RESUMO
BACKGROUND: Chemokine (C-C motif) receptor 8 (CCR8) is a chemokine receptor selectively expressed on tumor-infiltrating regulatory T cells (Tregs). Strong immunosuppression mediated by CCR8+ Tregs observed in breast and lung malignancies suggest for their functional significance in cancer therapy. To date, detailed characterization of tumor-infiltrating CCR8+ Tregs cells in colorectal cancer (CRC) is limited. METHODS: To study the presence and functional involvement of CCR8+ Tregs in CRC, we analyzed the proportions of CCR8-expressing T cells in different T cell subsets in tumor and adjacent normal tissues and peripheral blood mononuclear cells (PBMCs) from CRC patients by Flow cytometry. Also, we compared the distribution of CCR8+ T cells in malignant tissues and peripheral lymphoid organs from a subcutaneous CRC murine model. Bioinformatic analysis was performed to address the significance of CCR8 expression levels in CRC prognosis, immune regulatory gene expression profiles and potential molecular mechanisms associated with CCR8+ Tregs in CRC tumors. Further, we administrated an anti-CCR8 monoclonal antibody to CT26 tumor-bearing mice and examined the antitumor activity of CCR8-targeted therapy both in vivo and in an ex vivo confirmative model. RESULTS: Here, we showed that Tregs was predominantly presented in the tumors of CRC patients (13.4 ± 5.8, p < 0.0001) and the CRC subcutaneous murine model (35.0 ± 2.6, p < 0.0001). CCR8 was found to be preferentially expressed on these tumor-infiltrating Tregs (CRC patients: 63.6 ± 16.0, p < 0.0001; CRC murine model: 65.3 ± 9.5, p < 0.0001), which correlated with poor survival. We found that majority of the CCR8+ Tregs expressed activation markers and exhibited strong suppressive functions. Treatment with anti-CCR8 antibody hampered the growth of subcutaneous CRC tumor through effectively restoring the anti-tumor immunity of CD4+ conventional T cells (CD4+ Tconvs) and CD8+ T cells, which was confirmed in the ex vivo examinations. CONCLUSIONS: Collectively, these findings illustrate the importance of CCR8+ Tregs for an immunosuppressive microenvironment in CRC tumors by functional inhibition of CD4+ Tconvs and CD8+ T cells, and suggest for the applicable value of CCR8-targeted therapy for CRC.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias Colorretais , Linfócitos do Interstício Tumoral , Receptores CCR8 , Linfócitos T Reguladores , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Imunidade , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos BALB C , Linfócitos T Reguladores/imunologia , IdosoRESUMO
Chemotherapy is one of the primary treatments for malignant tumors. However, the acquired drug resistance hinders clinical efficacy and leads to treatment failure in most patients. Exosomes are cell-derived vesicles with a diameter of 30-150 nm carrying and delivering substances such as DNAs, RNAs, lipids, and proteins for cellular communication in tumor development. Circular RNAs (circRNAs) present covalently closed-loop RNA structures, which regulate tumor cell proliferation, apoptosis, and metastasis by controlling different genes and signaling pathways. CircRNAs are abundant and stably expressed in exosomes. Recent studies have shown that they play critical roles in chemotherapy resistance in various cancers. In this review, we summarized the origin of exosomes and discussed the regulation mechanism of exosomal circRNAs in cancer drug resistance.
Assuntos
Exossomos , Neoplasias , Humanos , RNA Circular/genética , RNA Circular/metabolismo , RNA/genética , RNA/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Exossomos/genética , Transdução de Sinais/genéticaRESUMO
Chronic prostatitis/chronic pelvic pain syndrome(CP/CPPS) is a common urological disease with complex etiology. The treatment effect of western medicine is not satisfactory, and the course of the disease is protracted, which brings great trouble to patients. Traditional Chinese medicine(TCM) has a variety of treatment methods based on syndrome differentiation and treatment, including internal treatment with TCM, acupuncture and massage, and other external treatment methods for comprehensive treatment, with significant effect. This study summarized the etiology and pathogenesis of CP/CPPS and found that western medicine cannot fully explain the etiology and pathogenesis of CP/CPPS. It was believed that CP/CPPS was mainly related to many factors such as special pathogen infection, voiding dysfunction, mental and psychological abnormalities, neuroendocrine abnormalities, immune abnormalities, excessive oxidative stress, pelvic diseases, and heredity. TCM believed that CP/CPPS was caused by damp heat, blood stasis, Qi stagnation, and poisoning and was closely related to the organs of the liver, spleen, kidney, lung, stomach, bladder, and meridians of Chong and Ren channels and three yin channels of the foot. In the treatment of TCM, multiple comprehensive treatment plans are currently used, including internal treatment with TCM(decoction, proprietary Chinese medicine, and unique therapies of famous doctors), acupuncture and massage treatment, and other external treatment methods(rectal administration, topical application of TCM, and ear acupoint pressure). Comprehensive regulation has significant clinical efficacy and prominent characteristics of TCM, and it is worth clinical promotion. This study aims to provide a reference for clinical prevention and treatment of CP/CPPS and points out potential directions for future research in this field.
Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Dor Pélvica , Prostatite , Humanos , Prostatite/terapia , Prostatite/tratamento farmacológico , Dor Pélvica/terapia , Dor Pélvica/tratamento farmacológico , Masculino , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Doença Crônica , Terapia por AcupunturaRESUMO
Tumor immunotherapy exerts its anti-tumor effects by stimulating and enhancing immune responses of the body. It has become another important modality of anti-tumor therapy with significant clinical efficacy and advantages compared to chemotherapy, radiotherapy and targeted therapy. Although various kinds of tumor immunotherapeutic drugs have emerged, the challenges faced in the delivery of these drugs, such as poor tumor permeability and low tumor cell uptake rate, had prevented their widespread application. Recently, nanomaterials had emerged as a means for treatment of different diseases due to their targeting properties, biocompatibility and functionalities. Moreover, nanomaterials possess various characteristics that overcome the defects of traditional tumor immunotherapy, such as large drug loading capacity, precise tumor targeting and easy modification, thus leading to their wide application in tumor immunotherapy. There are two main classes of novel nanoparticles mentioned in this review: organic (polymeric nanomaterials, liposomes and lipid nanoparticles) and inorganic (non-metallic nanomaterials and metallic nanomaterials). Besides, the fabrication method for nanoparticles, Nanoemulsions, was also introduced. In summary, this review article mainly discussed the research progress of tumor immunotherapy based on nanomaterials in the past few years and offers a theoretical basis for exploring novel tumor immunotherapy strategies in the future.
Assuntos
Imunoterapia , Nanoestruturas , Humanos , Nanoestruturas/uso terapêutico , Transporte BiológicoRESUMO
Vitellogenin receptors (VgRs) play crucial roles in oogenesis by mediating endocytosis of vitellogenin and other nutrients in ovipara. We conducted small RNA sequencing and screening with a luciferase reporter system, and found that bmo-miR-2739 and a novel miRNA (novel-miR-167) coordinately regulate the expression of VgR in Bombyx mori (BmVgR). Further analyses suggested that these two miRNAs direct target repression by binding directly to the BmVgR 3' untranslated region. Forced expression of either miRNA using the piggyBac system blocked vitellogenin (Vg) transport and retarded ovariole development. Antagomir silencing of bmo-miR-2739 or novel-miR-167 resulted in increased amounts of BmVgR protein in the ovaries and BmVgR mRNA in the fat body. This evidence, combined with spatiotemporal expression profiles, revealed that these two miRNAs function together to fine-tune the amount of BmVgR protein for ovarian development. Additionally, novel-miR-167 was mainly responsible for the post-transcriptional repression of BmVgR in non-ovarian tissues. The results of this study contribute to our understanding of the function of miRNAs during ovarian development of a lepidopteran and suggest a new strategy for controlling insect reproduction.
Assuntos
Bombyx/genética , Proteínas do Ovo/genética , Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/genética , Oogênese/genética , Receptores de Superfície Celular/genética , Regiões 3' não Traduzidas/genética , Animais , Animais Geneticamente Modificados , Proteínas do Ovo/metabolismo , Genes Reporter , Luciferases/metabolismo , MicroRNAs/metabolismo , Modelos Biológicos , Óvulo/metabolismo , Ligação Proteica , Receptores de Superfície Celular/metabolismoRESUMO
The genetic regulatory basis of qualitative and quantitative phenotypes of watermelon is being investigated in different types of molecular and genetic breeding studies around the world. In this study, biparental F2 mapping populations were developed over two experimental years, and the collected datasets of fruit and seed traits exhibited highly significant correlations. Whole-genome resequencing of comparative parental lines was performed and detected single nucleotide polymorphism (SNP) loci were converted into cleaved amplified polymorphic sequence (CAPS) markers. The screened polymorphic markers were genotyped in segregating populations and two genetic linkage maps were constructed, which covered a total of 2834.28 and 2721.45 centimorgan (cM) genetic lengths, respectively. A total of 22 quantitative trait loci (QTLs) for seven phenotypic traits were mapped; among them, five stable and major-effect QTLs (PC-8-1, SL-9-1, SWi-9-1, SSi-9-1, and SW-6-1) and four minor-effect QTLs (PC-2-1 and PC-2-2; PT-2-1 and PT-2-2; SL-6-1 and SSi-6-2; and SWi-6-1 and SWi-6-2) were observed with 3.77-38.98% PVE. The adjacent QTL markers showed a good fit marker-trait association, and a significant allele-specific contribution was also noticed for genetic inheritance of traits. Further, a total of four candidate genes (Cla97C09G179150, Cla97C09G179350, Cla97C09G180040, and Cla97C09G180100) were spotted in the stable colocalized QTLs of seed size linked traits (SL-9-1 and SWi-9-1) that showed non-synonymous type mutations. The gene expression trends indicated that the seed morphology had been formed in the early developmental stage and showed the genetic regulation of seed shape formation. Hence, we think that our identified QTLs and genes would provide powerful genetic insights for marker-assisted breeding aimed at improving the quality traits of watermelon.
Assuntos
Citrullus , Frutas , Mapeamento Cromossômico , Frutas/genética , Citrullus/genética , Ligação Genética , Melhoramento Vegetal , Sementes/genética , GenômicaRESUMO
BACKGROUND: Dysregulated activation of the inflammasome is involved in various human diseases including acute cerebral ischemia, multiple sclerosis and sepsis. Though many inflammasome inhibitors targeting NOD-like receptor protein 3 (NLRP3) have been designed and developed, none of the inhibitors are clinically available. Growing evidence suggests that targeting apoptosis-associated speck-like protein containing a CARD (ASC), the oligomerization of which is the key event for the assembly of inflammasome, may be another promising therapeutic strategy. Lonidamine (LND), a small-molecule inhibitor of glycolysis used as an antineoplastic drug, has been evidenced to have anti-inflammation effects. However, its anti-inflammatory mechanism is still largely unknown. METHODS: Middle cerebral artery occlusion (MCAO), experimental autoimmune encephalomyelitis (EAE) and LPS-induced sepsis mice models were constructed to investigate the therapeutic and anti-inflammasome effects of LND. The inhibition of inflammasome activation and ASC oligomerization by LND was evaluated using western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) in murine bone marrow-derived macrophages (BMDMs). Direct binding of LND with ASC was assessed using molecular mock docking, surface plasmon resonance (SPR), and drug affinity responsive target stability (DARTS). RESULTS: Here, we find that LND strongly attenuates the inflammatory injury in experimental models of inflammasome-associated diseases including autoimmune disease-multiple sclerosis (MS), ischemic stroke and sepsis. Moreover, LND blocks diverse types of inflammasome activation independent of its known targets including hexokinase 2 (HK2). We further reveal that LND directly binds to the inflammasome ligand ASC and inhibits its oligomerization. CONCLUSIONS: Taken together, our results identify LND as a broad-spectrum inflammasome inhibitor by directly targeting ASC, providing a novel candidate drug for the treatment of inflammasome-driven diseases in clinic.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Sepse , Humanos , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológicoRESUMO
As a crucial living feature inhabiting the soil-atmosphere boundary, biocrusts play a vital role in liquid water or vapor transport through surface soil and thus have strong effects on soil water regimes. However, it remains unclear how biocrusts affect annual or multiyear soil water budgets through the regulation of evaporation outputs and non-rainfall water (NRW) or infiltration inputs. Thus, we used automated microlysimeters to continually investigate the differences in evaporation and NRW rates between moss-dominated biocrusts and bare soil at 0-5 cm depth for 2 years. The upper 30 cm of soil moisture (θ) and water storage (W) of bare soil and biocrusts were also monitored. Our results showed that the daily evaporation rate (E) of biocrusts was 17% higher than bare soil. Especially after rainfall events, biocrusts had higher E and larger cumulative evaporation than bare soil. Besides, the daily NRW of biocrusts averaged 15% higher than bare soil over 2 years. Furthermore, biocrusts increased θ by 11%-76% at 0-10 cm depth but decreased θ by 32%-56% at 20-30 cm depth in comparison to bare soil, and they subsequently decreased W by 20% at 0-30 cm depth. Summarized annually, the NRW amount of biocrusts was 19% higher than bare soil, but at the same time, the cumulative evaporation of biocrusts was also 19% higher than bare soil. Finally, biocrusts resulted in more water loss at shallow depth through evaporation and lessened total W throughout 0-30 cm depth of soil. These findings demonstrate that although biocrusts input more NRW into surface soil, these water inputs partially offset their intensified evaporation. Given that all rainfall water infiltrates into the soil in our study system, our findings indicate that biocrusts may have an overall negative effect on soil water balance there, while at the same time increasing water storage and availability of the deeper soil underlying biocrusts.
Assuntos
Briófitas , Solo , Briófitas/fisiologia , Ecossistema , Microbiologia do Solo , ÁguaRESUMO
With the economy's globalization and the population's aging, cancer has become the leading cause of death in most countries. While imposing a considerable burden on society, the high morbidity and mortality rates have continuously prompted researchers to develop new oncology treatment options. Anti-tumor regimens have evolved from early single surgical treatment to combined (or not) chemoradiotherapy and then to the current stage of tumor immunotherapy. Tumor immunotherapy has undoubtedly pulled some patients back from the death. However, this strategy of activating or boosting the body's immune system hardly benefits most patients. It is limited by low bioavailability, low response rate and severe side effects. Thankfully, the rapid development of nanotechnology has broken through the bottleneck problem of anti-tumor immunotherapy. Multifunctional nanomaterials can not only kill tumors by combining anti-tumor drugs but also can be designed to enhance the body's immunity and thus achieve a multi-treatment effect. It is worth noting that the variety of nanomaterials, their modifiability, and the diversity of combinations allow them to shine in antitumor immunotherapy. In this paper, several nanobiotics commonly used in tumor immunotherapy at this stage are discussed, and they activate or enhance the body's immunity with their unique advantages. In conclusion, we reviewed recent advances in tumor immunotherapy based on nanomaterials, such as biological cell membrane modification, self-assembly, mesoporous, metal and hydrogels, to explore new directions and strategies for tumor immunotherapy.
Assuntos
Antineoplásicos , Nanoestruturas , Neoplasias , Humanos , Imunoterapia , Neoplasias/tratamento farmacológico , Nanotecnologia , Nanoestruturas/uso terapêutico , Antineoplásicos/uso terapêuticoRESUMO
Osteosarcoma occurs largely in children and adolescents and is the most common primary malignant tumour of bone. Although surgical advances and neoadjuvant chemotherapy have made great strides in recent years, rates of local recurrence and lung metastasis remain high, with a plateau in overall survival during the past decade. It is thus urgent to explore the pathogenesis of osteosarcoma and identify potential therapeutic targets. Parathyroid hormone receptor 1 (PTHR1) belongs to the broad family of G protein-coupled receptors, binding both parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP, a paracrine factor). Previous studies have shown that in tissues and cells of osteosarcoma, expression of PTHR1 is markedly increased, correlating with aggressive biologic behaviour and a poor prognosis. PTHR1 expression also correlates closely with epigenetic regulation, transcriptional regulation, post-translational modification and protein interaction. Herein, we have summarized the latest research on the role played by PTHR1 in progression of osteosarcoma, assessing its clinical utility as a novel biomarker and its therapeutic ramifications.
Assuntos
Neoplasias Ósseas/metabolismo , Osteossarcoma/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Humanos , Osteossarcoma/genética , Osteossarcoma/patologia , Osteossarcoma/terapia , Terapêutica com RNAi/métodos , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismoRESUMO
This study aimed to determine the interactions between parathyroid hormone type 1 receptor (PTHR1) and angiotensinogen (AGT) and the effects of these agents on osteosarcoma (OS). We constructed a stably transfected mouse OS K7M2 cell line (shPTHR1- K7M2) using shRNA and knocked down AGT in these cells using siRNA-AGT. The transfection efficiency and expression of AGT, chemokine C-C motif receptor 3 (CCR3), and chemokine (C-C motif) ligand 9 (CCL9) were determined using real-time quantitative PCR. Cell viability and colony formation were assessed using Cell Counting Kit-8 and crystal violet staining, respectively. Cell apoptosis and cycle phases were assessed by flow cytometry, and cell migration and invasion were evaluated using Transwell assays. Interference with PTHR1 upregulated the expression of AGT and CCR3, and downregulated that of CCL9, which was further downregulated by AGT knockdown. Cell viability, migration, invasion and colony formation were significantly decreased, while cell apoptosis was significantly increased in shPTHR1-K7M2, compared with those in K7M2 cells (P < .05 for all). However, AGT knockdown further inhibited cell viability after 72 h of culture but promoted cell migration and invasion. PTHR1 interference decreased and increased the numbers of cells in the G0/G1 and G2/M phases, respectively, compared with those in K7M2 cells. Angiotensinogen knockdown increased the number of cells in the G0/G1 phase compared with that in the shPTHR1-K7M2 cells. Therefore, PTHR1 affects cell viability, apoptosis, migration, invasion and colony formation, possibly by regulating AGT/CCL9 in OS cells.
Assuntos
Angiotensinogênio/metabolismo , Osteossarcoma/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Angiotensinogênio/genética , Animais , Apoptose , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Expressão Gênica , Técnicas de Silenciamento de Genes , Camundongos , Hormônio Paratireóideo/metabolismo , Ligação Proteica , RNA Interferente Pequeno/genética , Receptor Tipo 1 de Hormônio Paratireóideo/genéticaRESUMO
Clinically, it is difficult to efficaciously screen and diagnose osteosarcoma (OS) in advance due to the low sensitivity and poor specificity of the existing tumor markers. Exosomes (Exos) are nanoscale vesicles containing RNAs, lipids, and proteins with a diameter of 30-100 nm. They are multivesicular bodies formed during the invagination of lysosomal particles in cells and released extracellularly after fusing with cell membranes. Besides, Exos are important carriers of cell-to-cell communication signals and genetic materials in the tumor microenvironment. During tumorigenesis, the tumor cells interplay with immune cells, endothelial cells, and related fibroblasts through Exos and boost cancer development. After altering the surrounding microenvironment, the Exos drive tumor cells to proliferate, speed up angiogenesis, and boost cancers to develop along with body fluid transportation. Currently, Exos are becoming novel noninvasive tumor diagnostic markers with high sensitivity, exerting pivotal impacts in fundamental research and clinical applications. Here, we review the existing literature on the roles of exosomal noncoding RNAs in OS progression and their potential clinical applications as novel biomarkers and therapeutics.
Assuntos
Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica/genética , Osteossarcoma/genética , Microambiente Tumoral/genética , Carcinogênese/genética , Humanos , RNA Longo não Codificante/genéticaRESUMO
BACKGROUND: Circular RNAs (circRNAs), a class of noncoding RNAs (ncRNAs), may modulate gene expression by binding to miRNAs. Additionally, recent studies show that circRNAs participate in some pathological processes. However, there is a large gap in the knowledge about circDOCK1 expression and its biological functions in osteogenic sarcoma (OS). METHODS: Differentially expressed circRNAs in OS cell lines and tissues were identified by circRNA microarray analysis and quantitative real-time PCR (qRT-PCR). To explore the actions of circDOCK1 in vivo and in vitro, circDOCK1 was knocked down or overexpressed. To assess the binding and regulatory associations among miR-339-3p, circDOCK1 and IGF1R, we performed rescue experiments, RNA immunoprecipitation (RIP), RNA pulldown assays and dual-luciferase assays. Moreover, we performed apoptosis assays to reveal the regulatory effects of the circDOCK1/miR-339-3p/IGF1R axis on cisplatin sensitivity. RESULTS: CircDOCK1 expression remained stable in the cytoplasm and was higher in OS tissues and cells than in the corresponding controls. Overexpression of circDOCK1 increased oncogenicity in vivo and malignant transformation in vitro. In the U2OS and MG63 cell lines, circDOCK1 modulated tumor progression by regulating IGF1R through sponging of miR-339-3p. Additionally, in the U2OS/DDP and MG63/DDP cell lines, cisplatin sensitivity was regulated by circDOCK1 via the miR-339-3p/IGF1R axis. CONCLUSIONS: CircDOCK1 can promote progression and regulate cisplatin sensitivity in OS via the miR-339-3p/IGF1R axis. Thus, the circDOCK1/miR-339-3p/IGF1R axis may be a key mechanism and therapeutic target in OS.
Assuntos
Neoplasias Ósseas/etiologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Osteossarcoma/etiologia , RNA Circular/genética , Receptor IGF Tipo 1/genética , Proteínas rac de Ligação ao GTP/genética , Animais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Cisplatino/farmacologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Camundongos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Interferência de RNA , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Potent neutralizing antibodies (Abs) have been proven with therapeutic efficacy for the intervention against SARS-CoV-2. Majority of these Abs function by directly interfering with the virus entry to host cells. Here, we identified a receptor binding domain (RBD) specific monoclonal Ab (mAb) 82A6 with efficient neutralizing potency against authentic SARS-CoV-2 virus. As most Abs targeting the non-receptor binding motif (RBM) region, 82A6 was incapable to block the RBD-ACE2 interaction. In particular, it actively promoted the S1 subunit shedding from the S protein, which may lead to effective reduction of intact SARS-CoV-2 viruses. Importantly, it could block potential syncytia formation associated with post-infectious cell surface expression of S proteins. Our study evidenced a RBD specific Ab with unique beneficial efficacy against SARS-CoV-2 infection, which might bring informative significance to understand the collective effects of neutralizing Abs elicited in COVID-19 patients.
Assuntos
Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , COVID-19/terapia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Monoclonais/uso terapêutico , Especificidade de Anticorpos , Sítios de Ligação/imunologia , COVID-19/imunologia , COVID-19/virologia , Células Gigantes/imunologia , Células Gigantes/virologia , Células HEK293 , Humanos , Imunização Passiva , Técnicas In Vitro , Domínios Proteicos , Subunidades Proteicas , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/química , Eliminação de Partículas Virais , Soroterapia para COVID-19RESUMO
Bone sarcomas are rare cancers accompanied by metastatic disease, mainly including osteosarcoma, Ewing sarcoma and chondrosarcoma. Extracellular vesicles (EVs) are membrane vesicles released by cells in the extracellular matrix, which carry important signal molecules, can stably and widely present in various body fluids, such as plasma, saliva and scalp fluid, spinal cord, breast milk, and urine liquid. EVs can transport almost all types of biologically active molecules (DNA, mRNA, microRNA (miRNA), proteins, metabolites, and even pharmacological compounds). In this review, we summarized the basic biological characteristics of EVs and focused on their application in bone sarcomas. EVs can be use as biomarker vehicles for diagnosis and prognosis in bone sarcomas. The role of EVs in bone sarcoma has been analyzed point-by-point. In the microenvironment of bone sarcoma, bone sarcoma cells, mesenchymal stem cells, immune cells, fibroblasts, osteoclasts, osteoblasts, and endothelial cells coexist and interact with each other. EVs play an important role in the communication between cells. Based on multiple functions in bone sarcoma, this review provides new ideas for the discovery of new therapeutic targets and new diagnostic analysis.
Assuntos
Neoplasias Ósseas/patologia , Vesículas Extracelulares/metabolismo , Osteossarcoma/patologia , Biomarcadores/metabolismo , Neoplasias Ósseas/diagnóstico , Colágeno Tipo VI/metabolismo , Vesículas Extracelulares/genética , Humanos , MicroRNAs/metabolismo , Osteossarcoma/diagnóstico , Prognóstico , Microambiente TumoralRESUMO
OBJECTIVES: This study aimed to investigate the roles of adipose mesenchymal stem cell (AMSC)-derived extracellular vesicles (EVs) binding with chitosan oligosaccharides (COS) in cartilage injury, as well as the related mechanisms. RESULTS: IL-1ß treatment significantly inhibited the viability and migration of chondrocytes and enhanced cell apoptosis (P < 0.05), while chitosan oligosaccharides and extracellular vesicles-chitosan oligosaccharide conjugates (EVs-COS/EVs-COS conjugates) reversed the changes induced by IL-1ß (P < 0.05), and the effects of extracellular vesicles-chitosan oligosaccharide conjugates were better than those of chitosan oligosaccharides (P < 0.05). After cartilage damage, IL-1ß, OPN, and p53 were significantly upregulated, COL1A1, COL2A1, OCN, RUNX2, p-Akt/Akt, PI3K, c-Myc, and Bcl2 were markedly downregulated, and extracellular vesicles-chitosan oligosaccharide conjugates reversed the expression induced by cartilage injury. Through sequencing, 760 differentially expressed genes (DEGs) clustered into four expression patterns were associated with negative regulation of the canonical Wnt, PI3K-Akt, AMPK, and MAPK signaling pathways. CONCLUSION: Extracellular vesicles-chitosan oligosaccharide conjugates may serve as a new cell-free biomaterial to facilitate cartilage injury repair and improve osteoarthritis.
Assuntos
Cartilagem , Quitosana , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Cartilagem/efeitos dos fármacos , Cartilagem/lesões , Cartilagem/metabolismo , Células Cultivadas , Quitosana/química , Quitosana/farmacologia , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Vesículas Extracelulares/química , Feminino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Oligossacarídeos/química , Oligossacarídeos/farmacologia , Osteoartrite/metabolismo , Ratos , Ratos Wistar , Organismos Livres de Patógenos Específicos , Transcriptoma/genética , Cicatrização/efeitos dos fármacosRESUMO
BACKGROUND: Extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSCs) may play a vital role in a variety of biological processes, including cartilage regeneration. However, few studies reported their potential in the development of osteoarthritis (OA) previously. In this study, we explored the biological roles and underlying mechanism of MSCs-EVs in OA. RESULTS: Co-culture experiments revealed that MSCs-EVs could promote the expression of collagen type II alpha 1 chain (COL2A1), SRY-box transcription factor 9 (SOX9) and Aggrecan while negatively regulate the expression of chondrocyte hypertrophy markers matrix metallopeptidase 13 (MMP-13) and RUNX family transcription factor 2 (Runx2) in mouse chondrocytes in the OA model. Besides, the results of cell experiments indicated that MSCs-EVs could notably weaken the suppression of chondrocyte proliferation, migration and the promotion of chondrocyte apoptosis via interleukin1ß (IL-1ß) induction. In addition, MSCs-circHIPK3-EVs (EVs derived from MSCs overexpressing circHIPK3) considerably improved IL-1ß-induced chondrocyte injury. Mechanistically, we elucidated that circHIPK3 could directly bind to miR-124-3p and subsequently elevate the expression of the target gene MYH9. CONCLUSION: The findings in our study demonstrated that EVs-circHIPK3 participated in MSCs-EVs-mediated chondrocyte proliferation and migration induction and in chondrocyte apoptosis inhibition via the miR-124-3p/MYH9 axis. This offers a promising novel cell-free therapy for treating OA.
Assuntos
Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Osteoartrite/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Apoptose , Cartilagem/metabolismo , Movimento Celular , Proliferação de Células , Condrócitos/metabolismo , Técnicas de Cocultura , Colágeno Tipo II/metabolismo , Técnicas de Silenciamento de Genes , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Cadeias Pesadas de Miosina/genética , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Under the microenvironment, tumour progression is substantially affected by cell-cell communication. In spite of the mediating effect of extracellular nanovesicles (EVs) on cell-cell communication by packaging into circRNAs, the effect of EVs circRNA hsa_circ_0000190 (circ-0000190) in osteosarcoma is still not clear. Circ-0000190 expressions in tissues and EVs from plasma were compared between osteosarcoma patients and controls. Thereafter, receiver operating characteristic (ROC) curve was drawn and area under the curve was calculated to examine whether the diagnostic results were accurate, and the effect of EVs circ-0000190 was dug out via the determination of cell phenotypes and animal assays. Results showed circ-0000190 exhibited an obvious reduction in EVs and tissues of osteosarcoma patients (P < .05). It was also discovered that EVs encapsulated the majority of circ-0000190, and EVs-encapsulated circ-0000190 could be applied to make a distinction between osteosarcoma patients and controls. Besides, EVs circ-0000190 in osteosarcoma cells transported from normal cells weakened the capacities of osteosarcoma cells to migrate, proliferate and invade, so as to block their biological malignant behaviours (P < .05). In addition, under the action of EVs circ-0000190, tumour growth was impeded and the expression of TET1 was inhibited via the competitive binding to miR-767-5p. In all, EVs circ-0000190 has a good prospect as it can be regarded as a new biomarker for detecting osteosarcoma. EVs circ-0000190 transported from normal cells to osteosarcoma cells impeded the in vitro and in vivo development of osteosarcoma, implying that EVs circ-0000190 exerts an effect on communication between normal cells and osteosarcoma cells in the carcinogenesis process of osteosarcoma.
Assuntos
Osteossarcoma/genética , RNA Circular/genética , Animais , Apoptose/genética , Biomarcadores Tumorais/genética , Carcinogênese/genética , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Oxigenases de Função Mista/genética , Osteossarcoma/patologia , Curva ROC , Microambiente Tumoral/genéticaRESUMO
As one of the most aggressive malignancies, osteosarcoma has high risks of death. Although long noncoding RNAs (lncRNAs) may promote the osteosarcoma progression as verified, the potential molecular mechanism of lncRNAs in osteosarcoma remains unknown. Herein, we analyzed lncRNA microarray of osteosarcoma and selected LINC01278 as the study object. Then, we found that the expression of LINC01278 tested by quantitative reverse-transcription polymerase chain reaction was enhanced in tumor tissues compared with the para-carcinoma tissues and related to clinical stage, distant metastasis in osteosarcoma. In addition, the clinical outcomes were poor in osteosarcoma patients with high LINC01278 level. Moreover, LINC01278 promoted proliferation and restrained apoptosis in osteosarcoma cells. Afterward, mechanistic studies turned out that LINC01278 was a competing endogenous RNA of parathyroid hormone type 1 receptor (PTHR1) in osteosarcoma by sponging miR-133a-3p, which was considered as a tumor inhibitor in osteosarcoma. Furthermore, PTHR1 downregulation restored the impacts of inhibited miR-133a-3p on the processes in osteosarcoma cells. Our findings clarified that the carcinogenic effect of LINC01278 in osteosarcoma was mediated through miR-133a-3p/PTHR1 signaling, creating a novel insight into good targets for the therapy and prognosis of osteosarcoma.
RESUMO
BACKGROUND: Melanoma is the most aggressive skin cancer that derived from pigment cells, accounting for the majority of the skin-cancer-related deaths. Despite great development and evolution have been made in surgery, radiotherapy and adjuvant chemotherapy, the prognosis of melanoma patients exhibited no significant improvement. Long noncoding RNAs (lncRNAs) are frequently dysregulated and involved in the development of cancers. LncRNA AFAP1-AS1 has been explored in various cancers, whereas its role and regulatory mechanism in melanoma are not well understood. METHODS: The expression of AFAP1-AS1 was detected by qRT-PCR. CCK-8, colony formation, transwell and western blot assays were performed to investigate the biological role of AFAP1-AS1 in melanoma. Male BALB/c nude mice were applied for in vivo experiments. The interaction among AFAP1-AS1, miR-653-5p and RAI14 was investigated by RNA pull down, RIP and luciferase reporter assays. RESULTS: AFAP1-AS1 was highly expressed in melanoma cell lines. Suppression of AFAP1-AS1 impaired cell proliferation, migration, invasion and EMT in melanoma. Moreover, AFAP1-AS1 was a ceRNA of RAI14 by competitively binding with miR-653-5p. Besides, miR-653-5p overexpression or RAI14 inhibition could repress tumor growth. Eventually, rescue assays indicated that the function of AFAP1-AS1 in the cellular process of melanoma was dependent on miR-653-5p and RAI14. CONCLUSIONS: AFAP1-AS1 exerts its oncogenic function in melanoma by targeting miR-653-5p/RAI14 axis.