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INTRODUCTION: Pancreatic cancer (PC) remains a challenging malignancy, and adjuvant chemotherapy is critical in improving patient survival post-surgery. However, the intrinsic heterogeneity of PC necessitates personalized treatment strategies, highlighting the need for reliable preclinical models. OBJECTIVES: This study aimed to develop novel patient-derived preclinical PC models using three-dimensional bioprinting (3DP) technology. METHODS: Patient-derived PC models were established using 3DP technology. Genomic and histological analyses were performed to characterize these models and compare them with corresponding patient tissues. Chemotherapeutic drug sensitivity tests were conducted on the PC 3DP models, and correlations with clinical outcomes were analyzed. RESULTS: The study successfully established PC 3DP models with a modeling success rate of 86.96%. These models preserved genomic and histological features consistent with patient tissues. Drug sensitivity testing revealed significant heterogeneity among PC 3DP models, mirroring clinical variability, and potential correlations with clinical outcomes. CONCLUSION: The PC 3DP models demonstrated their utility as reliable preclinical tools, retaining key genomic and histological characteristics. Importantly, drug sensitivity profiles in these models showed potential correlations with clinical outcomes, indicating their promise in customizing treatment strategies and predicting patient prognoses. Further validation with larger patient cohorts is warranted to confirm their potential clinical utility.
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The utilization of three-dimensional (3D) bioprinting technology to create a transplantable bioartificial liver emerges as a promising remedy for the scarcity of liver donors. This study outlines our strategy for constructing a 3D-bioprinted liver, using in vitro-expanded primary hepatocytes recognized for their safety and enhanced functional robustness as hepatic cell sources for bioartificial liver construction. In addition, we have developed bioink biomaterials with mechanical and rheological properties, as well as printing capabilities, tailored for 3D bioprinting. Upon heterotopic transplantation into the mesentery of tyrosinemia or 90% hepatectomy mice, our 3D-bioprinted liver effectively restored lost liver functions, consequently extending the life span of mice afflicted with liver injuries. Notably, the inclusion of an artificial blood vessel in our 3D-bioprinted liver allowed for biomolecule exchange with host blood vessels, demonstrating, in principle, the rapid integration of the bioartificial liver into the host vascular system. This model underscores the therapeutic potential of transplantation for the treatment of liver failure diseases.
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Bioimpresión , Hepatocitos , Fallo Hepático , Hígado , Impresión Tridimensional , Animales , Hepatocitos/metabolismo , Hepatocitos/trasplante , Ratones , Bioimpresión/métodos , Hígado/metabolismo , Fallo Hepático/terapia , Ingeniería de Tejidos/métodos , Trasplante de Hígado/métodos , Hígado Artificial , Modelos Animales de Enfermedad , Tirosinemias/terapia , Tirosinemias/metabolismo , Andamios del Tejido/químicaRESUMEN
Methods accurately predicting the responses of colorectal cancer (CRC) and colorectal cancer liver metastasis (CRLM) to personalized chemotherapy remain limited due to tumor heterogeneity. This study introduces an innovative patient-derived CRC and CRLM tumor model for preclinical investigation, utilizing 3d-bioprinting (3DP) technology. Efficient construction of homogeneous in vitro 3D models of CRC/CRLM is achieved through the application of patient-derived primary tumor cells and 3D bioprinting with bioink. Genomic and histological analyses affirm that the CRC/CRLM 3DP tumor models effectively retain parental tumor biomarkers and mutation profiles. In vitro tests evaluating chemotherapeutic drug sensitivities reveal substantial tumor heterogeneity in chemotherapy responses within the 3DP CRC/CRLM models. Furthermore, a robust correlation is evident between the drug response in the CRLM 3DP model and the clinical outcomes of neoadjuvant chemotherapy. These findings imply a significant potential for the application of patient-derived 3DP cancer models in precision chemotherapy prediction and preclinical research for CRC/CRLM.
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Bioimpresión , Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Neoplasias Colorrectales/patología , Pronóstico , Neoplasias Hepáticas/genéticaRESUMEN
Nε-carboxymethyl-lysine (CML) is closely associated with vascular calcification in diabetes. Osteoclasts are the only cells with bone resorption activity that have the potential to reverse calcification. This study aimed to investigate the mechanism of CML in the bone resorption activity of macrophage-derived osteoclasts in diabetic calcified plaques. Macrophage-derived osteoclasts were found to be present in calcified plaques of the anterior tibial artery in patients with diabetic amputation. Furthermore, in vitro studies showed that CML induced the differentiation of macrophages into osteoclasts, although, the bone resorption activity of these macrophage-derived osteoclasts was impaired. CML significantly increased the levels of NFATc1and GNPTAB. In vivo studies showed that there was more calcium deposition and less TRAP was less in the CML group while this effect was reversed after silencing of NFATc1. In conclusion, CML mediates NFATc1-GNPTAB to regulate bone resorption activity of osteoclasts in diabetic calcified plaques. CML promotes macrophage differentiation into osteoclasts, but their function is impaired in diabetic calcified plaques through NFATc1-GNPTAB, which eventually leads to the further progression of vascular calcification in diabetes.
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Resorción Ósea , Diabetes Mellitus , Placa Aterosclerótica , Calcificación Vascular , Humanos , Osteoclastos , Factores de Transcripción , Diferenciación Celular , Factores de Transcripción NFATC , Transferasas (Grupos de Otros Fosfatos Sustitutos)RESUMEN
Atherosclerosis (AS) is the most common cause of death in cardiovascular diseases and poses severe challenges to human life and safety. Epigenetics plays a vital role in every single link of AS. Whereas, how epigenetics regulates its development and regression is still unknown. Sirt3, a recognized histone deacetylase, having been reported to be involved in other acylation processes in recent years, is broadening its role in epigenetic modifications. Sirt3 is an important factor in the normal physiology of blood vessels through deacetylation of mitochondrial proteins and participates in various metabolic activities. Besides, medical research targeting Sirt3 is in full swing as well. This review combining histone deacetylase Sirt3 with AS, aims to clarify the latest progress in the significant role of Sirt3 in the development and regression of AS and to provide a novel prospect for a new regulatory factor and potential intervention target for AS.
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Aterosclerosis/metabolismo , Sirtuina 3/metabolismo , Enfermedades Cardiovasculares/metabolismo , Epigénesis Genética/genética , Epigenómica , Histona Desacetilasas/metabolismo , Humanos , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Sirtuina 3/genética , Sirtuina 3/fisiologíaRESUMEN
Diabetes mellitus is a metabolic and endocrine disorder characterised by hyperglycaemia. Type 2 diabetes mellitus accounts for >90% of people with diabetes. Disorders of blood glucose metabolism and a series of adverse reactions triggered by hyperglycaemia-such as oxidative stress and inflammation-are conducive to the occurrence of diabetic macrovascular complications, which pose severe challenges to the quality of life and life expectancy of people with diabetes. In recent years, epigenetics has attracted more and more researchers' attention as they explore the causes and treatment of diabetes. Epigenetics refers to the regulation of gene expression without changes in gene content. Research focusses on DNA methylation, histone post-translational modification and non-coding RNA. A series of studies have shown that epigenetic regulation accelerates the development of atherosclerosis by interfering with the physiological activities of macrophages, endothelial cells and smooth muscle cells, such as inflammation, lipid deposition and apoptosis. Therefore, it is particularly important to explore new epigenetic discoveries to reduce the severity and harmfulness of diabetes. This study reviewed recent advances in epigenetics in the pathogenesis of diabetes mellitus and its macrovascular complications.