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1.
Artigo em Inglês | MEDLINE | ID: mdl-39460726

RESUMO

Cisplatin, a frontline chemotherapeutic agent against cancer, faces challenges in clinical application due to significant toxicities and suboptimal efficacy. Renal toxicity, a dose-limiting factor of cisplatin, results from multifactorial processes including cisplatin-induced cellular pyroptosis, oxidative damage, and inflammatory responses. Our findings reveal that Tea Polyphenols Nanoparticles (TPNs) derived from Epigallocatechin gallate (EGCG) effectively could address these diverse mechanisms, comprehensively alleviating cisplatin-induced nephrotoxicity. Leveraging TPNs as carriers, chemical conjugation enables the encapsulation of tetravalent cisplatin prodrug, extending its systemic half-life, enhancing tumor tissue accumulation, while simultaneously mitigating renal toxicity. Concurrently, employing a CRISPR/Cas9 kinase library, we identified CSNK2A1 as a target sensitizing tumor cells to cisplatin, enabling specific siRNA sequences to augment cisplatin susceptibility, thereby minimizing the dosage requirement. Benefiting from the versatile carrier properties of TPNs to codeliver cisplatin prodrug and anti-CSNK2A1 siRNA, we developed a codelivery system, Pt-TPNs/siRNA. Pt-TPNs/siRNA not only enhances the anticancer effects but also mitigates cisplatin-induced renal toxicity, achieving efficacy while reducing toxicity. Mechanistic and safety assessments of these nanoparticles were conducted at both cellular and animal levels, opening new avenues for improved clinical utilization of cisplatin.

2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 40(10): 887-893, 2024 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-39442987

RESUMO

Objective To explore the impact of M2 macrophages on the malignant biological behavior of esophageal cancer by inhibiting the anti-tumor ability of CD8+ T cells. Methods Using phorbol myristate acetate (PMA) combined with interleukin 4 (IL-4)/IL-13, we induced human monocytic leukemia cells (THP-1) to become M2 macrophages and the detected related inflammatory factors by real-time quantitative PCR. We used magnetic bead sorting to isolate CD8+ T cells from healthy volunteers' peripheral blood, and verified the purity of the sorted cells by flow cytometry. We established a non-contact co-culture system between CD8+ T cells and esophageal squamous carcinoma cells (CD8+ T cell), and established a non-contact co-culture system between M2 macrophages, CD8+ T cells, and esophageal squamous carcinoma cells (M2 macrophages combined with CD8+ T cell). The plate clone formation assay and CCK-8 cell toxicity assay were used to detect the proliferation ability of tumor cells in each group. The TranswellTM assay was used to detect the invasive and migratory abilities of tumor cells in each group. Flow cytometry was used to detect and analyze the apoptosis of tumor cells in each group. GraphPadPrism9.5 software was used for statistical analysis and graphing. Results After induction, the expression of IL-10 and arginase 1 (Arg1) in macrophages was upregulated, while the expression of IL-12 and tumor necrosis factor-alpha (TNF-α) was downregulated, showing the characteristics of M2 macrophages. Peripheral blood CD8+ T cells were successfully selected by magnetic bead sorting, with a positive rate of over 90%. The proliferation, invasion, migration and anti-apoptosis ability of esophageal squamous carcinoma cells co-cultured with CD8+ T cells in the non-contact manner were significantly lower than those of the single cancer cell group; while the proliferation, invasion, migration and the anti-apoptosis ability of esophageal squamous carcinoma cells co-cultured with CD8+ T cells pretreated with M2 macrophage conditioned medium were significantly enhanced compared with those of esophageal squamous carcinoma and CD8+ T cells co-cultured group. Conclusion M2 macrophages promote the proliferation, invasion, migration, and anti-apoptosis of esophageal cancer cells by inhibiting the anti-tumor ability of CD8+ T cells.


Assuntos
Linfócitos T CD8-Positivos , Técnicas de Cocultura , Neoplasias Esofágicas , Macrófagos , Humanos , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/genética , Linfócitos T CD8-Positivos/imunologia , Macrófagos/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Movimento Celular , Carcinoma de Células Escamosas do Esôfago/imunologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Células THP-1 , Arginase/genética , Arginase/metabolismo
3.
Mikrochim Acta ; 191(10): 584, 2024 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-39245760

RESUMO

Innovative chiral capillary silica monoliths (CSMs) were developed based on DNA nanoflowers (DNFs). Baseline separation of enantiomers such as atenolol, tyrosine, histidine, and nefopam was achieved by using DNF-modified CSMs, and the obtained resolution value was higher than 1.78. To further explore the effect of DNFs on enantioseparation, different types of chiral columns including DNA strand containing the complementary sequence of the template (DCT)-modified CSMs, DNF2-modified CSMs, and DNF3-modified CSMs were prepared as well. It was observed that DNF-modified CSMs displayed better chiral separation ability compared with DCT-based columns. The intra-day and inter-day repeatability of model analytes' retention time and resolution kept desirable relative standard deviation values of less than 8.28%. DNF2/DNF3-modified CSMs were able to achieve baseline separation of atenolol, propranolol, 2'-deoxyadenosine, and nefopam enantiomers. Molecular docking simulations were performed to investigate enantioselectivity mechanisms of DNA sequences for enantiomers. To indicate the successful construction of DNFs and DNF-modified CSMs, various charaterization approaches including scanning electron microscopy, agarose gel electrophoresis, dynamic light scattering analysis, electroosmotic flow, and Fourier-transform infrared spectroscopy were utilized. Moreover, the enantioseparation performance of DNF-modified CSMs was characterized in terms of sample volume, applied voltage, and buffer concentration. This work paves the way to applying DNF-based capillary electrochromatography microsystems for chiral separation.


Assuntos
DNA , Dióxido de Silício , Dióxido de Silício/química , DNA/química , DNA/isolamento & purificação , Estereoisomerismo , Simulação de Acoplamento Molecular , Atenolol/química , Atenolol/isolamento & purificação , Nanoestruturas/química , Propranolol/química , Propranolol/isolamento & purificação
4.
J Nanobiotechnology ; 22(1): 471, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39118143

RESUMO

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease, while there is a lack of pharmaceutical interventions to halt AAA progression presently. To address the multifaceted pathology of AAA, this work develops a novel multifunctional gene delivery system to simultaneously deliver two siRNAs targeting MMP-2 and MMP-9. The system (TPNs-siRNA), formed through the oxidative polymerization and self-assembly of epigallocatechin gallate (EGCG), efficiently encapsulates siRNAs during self-assembly. TPNs-siRNA safeguards siRNAs from biological degradation, facilitates intracellular siRNA transfection, promotes lysosomal escape, and releases siRNAs to silence MMP-2 and MMP-9. Additionally, TPNs, serving as a multi-bioactive material, mitigates oxidative stress and inflammation, fosters M1-to-M2 repolarization of macrophages, and inhibits cell calcification and apoptosis. In experiments with AAA mice, TPNs-siRNA accumulated and persisted in aneurysmal tissue after intravenous delivery, demonstrating that TPNs-siRNA can be significantly distributed in macrophages and VSMCs relevant to AAA pathogenesis. Leveraging the carrier's intrinsic multi-bioactive properties, the targeted siRNA delivery by TPNs exhibits a synergistic effect for enhanced AAA therapy. Furthermore, TPNs-siRNA is gradually metabolized and excreted from the body, resulting in excellent biocompatibility. Consequently, TPNs emerges as a promising multi-bioactive nanotherapy and a targeted delivery nanocarrier for effective AAA therapy.


Assuntos
Aneurisma da Aorta Abdominal , Metaloproteinase 9 da Matriz , Camundongos Endogâmicos C57BL , Nanopartículas , RNA Interferente Pequeno , Aneurisma da Aorta Abdominal/tratamento farmacológico , Animais , Camundongos , Nanopartículas/química , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Polifenóis/química , Polifenóis/farmacologia , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Chá/química , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Humanos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Técnicas de Transferência de Genes , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Apoptose/efeitos dos fármacos
5.
Small ; : e2401056, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39115137

RESUMO

One-lung ventilation (OLV) during thoracic surgery often leads to post-operative complications, yet effective pharmacological interventions are lacking. This study reports a baicalin-based metal-coordination nanomedicine with disulfiram (DSF) co-loading to address one-lung ventilation-induced lung injury and reperfusion injury (OLV-LIRI). Baicalin, known for its robust antioxidant properties, suffers from poor water solubility and stability. Leveraging nanotechnology, baicalin's coordination is systematically explored with seven common metal ions, designing iron/copper-mediated binary coordination nanoparticles to overcome these limitations. The self-assembled nanoparticles, primarily formed through metal coordination and π-π stacking forces, encapsulated DSF, ensuring high colloidal stability in diverse physiological matrices. Upon a single-dose administration via endotracheal intubation, the nanoparticles efficiently accumulate in lung tissues and swiftly penetrate the pulmonary mucosa. Intracellularly, baicalin exhibits free radical scavenging activity to suppress inflammation. Concurrently, the release of Cu2+ and DSF enables the in situ generation of CuET, a potent inhibitor of cell pyroptosis. Harnessing these multifaceted mechanisms, the nanoparticles alleviate lung injury symptoms without notable toxic side effects, suggesting a promising preventive strategy for OLV-LIRI.

6.
Dig Liver Dis ; 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39181823

RESUMO

BACKGROUND: The prognostic value and clinical relevance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) in esophageal squamous cell carcinoma (ESCC) remain unclear. AIMS: To investigate the prognostic value and functional involvement of TILs in ESCC. METHODS: We included 40 patients across different stages of ESCC from Xinjiang. Multiplex fluorescent immunohistochemistry characterized TILs and TAMs. TILs in different tumor regions were quantified and correlated with overall survival (OS) using log-rank test and Cox regression analyses. RESULTS: Invasive ESCC exhibited increased CD4 T cells and Tregs compared to carcinoma in situ, with a higher Tregs/CD4 T cells ratio (p < 0.05). TAMs, primarily in stromal regions, were significantly associated with Foxp3+ cells (p < 0.05). Higher infiltration of stromal TAMs and a higher CD4/CD8 T cells ratio correlated with poorer OS, while a higher CD8 T/Foxp3+ cells ratio indicated better survival. Multivariate Cox analysis revealed TNM stage, tumor length, and stromal CD4/CD8 T cells ratio as independent prognostic factors (p < 0.05). An immune prognostic risk score-based nomogram was constructed to predict patient outcomes. CONCLUSIONS: The spatial distribution and abundance of TILs significantly correlated with prognosis, providing a useful immune classification for ESCC.

7.
Mater Today Bio ; 27: 101132, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38994471

RESUMO

Pancreatic cancer is an aggressive and challenging malignancy with limited treatment options, largely attributed to the dense tumor stroma and intrinsic drug resistance. Here, we introduce a novel iron-containing nanoparticle formulation termed PTFE, loaded with the ferroptosis inducer Erastin, to overcome these obstacles and enhance pancreatic cancer therapy. The PTFE nanoparticles were prepared through a one-step assembly process, consisting of an Erastin-loaded PLGA core stabilized by a MOF shell formed by coordination between Fe3+ and tannic acid. PTFE demonstrated a unique capability to repolarize tumor-associated macrophages (TAMs) into the M1 phenotype, leading to the regulation of dense tumor stroma by modulating the activation of tumor-associated fibroblasts (TAFs) and reducing collagen deposition. This resulted in enhanced nanoparticle accumulation and deep penetration, as confirmed by in vitro multicellular tumor spheroids and in vivo mesenchymal-rich subcutaneous pancreatic tumor models. Moreover, PTFE effectively combated tumor resistance by synergistically employing the Fe3+-induced Fenton reaction and Erastin-induced ferroptosis, thereby disrupting the redox balance. As a result, significant tumor growth inhibition was achieved in mice-bearing tumor model. Comprehensive safety evaluations demonstrated PTFE's favorable biocompatibility, highlighting its potential as a promising therapeutic platform to effectively address the formidable challenges in pancreatic cancer treatment.

8.
Mater Horiz ; 11(17): 3975-3995, 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-38957038

RESUMO

Establishing an intimate relationship between similar individuals is the beginning of self-extension. Various self-similar chiral nanomaterials can be designed using an individual-to-family approach, accomplishing self-extension. This self-similarity facilitates chiral communication, transmission, and amplification of synthons. We focus on describing the marriage of discrete cages to develop self-similar extended frameworks. The advantages of utilizing cage-based frameworks for chiral recognition, enantioseparation, chiral catalysis and sensing are highlighted. To further promote self-extension, fractal chiral nanomaterials with self-similar and iterated architectures have attracted tremendous attention. The beauty of a fractal family tree lies in its ability to capture the complexity and interconnectedness of a family's lineage. As a type of fractal material, nanoflowers possess an overarching importance in chiral amplification due to their large surface-to-volume ratio. This review summarizes the design and application of state-of-the-art self-similar chiral nanomaterials including cage-based extended frameworks, fractal nanomaterials, and nanoflowers. We hope this formation process from individuals to families will inherit and broaden this great chirality.

9.
Mol Pharm ; 21(8): 3764-3776, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39049481

RESUMO

Pancreatic cancer remains a formidable challenge in oncology due to its aggressive nature and limited treatment options. The dense stroma surrounding pancreatic tumors not only provides structural support but also presents a formidable barrier to effective therapy, hindering drug penetration and immune cell infiltration. This review delves into the intricate interplay between stromal components and cancer cells, highlighting their impact on treatment resistance and prognosis. Strategies for stromal remodeling, including modulation of cancer-associated fibroblasts (CAFs), pancreatic stellate cells (PSCs) activation states, and targeting extracellular matrix (ECM) components, are examined for their potential to enhance drug penetration and improve therapeutic efficacy. Integration of stromal remodeling with conventional therapies, such as chemotherapy and immunotherapy, is discussed along with the emerging field of intelligent nanosystems for targeted drug delivery. This comprehensive overview underscores the importance of stromal remodeling in pancreatic cancer treatment and offers insights into promising avenues for future research and clinical translation.


Assuntos
Fibroblastos Associados a Câncer , Sistemas de Liberação de Medicamentos , Neoplasias Pancreáticas , Células Estreladas do Pâncreas , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/efeitos dos fármacos , Células Estreladas do Pâncreas/efeitos dos fármacos , Células Estreladas do Pâncreas/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Matriz Extracelular/metabolismo , Imunoterapia/métodos
10.
J Nanobiotechnology ; 22(1): 443, 2024 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-39068474

RESUMO

Engineered Salmonella has emerged as a promising microbial immunotherapy against tumors; however, its clinical effectiveness has encountered limitations. In our investigation, we unveil a non-dose-dependent type of behavior regarding Salmonella's therapeutic impact and reveal the regulatory role of neutrophils in diminishing the efficacy of this. While Salmonella colonization within tumors recruits a substantial neutrophil population, these neutrophils predominantly polarize into the pro-tumor N2 phenotype, elevating PD-L1 expression and fostering an immunosuppressive milieu within the tumor microenvironment. In order to bypass this challenge, we introduce MnO2 nanoparticles engineered to activate the STING pathway. Harnessing the STING pathway to stimulate IFN-ß secretion prompts a shift in neutrophil polarization from the N2 to the N1 phenotype. This strategic repolarization remodels the tumor immune microenvironment, making the infiltration and activation of CD8+ T cells possible. Through these orchestrated mechanisms, the combined employment of Salmonella and MnO2 attains the synergistic enhancement of anti-tumor efficacy, achieving the complete inhibition of tumor growth within 20 days and an impressive 80% survival rate within 40 days, with no discernible signs of significant adverse effects. Our study not only unveils the crucial in vivo constraints obstructing microbial immune therapy but also sets out an innovative strategy to augment its efficacy. These findings pave the way for advancements in cell-based immunotherapy centered on leveraging the potential of neutrophils.


Assuntos
Imunoterapia , Compostos de Manganês , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Nanopartículas , Neutrófilos , Óxidos , Salmonella , Microambiente Tumoral , Compostos de Manganês/química , Animais , Neutrófilos/imunologia , Neutrófilos/metabolismo , Imunoterapia/métodos , Camundongos , Proteínas de Membrana/metabolismo , Salmonella/imunologia , Nanopartículas/química , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Feminino , Neoplasias/terapia , Neoplasias/imunologia , Transdução de Sinais , Humanos
11.
Acta Pharm Sin B ; 14(6): 2698-2715, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38828135

RESUMO

Drug repurposing offers a valuable strategy for identifying new therapeutic applications for existing drugs. Recently, disulfiram (DSF), a drug primarily used for alcohol addiction treatment, has emerged as a potential treatment for inflammatory diseases by inhibiting pyroptosis, a form of programmed cell death. The therapeutic activity of DSF can be further enhanced by the presence of Cu2+, although the underlying mechanism of this enhancement remains unclear. In this study, we investigated the mechanistic basis of Cu2+-induced enhancement and discovered that it is attributed to the formation of a novel copper ethylthiocarbamate (CuET) complex. CuET exhibited significantly stronger anti-pyroptotic activity compared to DSF and employed a distinct mechanism of action. However, despite its potent activity, CuET suffered from poor solubility and limited permeability, as revealed by our druggability studies. To overcome these intrinsic limitations, we developed a scalable method to prepare CuET nanocrystals (CuET NCs) using a metal coordination-driven self-assembly approach. Pharmacokinetic studies demonstrated that CuET NCs exhibited a 6-fold improvement in bioavailability. Notably, CuET NCs exhibited high biodistribution in the intestine, suggesting their potential application for the treatment of inflammatory bowel diseases (IBDs). To evaluate their therapeutic efficacy in vivo, we employed a murine model of DSS-induced colitis and observed that CuET NCs effectively attenuated inflammation and ameliorated colitis symptoms. Our findings highlight the discovery of CuET as a potent anti-pyroptotic agent, and the development of CuET NCs represents a novel approach to enhance the druggability of CuET.

12.
Int J Nanomedicine ; 19: 5837-5858, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38887692

RESUMO

Purpose: Phototherapy, known for its high selectivity, few side effects, strong controllability, and synergistic enhancement of combined treatments, is widely used in treating diseases like cervical cancer. Methods: In this study, hollow mesoporous manganese dioxide was used as a carrier to construct positively charged, poly(allylamine hydrochloride)-modified nanoparticles (NPs). The NP was efficiently loaded with the photosensitizer indocyanine green (ICG) via the addition of hydrogen phosphate ions to produce a counterion aggregation effect. HeLa cell membrane encapsulation was performed to achieve the final M-HMnO2@ICG NP. In this structure, the HMnO2 carrier responsively degrades to release ICG in the tumor microenvironment, self-generates O2 for sensitization to ICG-mediated photodynamic therapy (PDT), and consumes GSH to expand the oxidative stress therapeutic effect [chemodynamic therapy (CDT) + PDT]. The ICG accumulated in tumor tissues exerts a synergistic PDT/photothermal therapy (PTT) effect through single laser irradiation, improving efficiency and reducing side effects. The cell membrane encapsulation increases nanomedicine accumulation in tumor tissues and confers an immune evasion ability. In addition, high local temperatures induced by PTT can enhance CDT. These properties of the NP enable full achievement of PTT/PDT/CDT and targeted effects. Results: Mn2+ can serve as a magnetic resonance imaging agent to guide therapy, and ICG can be used for photothermal and fluorescence imaging. After its intravenous injection, M-HMnO2@ICG accumulated effectively at mouse tumor sites; the optimal timing of in-vivo laser treatment could be verified by near-infrared fluorescence, magnetic resonance, and photothermal imaging. The M-HMnO2@ICG NPs had the best antitumor effects among treatment groups under near-infrared light conditions, and showed good biocompatibility. Conclusion: In this study, we designed a nano-biomimetic delivery system that improves hypoxia, responds to the tumor microenvironment, and efficiently loads ICG. It provides a new economical and convenient strategy for synergistic phototherapy and CDT for cervical cancer.


Assuntos
Verde de Indocianina , Compostos de Manganês , Imagem Multimodal , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Microambiente Tumoral , Neoplasias do Colo do Útero , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/tratamento farmacológico , Feminino , Microambiente Tumoral/efeitos dos fármacos , Humanos , Verde de Indocianina/química , Verde de Indocianina/farmacologia , Fotoquimioterapia/métodos , Animais , Células HeLa , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Nanopartículas/química , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Camundongos , Imagem Multimodal/métodos , Terapia Fototérmica/métodos , Óxidos/química , Óxidos/farmacologia , Camundongos Endogâmicos BALB C , Poliaminas/química , Poliaminas/farmacologia , Imageamento por Ressonância Magnética/métodos
13.
Asian J Pharm Sci ; 19(3): 100924, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38903130

RESUMO

Polyamine metabolism dysregulation is a hallmark of many cancers, offering a promising avenue for early tumor theranostics. This study presents the development of a nuclear probe derived from spermidine (SPM) for dual-purpose tumor PET imaging and internal radiation therapy. The probe, radiolabeled with either [68Ga]Ga for diagnostic applications or [177Lu]Lu for therapeutic use, was synthesized with exceptional purity, stability, and specific activity. Extensive testing involving 12 different tumor cell lines revealed remarkable specificity towards B16 melanoma cells, showcasing outstanding tumor localization and target-to-non-target ratio. Mechanistic investigations employing polyamines, non-labeled precursor, and polyamine transport system (PTS) inhibitor, consistently affirmed the probe's targetability through recognition of the PTS. Notably, while previous reports indicated PTS upregulation in various tumor types for targeted therapy, this study observed no positive signals, highlighting a concentration-dependent discrepancy between targeting for therapy and diagnosis. Furthermore, when labeled with [177Lu], the probe demonstrated its therapeutic potential by effectively controlling tumor growth and extending mouse survival. Investigations into biodistribution, excretion, and biosafety in healthy humans laid a robust foundation for clinical translation. This study introduces a versatile SPM-based nuclear probe with applications in precise tumor theranostics, offering promising prospects for clinical implementation.

14.
Cell Biochem Biophys ; 82(3): 2019-2028, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38822203

RESUMO

This study aims to explore the possible effect and mechanism of heterogeneous nuclear ribonucleoprotein L (HNRNPL) on the lipid droplet and proliferation ability of clear cell renal cell carcinoma (ccRCC). The mRNA and protein expressions of HNRNPL and WSB1 on ccRCC tissues and cells were detected using qRT-PCR and western blot. The lipid droplet of cells was assessed after Oil Red O staining and BODIPY 493/503 staining. Cell proliferation was detected by CCK-8 assay. The interaction between HNRNPL and WSB1 was verified using RNA immunoprecipitation (RIP) and RNA-pull down assay. WSB1 mRNA stability was measured by Actinomycin D. Elevated expressions of HNRNPL and WSB1 were found in both ccRCC tissues and cells. HNRNPL knockdown can lead to suppressed lipid droplet and cell proliferation ability of ccRCC cells, while expression pattern was found in cells with HNRNPL overexpression. RIP and RNA-pull down assay clarified the binding of HNRNPL with WSB1. HNRNPL can facilitate the stability and expression of WSB1 mRNA. Rescue assay identified the promotive effect of HNRNPL on lipid droplets and cell proliferation of ccRCC cells can be abolished in response to WSB1 knockdown. Collected evidence summarized that HNRNPL can increase the stability of WSB1 mRNA to promote lipid droplet and proliferation ability in ccRCC cells.


Assuntos
Carcinoma de Células Renais , Proliferação de Células , Neoplasias Renais , Gotículas Lipídicas , Estabilidade de RNA , Humanos , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Gotículas Lipídicas/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/genética , Linhagem Celular Tumoral , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , RNA Interferente Pequeno/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Interferência de RNA , Fatores de Processamento de RNA , Proteínas de Ciclo Celular , Ribonucleoproteínas Nucleares Heterogêneas Grupo L
15.
J Nanobiotechnology ; 22(1): 146, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38566213

RESUMO

Thrombotic diseases impose a significant global health burden, and conventional drug-based thrombolytic therapies are encumbered by the risk of bleeding complications. In this study, we introduce a novel drug-free nanomedicine founded on tea polyphenols nanoparticles (TPNs), which exhibits multifaceted capabilities for localized photothermal thrombolysis. TPNs were synthesized through a one-pot process under mild conditions, deriving from the monomeric epigallocatechin-3-gallate (EGCG). Within this process, indocyanine green (ICG) was effectively encapsulated, exploiting multiple intermolecular interactions between EGCG and ICG. While both TPNs and ICG inherently possessed photothermal potential, their synergy significantly enhanced photothermal conversion and stability. Furthermore, the nanomedicine was functionalized with cRGD for targeted delivery to activated platelets within thrombus sites, eliciting robust thrombolysis upon laser irradiation across diverse thrombus types. Importantly, the nanomedicine's potent free radical scavenging abilities concurrently mitigated vascular inflammation, thus diminishing the risk of disease recurrence. In summary, this highly biocompatible multifunctional nanomaterial holds promise as a comprehensive approach that combines thrombolysis with anti-inflammatory actions, offering precision in thrombosis treatment.


Assuntos
Nanomedicina , Trombose , Humanos , Polifenóis/farmacologia , Chá , Terapia Trombolítica , Verde de Indocianina/farmacologia , Verde de Indocianina/uso terapêutico , Inflamação/tratamento farmacológico , Trombose/tratamento farmacológico
16.
Mater Today Bio ; 26: 101018, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38516172

RESUMO

The cGAS-STING pathway holds tremendous potential as a regulator of immune responses, offering a means to reshape the tumor microenvironment and enhance tumor immunotherapy. Despite the emergence of STING agonists, their clinical viability is hampered by stability and delivery challenges, as well as variations in STING expression within tumors. In this study, we present Mn-phenolic networks as a novel carrier for ADU-S100, a hydrophilic STING agonist, aimed at bolstering immunotherapy. These nanoparticles, termed TMA NMs, are synthesized through the coordination of tannic acid and manganese ions, with surface modification involving bovine serum albumin to enhance their colloidal stability. TMA NMs exhibit pH/GSH-responsive disintegration properties, enabling precise drug release. This effectively addresses drug stability issues and facilitates efficient intracellular drug delivery. Importantly, TMA NMs synergistically enhance the effects of ADU-S100 through the concurrent release of Mn2+, which serves as a sensitizer of the STING pathway, resulting in significant STING pathway activation. Upon systemic administration, these nanoparticles efficiently accumulate within tumors. The activation of STING pathways not only induces immunogenic cell death (ICD) in tumor cells but also orchestrates systemic remodeling of the immunosuppressive microenvironment. This includes the promotion of cytokine release, dendritic cell maturation, and T cell infiltration, leading to pronounced suppression of tumor growth. Combining with the excellent biocompatibility and biodegradability, this Mn-based nanocarrier represents a promising strategy for enhancing tumor immunotherapy through the cGAS-STING pathway.

17.
Research (Wash D C) ; 7: 0295, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38269029

RESUMO

Photodynamic therapy (PDT) has emerged as a promising approach for squamous cell carcinoma treatment but hindered by tumor hypoxia, acquired resistance, phototoxicity, and so on. To address these issues, we developed a smart strategy utilizing activable photosensitizers delivered by an aptamer-functionalized DNA probe (ADP). The ADP incorporated an AS1411 aptamer for tumor targeting and a linear antisense oligonucleotide (ASO) for recognition of Survivin mRNA. In the absence of the target, PDT remained quenched, thereby avoiding phototoxicity during circulation and nonselective distribution. With the aid of the aptamer, ADP achieved selective targeting of tumors. Upon internalization, ADP targeted recognized Survivin mRNA, triggering PDT activation, and releasing ASO to down-regulate Survivin expression and reverse tumor resistance. Consequently, the activable photosensitizers exhibited an "AND" logic gate, combining tumor-targeting delivery and tumor-related gene activation, thus enhancing its specificity. Additionally, the incorporation of hemin into the ADP provided catalase activity, converting tumor-abundant H2O2 into O2, thereby ameliorating tumor hypoxia. The resulting functionalized G-quadruplex/hemin-DNA probe complex demonstrated targeted delivery and activation, minimized side effects, and enhanced PDT efficacy in both xenograft tumor-bearing mice and patient-derived xenograft models. This study offers a unique and promising platform for efficient and safe PDT, thus holding great potential for future clinical translation and improved cancer therapy.

18.
Small ; 20(8): e2307220, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37828643

RESUMO

Systematic management of infected wounds requires simultaneous antiinfection and wound healing, which has become the current treatment dilemma. Recently, a multifunctional silver nanoclusters (AgNCs)-based hydrogel dressing to meet these demands is developed. Here a diblock DNA with a cytosine-rich fragment (as AgNCs template) and a guanine-rich fragment (to form G-quadruplex/hemin DNAzyme, termed G4/hemin) is designed, for G4/hemin functionalization of AgNCs. Inside bacteria, G4/hemin can not only accelerate the oxidative release of Ag+ from AgNCs but also generate reactive oxygen species (ROS) via catalase- and peroxidase-mimic activities, which enhance the antibacterial effect. On the other hand, the AgNCs exhibit robust anti-inflammatory and antioxidative activities to switch M1 macrophages into M2 phenotype, which promotes wound healing. Moreover, the hemin is released to upregulate the heme oxygenase-1, an intracellular enzyme that can relieve oxidative stress, which significantly alleviates the cytotoxicity of silver. As a result, such silver-based dressing achieves potent therapeutic efficacy on infected wounds with excellent biosafety.


Assuntos
DNA Catalítico , Nanopartículas Metálicas , Prata , Hemina , DNA , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Hidrogéis
19.
Acta Pharm Sin B ; 13(12): 5074-5090, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38045045

RESUMO

Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy. However, its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment (ITM). Here, we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate (CaCO3) biomineralized Salmonella (Sal) as an in-situ cancer vaccine producer and systematical ITM regulator. CaCO3 can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading, and such biomineralization did not affect the bioactivities of the bacteria. Upon intratumoral accumulation, the CaCO3 shell was decomposed at an acidic microenvironment to attenuate tumor acidity, accompanied by the release of Sal and Ca2+/A23187. Specifically, Sal served as a cancer vaccine producer by inducing cancer cells' immunogenic cell death (ICD) and promoting the gap junction formation between tumor cells and dendritic cells (DCs) to promote antigen presentation. Ca2+, on the other hand, was internalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system, including DCs maturation, macrophages polarization, and T cells activation. As a result, such bio-vaccine achieved remarkable efficacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility. This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.

20.
Front Endocrinol (Lausanne) ; 14: 1308341, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38098865

RESUMO

Genistein (GN) has been highly recommended for its medicinal properties like anticancer, antidiabetic, antihyperlipidemic, antiviral, and antioxidant activities among others. Recently, scientists realized that Genistein is an endocrine disruptor. It is an obesogen that interferes with the endocrine system causing obesity through many mechanisms like inducing adipocyte differentiation, lipid accumulation, and transformation of some stem cells into adipocytes (bone marrow mesenchymal stem cells for example) in vitro. Animal studies show that GN upregulates genes associated with adipogenesis like CCAAT/enhancer binding protein alpha (Cebpα), CCAAT/enhancer binding protein beta (Cebpß), and PPARγ. In silico studies reveal a strong binding affinity for estrogen receptors. All these findings were contingent on concentration and tissues. It is beyond dispute that obesity is one of the most frustrating medical conditions under the sun. The pathophysiology of this disease was first attributed to a high-calorie diet and lack of physical activity. However, studies proved that these two factors are not enough to account for obesity in both children and adults. This mini review highlights how Genistein interaction with the peroxisome proliferator-activated receptor gamma protein can cause obesity.


Assuntos
Adipogenia , Genisteína , Animais , Criança , Humanos , Genisteína/farmacologia , Diferenciação Celular , Obesidade
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