical application remains limited by their high toxicity. Here we show a cell membrane-targeting cationic polymer with antineoplastic activity (Pmt) and a second near-infrared (NIR-II) fluorescent biodegradable polymer with photosensitizer Bodipy units and reactive oxygen species (ROS) responsive thioketal bonds (PBodipy). Subsequently, these two polymers can self-assemble into antineoplastic nanoparticles (denoted mt-NPBodipy) which could further accumulate at the tumor and destroy cell membranes through electrostatic interactions, resulting in cell membrane destabilization. Meanwhile, the photosensitizer Bodipy produces ROS to induce damage to cell membranes, proteins, and DNAs to kill cancer cells concertedly, finally resulting in cell membrane lysis and cancer cell death. This work highlights the use of near-infrared light to spatially and temporarily control cationic polymers for photodynamic therapy, photo-immunotherapy, and NIR-II fluorescence for bio-imaging.
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Membrana Celular , Imunoterapia , Raios Infravermelhos , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio , Humanos , Nanopartículas/química , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Imunoterapia/métodos , Animais , Espécies Reativas de Oxigênio/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Camundongos , Fotoquimioterapia/métodos , Linhagem Celular Tumoral , Compostos de Boro/química , Compostos de Boro/farmacologia , Neoplasias/terapia , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Polímeros/química , Antineoplásicos/farmacologia , Antineoplásicos/química , FemininoRESUMO
Dinuclear iridium(III) complexes activated by light-inducible spatiotemporal control are emerging as promising candidates for cancer therapy. However, broader applications of current light-activated dinuclear iridium(III) complexes are limited by the ineffective tissue penetration and undesirable feedback on guidance activation. Here, an ultrasound (US) triggered near infrared-fluorescent dinuclear iridium(III) nanoparticle, NanoIr, is first reported to precisely and spatiotemporally inhibit tumor growth. It is demonstrated that reactive oxygen species can be generated by NanoIr upon exposure to US irradiation (NanoIr + US), thereby inducing immunogenic cell death. When combined with cisplatin, NanoIr + US elicits synergistic effects in patient-derived tumor xenograft mice models of ovarian cancer. This work first provides a design of dinuclear iridium(III) nanoparticles for immunogenic sonodynamic therapy.
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The utilization of seawater for hydrogen production via water splitting is increasingly recognized as a promising avenue for the future. The key dilemma for seawater electrolysis is the incompatibility of superior hydrogen- and oxygen-evolving activities at ampere-scale current densities for both cathodic and anodic catalysts, thus leading to large electric power consumption of overall seawater splitting. Here, in situ construction of Fe4N/Co3N/MoO2 heterostructure arrays anchoring on metallic nickel nitride surface with multilevel collaborative catalytic interfaces and abundant multifunctional metal sites is reported, which serves as a robust bifunctional catalyst for alkaline freshwater/seawater splitting at ampere-level current density. Operando Raman and X-ray photoelectron spectroscopic studies combined with density functional theory calculations corroborate that Mo and Co/Fe sites situated on the Fe4N/Co3N/MoO2 multilevel interfaces optimize the reaction pathway and coordination environment to enhance water adsorption/dissociation, hydrogen adsorption, and oxygen-containing intermediate adsorption, thus cooperatively expediting hydrogen/oxygen evolution reactions in base. Inspiringly, this electrocatalyst can substantially ameliorate overall freshwater/seawater splitting at 1000 mA cm-2 with low cell voltages of 1.65/1.69 V, along with superb long-term stability at 500-1500 mA cm-2 for over 200 h, outperforming nearly all the ever-reported non-noble electrocatalysts for freshwater/seawater electrolysis. This work offers a viable approach to design high-performance bifunctional catalysts for seawater splitting.
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Celastrol (CEL), an active compound isolated from the root of Tripterygium wilfordii, exhibits broad anticancer activities. However, its poor stability, narrow therapeutic window and numerous adverse effects limit its applications in vivo. In this study, an adenosine triphosphate (ATP) activatable CEL-Fe(III) chelate was designed, synthesized, and then encapsulated with a reactive oxygen species (ROS)-responsive polymer to obtain CEL-Fe nanoparticles (CEL-Fe NPs). In normal tissues, CEL-Fe NPs maintain structural stability and exhibit reduced systemic toxicity, while at the tumor site, an ATP-ROS-rich tumor microenvironment, drug release is triggered by ROS, and antitumor potency is restored by competitive binding of ATP. This intelligent CEL delivery system improves the biosafety and bioavailability of CEL for cancer therapy. Such a CEL-metal chelate strategy not only mitigates the challenges associated with CEL but also opens avenues for the generation of CEL derivatives, thereby expanding the therapeutic potential of CEL in clinical settings.
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Trifosfato de Adenosina , Triterpenos Pentacíclicos , Pró-Fármacos , Espécies Reativas de Oxigênio , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Trifosfato de Adenosina/metabolismo , Humanos , Animais , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Linhagem Celular Tumoral , Triterpenos/química , Triterpenos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Quelantes/química , Quelantes/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente Tumoral/efeitos dos fármacos , Liberação Controlada de Fármacos , Nanopartículas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Compostos Férricos/químicaRESUMO
Adipose tissue, an indispensable organ, fulfils the pivotal role of energy storage and metabolism and is instrumental in maintaining the dynamic equilibrium of energy and health of the organism. Adipocyte hypertrophy and adipocyte hyperplasia (adipogenesis) are the two primary mechanisms of fat deposition. Mature adipocytes are obtained by differentiating mesenchymal stem cells into preadipocytes and redifferentiation. However, the mechanisms orchestrating adipogenesis remain unclear. Autophagy, an alternative cell death pathway that sustains intracellular energy homeostasis through the degradation of cellular components, is implicated in regulating adipogenesis. Furthermore, adipose tissue functions as an endocrine organ, producing various cytokines, and certain inflammatory factors, in turn, modulate autophagy and adipogenesis. Additionally, autophagy influences intracellular redox homeostasis by regulating reactive oxygen species, which play pivotal roles in adipogenesis. There is a growing interest in exploring the involvement of autophagy, inflammation, and oxidative stress in adipogenesis. The present manuscript reviews the impact of autophagy, oxidative stress, and inflammation on the regulation of adipogenesis and, for the first time, discusses their interactions during adipogenesis. An integrated analysis of the role of autophagy, inflammation and oxidative stress will contribute to elucidating the mechanisms of adipogenesis and expediting the exploration of molecular targets for treating obesity-related metabolic disorders.
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Adipogenia , Autofagia , Inflamação , Estresse Oxidativo , Adipogenia/fisiologia , Humanos , Autofagia/fisiologia , Estresse Oxidativo/fisiologia , Inflamação/metabolismo , Inflamação/patologia , Animais , Adipócitos/metabolismo , Adipócitos/patologia , Obesidade/metabolismo , Obesidade/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologiaRESUMO
Over the last decades, a variety of metal complexes have been developed as chemotherapeutic agents. Despite the promising therapeutic prospects, the vast majority of these compounds suffer from low solubility, poor pharmacological properties, and most importantly poor tumor accumulation. To circumvent these limitations, herein, the incorporation of cytotoxic Ir(III) complexes and a variety of photosensitizers into polymeric gemini nanoparticles that selectively accumulate in the tumorous tissue and could be activated by near-infrared (NIR) light to exert an anticancer effect is reported. Upon exposure to light, the photosensitizer is able to generate singlet oxygen, triggering the rapid dissociation of the nanostructure and the activation of the Ir prodrug, thereby initiating a cascade of mitochondrial targeting and damage that ultimately leads to cell apoptosis. While selectively accumulating into tumorous tissue, the nanoparticles achieve almost complete eradication of the cisplatin-resistant cervical carcinoma tumor in vivo upon exposure to NIR irradiation.
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Antineoplásicos , Compostos de Boro , Raios Infravermelhos , Irídio , Nanopartículas , Polímeros , Nanopartículas/química , Humanos , Animais , Compostos de Boro/química , Compostos de Boro/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Irídio/química , Polímeros/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Feminino , Camundongos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Fotoquimioterapia/métodos , Células HeLa , Camundongos NusRESUMO
Nanomaterials have attractive physicochemical properties. A variety of nanomaterials such as inorganic, lipid, polymers, and protein nanoparticles have been widely developed for nanomedicine via chemical conjugation or physical encapsulation of bioactive molecules. Superior to traditional drugs, nanomedicines offer high biocompatibility, good water solubility, long blood circulation times, and tumor-targeting properties. Capitalizing on this, several nanoformulations have already been clinically approved and many others are currently being studied in clinical trials. Despite their undoubtful success, the molecular mechanism of action of the vast majority of nanomedicines remains poorly understood. To tackle this limitation, herein, this review critically discusses the strategy of applying multiomics analysis to study the mechanism of action of nanomedicines, named nanomedomics, including advantages, applications, and future directions. A comprehensive understanding of the molecular mechanism could provide valuable insight and therefore foster the development and clinical translation of nanomedicines.
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Nanomedicina , Humanos , Animais , Nanoestruturas/química , GenômicaRESUMO
The integration of nanomedicine and immunotherapy has presented a promising opportunity for the treatment of cancer and diverse diseases. However, achieving spatiotemporal controllable immunotherapy with excellent efficacy and safety performances remains a significant challenge. This study develops a biodegradable near-infrared II (NIR-II) photothermal response polymer nanoparticle (PTEQ) system. This platform exhibits intrinsic immunostimulatory properties while concurrently delivering siRNA for Programmed Death-Ligand 1 (siPD-L1), leveraging enhanced immune responses and immune checkpoint blockade for safe and effective cancer therapy. In the CT26 tumor-bearing mouse model, PTEQ, as an immune stimulant, significantly boosts the infiltration of CD4+ and CD8+ T cells within the tumor microenvironment (TME). The PTEQ/siPD-L1+laser group not only initiates NIR-II photothermal therapy but also promotes the activation and infiltration of T cells, M1 macrophage polarization, and maturation of dendritic cells in the TME, resulting in the complete elimination of tumors in 7/10 cases, achieving a 100% survival rate. In another in vivo vaccine experiment, all tumors on the right side are completely eliminated in the PTEQ/siPD-L1+laser group, reaching a 100% tumor eradication rate. These findings underscore the potential of this strategy to overcome the current immunotherapeutic limitations and achieve immune therapy normalization.
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Imunoterapia , Raios Infravermelhos , Nanopartículas , Polímeros , Microambiente Tumoral , Animais , Camundongos , Nanopartículas/química , Microambiente Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Polímeros/química , Antígeno B7-H1/metabolismo , RNA Interferente Pequeno/química , Neoplasias/terapia , Neoplasias/imunologia , Terapia Fototérmica , Linfócitos T CD8-Positivos/imunologia , HumanosRESUMO
Recent years have witnessed substantial progress in cancer immunotherapy, specifically T cell-based therapies. However, the application of T cell therapies has been primarily limited to hematologic malignancies, with limited success in the treatment of solid tumors. The main challenge in treating solid tumor is immune escape, which is characterized by reduced antigenicity, diminished immunogenicity, and the development of suppressive tumor immune microenvironments. To address these obstacles and restore T cell-mediated anti-tumor responses, a novel nanoparticle formulation known as PRA@Oxa-c16 is developed. This innovative approach combines retinoic acid and Pt(IV) to specifically target and overcome immune escape. Notably, the therapeutic efficacy of PRA@Oxa-c16 primarily relies on its ability to induce anti-tumor T cell responses, in contrast to the cytotoxicity associated with conventional chemotherapeutic agents. When combined with an immune checkpoint blockade, anti-programmed death-ligand 1 antibody, PRA@Oxa-c16 effectively eliminates solid tumors and induces immune memory responses, which prevent tumor metastasis and recurrence. This promising approach holds great potential for enhancing the treatment of solid tumors with T cell-based immunotherapy.
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Antígeno B7-H1 , Linfócitos T CD8-Positivos , Imunoterapia , Nanomedicina , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Pró-Fármacos/farmacologia , Imunoterapia/métodos , Linfócitos T CD8-Positivos/imunologia , Animais , Nanomedicina/métodos , Camundongos , Linhagem Celular Tumoral , Antígeno B7-H1/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Nanopartículas/química , Neoplasias/terapia , Neoplasias/imunologia , Humanos , Platina/química , Tretinoína/química , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
Mild-heat photothermal antibacterial therapy avoids heat-induced damage to normal tissues but causes bacterial tolerance. The use of photothermal therapy in synergy with chemodynamic therapy is expected to address this issue. Herein, two pseudo-conjugated polymers PM123 with photothermal units and PFc with ferrocene (Fc) units are designed to co-assemble with DSPE-mPEG2000 into nanoparticle NPM123/Fc. NPM123/Fc under 1064 nm laser irradiation (NPM123/Fc+NIR-II) generates mild heat and additionally more toxic âOH from endogenous H2O2, displaying a strong synergistic photothermal and chemodynamic effect. NPM123/Fc+NIR-II gives >90% inhibition rates against MDR ESKAPE pathogens in vitro. Metabolomics analysis unveils that NPM123/Fc+NIR-II induces bacterial metabolic dysregulation including inhibited nucleic acid synthesis, disordered energy metabolism, enhanced oxidative stress, and elevated DNA damage. Further, NPM123/Fc+NIR-II possesses >90% bacteriostatic rates at infected wounds in mice, resulting in almost full recovery of infected wounds. Immunodetection and transcriptomics assays disclose that the therapeutic effect is mainly dependent on the inhibition of inflammatory reactions and the promotion of wound healing. What is more, thioketal bonds in NPM123/Fc are susceptible to ROS, making it degradable with highly favorable biosafety in vitro and in vivo. NPM123/Fc+NIR-II with a unique synergistic antibacterial strategy would be much less prone to select bacterial resistance and represent a promising antibiotics-alternative anti-infective measure.
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Antibacterianos , Modelos Animais de Doenças , Nanopartículas , Terapia Fototérmica , Polímeros , Infecção dos Ferimentos , Animais , Camundongos , Nanopartículas/química , Polímeros/química , Polímeros/farmacologia , Infecção dos Ferimentos/tratamento farmacológico , Antibacterianos/farmacologia , Terapia Fototérmica/métodosRESUMO
The key dilemma for green hydrogen production via electrocatalytic water splitting is the high overpotential required for anodic oxygen evolution reaction (OER). Co/Fe-based materials show superior catalytic OER activity to noble metal-based catalysts, but still lag far behind the state-of-the-art Ni/Fe-based catalysts probably due to undesirable side segregation of FeOOH with poor conductivity and unsatisfied structural durability under large current density. Here, a robust and durable OER catalyst affording current densities of 500 and 1000 mA cm-2 at extremely low overpotentials of 290 and 304 mV in base is reported. This catalyst evolves from amorphous bimetallic FeOOH/Co(OH)2 heterostructure microsheet arrays fabricated by a facile mechanical stirring strategy. Especially, in situ X-ray photoelectron spectroscopy (XPS) and Raman analysis decipher the rapid reconstruction of FeOOH/Co(OH)2 into dynamically stable Co1-x Fex OOH active phase through in situ iron incorporation into CoOOH, which perform as the real active sites accelerating the rate-determining step supported by density functional theory calculations. By coupling with MoNi4 /MoO2 cathode, the self-assembled alkaline electrolyzer can deliver 500 mA cm-2 at a low cell voltage of 1.613 V, better than commercial IrO2 (+) ||Pt/C(-) and most of reported transition metal-based electrolyzers. This work provides a feasible strategy for the exploration and design of industrial water-splitting catalysts for large-scale green hydrogen production.
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Photodynamic therapy (PDT), as a new type of light-mediated reactive oxygen species (ROS) cancer therapy, has the advantages of high therapeutic efficiency, non-resistance, and less trauma than traditional cancer therapy such as surgery, radiotherapy, and chemotherapy. However, oxygen-dependent PDT further exacerbates tumor metastasis. To this end, a strategy that circumvents tumor metastasis to improve the therapeutic efficacy of PDT is proposed. Herein, a near-infrared light-activated photosensitive polymer is synthesized and branched the anti-metastatic ruthenium complex NAMI-A on the side, which is further assembled to form nanoparticles (NP2) for breast cancer therapy. NP2 can kill tumor cells by generating ROS under 808 nm radiation (NP2 + L), reduce the expression of matrix metalloproteinases (MMP2/9) in cancer cells, decrease the invasive and migration capacity of cancer cells, and eliminate cancer cells. Further animal experiments show that NP2 + L can inhibit tumor growth and reduce liver and lung metastases. In addition, NP2 + L can activate the immune system in mice to avoid tumor recurrence. In conclusion, a PDT capable of both preventing tumor metastasis and precisely hitting the primary tumor to achieve effective treatment of highly metastatic cancers is developed.
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Dimetil Sulfóxido/análogos & derivados , Nanopartículas , Compostos Organometálicos , Fotoquimioterapia , Compostos de Rutênio , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Nanopartículas/uso terapêutico , Polímeros , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Nitric oxide (NO) enhanced photodynamic therapy (PDT) is a promising approach to overcome drug tolerance and resistance to biofilm but is limited by its short excitation wavelengths and low yield of reactive oxygen species (ROS). Herein, we develop a compelling degradable polymer-based near-infrared II (NIR-II, 1000-1700 nm) photosensitizer (PNIR-II), which can maintain 50 % PDT efficacy even under a 2.6 cm tissue barrier. Remarkably, PNIR-II is synthesized by alternately connecting the electron donor thiophene to the electron acceptors diketopyrrolopyrrole (DPP) and boron dipyrromethene (BODIPY), where the intramolecular charge transfer properties can be tuned to increase the intersystem crossover rate and decrease the internal conversion rate, thereby stabilizing the NIR-II photodynamic rather than photothermal effect. For exerting a combination therapy to eradicate multidrug-resistant biofilms, PNIR-II is further assembled into nanoparticles (NPs) with a synthetic glutathione-triggered NO donor polymer. Under 1064 nm laser radiation, NPs precisely release ROS and NO that triggered by over-expressed GSH in the biofilm microenvironment, thereby forming more bactericidal reactive nitrogen species (RNS) in vitro and in vivo in the mice model that orderly destroy biofilm of multidrug-resistant Staphylococcus aureus cultures from clinical patients. It thus provides a new outlook for destroy the biofilm of deep tissues.
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Photodynamic therapy (PDT) has been widely employed in tumor treatment due to its effectiveness. However, the tumor hypoxic microenvironment which is caused by abnormal vasculature severely limits the efficacy of PDT. Furthermore, the abnormal vasculature has been implicated in the failure of immunotherapy. In this study, a novel nanoparticle denoted as Combo-NP is introduced, composed of a biodegradable NIR II fluorescent pseudo-conjugate polymer featuring disulfide bonds within its main chain, designated as TPA-BD, and the vascular inhibitor Lenvatinib. Combo-NP exhibits dual functionality by not only inducing cytotoxic reactive oxygen species (ROS) to directly eliminate tumor cells but also eliciting immunogenic cell death (ICD). This ICD response, in turn, initiates a robust cascade of immune reactions, thereby augmenting the generation of cytotoxic T lymphocytes (CTLs). In addition, Combo-NP addresses the issue of tumor hypoxia by normalizing the tumor vasculature. This normalization process enhances the efficacy of PDT while concurrently fostering increased CTLs infiltration within the tumor microenvironment. These synergistic effects synergize to potentiate the photodynamic-immunotherapeutic properties of the nanoparticles. Furthermore, when combined with anti-programmed death-ligand 1 (PD-L1), they showcase notable inhibitory effects on tumor metastasis. The findings in this study introduce an innovative nanomedicine strategy aimed at triggering systemic anti-tumor immune responses for the treatment of Uveal melanoma.
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Nanopartículas , Fotoquimioterapia , Inibidores de Checkpoint Imunológico , Linhagem Celular Tumoral , Polímeros/química , Imunoterapia , Nanopartículas/químicaRESUMO
Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss. Emerging evidence suggests that autophagy plays an important role in the pathogenesis of AD through the regulation of amyloid-beta (Aß) and tau metabolism, and that autophagy dysfunction exacerbates amyloidosis and tau pathology. Therefore, targeting autophagy may be an effective approach for the treatment of AD. Animal models are considered useful tools for investigating the pathogenic mechanisms and therapeutic strategies of diseases. This review aims to summarize the pathological alterations in autophagy in representative AD animal models and to present recent studies on newly discovered autophagy-stimulating interventions in animal AD models. Finally, the opportunities, difficulties, and future directions of autophagy targeting in AD therapy are discussed.
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Doença de Alzheimer , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/veterinária , Peptídeos beta-Amiloides , Autofagia/fisiologia , Modelos AnimaisRESUMO
Traditional pig breeding has a long cycle and high cost, and there is an urgent need to use new technologies to revitalize the pig breeding industry. The recently emerged CRISPR/Cas9 genome editing technique shows great potential in pig genetic improvement, and has since become a research hotspot. Base editor is a new base editing technology developed based on the CRISPR/Cas9 system, which can achieve targeted mutation of a single base. CRISPR/Cas9 technology is easy to operate and simple to design, but it can lead to DNA double strand breaks, unstable gene structures, and random insertion and deletion of genes, which greatly restricts the application of this technique. Different from CRISPR/Cas9 technique, the single base editing technique does not produce double strand breaks. Therefore, it has higher accuracy and safety for genome editing, and is expected to advance the pig genetic breeding applications. This review summarized the working principle and shortcomings of CRISPR/Cas9 technique, the development and advantages of single base editing, the principles and application characteristics of different base editors and their applications in pig genetic improvement, with the aim to facilitate genome editing-assisted genetic breeding of pig.
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Sistemas CRISPR-Cas , Edição de Genes , Animais , Suínos/genética , Sistemas CRISPR-Cas/genética , Quebras de DNA de Cadeia DuplaRESUMO
BACKGROUND: NK cells play an important role in immune response, immune surveillance, and metabolism regulation. Therefore, NK cells are involved in the occurrence and development of various diseases, such as infectious diseases, cancer, obesity, and diabetes. IL-25 is a special member of the IL-17 family with anti-inflammatory function. IL-25 can regulate inflammatory response and metabolism via various immune cells; however, the role and regulatory mechanism of IL-25 in NK cells are still unclear. METHOD: In this study, we investigate the role of IL-25 in NK-cell protein profile via 4D label-free mass spectrum and validate the differential proteins via PRM analysis. In addition, GO analysis, KEGG analysis, and other bioinformatic analysis methods are used to explore the enriched function and signal pathway of differentially expressed proteins. RESULT AND DISCUSSION: The GO and KEGG analyses suggest that IL-25 may affect the processes, such as metabolism, thermogenesis, and oxidative phosphorylation of NK cells. There are 7 down-regulated proteins (NCR1, GZMB, PRF1, KLRC1, NDUFA11, LAMTOR5, and IKBIP) and 1 up-regulated protein (PSMD7) in IL-25-treated NK cells versus the control group for PRM validation. Our results indicate that IL-25 may regulate metabolism and other biological processes via NK cells, which will be beneficial in revealing the role and regulatory mechanisms of IL-25 in NK cells in various diseases. CONCLUSION: Proteomics combined with bioinformatic analysis will help to mine more information hidden behind mass spectrometry data and lay the foundation for finding clinical biomarkers and mechanisms of diseases.
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Interleucina-17 , Proteômica , Interleucina-17/metabolismo , Células Matadoras Naturais/metabolismo , Espectrometria de Massas , Proteínas/metabolismo , Proteômica/métodos , HumanosRESUMO
Photodynamic therapy (PDT) and photothermal therapy (PTT) leverage reactive oxygen species (ROS) and control local hyperthermia by photosensitizer to perturb intracellular redox equilibrium, inducing DNA damage in both mitochondria and nucleus, activating the cGAS-STING pathway, ultimately eliciting antitumor immune responses. However, current photosensitizers are encumbered by limitations such as suboptimal tumor targeting, aggregation-caused quenching (ACQ), and restricted excitation and emission wavelengths. Here, this work designs novel nanoparticles based on aggregation-induced emission (AIE) photosensitizer (BODTPE) for targeted tumor therapy and near-infrared II fluorescence imaging (NIR-II FLI) with enhanced PDT/PTT effects. BODTPE is employed as a monomer, dibenzocyclooctyne (DBCO)-PEG2k -amine serving as an end-capping polymer, to synthesize a BODTPE-containing polymer (DBD). Further, through self-assembly, DBD and mPEG-DSPE2k combined to form nanoparticles (NP-DBD). Notably, the DBCO on the surface of NP-DBD can react with azide groups on cancer cells pretreated with Ac4 ManNAz through a copper-free click reaction. This innovative formulation led to targeted accumulation of NP-DBD within tumor sites, a phenomenon convincingly demonstrated in murine tumor models subjected to N-azidoacetylmannosamine-tetraacylated (Ac4 ManNAz) pretreatment. Significantly, NP-DBD exhibits a multifaceted effect encompassing PDT/PTT/NIR-II FLI upon 808 nm laser irradiation, thereby better activating the cGAS-STING pathway, culminating in a compelling tumor inhibition effect augmented by robust immune modulation.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Animais , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Polímeros , Linhagem Celular TumoralRESUMO
Tumor metastases are considered the leading cause of cancer-associated deaths. While clinically applied drugs have demonstrated to efficiently remove the primary tumor, metastases remain poorly accessible. To overcome this limitation, herein, the development of a theranostic nanomaterial by incorporating a chromophore for imaging and a photosensitizer for treatment of metastatic tumor sites is presented. The mechanism of action reveals that the nanoparticles are able to intervene by local generation of cellular damage through photodynamic therapy as well as by systemic induction of an immune response by immunotherapy upon inhibition of the mTOR signaling pathway which is of crucial importance for tumor onset, progression and metastatic spreading. The nanomaterial is able to strongly reduce the volume of the primary tumor as well as eradicates tumor metastases in a metastatic breast cancer and a multi-drug resistant patient-derived hepatocellular carcinoma models in female mice.
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Neoplasias Hepáticas , Fotoquimioterapia , Feminino , Animais , Camundongos , Medicina de Precisão , Transdução de Sinais , Serina-Treonina Quinases TOR , ImunoterapiaRESUMO
Low-voltage Zn-doped CuI thin film transistors (TFTs) gated by chitosan dielectric were fabricated at a low temperature. The Zn-doped CuI TFT exhibited a more superior on/off current ratio than CuI TFT due to the substitution or supplementation of copper vacancies by Zn ions. The Zn-doped CuI films were characterized by scanning electron microscope, X-ray diffraction, and X-ray photoelectron spectroscopy. The Zn-doped CuI TFTs exhibited an on/off current ratio of 1.58 × 104, a subthreshold swing of 70 mV/decade, and a field effect mobility of 0.40 cm2V-1s-1, demonstrating good operational stability. Due to the electric-double-layer (EDL) effect and high specific capacitance (17.3 µF/cm2) of chitosan gate dielectric, Zn-doped CuI TFT operates at a voltage below -2 V. The threshold voltage is -0.2 V. In particular, we have prepared Zn-doped CuI TFTs with two in-plane gates and NOR logic operation is implemented on such TFTs. In addition, using the ion relaxation effect and EDL effect of chitosan film, a simple pain neuron simulation is realized on such a p-type TFTs for the first time through the bottom gate to regulate the carrier transport of the channel. This p-type device has promising applications in low-cost electronic devices, complementary electronic circuit, and biosensors.