ABSTRACT
AIMS: Hypoperfusion induces significant white matter injury in cerebral vascular disorders, including arteriosclerotic cerebral small vessel disease (aCSVD), which is prevalent among the elderly. Iron transport by blood vessel endothelial cells (BVECs) from the periphery supports oligodendrocyte maturation and white matter repair. This study aims to elucidate the association between iron homeostasis changes and white matter injury severity, and explore the crosstalk between BVECs and oligodendroglial lineage cells. METHODS: In vivo: C57BL/6 mice were subjected to unilateral common carotid artery occlusion (UCCAO). In vitro: BVECs with myelin pretreatment were co-cultured with oligodendrocyte progenitor cells (OPCs) or organotypic cerebellar slices subjected to oxygen and glucose deprivation. RESULTS: Circulatory iron tends to be stored in aCSVD patients with white matter injury. Myelin debris endocytosis by BVECs impairs iron transport, trapping iron in the blood and away from the brain, worsening oligodendrocyte iron deficiency in hypoperfusion-induced white matter injury. Iron accumulation in BVECs triggers ferroptosis, suppressing iron transport and hindering white matter regeneration. Intranasal holo-transferrin (hTF) administration bypassing the BBB alleviates oligodendrocyte iron deficiency and promotes myelin regeneration in hypoperfusion-induced white matter injury. CONCLUSION: The iron imbalance between BVECs and oligodendroglial lineage cells is a potential therapeutic target in hypoperfusion-induced white matter injury.
Subject(s)
Endocytosis , Endothelial Cells , Iron , Mice, Inbred C57BL , Myelin Sheath , Oligodendroglia , White Matter , Animals , Endothelial Cells/metabolism , Endothelial Cells/pathology , Mice , Oligodendroglia/metabolism , Oligodendroglia/pathology , White Matter/metabolism , White Matter/pathology , Iron/metabolism , Myelin Sheath/metabolism , Myelin Sheath/pathology , Endocytosis/physiology , Endocytosis/drug effects , Male , Iron Overload/metabolism , Iron Overload/pathology , Brain/metabolism , Brain/pathology , Oligodendrocyte Precursor Cells/metabolism , Oligodendrocyte Precursor Cells/drug effects , Oligodendrocyte Precursor Cells/pathologyABSTRACT
White matter injury contributes to neurological disorders after acute ischemic stroke (AIS). The repair of white matter injury is dependent on the re-myelination by oligodendrocytes. Both melatonin and serotonin antagonist have been proved to protect against post-stroke white matter injury. Agomelatine (AGM) is a multi-functional treatment which is both a melatonin receptor agonist and selective serotonin receptor antagonist. Whether AGM protects against white matter injury after stroke and the underlying mechanisms remain elusive. Here, using the transient middle cerebral artery occlusion (tMCAO) model, we evaluated the therapeutic effects of AGM in stroke mice. Sensorimotor and cognitive functions, white matter integrity, oligodendroglial regeneration and re-myelination in stroke hemisphere after AGM treatment were analyzed. We found that AGM efficiently preserved white matter integrity, reduced brain tissue loss, attenuated long-term sensorimotor and cognitive deficits in tMCAO models. AGM treatment promoted OPC differentiation and enhanced re-myelination both in vitro, ex vivo and in vivo, although OPC proliferation was unaffected. Mechanistically, AGM activated low density lipoprotein receptor related protein 1 (LRP1), peroxisome proliferator-activated receptor γ (PPARγ) signaling thus promoted OPC differentiation and re-myelination after stroke. Inhibition of PPARγ or knock-down of LRP1 in OPCs reversed the beneficial effects of AGM. Altogether, our data indicate that AGM represents a novel therapy against white matter injury after cerebral ischemia.
ABSTRACT
Liver fibrosis is the integral process of chronic liver diseases caused by multiple etiologies and characterized by excessive deposition of extracellular matrix (ECM). During liver fibrosis, hepatic stellate cells (HSCs) transform into a highly proliferative, activated state, producing various cytokines, chemokines, and ECM. However, the precise mechanisms that license HSCs into the highly proliferative state remain unclear. Cyclin-dependent kinase 1 (CDK1) is a requisite event for the transition of the G1/S and G2/M phases in eukaryotic cells. In this study, it is demonstrated that CDK1 and its activating partners, Cyclin A2 and Cyclin B1, are upregulated in both liver fibrosis/cirrhosis patient specimens and the murine hepatic fibrosis models, especially in activated HSCs. In vitro, CDK1 is upregulated in spontaneously activated HSCs, and inhibiting CDK1 with specific small-molecule inhibitors (CGP74514A, RO-3306, or Purvalanol A) orshort hairpin RNAs (shRNAs) resulted in HSC apoptosis and cell cycle arrest by regulating Survivin expression. Above all, it is illustrated that increased CDK1 expression licenses the HSCs into a highly proliferative state and can serve as a potential therapeutic target in liver fibrosis.
Subject(s)
CDC2 Protein Kinase , Hepatic Stellate Cells , Animals , Humans , Mice , Apoptosis/genetics , CDC2 Protein Kinase/genetics , CDC2 Protein Kinase/metabolism , Cell Cycle Checkpoints/genetics , Cell Proliferation , Fibrosis , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Liver Cirrhosis/genetics , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolismABSTRACT
Metabolite isomers play diverse and crucial roles in various metabolic processes. However, in untargeted metabolomics analysis, it remains a great challenge to distinguish between the constitutional isomers and enantiomers of amine-containing metabolites due to their similar chemical structures and physicochemical properties. In this work, the triplex stable isotope N-phosphoryl amino acids labeling (SIPAL) is developed to identify and relatively quantify the amine-containing metabolites and their isomers by using chiral phosphorus reagents coupled with high-resolution tandem mass spectroscopy. The constitutional isomers could be effectively distinguished with stereo isomers by using the diagnosis ions in MS/MS spectra. The in-house software MS-Isomerism has been parallelly developed for high-throughput screening and quantification. The proposed strategy enables the unbiased detection and relative quantification of isomers of amine-containing metabolites. Based on the characteristic triplet peaks with SIPAL tags, a total of 854 feature peaks with 154 isomer groups are successfully recognized as amine-containing metabolites in liver cells, in which 37 amine-containing metabolites, including amino acids, polyamines, and small peptides, are found to be significantly different between liver cancer cells and normal cells. Notably, it is the first time to identify S-acetyl-glutathione as an endogenous metabolite in liver cells. The SIPAL strategy could provide spectacular insight into the chemical structures and biological functions of the fascinating amine-containing metabolite isomers. The feasibility of SIPAL in isomeric metabolomics analysis may reach a deeper understanding of the mirror-chemistry in life and further advance the discovery of novel biomarkers for disease diagnosis.
Subject(s)
Amino Acids , Tandem Mass Spectrometry , Tandem Mass Spectrometry/methods , Indicators and Reagents , Isomerism , Chromatography, Liquid/methods , Amino Acids/chemistry , Metabolomics/methods , PolyaminesABSTRACT
Pneumonia is one of the leading causes of death in patients with acute ischemic stroke (AIS). Antibiotics fail to improve prognosis of patients with post-stroke pneumonia, albeit suppressing infection, due to adverse impacts on the immune system. The current study reports that bone marrow mesenchymal stem cells (BM-MSC) downregulate bacterial load in the lungs of stroke mice models. RNA-sequencing of the lung from BM-MSC-treated stroke models indicates that BM-MSC modulates pulmonary macrophage activities after cerebral ischemia. Mechanistically, BM-MSC promotes the bacterial phagocytosis of pulmonary macrophages through releasing migrasomes, which are migration-dependent extracellular vesicles. With liquid chromatography-tandem mass spectrometry (LC-MS/MS), the result shows that BM-MSC are found to load the antibacterial peptide dermcidin (DCD) in migrasomes upon bacterial stimulation. Besides the antibiotic effect, DCD enhances LC3-associated phagocytosis (LAP) of macrophages, facilitating their bacterial clearance. The data demonstrate that BM-MSC is a promising therapeutic candidate against post-stroke pneumonia, with dual functions of anti-infection and immunol modulation, which is more than a match for antibiotics treatment.
Subject(s)
Dermcidins , Ischemic Stroke , Mesenchymal Stem Cells , Pneumonia , Stroke , Mice , Animals , Macrophages, Alveolar , Chromatography, Liquid , Tandem Mass Spectrometry , Stroke/complications , Stroke/therapy , Phagocytosis , Anti-Bacterial AgentsABSTRACT
Many evidences show that exosomes play an important role in cancer development, invasion and metastasis. This study is based on the need to explore exosomal protein that promote breast cancer metastasis. We found that tyrosine kinase EphA2 was enriched in Triple-negative breast cancer -derived exosomes and it could disrupt the endothelial monolayer barrier through downregulating tight junction proteins of endothelial cells. These mechanisms were confirmed by in vivo experiments. After periodical injection of exosomal EphA2 into mice caudal vein, we found increased vascular permeability and breast cancer metastases in distant organs, and this phenomenon decreased dramatically after exosomal EphA2 knockdown. This study provides a new mechanism of exosome promoting breast cancer metastasis and suggests a new therapeutic target for the prevention and treatment of breast cancer metastasis.
Subject(s)
MicroRNAs , Triple Negative Breast Neoplasms , Humans , Animals , Mice , Endothelial Cells , Cell Line, Tumor , Neoplasm Metastasis , MicroRNAs/metabolismABSTRACT
This study is aimed at screening genes for predicting the sensitivity response and favorable outcome of neoadjuvant therapy in breast cancer. We downloaded neoadjuvant therapy genetic data of breast cancer and separated it into the pathological complete response (pCR) group and the non-pCR group. Differential expression analysis was performed to select the differentially expressed genes (DEGs). After that, we investigated the enriched biological processes and pathways of DEGs. Then, core up/down protein-protein interaction (PPI) network was, respectively, constructed to identify the hub genes. A transcription factor-target gene regulation network was built to screen core transcription factors (TFs). We found one upregulated DEG (KLHDC7B) and four downregulated DEGs (TFF1, LOC440335, SLC39A6, and MLPH) overlapped in three datasets. All DEGs were mainly enriched in pathways related to DNA biosynthesis, cell cycle, immune response, metabolism, and angiogenesis. The hub genes were KRT18, IL7R, HIST1H1A, and E2F1. The core TFs were HOXA9, SPDEF, FOXA1, E2F1, and PGR. RT-qPCR suggested that E2F1 was overexpressed in MCF-7, but HOXA9 was low-expressed. Western blot suggested that the MAPK signal pathway was inhibited in MCF-7/ADR. That is to say, some genes and core TFs can predict the sensitivity response of neoadjuvant therapy in breast cancer. And E2F1 may be involved in the process of drug resistance by regulating the MAPK signaling pathway. These might be useful as sensitive genes for the efficacy evaluation of neoadjuvant chemotherapy in breast cancer.
Subject(s)
Breast Neoplasms , E2F1 Transcription Factor , Neoadjuvant Therapy , Breast Neoplasms/therapy , E2F1 Transcription Factor/genetics , E2F1 Transcription Factor/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Up-RegulationABSTRACT
Activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Previous investigations have identified various altered epigenetic landscapes during the cellular progression of HSC activation. N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic cells and is dynamically regulated under various physiological and pathophysiological conditions. However, the functional role of Mettl3-mediated m6A in liver fibrosis remains elusive. Here, we found that the HSC-specific knockout of m6A methyltransferase Mettl3 suppressed HSC activation and significantly alleviated liver fibrosis. Multi-omics analysis of HSCs showed that Mettl3 depletion reduced m6A deposition on mRNA transcripts of Lats2 (a central player of the Hippo/YAP signaling pathway) and slowed down their degradation. Elevated Lats2 increased phosphorylation of the downstream transcription factor YAP, suppressed YAP nuclear translocation, and decreased pro-fibrotic gene expression. Overexpressing YAP mutant resistant to phosphorylation by Lats2 partially rescued the activation and pro-fibrotic gene expression of Mettl3-deficient HSCs. Our study revealed that disruption of Mettl3 in HSCs mitigated liver fibrosis by controlling the Hippo/YAP signaling pathway, providing potential therapeutic strategies to alleviate liver fibrosis by targeting epitranscriptomic machinery.
Subject(s)
Hepatic Stellate Cells , Liver Cirrhosis , Methyltransferases , Liver Cirrhosis/genetics , Methyltransferases/deficiency , Methyltransferases/genetics , Multiomics , Protein Serine-Threonine Kinases/genetics , Tumor Suppressor Proteins , Animals , MiceABSTRACT
Hepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m6A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m6A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m6A modification in postnatal liver development and homeostasis. Knocking out Mettl3 perinatally with Alb-Cre (Mettl3 cKO) induces apoptosis and steatosis of hepatocytes, results in severe liver injury, and finally leads to postnatal lethality within 7 weeks. m6A-RIP sequencing and RNA-sequencing reveal that mRNAs of a series of crucial liver-enriched transcription factors are modified by m6A, including Hnf4a, a master regulator for hepatic parenchymal formation. Deleting Mettl3 reduces m6A modification on Hnf4a, decreases its transcript stability in an Igf2bp1-dependent manner, and down-regulates Hnf4a expression, while overexpressing Hnf4a with AAV8 alleviates the liver injury and prolongs the lifespan of Mettl3 cKO mice. However, knocking out Mettl3 in adults using Alb-CreERT2 does not affect liver homeostasis. Our study identifies a dynamic role of Mettl3-mediated RNA m6A modification in liver development.
Subject(s)
Methyltransferases , Transcription Factors , Adenosine/metabolism , Animals , Hepatocyte Nuclear Factor 4/genetics , Liver/metabolism , Methyltransferases/metabolism , Mice , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription Factors/geneticsABSTRACT
N6-methyladenosine (m6A) modification plays a pivotal role in cell fate determination. Previous studies show that eliminating m6A using Mb1-Cre dramatically impairs B cell development. However, whether disturbing m6A modification at later stages affects B cell development and function remains elusive. Here, we deleted m6A methyltransferase Mettl3 from the pro-B stage on using Cd19-Cre (Mettl3 cKO) and found that the frequency of total B cells in peripheral blood, peritoneal cavity, and liver is comparable between Mettl3 cKO mice and wild-type (WT) littermates, while the percentage of whole splenic B cells slightly increases in Mettl3 cKO individuals. The proportion of pre-pro-B, pro-B, pre-B, immature, and mature B cells in the bone marrow were minimally affected. Loss of Mettl3 resulted in increased apoptosis but barely affected B cells' proliferation and IgG production upon LPS, CD40L, anti-IgM, or TNF-α stimulation. Different stimuli had different effects on B cell activation. In addition, B cell-specific Mettl3 knockout had no influence on the pro-fibrogenic activity of B cells in liver fibrosis, evidenced by comparable fibrosis in carbon tetrachloride- (CCl4-) treated Mettl3 cKO mice and WT controls. In summary, our study demonstrated that deletion of Mettl3 from the pro-B stage on has minimal effects on B cell development and function, as well as profibrogenic activity of B cells in liver fibrosis, revealing a stage-specific dependence on Mettl3-mediated m6A of B cell development.
Subject(s)
Adenosine , Methyltransferases , Animals , Cell Differentiation , Liver Cirrhosis/genetics , Methyltransferases/genetics , MiceABSTRACT
Recurrent metastasis is a major fatal cause of breast cancer. Regretfully, the driving force and the molecular beneath have not been fully illustrated yet. In this study, a cohort of breast cancer patients with locoregional metastasis was recruited. For them, we collected the matched samples of the primary tumor and metastatic tumor, and then we determined the mutation profiles with whole-exome sequencing (WES). On basis of the profiles, we identified a list of deleterious variants in eight susceptible genes. Of them, filamin A (FLNA) was considered a potential driver gene of metastasis, and its low expression could enhance 5 years' relapse survival rate by 15%. To prove the finding, we constructed a stable FLNA knockout tumor cell line, which manifested that the cell abilities of proliferation, migration, and invasion were significantly weakened in response to the gene knockout. Subsequently, xenograft mouse experiments further proved that FLNA knockout could inhibit local or distal metastasis. Putting all the results together, we consolidated that FLNA could be a potential driver gene to metastasis of breast cancer, in particular triple-negative breast cancer. Additional experiments also suggested that FLNA might intervene in metastasis via the regulation of MMP-1 expression. In summary, this study demonstrates that FLNA may play as a positive regulator in cancer proliferation and recurrence. It provides new insight into breast cancer metastasis and suggests a potential new therapeutic target for breast cancer therapy.
ABSTRACT
BACKGROUND: Fulminant hepatitis is a severe life-threatening clinical condition with rapid progressive loss of liver function. It is characterized by massive activation and infiltration of immune cells into the liver and disturbance of inflammatory cytokine production. Mesenchymal stem cells (MSCs) showed potent immunomodulatory properties. Transplantation of MSCs is suggested as a promising therapeutic approach for a host of inflammatory conditions. METHODS: In the current study, a well-established concanavalin A (Con A)-induced fulminant hepatitis mouse model was used to investigate the effects of transplanting human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on fulminant hepatitis. RESULTS: We showed that hWJ-MSCs effectively alleviate fulminant hepatitis in mouse models, primarily through inhibiting T cell immunity. RNA sequencing of liver tissues and human T cells co-cultured with hWJ-MSCs showed that NF-κB signaling and glycolysis are two main pathways mediating the protective role of hWJ-MSCs on both Con A-induced hepatitis in vivo and T cell activation in vitro. CONCLUSION: In summary, our data confirmed the potent therapeutic role of MSCs-derived from Wharton's jelly of human umbilical cord on Con A-induced fulminant hepatitis, and uncovered new mechanisms that glycolysis metabolic shift mediates suppression of T cell immunity by hWJ-MSCs.
Subject(s)
Massive Hepatic Necrosis , Mesenchymal Stem Cells , Wharton Jelly , Animals , Cell Differentiation , Cells, Cultured , Concanavalin A/toxicity , Glycolysis , Humans , Mice , NF-kappa B/genetics , Umbilical CordABSTRACT
Filamin A(FLNa) is an actin-binding protein, which participates in the formation of the cytoskeleton, anchors a variety of proteins in the cytoskeleton and regulates cell adhesion and migration. It is involved in signal transduction, cell proliferation and differentiation, pseudopodia formation, vesicle transport, tumor resistance and genetic diseases by binding with interacting proteins. In order to fully elucidate the structure, function and pathogenesis of FLNa, we summarized all substances which directly or indirectly act on FLNa so far, upstream and downstream targets which having effect on it, signaling pathways and their functions. It also recorded the expression and effect of FLNa in different diseases, including hereditary disease and tumors.
Subject(s)
Drug Resistance, Neoplasm , Filamins/genetics , Filamins/metabolism , Neoplasms/genetics , Actin Cytoskeleton/metabolism , Cell Adhesion , Cell Movement , Genetic Predisposition to Disease , Humans , Neoplasms/metabolismABSTRACT
Liver diseases with different pathogenesis share common pathways of immune-mediated injury. Chitinase-3-like protein 1 (CHI3L1) was induced in both acute and chronic liver injuries, and recent studies reported that it possesses an immunosuppressive ability. CHI3L1 was also expressed in mesenchymal stem cells (MSCs), thus we investigates the role of CHI3L1 in MSC-based therapy for immune-mediated liver injury here. We found that CHI3L1 was highly expressed in human umbilical cord MSCs (hUC-MSCs). Downregulating CHI3L1 mitigated the ability of hUC-MSCs to inhibit T cell activation, proliferation and inflammatory cytokine secretion in vitro. Using Concanavalin A (Con A)-induced liver injury mouse model, we found that silencing CHI3L1 significantly abrogated the hUC-MSCs-mediated alleviation of liver injury, accompanying by weakened suppressive effects on infiltration and activation of hepatic T cells, and secretion of pro-inflammatory cytokines. In addition, recombinant CHI3L1 (rCHI3L1) administration inhibited the proliferation and function of activated T cells, and alleviated the Con A-induced liver injury in mice. Mechanistically, gene set enrichment analysis showed that JAK/STAT signalling pathway was one of the most significantly enriched gene pathways in T cells co-cultured with hUC-MSCs with CHI3L1 knockdown, and further study revealed that CHI3L1 secreted by hUC-MSCs inhibited the STAT1/3 signalling in T cells by upregulating peroxisome proliferator-activated receptor δ (PPARδ). Collectively, our data showed that CHI3L1 was a novel MSC-secreted immunosuppressive factor and provided new insights into therapeutic treatment of immune-mediated liver injury.
Subject(s)
Chemical and Drug Induced Liver Injury/prevention & control , Chitinase-3-Like Protein 1/metabolism , Liver/enzymology , Lymphocyte Activation , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/enzymology , Paracrine Communication , T-Lymphocytes/enzymology , Animals , Cell Proliferation , Cells, Cultured , Chemical and Drug Induced Liver Injury/enzymology , Chemical and Drug Induced Liver Injury/immunology , Chemical and Drug Induced Liver Injury/pathology , Coculture Techniques , Concanavalin A , Cytokines/metabolism , Disease Models, Animal , Female , Humans , Liver/immunology , Liver/pathology , Mice, Inbred C57BL , Phosphorylation , Receptors, Cytoplasmic and Nuclear/metabolism , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor/metabolism , T-Lymphocytes/immunology , Umbilical Cord/cytologyABSTRACT
Due to their excellent mechanical and thermal properties and medium resistance, epoxy/carbon nanotubes and nanocomposites have been widely used in many fields. However, the conventional thermosetting process is not only time- and energy-consuming, but also causes the agglomeration of nanofillers, which leads to unsatisfactory properties of the obtained composites. In this study, multi-walled carbon nanotubes (MWCNTs)/epoxy nanocomposites were prepared using UV photoinduced frontal polymerization (PIFP) in a rapid fashion. The addition of MWCNTs modified by a surface carboxylation reaction was found to enhance the impact strength and heat resistance of the epoxy matrix effectively. The experimental results indicate that with 0.4 wt % loading of modified MWCNTs, increases of 462.23% in the impact strength and 57.3 °C in the glass transition temperature Tg were achieved. A high-performance nanocomposite was prepared in only a few minutes using the PIFP approach. Considering its fast, energy-saving, and environmentally friendly production, the PIFP approach displays considerable potential in the field of the fast preparation, repair, and deep curing of nanocomposites and coatings.
ABSTRACT
Death-associated protein kinase 1 (DAPK1) is a Ca2+/calmodulin regulated Ser/Thr kinase involved in various cellular processes including cell death, autophagy and inflammation. Its dysregulation has been linked to tumour metastasis, anti-viral responses, Alzheimer's disease and other neurological disorders. To further investigate the role of DAPK1 in these processes, we generated a DAPK1 knockout first (conditional ready) human embryonic stem (hES) cell line in which the endogenous DAPK1 can be easily restored with expression of FLPe. This cell line provides an ideal model to study the role of DAPK1 in human development and various pathologies related to DAPK1 dysregulation in vitro.
Subject(s)
CRISPR-Cas Systems/genetics , Death-Associated Protein Kinases/genetics , Human Embryonic Stem Cells/metabolism , Cell Line , Humans , MaleABSTRACT
Immunoglobulin G against myelin oligodendrocyte glycoprotein (MOG-IgG) is detectable in neuromyelitis optica spectrum disorder (NMOSD) without aquaporin-4 IgG (AQP4-IgG), but its pathogenicity remains unclear. In this study, we explored the pathogenic mechanisms of MOG-IgG in vitro and in vivo and compared them with those of AQP4-IgG. MOG-IgG-positive serum induced complement activation and cell death in human embryonic kidney (HEK)-293T cells transfected with human MOG. In C57BL/6 mice and Sprague-Dawley rats, MOG-IgG only caused lesions in the presence of complement. Interestingly, AQP4-IgG induced astroglial damage, while MOG-IgG mainly caused myelin loss. MOG-IgG also induced astrocyte damage in mouse brains in the presence of complement. Importantly, we also observed ultrastructural changes induced by MOG-IgG and AQP4-IgG. These findings suggest that MOG-IgG directly mediates cell death by activating complement in vitro and producing NMOSD-like lesions in vivo. AQP4-IgG directly targets astrocytes, while MOG-IgG mainly damages oligodendrocytes.
Subject(s)
Aquaporin 4/toxicity , Astrocytes/pathology , Complement System Proteins , Immunoglobulin G/toxicity , Myelin-Oligodendrocyte Glycoprotein/toxicity , Oligodendroglia/pathology , Adolescent , Adult , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Cell Death/drug effects , Cell Death/physiology , Child , Complement System Proteins/metabolism , Female , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Middle Aged , Oligodendroglia/drug effects , Oligodendroglia/metabolism , Rats , Rats, Sprague-Dawley , Young AdultABSTRACT
Cancer stem cells are enriched in triple-negative breast cancer (TNBC) tumor tissues, which present strong capacities of proliferation and tumorigenicity. The present study detected the distribution of cancer stem cell markers cluster of differentiation (CD)44/CD24 and analyzed the clinical outcomes of different CD44/CD24 phenotypes in patients with TNBC. Multivariate Cox regression analyses were performed with regard to the prognostic value of cancer stem cell markers CD44/CD24, aldehyde dehydrogenase 1 and other baseline clinical characteristics, including tumor size, lymph node involved, adjuvant chemotherapy, Ki-67, breast cancer susceptibility gene 1, cellular tumor antigen p53, vimentin and basal-like status. The multivariate analyses showed that three of these factors, CD44/CD24 phenotype, basal-like status and number of lymph nodes involved, had an impact on overall survival. Furthermore, patients with CD44+/CD24- phenotype, basal-like tumors and ≥4 lymph nodes involved had a significantly worse prognosis. The expression of CD44 and CD24 was detected by double-staining immunohistochemistry, which can locate cancer stem cells individually. Overall, the present results indicated that CD44/CD24 status evaluated by double-staining immunohistochemistry constitutes an independent prognostic factor for TNBC.
ABSTRACT
BACKGROUND: Recent studies have indicated that long non-coding RNA actin filament-associated protein 1 antisense RNA 1 (lncRNA AFAP1-AS1) was increased in non-small cell lung cancer and associated with unfavorable patient prognosis. AFAP1-AS1 also participates in promoting invasion and metastasis in non-small cell lung cancer cells. However, the diagnosis value of serum AFAP1-AS1 in non-small cell lung cancer was unclear. In this study, we aimed to explore whether circulating AFAP1-AS1 can be used as a diagnostic biomarker for non-small cell lung cancer. METHOD: The serum AFAP1-AS1 expression level in 126 non-small cell lung cancer patients and 60 healthy controls was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The concentrations of serum cyfra21-1 were detected through chemiluminescence method using the Roche Cobas e601. Receiver operating characteristic curve analysis was applied to assess the diagnostic value of serum AFAP1-AS1 and cyfra21-1 in non-small cell lung cancer. RESULT: The results demonstrated that AFAP1-AS1 expression level was significantly elevated in non-small cell lung cancer patients compared with that in normal controls (p=0.000). Serum AFAP1-AS1 could be used as molecular marker for distinguishing non-small cell lung cancer patients from healthy people with an area under the curve of 0.759 (95% confidence interval=0.692-0.826; p=0.000). The combination of FAP1-AS1 and cyfra21-1 showed that the area under the curve was 0.860 (95% confidence interval=0.808-0.912; p=0.000). Further analysis found that high serum AFAP1-AS1 expression levels correlated with distant metastasis (p=0.03), lymph node metastasis (p=0.017), poor clinical stage (p=0.019), and larger tumor size (p=0.015). Furthermore, AFAP1-AS1 was significantly upregulated in positive distant metastasis group (p=0.003), positive lymph node metastasis (p=0.017), poor clinical stage group (p=0.019), and larger tumor size group (p=0.015). CONCLUSION: Serum AFAP1-AS1 could serve as an ideal combined biomarker for the diagnosis of non-small cell lung cancer.
Subject(s)
Antigens, Neoplasm/genetics , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/diagnosis , Gene Expression Regulation, Neoplastic , Keratin-19/genetics , Lung Neoplasms/diagnosis , RNA, Long Noncoding/genetics , Aged , Antigens, Neoplasm/blood , Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Case-Control Studies , Female , Humans , Keratin-19/blood , Lung Neoplasms/blood , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lymph Nodes/metabolism , Lymph Nodes/pathology , Lymphatic Metastasis , Male , Middle Aged , Prognosis , RNA, Long Noncoding/blood , Tumor BurdenABSTRACT
Taurine up-regulated gene 1 (TUG1) is a long non-coding RNA (lncRNA), has been reported that be dysregulated in various tumors, involved in proliferation and apoptosis in a variety of tumor cells. To detect the clinical significance of TUG1 expression in tumor patients, we carried out current systematic review and meta-analysis investigating its relation with the prognosis and clinicopathological features of cancers. A total of 15 studies comprise 1560 patients were analyzed. The pooled results showed that no significant relationship between high TUG1 expression and overall survival (OS) (HR = 1.28, 95% CI: 0.96-1.69, P = 0.091) in various tumors. In the subgroup analysis by cancer type, elevated TUG1 expression was associated with poorer survival in cancer patients with high TUG1 expression subgroup but better survival in patients with low TUG1 expression subgroup. Over-expression of TUG1 associated with significantly unfavorable survival for bladder cancer (HR=2.67, 95% CI: 1.47-4.87, P = 0.001). Up-regulation of TUG1 correlated with distant metastasis (DM) (OR = 4.22, 95% CI: 2.66-6.70, P < 0.001) and tumor differentiation (OR = 2.45, 95% CI: 1.28-4.70, P = 0.007), but failed to show inline to gender (OR = 1.04, 95% CI: 0.77-1.42, P = 0.774), age (OR = 0.75, 95% CI: 0.51-1.10, P = 0.136), lymph node metastasis (LNM) (OR = 1.45, 95% CI: 0.85-2.50, P = 0.177), and TNM stage (OR = 0.55, 95% CI: 0.17-1.81, P = 0.326). The overall results suggest lncRNA TUG1 may be a useful prognostic biomarker in cancer patients.