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1.
Heliyon ; 10(16): e35836, 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39247380

RESUMEN

Stem cell transplantation has emerged as a promising avenue in regenerative medicine, potentially facilitating tissue repair in degenerative diseases and injuries. This review comprehensively examines recent developments and challenges in stem cell transplantation. It explores the identification and isolation of various stem cell types, including embryonic, induced pluripotent, and adult stem cells derived from multiple sources. Additionally, the review highlights the tissue-specific applications of these stem cells, focusing on bone and cartilage regeneration, treatment of neurological disorders, and management of hematological conditions. Future advancements and effective resolution of current challenges will be crucial in fully realizing the potential of stem cell transplantation in regenerative medicine. With responsible and ethical practices, the field can potentially transform disease and injury treatment, ultimately improving the quality of life for countless individuals.

2.
Heliyon ; 10(15): e35313, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39170348

RESUMEN

In recent decades, the prevalence of myopia has been on the rise globally, attributed to changes in living environments and lifestyles. This increase in myopia has become a significant public health concern. High myopia can result in thinning of the sclera and localized ectasia of the posterior sclera, which is the primary risk factor for various eye diseases and significantly impacts patients' quality of life. Therefore, it is essential to explore effective prevention strategies and programs for individuals with myopia. Collagen serves as the principal molecule in the extracellular matrix (ECM) of scleral tissue, consisting of irregular collagen fibrils. Collagen plays a crucial role in myopia progression and control. During the development of myopia, the sclera undergoes a thinning process which is primarily influenced by collagen expression decreased and remodeled, thus leading to a decrease in its biomechanical properties. Improving collagen expression and promoting collagen crosslinking can slow down the progression of myopia. In light of the above, improving collagen expression or enhancing the mechanical properties of collagen fibers via medication or surgery represents a promising approach to control myopia.

3.
Biomed Pharmacother ; 179: 117309, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39151312

RESUMEN

Esophageal cancer ranks among the most prevalent malignant tumors globally. The prognosis for esophageal squamous cell carcinoma remains poor, with a 5-year survival rate below 20 % due to limited advances in therapy. Ferroptosis, a novel form of iron-dependent lipid peroxidation-driven regulated cell death (RCD), shows significant promise in cancer treatment. Berbamine (BBM), a natural bisbenzylisoquinoline alkaloid derived from Berberis amurensis, exhibits anti-tumor effects against various cancers, yet its impact on esophageal cancer remains to be elucidated. This study aimed to explore the role of BBM in inducing ferroptosis in the treatment of esophageal cancer, focusing on its molecular mechanisms. Gene set enrichment analysis(GSEA) analysis highlighted the potential of BBM as an anti-cancer agent through ferroptosis induction. We found that BBM inhibited growth and epithelial-mesenchymal transition (EMT) in esophageal cancer cell lines, promoting Fe accumulation, ROS, and malondialdehyde (MDA) production, thereby triggering cell death. These suppressive effects were successfully reversed by Ferrostatin-1 (Fer-1). Mechanistically, BBM decreased deubiquitination enzyme USP51 levels, leading to ubiquitin degradation and glutathione peroxidase 4(GPX4) instability, and it stimulated ferroptosis. The Overexpression of USP51 mitigated the downregulation of GPX4 induced by BBM.BBM significantly inhibited tumor xenograft growth in nude mice. This discovery positions BBM as a promising therapeutic candidate for the treatment of esophageal cancer.


Asunto(s)
Bencilisoquinolinas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Ferroptosis , Ratones Desnudos , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Ubiquitinación , Ferroptosis/efectos de los fármacos , Humanos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Animales , Bencilisoquinolinas/farmacología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/genética , Ubiquitinación/efectos de los fármacos , Línea Celular Tumoral , Proteasas Ubiquitina-Específicas/metabolismo , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C , Transición Epitelial-Mesenquimal/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Proliferación Celular/efectos de los fármacos , Proteolisis/efectos de los fármacos , Masculino
4.
Int Heart J ; 65(4): 612-620, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39010223

RESUMEN

Currently, providing patients, particularly those with acute myocardial infarction (AMI), with comprehensive cardiac rehabilitation (CR) has been challenging because of the inadequate availability of medical resources in developing countries. To ensure balance between disease instability and early rehabilitation, strategies for facilitating professional and comprehensive CR opportunities for patients with AMI must be explored.A prospective cohort study was carried out on 1,533 patients with AMI who were admitted to a tertiary hospital between July 2018 and October 2019. Following the principle of voluntarism, 286 patients with AMI participated in home-center-based CR (HCB group), whereas 1,247 patients received usual care (UC group). The primary endpoint of this study was the occurrence of cardiovascular events at 30 months after AMI. Moreover, the study analyzed factors that influence participation rate and effectiveness of the CR model.After analysis, a significant difference in the occurrence of cardiovascular endpoints between the HCB group and the UC group was observed (harzard ratio, 0.68 [95%CI, 0.51-0.91], P = 0.008), with participation in home-center-based CR being an independent influencing factor. Multivariate regression analysis revealed age, gender, smoking history, triglyceride levels, and ejection fraction as independent factors that influence participation rate. Female gender, peak oxygen uptake per kilogram body weight, and ventilation/carbon dioxide production slope were identified as factors that affect the effectiveness of the CR model.In the context of developing countries, this study demonstrates that the home-center-based CR model is efficient and analyzes factors that influence participation rate and effectiveness of the model. These findings provide practical insights for further development of CR programs.


Asunto(s)
Rehabilitación Cardiaca , Infarto del Miocardio , Humanos , Masculino , Femenino , Rehabilitación Cardiaca/métodos , Infarto del Miocardio/rehabilitación , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Resultado del Tratamiento , Servicios de Atención de Salud a Domicilio
5.
World J Surg Oncol ; 22(1): 83, 2024 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-38523264

RESUMEN

BACKGROUND: Aimed to assess clinical effect of three-port inflatable robot-assisted thoracoscopic surgery in mediastinal tumor resection by comparing results of the robot group with the video group. METHODS: Retrospectively analyze 179 patients diagnosed with anterior mediastinal tumor from May 2017 to August 2021. Two groups were divided according to the surgical approach, including 92 cases in the RATS group and 87 cases in the VATS group. The results were analyzed between two groups with variables of age, sex, BMI, tumor size, and diagnosis. Perioperative clinical data was gathered to compare. RESULT: There were no significant differences between the 2 groups with regards to demographic data and clinical features. There were no significant differences inoperative time and duration of chest tube via RATS vs. VATS. The intraoperative blood loss was statistically significantly different among the RATS and VATS groups (75.9 ± 39.6 vs. 97.4 ± 35.8 ml p = 0.042). The postoperative stay of patients in RATS group were significantly shorter than that in VATS group (2.3 ± 1.0 vs. 3.4 ± 1.4 day p = 0.035), CONCLUSION: Three-port inflatable robot-assisted thoracoscopic surgery for mediastinal tumor is feasible and reliable it is more advantageous, and it provides the surgeon with advice on treatment choice.


Asunto(s)
Neoplasias del Mediastino , Procedimientos Quirúrgicos Robotizados , Robótica , Humanos , Neoplasias del Mediastino/cirugía , Estudios Retrospectivos , Cirugía Torácica Asistida por Video/métodos
6.
J Control Release ; 367: 167-183, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37562556

RESUMEN

The tumor microenvironment is a barrier to breast cancer therapy. Cancer-associated fibroblast cells (CAFs) can support tumor proliferation, metastasis, and drug resistance by secreting various cytokines and growth factors. Abnormal angiogenesis provides sufficient nutrients for tumor proliferation. Considering that CAFs express the sigma receptor (which recognizes anisamide, AA), we developed a CAFs and breast cancer cells dual-targeting nano drug delivery system to transport the LightOn gene express system, a spatiotemporal controlled gene expression consisting of a light-sensitive transcription factor and a specific minimal promoter. We adopted RGD (Arg-Gly-Asp) to selectively bind to the αvß3 integrin on activated vascular endothelial cells and tumor cells. After the LightOn system has reached the tumor site, LightOn gene express system can spatiotemporal controllably express toxic Pseudomonas exotoxin An under blue light irradiation. The LightOn gene express system, combined with multifunctional nanoparticles, achieved high targeting delivery efficiency both in vitro and in vivo. It also displayed strong tumor and CAFs inhibition, anti-angiogenesis ability and anti-metastasis ability, with good safety. Moreover, it improved survival rate, survival time, and lung metastasis rate in a mouse breast cancer model. This study proves the efficacy of combining the LightOn system with targeted multifunctional nanoparticles in tumor and anti-metastatic therapy and provides new insights into tumor microenvironment regulation.


Asunto(s)
Nanopartículas Multifuncionales , Nanopartículas , Neoplasias , Ratones , Animales , Células Endoteliales , Exotoxinas/genética , Exotoxinas/uso terapéutico , Regulación de la Expresión Génica , Transgenes , Línea Celular Tumoral , Microambiente Tumoral , Nanopartículas/uso terapéutico
8.
Adv Mind Body Med ; 37(2): 9-23, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37315228

RESUMEN

Objectives: The aim of this study is to comprehensively review empirical evidence on the effectiveness of Baduanjin exercise, one type of mind-body focused qigong exercise, on individuals' physical, cognitive, and mental well-being; outline potential mechanisms; and, suggest potential implication strategies for using Baduanjin in clinical practices and for future research. Methods: Recent randomized-controlled studies and systematic reviews/meta-analyses published in English were searched in PubMed, PsycINFO, and Scopus up to July 2022. The search terms include Baduanjin and sleep, chronic illness, cognition, mental health, etc. We only selected papers that specifically studied the health effects of Baduanjin, excluding those that involved other forms of Qigong or other traditional Chinese medical practices. Since many RCT studies have already been included in the review papers that we selected, only those not covered in the review papers were selected to avoid repetition. Results: 19 recent randomized-controlled studies and 8 systematic reviews were identified. In general, the effectiveness of Baduanjin exercise on individuals' physical, cognitive, and mental health is evident. Baduanjin has proven to be effective in improving sleep quality, including reducing difficulties in getting asleep and reducing daytime sleepiness. It also reduces fatigue and improves the quality of life for patients with other physical health issues, such as cancer, musculoskeletal pain, and chronic illnesses. The effectiveness of Baduanjin exercise is also evident in cognition, improving executive functions, and slowing down age-related cognitive deterioration. Similarly, Baduanjin alleviates various types of mental illnesses, increases patients' social competence, and enhances emotional regulation. Conclusion: There is initial evidence on the safety and efficacy of Baduanjin in improving individuals' various aspects of health and well-being, suggesting that Baduanjin may serve as an effective adjunct to conventional treatments for a variety of clinical health benefits. More research is needed to confirm the efficacy and safety of Baduanjin in other non-Chinese ethnic populations.


Asunto(s)
Salud Mental , Qigong , Humanos , Calidad de Vida , Bienestar Psicológico , Cognición
9.
Am J Cancer Res ; 13(3): 1091-1102, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37034205

RESUMEN

Lung cancer is ranked as the leading cause of cancer-related death worldwide, and the development of novel biomarkers is helpful to improve the prognosis of non-small cell lung cancer (NSCLC). Cell-in-cell structures (CICs), a novel functional surrogate of complicated cell behaviors, have shown promise in predicting the prognosis of cancer patients. However, the CIC profiling and its prognostic value remain unclear in NSCLC. In this study, we retrospectively explored the CIC profiling in a cohort of NSCLC tissues by using the "Epithelium-Macrophage-Leukocyte" (EML) method. The distribution of CICs was examined by the Chi-square test, and univariate and multivariate analyses were performed for survival analysis. Four types of CICs were identified in lung cancer tissues, namely, tumor-in-tumor (TiT), tumor-in-macrophage (TiM), lymphocyte-in-tumor (LiT), and macrophage-in-tumor (MiT). Among them, the latter three constituted the heterotypic CICs (heCICs). Overall, CICs were more frequently present in adenocarcinoma than in squamous cell carcinoma (P = 0.009), and LiT was more common in the upper lobe of the lung compared with other lobes (P = 0.020). In univariate analysis, the presence of TiM, heCIC density, TNM stage, T stage, and N stage showed association with the overall survival (OS) of NSCLC patients. Multivariate analysis revealed that heCICs (HR = 2.6, 95% CI 1.25-5.6) and lymph node invasion (HR = 2.6, 95% CI 1.33-5.1) were independent factors associated with the OS of NSCLC. Taken together, we profiled the CIC subtypes in NSCLC for the first time and demonstrated the prognostic value of heCICs, which may serve as a type of novel functional markers along with classical pathological factors in improving prognosis prediction for patients with NSCLC.

11.
Neuromolecular Med ; 25(3): 375-387, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-36971954

RESUMEN

The medial prefrontal cortex (mPFC) is critical for both the sensory and emotional/cognitive components of pain. However, the underlying mechanism remains largely unknown. Here, we examined changes in the transcriptomic profiles in the mPFC of mice with chronic pain using RNA sequencing (RNA-seq) technology. A mouse model of peripheral neuropathic pain was established via chronic constriction injury (CCI) of the sciatic nerve. CCI mice developed sustained mechanical allodynia and thermal hyperalgesia, as well as cognitive impairment four weeks after surgery. RNA-seq was conducted 4 weeks after CCI surgery. Compared with contral group, RNA-seq identified a total 309 and 222 differentially expressed genes (DEGs) in the ipsilateral and contralateral mPFC of CCI model mice, respectively. GO analysis indicated that the functions of these genes were mainly enriched in immune- and inflammation-related processes such as interferon-gamma production and cytokine secretion. KEGG analysis further showed the enrichment of genes involved in the neuroactive ligand-receptor interaction signaling pathway and Parkinson disease pathway that have been reported to be importantly involved in chronic neuralgia and cognitive dysfunction. Our study may provide insights into the possible mechanisms underlying neuropathic pain and pain-related comorbidities.


Asunto(s)
Hiperalgesia , Neuralgia , Ratones , Animales , Constricción , Hiperalgesia/genética , Neuralgia/genética , Perfilación de la Expresión Génica , Corteza Prefrontal/metabolismo
12.
J Control Release ; 355: 538-551, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36063962

RESUMEN

Individualized immunotherapy has attracted great attention due to its high specificity, effectiveness, and safety. We used an exogenous antigen to label tumor cells with MHC I molecules, which allowed neoantigen-specific T cells to recognize and kill tumor cells. A neoantigen vaccine alone cannot achieve complete tumor clearance due to a tumor immunosuppressive microenvironment. The LightOn system was developed to effectively eliminate tumor cells through the spatiotemporally controllable expression of diphtheria toxin A fragment, leading to antigen release in the tumor region. These antigens stimulated and enhanced immunological function and thus, recruited neoantigen-specific T cells to infiltrate tumor tissue. Using the nanoparticle delivery system, neoantigens produced higher delivery efficiency to lymph nodes and improved tumor targeting ability for tumor cell labelling. Good tumor inhibition and prolonged survival were achieved, while eliciting a strong immune response. The combination of a spatiotemporally controllable transgene system with tumor neoantigen labeling has great potential for tumor immunotherapy.


Asunto(s)
Vacunas contra el Cáncer , Neoplasias , Humanos , Antígenos de Neoplasias , Neoplasias/terapia , Linfocitos T , Inmunoterapia , Antígenos de Histocompatibilidad Clase I , Vacunas contra el Cáncer/genética , Microambiente Tumoral
13.
Int J Pharm ; 618: 121613, 2022 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-35217071

RESUMEN

Breast cancer is a common malignancy in women. The abnormally dense collagen network in breast cancer forms a therapeutic barrier that hinders the penetration and anti-tumor effect of drugs. To overcome this hurdle, we adopted a therapeutic strategy to treat breast cancer which combined a light-switchable transgene system and losartan. The light-switchable transgene system could regulate expression of the diphtheria toxin A fragment (DTA) gene with a high on/off ratio under blue light and had great potential for spatiotemporally controllable gene expression. We developed a nanoparticle drug delivery system to achieve tumor microenvironment-responsive and targeted delivery of DTA-encoded plasmids (pDTA) to tumor sites via dual targeting to cluster of differentiation-44 and αvß3 receptors. In vivo studies indicated that the combination of pDTA and losartan reduce the concentration of collagen type I from 5.9 to 1.9 µg/g and decreased the level of active transforming growth factor-ß by 75.0% in tumor tissues. Moreover, deeper tumor penetration was achieved, tumor growth was inhibited, and the survival rate was increased. Our combination strategy provides a novel and practical method for clinical treatment of breast cancer.


Asunto(s)
Neoplasias de la Mama , Nanopartículas , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Losartán , Sistema de Administración de Fármacos con Nanopartículas , Transgenes , Microambiente Tumoral
14.
Cell Death Dis ; 12(1): 119, 2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33483474

RESUMEN

The nonautonomous cell death by entosis was mediated by the so-called cell-in-cell structures, which were believed to kill the internalized cells by a mechanism dependent on acidified lysosomes. However, the precise values and roles of pH critical for the death of the internalized cells remained undetermined yet. We creatively employed keima, a fluorescent protein that displays different excitation spectra in responding to pH changes, to monitor the pH dynamics of the entotic vacuoles during cell-in-cell mediated death. We found that different cells varied in their basal intracellular pH, and the pH was relatively stable for entotic vacuoles containing live cells, but sharply dropped to a narrow range along with the inner cell death. In contrast, the lipidation of entotic vacuoles by LC3 displayed previously underappreciated complex patterns associated with entotic and apoptotic death, respectively. The pH decline seemed to play distinct roles in the two types of inner cell deaths, where apoptosis is preceded with moderate pH decline while a profound pH decline is likely to be determinate for entotic death. Whereas the cancer cells seemed to be lesser tolerant to acidified environments than noncancerous cells, manipulating vacuolar pH could effectively control inner cell fates and switch the ways whereby inner cell die. Together, this study demonstrated for the first time the pH dynamics of entotic vacuoles that dictate the fates of internalized cells, providing a rationale for tuning cellular pH as a potential way to treat cell-in-cell associated diseases such as cancer.


Asunto(s)
Muerte Celular/fisiología , Vacuolas/metabolismo , Apoptosis , Humanos , Concentración de Iones de Hidrógeno , Transfección
15.
Ann Palliat Med ; 10(12): 12650-12656, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35016422

RESUMEN

BACKGROUND: Currently, there is no consensus on the standard of care for patients with recurrent glioma. This study investigated the efficacy of combined carboplatin and etoposide (CE) treatment in recurrent glioma. METHODS: A retrospective analysis was performed on adult patients with recurrent glioma who received combination chemotherapy consisting of CE from September 2017 to November 2020 at the Beijing Shijitan Hospital, Capital Medical University, Beijing. The response rate (RR), defined as the complete response (CR) + partial response (PR), and the disease control rate (DCR), defined as CR + PR + stable disease (SD), were analyzed by Chi-square or Fisher's exact test according to different clinical characteristics. Time to progression (TTP) was estimated using Kaplan-Meier plots and the log-rank test was used to compare differences. RESULTS: A total of 55 patients were assessed and 47 patients were eligible to be enrolled in this study. There was 1 case of CR (2.1%), 3 patients with PR (6.4%), and 18 patients with SD (38.3%). The RR was 8.5% and the DCR was 46.8%. When the patients were stratified by World Health Organization (WHO) grade, the DCR was significantly higher in patients with grade 2 and 3 tumors (83.3% and 50%, respectively) compared to patients with grade 4 tumors (29.6%; P=0.039). For patients with grade 4 gliomas, the median TTP and median overall survival (OS) were 2 [95% confidence interval (CI): 0.988 to 3.012] and 7 (95% CI: 3.626 to 10.374) months, respectively. By comparison, the TTP and OS for patients with grade 2-3 gliomas were 4 (95% CI: 1.947 to 6.053) and 13 (95% CI: 0.000 to 26.47) months, respectively. The 6-month progression free survival (PFS) and 12-month OS were 11.1% and 16.3%, respectively, in patients with grade 4 glioma, compared to 37.9% and 48%, respectively, in patients with grade 2-3 gliomas. CONCLUSIONS: CE regimen may be effective as a salvage treatment for recurrent glioma. Patients with anaplastic or low-grade glioma may benefit more from such therapy compared to patients with grade 4 tumors.


Asunto(s)
Neoplasias Encefálicas , Glioma , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Carboplatino/uso terapéutico , Etopósido/uso terapéutico , Glioma/tratamiento farmacológico , Humanos , Estudios Retrospectivos , Resultado del Tratamiento
16.
Acta Pharm Sin B ; 10(9): 1741-1753, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33088693

RESUMEN

A light-switchable transgene system called LightOn gene expression system could regulate gene expression with a high on/off ratio under blue light, and have great potential for spatiotemporally controllable gene expression. We developed a nanoparticle drug delivery system (NDDS) to achieve tumor microenvironment-responsive and targeted delivery of diphtheria toxin A (DTA) fragment-encoded plasmids to tumor sites. The expression of DTA was induced by exposure to blue light. Nanoparticles composed of polyethylenimine and vitamin E succinate linked by a disulfide bond, and PEGylated hyaluronic acid modified with RGD peptide, accumulated in tumor tissues and were actively internalized into 4T1 cells via dual targeting to CD44 and α v ß 3 receptors. The LightOn gene expression system was able to control target protein expression through regulation of the intensity or duration of blue light exposure. In vitro studies showed that light-induced DTA expression reduced 4T1 cell viability and induced apoptosis. Furthermore, the LightOn gene expression system enabled spatiotemporal control of the expression of DTA in a mouse 4T1 tumor xenograft model, which resulted in excellent antitumor effects, reduced tumor angiogenesis, and no systemic toxicity. The combination of the LightOn gene expression system and NDDS may be an effective strategy for treatment of breast cancer.

17.
Mol Pharm ; 17(1): 301-315, 2020 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-31765570

RESUMEN

The controversy surrounding the use of diphtheria toxin (DT) as a therapeutic agent against tumor cells arises mainly from its unexpected harmfulness to healthy tissues. We encoded the cytotoxic fragment A of DT (DTA) as an objective gene in the Light-On gene-expression system to construct plasmids pGAVPO (pG) and pU5-DTA (pDTA). Meanwhile, a cRGD-modified ternary complex comprising plasmids, chitosan, and liposome (pG&pDTA@cRGD-CL) was prepared as a nanocarrier to ensure transfection efficiency. Benefiting from spatiotemporal control of this light-switchable transgene system and the superior tumor targeting of the carrier, toxins were designed to be expressed selectively in illuminated lesions. In vitro studies suggested that pG&pDTA@cRGD-CL exerted arrest of the S phase in B16F10 cells upon blue light irradiation and, ultimately, induced the apoptosis and necrosis of tumor cells. Such DTA-based treatment exerted enhanced antitumor activity in mice bearing B16F10 xenografts and displayed prolonged survival time with minimal side effects. Hence, we described novel DTA-based therapy combined with nanotechnology and the Light-On gene-expression system: such treatment could be a promising strategy against melanoma.


Asunto(s)
Toxina Diftérica/genética , Expresión Génica/efectos de la radiación , Terapia Genética , Liposomas/química , Melanoma Experimental/terapia , Nanotecnología/métodos , Fragmentos de Péptidos/genética , Animales , Apoptosis/genética , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Quitosano/química , Expresión Génica/genética , Liposomas/ultraestructura , Masculino , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Microscopía Electrónica de Transmisión , Tamaño de la Partícula , Péptidos Cíclicos/química , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase S del Ciclo Celular/genética , Puntos de Control de la Fase S del Ciclo Celular/efectos de la radiación , Esferoides Celulares/efectos de la radiación , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
18.
J Control Release ; 319: 1-14, 2020 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-31838205

RESUMEN

Gene therapy with external gene insertion (e. g. a suicide gene) and expression specifically in mutated tumor cells has shown to be a promising strategy in treatment of tumors. However, current tumor gene therapy often suffered from low efficiency in gene expression and off-target effects which may cause damage to normal tissues. To address these issues, in this study, a light-switchable transgene nanoparticle delivery system loaded with a diphtheria toxin A (DTA) segment encoded gene, a suicide gene for tumor cells, was developed. The nanoparticles contained vitamin E succinate-grafted polyethyleneimine core and arginylglycylaspartic acid (RGD)-modified pegylated hyaluronic acid shell for targeted delivery of the loaded gene to tumor cells via receptor-mediated (CD44 and αvß3) endocytosis. Notably, the expression of target proteins in tumor cells could be conveniently regulated by adjusting the blue light intensity in the Light-On system. In in-vitro studies in cultured B16-F10 cells, the pG-DTA-loaded nano-micelles showed greatly improved inhibitory rate compared with the pG-DTA group. Moreover, in the tumor-bearing C57BL/6 mice model, the pG-DTA-loaded nanoparticle exhibited greatly improved efficacy and reduced systemic toxicity with significantly increased survival rate after 21 days. Significantly suppressed tumor angiogenesis was also identified in the nanoparticle-treated group likely due to the targeting ability of the RGD-modified nanoparticle. All the above results indicated that the combination of a light-switchable transgene system with a nanoparticle-based targeted delivery system have great potentials in gene therapy of malignant tumors with improved precision and efficacy.


Asunto(s)
Melanoma , Nanopartículas Multifuncionales , Nanopartículas , Animales , Línea Celular Tumoral , Toxina Diftérica , Sistemas de Liberación de Medicamentos , Melanoma/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Transgenes
19.
Theranostics ; 9(12): 3425-3442, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31281488

RESUMEN

Rationale: Tolerogenic dendritic cells (tol-DCs) play essential roles in immune-related diseases and induce immune tolerance by shaping T-cell responses. Accumulating evidence suggests that long noncoding RNAs (lncRNAs) play important regulatory roles in the immune system. However, the potential roles and underlying mechanisms of lncRNAs in tol-DCs remain unclear. Methods: RNA in-situ hybridization, histochemistry, and qRT-PCR were performed to determine the distribution and expression of NEAT1 in DCs. Flow cytometry was used to analyze the tolerogenic function of DCs. Small sequencing, followed by bioinformatic analysis, was performed to determine the target genes of NEAT1. The mechanism of NEAT1 was explored using a luciferase reporter, chromatin immunoprecipitation assays, and Immunofluorescence. In-vivo experiments were used to investigate the induction of immune tolerance via NEAT1-knockdown DCs. Results: Our results show that lncRNA NEAT1 can induce tolerogenic phenotype in DCs. Mechanistically, small RNA-seq analysis revealed that NEAT1 knockdown preferentially affected the expression of miR-3076-3p. Furthermore, NEAT1 used the NLRP3 inflammasome as a molecular decoy for miR-3076-3p, thus facilitating the expression of tolerogenic phenotype in DCs. Moreover, the transcription factor E2F1 acted as a repressor of NEAT1 transcription via activity of H3K27ac. Our results also indicate that NEAT1 knockdown in DCs can induce immune tolerance in models of experimental autoimmune myocarditis and heart transplantation. Conclusions: Taken together, our study shows the mechanism used by NEAT1 in inducing tol-DCs and highlights the therapeutic potential of targeting NEAT1 for the treatment of immune-related diseases.


Asunto(s)
Células Dendríticas/inmunología , Tolerancia Inmunológica , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , ARN Largo no Codificante/genética , Animales , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Proliferación Celular , Factor de Transcripción E2F1/metabolismo , Técnicas de Silenciamiento del Gen , Antígenos de Histocompatibilidad Clase II/metabolismo , Inflamasomas , Histona Demetilasas con Dominio de Jumonji/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Cultivo Primario de Células , ARN Largo no Codificante/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo
20.
Mol Pharm ; 16(5): 2172-2183, 2019 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-30978027

RESUMEN

Although photodynamic therapy (PDT) has been an attractive strategy for several cancer treatments in the clinical setting, PDT efficacy is attenuated by consumption of oxygen. To address this photodynamic issue, we adopted a phototherapy-chemotherapy combination strategy based on targeted delivery of the near-infrared photosensitizer indocyanine green (ICG), photothermal conversion agent polydopamine (PDA), and tirapazamine (TPZ), a hypoxia-activated prodrug. Under laser irradiation, ICG consumption of oxygen and aggravated hypoxia in tumor sites can activate TPZ to damage DNA. In parallel, ICG produces reactive oxygen species which work in synergy with PDA to enhance phototherapeutic efficiency. Herein, hybrid CaCO3/TPGS nanoparticles delivering ICG, PDA, and TPZ (ICG-PDA-TPZ NPs) were designed for effective and safe cancer therapy. ICG-PDA-TPZ NPs showed significantly improved cellular uptake and accumulation in tumors. Furthermore, we demonstrated that ICG-PDA-TPZ NPs showed intensive photodynamic and photothermal effects in vitro and in vivo, which synergized with TPZ in subcutaneous U87 malignant glioma growth and orthotopic B16F10 tumor inhibition, with negligible side effects. Thus, ICG-PDA-TPZ NPs could be an effective strategy for improvement of PDT.


Asunto(s)
Hipertermia Inducida , Verde de Indocianina , Indoles , Nanopartículas , Neoplasias , Fotoquimioterapia , Profármacos , Fármacos Sensibilizantes a Radiaciones , Tirapazamina , Animales , Humanos , Ratones , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Hipertermia Inducida/métodos , Verde de Indocianina/metabolismo , Verde de Indocianina/uso terapéutico , Indoles/metabolismo , Indoles/uso terapéutico , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/efectos adversos , Fotoquimioterapia/métodos , Polímeros/metabolismo , Polímeros/uso terapéutico , Profármacos/metabolismo , Profármacos/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/metabolismo , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Especies Reactivas de Oxígeno/efectos de la radiación , Tirapazamina/metabolismo , Tirapazamina/uso terapéutico , Distribución Tisular , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
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