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Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.
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Células Presentadoras de Antígenos , Vacunas contra el Cáncer , Inmunoterapia , Nanopartículas , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia/métodos , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Nanopartículas/administración & dosificación , Células Presentadoras de Antígenos/inmunología , Biomimética/métodos , Materiales Biomiméticos/administración & dosificación , Animales , Liposomas , NanovacunasRESUMEN
A hallmark of Alzheimer's disease (AD) is amyloid-ß (Aß) plaque deposition in the brain, causing deficits in cognitive function. Amyloid-beta oligomers (AßOs), the soluble precursor peptides producing Aß plaques, also produce neurotoxicity and microgliosis together with glycolytic reprogramming. Recently, monocarboxylate transporter 1 (MCT1), a key glycolysis regulator, and its ancillary protein, CD147, are found to play an important role in the secretion of exosomes, 30-200 nm vesicles in size, which are considered as toxic molecule carriers in AD. However, the effect of low-concentration AßOs (1 nM) on microglia MCT1 and CD147 expression as well as 1 nM AßOs-treated microglia-derived exosomes on neuronal toxicity remain largely elusive. In this study, 1 nM AßOs induce significant axonopathy and microgliosis. Furthermore, 1 nM AßOs-treated neurons- or microglia-derived exosomes produce axonopathy through their autologous or heterologous uptake by neurons, supporting the role of exosomes as neurotoxicity mediators in AD. Interestingly, MCT1 and CD147 are enhanced in microglia by treatment with 1 nM AßOs or exosomes from 1 nM AßOs-treated- microglia or neurons, suggesting the implication of AßOs-induced enhanced MCT1 and CD147 in microglia with AD neuropathogenesis, which is consistent with the in-silico analysis of the single cell RNA sequencing data from microglia in mouse models of AD and AD patients.
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Péptidos beta-Amiloides , Exosomas , Microglía , Neuronas , Exosomas/metabolismo , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Microglía/metabolismo , Microglía/patología , Microglía/efectos de los fármacos , Animales , Neuronas/metabolismo , Neuronas/patología , Neuronas/efectos de los fármacos , Ratones , Basigina/metabolismo , Basigina/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Células Cultivadas , Simportadores/metabolismo , Simportadores/genética , Ratones Endogámicos C57BL , HumanosRESUMEN
Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.
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Antineoplásicos , Neoplasias de la Mama , Indazoles , Macrófagos , Estructuras Metalorgánicas , Nanopartículas , Pirimidinas , Sulfonamidas , Animales , Femenino , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Humanos , Macrófagos/efectos de los fármacos , Indazoles/farmacología , Indazoles/química , Ratones , Pirimidinas/farmacología , Pirimidinas/química , Línea Celular Tumoral , Nanopartículas/química , Sulfonamidas/farmacología , Sulfonamidas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Ratones Endogámicos BALB C , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Environmental pollution, including air pollution, plastic contamination, and heavy metal exposure, is a pressing global issue. This crisis contributes significantly to pollution-related diseases and is a critical risk factor for chronic health conditions, including cancer. Mounting evidence underscores the pivotal role of N6-methyladenosine (m6A) as a crucial regulatory mechanism in pathological processes and cancer progression. Governed by m6A writers, erasers, and readers, m6A orchestrates alterations in target gene expression, consequently playing a vital role in a spectrum of RNA processes, covering mRNA processing, translation, degradation, splicing, nuclear export, and folding. Thus, there is a growing need to pinpoint specific m6A-regulated targets in environmental pollutant-induced carcinogenesis, an emerging area of research in cancer prevention. This review consolidates the understanding of m6A modification in environmental pollutant-induced tumorigenesis, explicitly examining its implications in lung, skin, and bladder cancer. We also investigate the biological mechanisms that underlie carcinogenesis originating from pollution. Specific m6A methylation pathways, such as the HIF1A/METTL3/IGF2BP3/BIRC5 network, METTL3/YTHDF1-mediated m6A modification of IL 24, METTL3/YTHDF2 dynamically catalyzed m6A modification of AKT1, METTL3-mediated m6A-modified oxidative stress, METTL16-mediated m6A modification, site-specific ATG13 methylation-mediated autophagy, and the role of m6A in up-regulating ribosome biogenesis, all come into play in this intricate process. Furthermore, we discuss the direction regarding the interplay between pollutants and RNA metabolism, particularly in immune response, providing new information on RNA modifications for future exploration.
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Adenosina , Carcinogénesis , Contaminantes Ambientales , Animales , Humanos , Adenosina/análogos & derivados , Carcinogénesis/inducido químicamente , Contaminantes Ambientales/toxicidad , ARN/genética , Metilación de ARNRESUMEN
Gastrointestinal cancers are a major global health challenge, with high mortality rates. This study investigated the anti-cancer activities of 30 monomers extracted from Morus alba L. (mulberry) against gastrointestinal cancers. Toxicological assessments revealed that most of the compounds, particularly immunotoxicity, exhibit some level of toxicity, but it is generally not life-threatening under normal conditions. Among these components, Sanggenol L, Sanggenon C, Kuwanon H, 3'-Geranyl-3-prenyl-5,7,2',4'-tetrahydroxyflavone, Morusinol, Mulberrin, Moracin P, Kuwanon E, and Kuwanon A demonstrate significant anti-cancer properties against various gastrointestinal cancers, including colon, pancreatic, and gastric cancers. The anti-cancer mechanism of these chemical components was explored in gastric cancer cells, revealing that they inhibit cell cycle and DNA replication-related gene expression, leading to the effective suppression of tumor cell growth. Additionally, they induced unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, potentially resulting in DNA damage, autophagy, and cell death. Moracin P, an active monomer characterized as a 2-arylbenzofuran, was found to induce ER stress and promote apoptosis in gastric cancer cells, confirming its potential to inhibit tumor cell growth in vitro and in vivo. These findings highlight the therapeutic potential of Morus alba L. monomers in gastrointestinal cancers, especially focusing on Moracin P as a potent inducer of ER stress and apoptosis.
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Neoplasias Gastrointestinales , Morus , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Estrés del Retículo Endoplásmico , Respuesta de Proteína Desplegada , Neoplasias Gastrointestinales/tratamiento farmacológicoRESUMEN
Natural compounds are widely used to prevent and treat various diseases due to their antioxidant and anti-inflammatory effects. As a kind of promising natural compound, plant-derived exosome-like nanoparticles (PELNs) are extracted from multivesicular bodies of various edible plants, including vegetables, foods, and fruits, and mainly regulate the cellular immune response to pathogen attacks. Moreover, PELNs could remarkably interfere with the dynamic imbalance between pro-inflammatory and anti-inflammatory effects, facilitating to maintain the homeostasis of cellular immune microenvironment. PELNs may serve as a better alternative to animal-derived exosomes (ADEs) owing to their widespread sources, cost-effectiveness, and easy accessibility. PELNs can mediate interspecies communication by transferring various cargoes such as proteins, lipids, and nucleic acids from plant cells to mammalian cells. This review summarizes the biogenesis, composition, and classification of exosomes; the common separation, purification, and characterization methods of PELNs, the potential advantages of PELNs over ADEs; and the anti-inflammatory and immunomodulatory functions of PELNs in various diseases including colitis, cancer, and inflammation-associated metabolic diseases. Additionally, the future perspectives of PELNs and the challenges associated with their clinical application are discussed.
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Exosomas , Nanopartículas , Neoplasias , Animales , Exosomas/metabolismo , Sistema Inmunológico/metabolismo , Plantas , Neoplasias/metabolismo , Mamíferos , Microambiente TumoralRESUMEN
BACKGROUND: The past few years have witnessed a significant increase in research related to plant-derived extracellular vesicles (PDEVs) in biological and medical applications. Using biochemical technologies, multiple independent groups have demonstrated the important roles of PDEVs as potential mediators involved in cell-cell communication and the exchange of bio-information between species. Recently, several contents have been well identified in PDEVs, including nucleic acids, proteins, lipids, and other active substances. These cargoes carried by PDEVs could be transferred into recipient cells and remarkably influence their biological behaviors associated with human diseases, such as cancers and inflammatory diseases. This review summarizes the latest updates regarding PDEVs and focuses on its important role in nanomedicine applications, as well as the potential of PDEVs as drug delivery strategies to develop diagnostic and therapeutic agents for the clinical management of diseases, especially like cancers. CONCLUSION: Considering its unique advantages, especially high stability, intrinsic bioactivity and easy absorption, further elaboration on molecular mechanisms and biological factors driving the function of PDEVs will provide new horizons for the treatment of human disease.
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Vesículas Extracelulares , Neoplasias , Humanos , Nanomedicina , Vesículas Extracelulares/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Sistemas de Liberación de Medicamentos , Comunicación CelularRESUMEN
Staging lymph nodes (LN) is crucial in diagnosing and treating cancer metastasis. Biotechnologies for the specific localization of metastatic lymph nodes (MLNs) have attracted significant attention to efficiently define tumor metastases. Bioimaging modalities, particularly magnetic nanoparticles (MNPs) such as iron oxide nanoparticles, have emerged as promising tools in cancer bioimaging, with great potential for use in the preoperative and intraoperative tracking of MLNs. As radiation-free magnetic resonance imaging (MRI) probes, MNPs can serve as alternative MRI contrast agents, offering improved accuracy and biological safety for nodal staging in cancer patients. Although MNPs' application is still in its initial stages, exploring their underlying mechanisms can enhance the sensitivity and multifunctionality of lymph node mapping. This review focuses on the feasibility and current application status of MNPs for imaging metastatic nodules in preclinical and clinical development. Furthermore, exploring novel and promising MNP-based strategies with controllable characteristics could lead to a more precise treatment of metastatic cancer patients.
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Nanopartículas de Magnetita , Neoplasias , Humanos , Neoplasias/diagnóstico por imagen , Fenómenos Físicos , Biotecnología , Ganglios Linfáticos/diagnóstico por imagenRESUMEN
World is witnessing one of the worst pandemics of this century caused by SARS-CoV-2 virus which has affected millions of individuals. Despite rapid efforts to develop vaccines and drugs for COVID-19, the disease is still not under control. Chloroquine (CQ) and Hydroxychloroquine (HCQ) are two very promising inhibitors which have shown positive effect in combating the disease in preliminary experimental studies, but their use was reduced due to severe side-effects. Here, we performed a theoretical investigation of the same by studying the binding of the molecules with SARS-COV-2 Spike protein, the complex formed by Spike and ACE2 human receptor and a human serine protease TMPRSS2 which aids in cleavage of the Spike protein to initiate the viral activation in the body. Both the molecules had shown very good docking energies in the range of -6kcal/mol. Subsequently, we did a high throughput screening for other potential quinoline candidates which could be used as inhibitors. From the large pool of ligand candidates, we shortlisted the top three ligands (binding energy -8kcal/mol). We tested the stability of the docked complexes by running Molecular Dynamics (MD) simulations where we observed the stability of the quinoline analogues with the Spike-ACE2 and TMPRSS2 nevertheless the quinolines were not stable with the Spike protein alone. Thus, although the inhibitors bond very well with the protein molecules their intrinsic binding affinity depends on the protein dynamics. Moreover, the quinolines were stable when bound to electronegative pockets of Spike-ACE2 or TMPRSS2 but not with Viral Spike protein. We also observed that a Fluoride based compound: 3-[3-(Trifluoromethyl)phenyl]quinoline helps the inhibitor to bind with both Spike-ACE2 and TMPRSS2 with equal probability. The molecular details presented in this study would be very useful for developing quinoline based drugs for COVID-19 treatment.
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Extracellular vesicles (EVs) play major roles in intracellular communication and participate in several biological functions in both normal and pathological conditions. Surface modification of EVs via various ligands, such as proteins, peptides, or aptamers, offers great potential as a means to achieve targeted delivery of therapeutic cargo, i.e., in drug delivery systems (DDS). This review summarizes recent studies pertaining to the development of EV-based DDS and its advantages compared to conventional nano drug delivery systems (NDDS). First, we compare liposomes and exosomes in terms of their distinct benefits in DDS. Second, we analyze what to consider for achieving better isolation, yield, and characterization of EVs for DDS. Third, we summarize different methods for the modification of surface of EVs, followed by discussion about different origins of EVs and their role in developing DDS. Next, several major methods for encapsulating therapeutic cargos in EVs have been summarized. Finally, we discuss key challenges and pose important open questions which warrant further investigation to develop more effective EV-based DDS.
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Sistemas de Liberación de Medicamentos/métodos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/fisiología , Exosomas/metabolismo , Exosomas/fisiología , Humanos , Liposomas/aislamiento & purificación , Liposomas/metabolismoRESUMEN
5-lipoxygenase (ALOX5) is an enzyme involved in arachidonic acid (AA) metabolism, a metabolic pathway in which cysteinyl leukotrienes (CysLTs) are the resultant metabolites. Both ALOX5 and CysLTs are clinically significant in a number of inflammatory diseases, such as in asthma and allergic rhinitis, and drugs antagonizing the effect of these molecules have long been successfully used to counter these diseases. Interestingly, recent advances in 'neuroinflammation' research has led to the discovery of several novel inflammatory pathways regulating many cerebral pathologies, including the ALOX5 pathway. By means of pharmacological and genetic studies, both ALOX5 and CysLTs receptors have been shown to be involved in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative/neurological diseases, such as in Parkinson's disease, multiple sclerosis, and epilepsy. In both transgenic and sporadic models of AD, it has been shown that the levels of ALOX5/CysLTs are elevated, and that genetic/pharmacological interventions of these molecules can alleviate AD-related behavioral and pathological conditions. Clinical relevance of these molecules has also been found in AD brain samples. In this review, we aim to summarize such important findings on the role of ALOX5/CysLTs in AD pathophysiology, from both the cellular and the molecular aspects, and also discuss the potential of their blockers as possible therapeutic choices to curb AD-related conditions.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Araquidonato 5-Lipooxigenasa/metabolismo , Asma , Humanos , Leucotrienos/metabolismo , Metabolismo de los LípidosRESUMEN
Plasma free fatty acids levels are increased in subjects with obesity and type 2 diabetes, playing detrimental roles in the pathogenesis of atherosclerosis and cardiovascular diseases. Increasing evidence showing that dysfunction of the vascular endothelium, the inner lining of the blood vessels, is the key player in the pathogenesis of atherosclerosis. In this review, we aimed to summarize the roles and the underlying mechanisms using the evidence collected from clinical and experimental studies about free fatty acid-mediated endothelial dysfunction. Because of the multifaceted roles of plasma free fatty acids in mediating endothelial dysfunction, elevated free fatty acid level is now considered as an important link in the onset of endothelial dysfunction due to metabolic syndromes such as diabetes and obesity. Free fatty acid-mediated endothelial dysfunction involves several mechanisms including impaired insulin signaling and nitric oxide production, oxidative stress, inflammation and the activation of the renin-angiotensin system and apoptosis in the endothelial cells. Therefore, targeting the signaling pathways involved in free fatty acid-induced endothelial dysfunction could serve as a preventive approach to protect against the occurrence of endothelial dysfunction and the subsequent complications such as atherosclerosis.
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Endotelio Vascular/fisiopatología , Ácidos Grasos no Esterificados/metabolismo , Transducción de Señal , Animales , HumanosRESUMEN
Pulmonary neuroendocrine cells (PNECs) are unique airway epithelial cells that blend neuronal and endocrine functions, acting as key sensors in the lung. They respond to environmental stimuli like allergens by releasing neuropeptides and neurotransmitters. PNECs stand out as the only lung epithelial cells innervated by neurons, suggesting a significant role in airway-nerve communication via direct neural pathways and hormone release. Pathological conditions such as asthma are linked to increased PNECs counts and elevated calcitonin gene-related peptide (CGRP) production, which may affect neuroprotection and brain function. CGRP is also associated with neurodegenerative diseases, including Parkinson's and Alzheimer's, potentially due to its influence on inflammation and cholinergic activity. Despite their low numbers, PNECs are crucial for a wide range of functions, highlighting the importance of further research. Advances in technology for producing and culturing human PNECs enable the exploration of new mechanisms and cell-specific responses to targeted therapies for PNEC-focused treatments.
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Aspartame, a widely used artificial sweetener, is present in many food products and beverages worldwide. It has been linked to potential neurotoxicity and developmental defects. However, its teratogenic effect on embryonic development and the underlying potential mechanisms need to be elucidated. We investigated the concentration- and time-dependent effects of aspartame on zebrafish development and teratogenicity. We focused on the role of sirtuin 1 (SIRT1) and Forkhead-box transcription factor (FOXO), two proteins that play key roles in neurodevelopment. It was found that aspartame exposure reduced the formation of larvae and the development of cartilage in zebrafish. It also delayed post-fertilization development by altering the head length and locomotor behavior of zebrafish. RNA-sequencing-based DEG analysis showed that SIRT1 and FOXO3a are involved in neurodevelopment. In silico and in vitro analyses showed that aspartame could target and reduce the expression of SIRT1 and FOXO3a proteins in neuron cells. Additionally, aspartame triggered the reduction of autophagy flux by inhibiting the nuclear translocation of SIRT1 in neuronal cells. The findings suggest that aspartame can cause developmental defects and teratogenicity in zebrafish embryos and reduce autophagy by impairing the SIRT1/FOXO3a axis in neuron cells.
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The cGAS-STING signaling pathway has emerged as a critical mediator of innate immune responses, playing a crucial role in improving antitumor immunity through immune effector responses. Targeting the cGAS-STING pathway holds promise for overcoming immunosuppressive tumor microenvironments (TME) and promoting effective tumor elimination. However, systemic administration of current STING agonists faces challenges related to low bioavailability and potential adverse effects, thus limiting their clinical applicability. Recently, nanotechnology-based strategies have been developed to modulate TMEs for robust immunotherapeutic responses. The encapsulation and delivery of STING agonists within nanoparticles (STING-NPs) present an attractive avenue for antitumor immunotherapy. This review explores a range of nanoparticles designed to encapsulate STING agonists, highlighting their benefits, including favorable biocompatibility, improved tumor penetration, and efficient intracellular delivery of STING agonists. The review also summarizes the immunomodulatory impacts of STING-NPs on the TME, including enhanced secretion of pro-inflammatory cytokines and chemokines, dendritic cell activation, cytotoxic T cell priming, macrophage re-education, and vasculature normalization. Furthermore, the review offers insights into co-delivered nanoplatforms involving STING agonists alongside antitumor agents such as chemotherapeutic compounds, immune checkpoint inhibitors, antigen peptides, and other immune adjuvants. These platforms demonstrate remarkable versatility in inducing immunogenic responses within the TME, ultimately amplifying the potential for antitumor immunotherapy.
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COVID-19 is an infectious disease caused by the novel coronavirus (SARS-CoV-2) that first appeared in late 2019 and has since spread across the world. It is characterized by symptoms such as fever, cough, and shortness of breath and can lead to death in severe cases. To help contain the virus, measures such as social distancing, handwashing, and other public health measures have been implemented. Vaccine and drug candidates, such as those developed by Pfizer/BioNTech, AstraZeneca, Moderna, Novavax, and Johnson & Johnson, have been developed and are being distributed worldwide. Clinical trials for drug treatments such as remdesivir, dexamethasone, and monoclonal antibodies are underway and have shown promising results. Recently, exosomes have gained attention as a possible mediator of the COVID-19 infection. Exosomes, small vesicles with a size of around 30-200 nm, released from cells, contain viral particles and other molecules that can activate the immune system and/or facilitate viral entry into target cells. Apparently, the role of exosomes in eliciting various immune responses and causing tissue injury in COVID-19 pathogenesis has been discussed. In addition, the potential of exosomes as theranostic and therapeutic agents for the treatment of COVID-19 has been elaborated.
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BACKGROUND: Endothelial dysfunction is implicated in various inflammatory diseases such as ischemic stroke, heart attack, organ failure, and COVID-19. Recent studies have shown that endothelial dysfunction in the brain is attributed to excessive inflammatory responses caused by the SARS-CoV-2 infection, leading to increased permeability of the blood-brain barrier and consequently neurological damage. Here, we aim to examine the single-cell transcriptomic landscape of endothelial dysfunction in COVID-19 and its implications for glioblastoma (GBM) progression. METHODS: Single-cell transcriptome data GSE131928 and GSE159812 were obtained from the gene expression omnibus (GEO) to analyze the expression profiles of key players in innate immunity and inflammation between brain endothelial dysfunction caused by COVID-19 and GBM progression. RESULTS: Single-cell transcriptomic analysis of the brain of COVID-19 patients revealed that endothelial cells had undergone significant transcriptomic changes, with several genes involved in immune responses and inflammation upregulated. Moreover, transcription factors were observed to modulate this inflammation, including interferon-regulated genes. CONCLUSIONS: The results indicate a significant overlap between COVID-19 and GBM in the context of endothelial dysfunction, suggesting that there may be an endothelial dysfunction link connecting severe SARS-CoV-2 infection in the brain to GBM progression.
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Background: Chemotherapy is one of the primary treatments for ovarian cancer patients. Autophagy has been linked to chemotherapy resistance in tumor cells. Recent studies have suggested that fibroblast growth factor 19 (FGF19) may be involved in the onset and progression of malignancies. However, the relationship between FGF19 and autophagy in ovarian cancer is still unknown. Methods: Next-generation sequencing (NGS) was conducted to analyze gene mutation profiles of 62 cases of high grade serous ovarian cancer (HGSOC). Fluorescence in situ hybridization (FISH) was performed to validate the amplification of FGF19 in HGSOC tissues. Quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to analyze the difference of FGF19 in mRNA and protein expression. Meanwhile, bioinformatics techniques were used to analyze the expression profiles of FGF19 and the correlation with prognosis. Besides, immunofluorescence, transmission electron microscopy and Cell Counting Kit 8 (CCK-8) were used to investigate the potential mechanisms. Results: In this study, we found that FGF19 promotes cisplatin resistance in ovarian cancer cells by inducing autophagy. NGS analysis of 62 HGSOC cases identified a significantly amplified gene, FGF19. In addition, the expression level of FGF19 in ovarian cancer samples was higher than that in normal samples. FISH results showed a positive correlation between amplification and expression of FGF19. Knockdown of FGF19 inhibited the cell autophagy through decrease in the expression of LC3 and Beclin 1, and increase in the expression of SQSTM1/p62. Furthermore, we observed that p38 MAPK phosphorylation was down-regulated after FGF19 knockdown. IFN-γ, a potential p38 MAPK activator, counteracted the inhibition of cell autophagy and the anti-proliferation effect of cisplatin induced by FGF19 knockdown in ovarian cancer cells. Conclusion: FGF19 increases autophagy and chemoresistance in ovarian cancer by activating the p38 MAPK pathway. These results could point to FGF19 being a potential therapeutic target for ovarian cancer.
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Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , Cisplatino , Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Hibridación Fluorescente in Situ , Línea Celular Tumoral , Neoplasias Ováricas/tratamiento farmacológico , Autofagia , Factores de Crecimiento de Fibroblastos/genéticaRESUMEN
Background: Immune cell death (ICD) is a type of tumor cell death that has recently been shown to activate and regulate tumor immunity. However, the role of ICD-related long non-coding RNAs (lncRNAs) in gastric cancer remains to be clarified. Methods: We obtained 375 tumor samples from the Cancer Genome Atlas (TCGA) database and randomly assigned them to training and verification groups. LASSO and Cox regression analysis were utilized to identify ICD-related lncRNAs and establish a risk model. The changes in the immune microenvironment of the two groups were compared by examining the tumor-infiltrating immune cells. Results: We established a tumor signature based on nine ICD-related lncRNAs. In light of the receiver operating characteristic and Kaplan-Meier curves, the prognostic values of this risk model were verified. Multivariate regression analysis showed that the risk score was an independent risk factor for the prognosis of patients in both the training cohort (HR 2.52; 95% CI: 1.65-3.87) and validation cohort (HR 2.70; 95% CI: 1.54-4.8). A nomogram was developed to predict the 1-, 3-, and 5-year survival of patients with gastric cancer, and the signature was linked to high levels of immunological checkpoint expression (B7-H3, VSIR). Conclusions: An ICD-related lncRNA signature could predict the immune response and prognosis of patients with gastric cancer. This prognostic signature could be employed to independently monitor the efficacy of immunotherapy for gastric cancer patients.
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BACKGROUND: It is critical to understand the mechanisms of human cancers in order to develop the effective anti-cancer therapeutic strategies. Recent studies indicated that primase polymerase (PRIMPOL) is strongly associated with the development of human cancers. Nevertheless, a systematic pan-cancer analysis of PRIMPOL remains to be further clarified. METHOD: Comprehensive multi-omics bioinformatics algorithms, such as TIMER2.0, GEPIA2.0 and cBioPortal, were utilized to evaluate the biological roles of PRIMPOL in pan-cancer, including the expression profiles, genomic alterations, prognostic values and immune regulation. RESULTS: PRIMPOL was upregulated in glioblastoma multiforme and kidney renal clear cell carcinoma. The brain lower grade glioma patients with enhanced PRIMPOL expression displayed poor prognostic values. We also demonstrated the PRIMPOL's immunomodulating effects on pan-cancer as well as its genomic changes and methylation levels. The aberrant expression of PRIMPOL was linked to various cancer-associated pathways, including DNA damage response, DNA repair, and angiogenesis, according to single-cell sequencing and function enrichment. CONCLUSIONS: This pan-cancer analysis offers a thorough review of the functional roles of PRIMPOL in human cancers, suggesting PRIMPOL as a potentially important biomarker for the progression and immunotherapy of various cancers.