ABSTRACT
AIMS: Despite islet transplantation has proved a great potential to become the standard therapy for type 1 diabetes mellitus (T1DM), this approach remains limited by ischemia, hypoxia, and poor revascularization in early post-transplant period as well as inflammation and life-long host immune rejection. Here, we investigate the potential and mechanism of human amniotic mesenchymal stem cells (hAMSCs)-islet organoid to improve the efficiency of islet engraftment in immunocompetent T1DM mice. MAIN METHODS: We generated the hAMSC-islet organoid structure through culturing the mixture of hAMSCs and islets on 3-dimensional-agarose microwells. Flow cytometry, whole-body fluorescent imaging, immunofluorescence, Calcein-AM/PI staining, ELISA, and qPCR were used to assess the potential and mechanism of shielding hAMSCs to improve the efficiency of islet transplantation. KEY FINDINGS: Transplant of hAMSC-islet organoids results in remarkably better glycemic control, an enhanced glucose tolerance, and a higher ß cell mass in vivo compared with control islets. Our results show that hAMSCs shielding provides an immune privileged microenvironment for islets and promotes graft revascularization in vivo. In addition, hAMSC-islet organoids show higher viability and reduced dysfunction after exposure to hypoxia and inflammatory cytokines in vitro. Finally, our results show that shielding with hAMSCs leads to the activation of PKA-CREB-IRS2-PI3K and PKA-PDX1 signaling pathways, up-regulation of SIL1 mRNA levels, and down-regulation of MT1 mRNA levels in ß cells, which ultimately promotes the synthesis, folding and secretion of insulin, respectively. SIGNIFICANCE: hAMSC-islet organoids can evidently increase the efficiency of islet engraftment and might develop into a promising alternative for the clinical treatment of T1DM.
Subject(s)
Amnion , Diabetes Mellitus, Experimental , Islets of Langerhans Transplantation , Islets of Langerhans , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Organoids , Animals , Mesenchymal Stem Cells/cytology , Mice , Humans , Islets of Langerhans Transplantation/methods , Diabetes Mellitus, Experimental/therapy , Islets of Langerhans/metabolism , Islets of Langerhans/cytology , Amnion/cytology , Mesenchymal Stem Cell Transplantation/methods , Diabetes Mellitus, Type 1/therapy , Mice, Inbred C57BL , MaleABSTRACT
Chlorinated polyfluorinated ether sulfonate, commercially known as F-53B, has been associated with adverse birth outcomes. However, the reproductive toxicology of F-53B on the placenta remains poorly understood. To address this gap, we examined the impact of F-53B on placental injury and its underlying molecular mechanisms in vivo. Pregnant C57BL/6â¯J female mice were randomly allocated to three groups: the control group, F-53B 0.8⯵g/kg/day group, and F-53B 8⯵g/kg/day group. After F-53B exposure through free drinking water from gestational day (GD) 0.5-14.5, the F-53B 8⯵g/kg/day group exhibited significant increases in placental weights and distinctive histopathological alterations, including inflammatory cell infiltration, heightened syncytiotrophoblast knots, and a loosened trophoblastic basement membrane. Within the F-53B 8⯵g/kg/day group, placental tissue exhibited increased apoptosis, as indicated by increased caspase3 activation. Furthermore, F-53B potentially induced the NF-κB signaling pathway activation through IκB-α phosphorylation. Subsequently, this activation upregulated the expression of inflammatory cytokines and components of the NLRP3 inflammasome, including activated caspase1, IL-1ß, IL-18, and cleaved gasdermin D (GSDMD), ultimately leading to pyroptosis in the mouse placenta. Our findings reveal a pronounced inflammatory injury in the placenta due to F-53B exposure, suggesting potential reproductive toxicity at concentrations relevant to the human population. Further toxicological and epidemiological investigations are warranted to conclusively assess the reproductive health risks posed by F-53B.
Subject(s)
Inflammasomes , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein , Placenta , Animals , Female , Pregnancy , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Placenta/drug effects , Placenta/pathology , Mice , Inflammasomes/drug effects , Inflammation/chemically induced , Inflammation/pathology , Apoptosis/drug effects , NF-kappa B/metabolism , Fluorocarbons/toxicity , Signal Transduction/drug effectsABSTRACT
Maternal exposure to environment toxicants is an important risk factor for neurobehavioral health in their offspring. In our study, we investigated the impact of maternal exposure to chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs, commercial name: F-53B) on behavioral changes and the potential mechanism in the offspring larvae of zebrafish. Adult zebrafish exposed to Cl-PFESAs (0, 0.2, 2, 20 and 200 µg/L) for 21 days were subsequently mated their embryos were cultured for 5 days. Higher concentrations of Cl-PFESAs in zebrafish embryos were observed, along with, reduced swimming speed and distance travelled in the offspring larvae. Molecular docking analysis revealed that Cl-PFESAs can form hydrogen bonds with brain-derived neurotropic factor (BDNF), protein kinase C, alpha, (PKCα), Ca2+-ATPase and Na, K - ATPase. Molecular and biochemical studies evidenced Cl-PFESAs induce dopaminergic dysfunction, eye developmental defects and disrupted Ca2+ homeostasis. Together, our results showed that maternal exposure to Cl-PFESAs lead to behavioral alteration in offspring mediated by disruption in Ca2+ homeostasis, dopaminergic dysfunction and eye developmental defects.
Subject(s)
Alkanesulfonic Acids , Fluorocarbons , Water Pollutants, Chemical , Animals , Female , Zebrafish/metabolism , Alkanesulfonic Acids/metabolism , Calcium/metabolism , Larva , Molecular Docking Simulation , Fluorocarbons/metabolism , Water Pollutants, Chemical/metabolism , Adenosine Triphosphatases/metabolismABSTRACT
Environmental pollutants exposure might disrupt cardiac function, but evidence about the associations of per- and polyfluoroalkyl substances (PFASs) exposure and cardiac conduction system remains sparse. To explore the associations between serum PFASs exposure and electrocardiogram (ECG) parameters changes in adults, we recruited 1229 participants (mean age: 55.1 years) from communities of Guangzhou, China. 13 serum PFASs with detection rate > 85% were analyzed finally. We selected 6 ECG parameters [heart rate (HR), PR interval, QRS duration, Bazett heart rate-corrected QT interval (QTc), QRS electric axis and RV5 + SV1 voltage] as outcomes. Generalized linear models (GLMs) and Bayesian kernel machine regression (BKMR) model were conducted to explore the associations of individual and joint PFASs exposure and ECG parameters changes, respectively. We detected significant associations of PFASs exposure with decreased HR, QRS duration, but with increased PR interval. For example, at the 95th percentile of 6:2 Cl-PFESA, HR and QRS duration were - 6.98 [95% confidence interval (CI): - 9.07, - 4.90] and - 6.54(95% CI: -9.05, -4.03) lower, but PR interval was 7.35 (95% CI: 3.52, 11.17) longer than those at the 25th percentile. Similarly, significant joint associations were observed in HR, PR interval and QRS duration when analyzed by BKMR model.
Subject(s)
Environmental Pollutants , Fluorocarbons , Humans , Adult , Middle Aged , Bayes Theorem , Environmental Exposure , Electrocardiography , Fluorocarbons/toxicityABSTRACT
As a typical type of persistent organic pollutant, perfluorooctanoic acid (PFOA) is pervasive in the environment. Multiple studies have found that PFOA has hepatotoxicity, but the mechanism remains poorly understood. In this study, the toxic effects of different concentrations of PFOA on zebrafish liver cells were systematically assessed by recording cell survival, ultrastructural observations, and transcriptome analyses. The results showed that the inhibition of cell viability and the massive accumulation of autophagic vacuoles were observed at 400 µM PFOA, while transcriptomic changes occurred with treatments of 1 and 400 µM PFOA. The transcription levels of 1055 (977 up- and 78 down-regulated genes) and 520 (446 up- and 74 down-regulated genes) genes were significantly changed after treatment with 1 and 400 µM PFOA, respectively. Based on Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, significant expression changes were observed in autophagy, tight junction, signal transduction, immune system, endocrine system, and metabolism-related pathways, indicating that such processes were greatly affected by PFOA exposure. The findings of this study will provide a scientific basis for the toxic effects and potential toxic mechanisms of PFOA on zebrafish, and provide information for ecological risk assessments.
Subject(s)
Water Pollutants, Chemical , Zebrafish , Animals , Zebrafish/metabolism , Water Pollutants, Chemical/toxicity , Caprylates/toxicity , Caprylates/metabolism , LiverABSTRACT
Background: To determine if the use of the Proton Pump Inhibitors (PPI) impacts the clinical efficacy of Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC), a meta-analysis was conducted. Method: Eleven studies from PubMed, EMBASE, Cochrane Library, Web of Science, and other databases up to May 2022, were selected. The pertinent clinical outcomes were assessed by applying the Progression-free survival (PFS), Overall Survival (OS), Hazard Ratio (HR), and 95% Confidence Interval (CI). Result: This study included eleven articles containing 7,893 NSCLC patients. The result indicated that PPI use was dramatically related to poor OS (HR: 1.30 [1.10-1.54]), and poor PFS (HR: 1.25 [1.09-1.42]) in case of patients treated with ICIs. With regard to the subgroup analysis, PPI use was dramatically associated with poor OS (Europe: HR = 1.48 [1.26, 1.74], Worldwide: HR = 1.54 [1.24, 1.91]), and poor PFS (Europe: HR = 1.36 [1.18, 1.57], Worldwide: HR = 1.34 [1.16, 1.55]) in patients from Europe and multi-center studies across the world, poor OS in patients with age less than or equal to 65 (HR = 1.56 [1.14, 2.15]), poor PFS in patients aged more than 65 (HR = 1.36 [1.18, 1.57]), poor OS for patients receiving with PD-1 (HR = 1.37 [1.04, 1.79]), poor PFS for patients receiving with PD-L1 (HR = 1.33 [1.19, 1.49]), and poor OS (-30: HR = 1.89 [1.29, 2.78], ±30: HR = 1.44 [1.27, 1.64]) and poor PFS (-30: HR = 1.51 [1.11, 2.05], ±30: HR = 1.32 [1.20, 1.45]) for patients who received PPI at 30 days before and/or after starting the ICIs treatment. Conclusion: Our meta-analysis indicated that PPI combined with ICIs in the treatment of NSCLC patients could result in poor OS and PFS. PPI use should be extremely cautious in clinical practices to avoid the impact on the efficacy of the ICIs.
ABSTRACT
BACKGROUND: Liver fibrosis is an outcome of restoring process in chronic liver injury. Human amniotic mesenchymal stem cells (hAMSCs) derived from amniotic membrane have multilineage differentiation, immunosuppressive, and anti-inflammatory potential which makes them suitable for treating liver fibrosis. This study aimed to explore the effect and mechanism of hAMSCs on liver fibrosis. METHODS: hAMSCs were transplanted into carbon tetrachloride (CCl4)-induced liver fibrosis mice via tail vein, and the effects of hAMSCs on hepatic fibrosis were assessed. The effects of hAMSCs and hAMSCs conditional medium (CM) on the activation of hepatic stellate cells (HSCs) were investigated in vivo and in vitro. Antibody array assay was used to identify the cytokines secreted by hAMSCs that may inhibit the activation of HSCs. Finally, the underlying mechanisms were explored by assessing IGF-1R/PI3K/AKT and GSK3ß/ß-catenin signaling pathways in the activated HSCs (LX-2) with hAMSCs and hAMSCs transfected with corresponding siRNAs. RESULTS: Our results showed that hAMSCs possessed the characterizations of mesenchymal stem cells. hAMSCs significantly reduced liver fibrosis and improved liver function in mice by inhibiting HSCs activation in vivo. Both hAMSCs and hAMSC-CM remarkably inhibited the collagen deposition and activation of LX-2 cells in vitro. Antibody array assay showed that insulin-like growth factor binding protein-3 (IGFBP-3), Dickkopf-3 (DKK-3), and Dickkopf-1 (DKK-1) were highly expressed in the co-culture group and hAMSC-CM group compared with LX-2 group. Western blot assay demonstrated that IGFBP-3, DKK-3, and DKK-1 derived from hAMSCs inhibit LX-2 cell activation through blocking canonical Wnt signaling pathway. CONCLUSIONS: Our results demonstrated that IGFBP-3, Dkk3, and DKK-1 secreted by hAMSCs attenuated liver fibrosis in mice through inhibiting HSCs activation via depression of Wnt/ß-catenin signaling pathway, suggesting that hAMSCs or hAMSC-CM provides an alternative therapeutic approach for the treatment of liver fibrosis.
Subject(s)
Mesenchymal Stem Cells , Wnt Signaling Pathway , Amnion , Animals , Hepatic Stellate Cells/metabolism , Humans , Insulin-Like Growth Factor Binding Protein 3/metabolism , Liver Cirrhosis/chemically induced , Liver Cirrhosis/therapy , Mesenchymal Stem Cells/metabolism , Mice , Phosphatidylinositol 3-Kinases/metabolismABSTRACT
Oncogenic imbalance of DNA methylation is well recognized in cancer development. The ten-eleven translocation (TET) family of dioxygenases, which facilitates DNA demethylation, is frequently dysregulated in cancers. How such dysregulation contributes to tumorigenesis remains poorly understood, especially in solid tumors which present infrequent mutational incidence of TET genes. Here, we identify loss-of-function mutations of TET in 7.4% of human lung adenocarcinoma (LUAD), which frequently co-occur with oncogenic KRAS mutations, and this co-occurrence is predictive of poor survival in LUAD patients. Using an autochthonous mouse model of KrasG12D -driven LUAD, we show that individual or combinational loss of Tet genes markedly promotes tumor development. In this Kras-mutant and Tet-deficient model, the premalignant lung epithelium undergoes neoplastic reprogramming of DNA methylation and transcription, with a particular impact on Wnt signaling. Among the Wnt-associated components that undergo reprogramming, multiple canonical Wnt antagonizing genes present impaired expression arising from elevated DNA methylation, triggering aberrant activation of Wnt signaling. These impairments can be largely reversed upon the restoration of TET activity. Correspondingly, genetic depletion of ß-catenin, the transcriptional effector of Wnt signaling, substantially reverts the malignant progression of Tet-deficient LUAD. These findings reveal TET enzymes as critical epigenetic barriers against lung tumorigenesis and highlight the therapeutic vulnerability of TET-mutant lung cancer through targeting Wnt signaling.
Subject(s)
Adenocarcinoma of Lung/metabolism , DNA Methylation , DNA, Neoplasm/metabolism , Lung Neoplasms/metabolism , Neoplasms, Experimental/metabolism , Proto-Oncogene Proteins/deficiency , Wnt Signaling Pathway , Adenocarcinoma of Lung/genetics , Animals , DNA, Neoplasm/genetics , Humans , Lung Neoplasms/genetics , Mice , Mice, Transgenic , Neoplasms, Experimental/genetics , Proto-Oncogene Proteins/metabolismABSTRACT
BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer death worldwide with complicated molecular and cellular heterogeneity. Iron metabolism and ferroptosis play crucial roles in the pathogenesis of GC. However, the prognostic role and immunotherapy biomarker potential of ferroptosis-related genes (FRGs) in GC still remains to be clarified. METHODS: We comprehensively analyzed the prognosis of different expression FRGs, based on gastric carcinoma patients in the TCGA cohort. The functional enrichment and immune microenvironment associated with these genes in gastric cancer were investigated. The prognostic model was constructed to clarify the relation between FRGs and the prognosis of GC. Meanwhile, the ceRNA network of FRGs in the prognostic model was performed to explore the regulatory mechanisms. RESULTS: Gastric carcinoma patients were classified into the A, B, and C FRGClusters with different features based on 19 prognostic ferroptosis-related differentially expressed genes in the TCGA database. To quantify the FRG characteristics of individual patients, FRGScore was constructed. And the research shows the GC patients with higher FRGScore had worse survival outcome. Moreover, thirteen prognostic ferroptosis-related differentially expressed genes (DEGs) were selected to construct a prognostic model for GC survival outcome with a superior accuracy in this research. And we also found that FRG RiskScore can be an independent biomarker for the prognosis of GC patients. Interestingly, GC patients with lower RiskScore had less immune dysfunction and were more likely to respond to immunotherapy according to TIDE value analysis. Finally, a ceRNA network based on FRGs in the prognostic model was analyzed to show the concrete regulation mechanisms. CONCLUSIONS: The ferroptosis-related gene risk signature has a superior potent in predicting GC prognosis and acts as the biomarkers for immunotherapy, which may provide a reference in clinic.
Subject(s)
Biomarkers, Tumor/genetics , Ferroptosis/genetics , Genetic Predisposition to Disease , Immune Checkpoint Inhibitors/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Cohort Studies , Gene Expression Regulation, Neoplastic , Humans , Nomograms , Prognosis , RNA, Neoplasm/geneticsABSTRACT
BACKGROUND: Colorectal cancer (CRC) is the third most common malignancies worldwide. Ferroptosis is a programmed, iron-dependent cell death observed in cancer cells. However, the prognostic potential and immunotherapy biomarker potential of ferroptosis-related genes (FRGs) in CRC patients remains to be clarified. METHODS: At first, we comprehensively analysed the different expression and prognosis of related FRGs in CRC patients based on TCGA cohort. The relationship between functional enrichment of these genes and immune microenvironment in CRC was investigated using the TCGA database. Prognostic model was constructed to determine the association between FRGs and the prognosis of CRC. Relative verification was done based on the GEO database. Meanwhile, the ceRNA network of FRGs in the model was also performed to explore the regulatory mechanisms. RESULTS: Eight differentially expressed FRGs were associated with the prognosis of CRC patients. Patients from the TCGA database were classified into the A, B, and C FRG clusters with different features. And FRG scores were constructed to quantify the FRG pattern of individual patients with colorectal cancer. The CRC patients with higher FRG score showed worse survival outcomes, higher immune dysfunction, and lower response to immunotherapy. The prognostic model showed a high accuracy for predicting the OS of CRC. Finally, a ceRNA network was analysed to show the concrete regulation mechanisms of critical FRGs in CRC. CONCLUSIONS: The FRG risk score prognostic model based on 8 FRGs exhibit superior predictive performance, providing a novel prognostic model with a high accuracy for CRC patients. Moreover, FRG score can be the potential biomarker of the response of immunotherapy for CRC.
Subject(s)
Colorectal Neoplasms/therapy , Ferroptosis/genetics , Immunotherapy , Cohort Studies , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Databases, Genetic , Gene Expression Regulation, Neoplastic , Humans , Prognosis , Tumor MicroenvironmentABSTRACT
PURPOSE: To reveal differences in the pattern of trabecular architecture in the epiphysis and metaphysis of the proximal tibia. METHODS: The trabecular architecture of the proximal tibia was observed in 27 P45 plastinated knee specimens. RESULTS: In the medial and lateral condyles, under the articular cartilage surrounded by the medial or lateral meniscus, the cancellous bone is formed by thick and dense trabecular bands, which run longitudinally in the epiphysis and then pass through the epiphyseal line to terminate on the slanted cortex of the metaphysis. In the intercondylar eminence, the trabeculae are arranged basically in a network. In the central portion of the tibial metaphysis, cancellous bone consists of fine arcuate trabeculae, which extend to the anterior and posterior cortices, respectively. These trabeculae are intersected sparsely and form trusses over the medullary cavity. Near the areas of attachment of the iliotibial tract, tibial collateral ligament, anterior and posterior cruciate ligaments, and patellar ligament, the cancellous bone is locally reinforced with patchy trabeculae, dense radiating trabeculae, or two orthotropic trabecular bands. CONCLUSION: This study provides further accurate anatomical information on the trabeculae of the proximal tibia. The soft structures of knee joint, including the articular cartilage, menisci, and ligaments, and the slanted cortices of the metaphysis are important landmarks for the location of different arrangements of the cancellous architecture. The present results are beneficial for clinical diagnosis and treatment of pathologies of the knee joint, or the establishment of a finite element analysis model of the knee joint.
Subject(s)
Posterior Cruciate Ligament , Tibia , Cancellous Bone , Humans , Knee Joint/diagnostic imaging , Menisci, Tibial , Tibia/diagnostic imagingABSTRACT
Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degradation of Nur77. Cocrystallographic and functional analysis revealed that Csn-B, a Nur77-targeting compound, promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77's inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.
Subject(s)
Breast Neoplasms/pathology , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , PPAR gamma/metabolism , Phenylacetates/pharmacology , Adult , Aged , Aged, 80 and over , Animals , Breast/pathology , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Cell Proliferation , DNA-Binding Proteins/metabolism , Disease Models, Animal , Disease Progression , Fatty Acids/metabolism , Female , Humans , Kaplan-Meier Estimate , Lipid Metabolism/drug effects , Mammary Glands, Animal/pathology , Mice , Middle Aged , Nuclear Receptor Subfamily 4, Group A, Member 1/agonists , PPAR gamma/agonists , Primary Cell Culture , Prognosis , Proteolysis/drug effects , Tissue Array Analysis , Tumor Cells, Cultured , Tumor Suppressor Proteins/metabolism , Ubiquitination/drug effectsABSTRACT
Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.
Subject(s)
Carrier Proteins/metabolism , Cell-Derived Microparticles/metabolism , Membrane Proteins/metabolism , Thyroid Hormones/metabolism , Adult , Aged , Aged, 80 and over , Animals , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Carrier Proteins/genetics , Cell Differentiation/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Cell-Derived Microparticles/genetics , Cell-Derived Microparticles/pathology , Chemokine CCL1/metabolism , Disease Progression , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Macrophages/metabolism , Male , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Middle Aged , Monocytes/metabolism , Prognosis , STAT3 Transcription Factor/metabolism , Thyroid Hormones/genetics , Tumor Microenvironment , Thyroid Hormone-Binding ProteinsABSTRACT
OBJECTIVES: The objective of this study was to address the biological function of miR-7 in an animal model of systemic lupus erythematosus. METHODS: MRLlpr/lpr lupus mice were administrated antagomiR-7 or a scramble control by tail vein for 5weeks. Three groups of animals' tissues were assessed for lupus manifestations by immunofluorescence and immunohistochemistry, and serum was examined for levels of autoantibodies and inflammatory cytokines. Splenic B cell subsets were assessed for intracellular expression of PI3K signaling by FACS. Finally, the ability of the miR-7 antagomir to regulate the expansion of T follicular helper (Tfh) cells and B cell hyperresponsiveness was further explored. RESULTS: We found that miR-7 was up-regulated in MRLlpr/lpr lupus mice and directly targeted PTEN mRNA in B cells. Up-regulated miR-7 in MRLlpr/lpr lupus B cells was negatively correlated with PTEN expression. Notably, miR-7 antagomir treatment reduced lupus manifestations in MRLlpr/lpr lupus mice. miR-7-mediated down-regulation of PTEN/AKT signaling promoted B cell differentiation into plasmablasts/plasma cells and spontaneous germinal center (GC) formation, whereas miR-7 antagomir normalized splenic B cell subtypes. Besides suppressing the activation of B cells, miR-7 antagomir intervention also down-regulated STAT3 phosphorylation and production of IL-21 and reduced Tfh expansion. CONCLUSION: The above data have demonstrated the critical roles of miR-7 not only in regulating PTEN expression and also B cell and Tfh cell function in lupus-prone MRLlpr/lpr lupus mice. Furthermore, the disease manifestations in MRLlpr/lpr lupus mice are efficiently improved by miR-7 antagomir, indicating miR-7 as a potential treatment strategy in SLE.
Subject(s)
B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Lupus Erythematosus, Systemic/etiology , Lupus Erythematosus, Systemic/metabolism , Lymphocyte Activation/genetics , MicroRNAs/genetics , Animals , Biomarkers , Disease Models, Animal , Disease Susceptibility , Lupus Erythematosus, Systemic/pathology , Mice , Mice, Inbred MRL lpr , PTEN Phosphohydrolase/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolismABSTRACT
OBJECTIVE: Gut dysbiosis has been reported implicated in ankylosing spondylitis (AS), a common chronic inflammatory disease mainly affects sacroiliac joints and spine. Utilizing deep sequencing on the feces of untreated AS patients, our study aimed at providing an in-depth understanding of AS gut microbiota. METHODS: We analyzed the fecal metagenome of 85 untreated AS patients and 62 healthy controls by metagenomic shotgun sequencing, and 23 post-treatment feces of those AS patients were collected for comparison. Comparative analyses among different cohorts including AS, rheumatoid arthritis and Behcet's disease were performed to uncover some common signatures related to inflammatory arthritis. Molecular mimicry of a microbial peptide was also demonstrated by ELISpot assay. RESULTS: We identified AS-enriched species including Bacteroides coprophilus, Parabacteroides distasonis, Eubacterium siraeum, Acidaminococcus fermentans and Prevotella copri. Pathway analysis revealed increased oxidative phosphorylation, lipopolysaccharide biosynthesis and glycosaminoglycan degradation in AS gut microbiota. Microbial signatures of AS gut selected by random forest model showed high distinguishing accuracy. Some common signatures related to autoimmunity, such as Bacteroides fragilis and type III secretion system (T3SS), were also found. Finally, in vitro experiments demonstrated an increased amount of IFN-γ producing cells triggered by a bacterial peptide of AS-enriched species, mimicking type II collagen. CONCLUSIONS: These findings collectively indicate that gut microbiota was perturbed in untreated AS patients with diagnostic potential, and some AS-enriched species might be triggers of autoimmunity by molecular mimicry. Additionally, different inflammatory arthritis shared some common microbial signatures.
Subject(s)
Gastrointestinal Microbiome , Inflammation Mediators/metabolism , Metagenome , Metagenomics , Spondylitis, Ankylosing/etiology , Spondylitis, Ankylosing/metabolism , Autoimmunity , Case-Control Studies , Disease Susceptibility , Dysbiosis , High-Throughput Nucleotide Sequencing , Host-Pathogen Interactions/immunology , Humans , Metagenomics/methods , Spondylitis, Ankylosing/pathologyABSTRACT
Molybdenum disulfide (MoS2) was synthesized via hydrothermal process under the assistance of citric acid, which exhibited high photocatalytic property in the application of methylene blue (MB) degradation. The flower ball microstructure of MoS2 changed with different amounts of citric acid. X-ray diffraction (XRD), Scanning electron microscope (SEM), UV-Vis diffuse reflectance spectra have been employed to characterize the samples. It improved the photocatalytic efficiency nearly 19.77% compared to MoS2 without citric acid. When H2O2 was added, the synergistic effect of MoS2 and hydrogen peroxide (H2O2) was observed in photocatalytic reaction system, which degraded MB completely within 40 min under visible light irradiation.
ABSTRACT
OBJECTIVES: To explore the role of Vδ2 T cells in the pathogenesis of rheumatoid arthritis (RA). METHODS: Sixty-eight patients with RA, 21 patients with osteoarthritis and 21 healthy controls were enrolled in the study. All patients with RA fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA. Peripheral Vδ2T population, chemokine receptor expression and proinflammatory cytokine secretion were quantified by flow cytometry. The infiltration of Vδ2 T cells within the synovium was examined by immunohistochemistry and flow cytometry. The effect of tumour necrosis factor (TNF)-α and interleukin (IL)-6 on Vδ2 T migration was determined by flow cytometry and transwell migration assay. RESULTS: Peripheral Vδ2T cells, but not Vδ1 T cells, were significantly lower in patients with RA, which was negatively correlated with disease activity gauged by Disease Activity Score in 28 joints. Vδ2 T cells from RA accumulated in the synovium and produced high levels of proinflammatory cytokines including interferon-γ and IL-17. Phenotypically, Vδ2 T cells from RA showed elevated chemotaxis potential and expressed high levels of chemokine receptors CCR5 and CXCR3, which was driven by increased serum TNF-α through nuclear factor kappa B signalling. In vivo, TNF-α neutralising therapy dramatically downregulated CCR5 and CXCR3 on Vδ2 T cells and repopulated the peripheral Vδ2 T cells in patients with RA. CONCLUSIONS: High levels of TNF-α promoted CCR5 and CXCR3 expression in Vδ2 T cells from RA, which potentially infiltrated into the synovium and played crucial roles in the pathogenesis of RA. Targeting Vδ2 T cells might be a potential approach for RA.
Subject(s)
Arthritis, Rheumatoid/physiopathology , Chemotaxis , Receptors, Antigen, T-Cell, gamma-delta , Synovial Membrane/cytology , T-Lymphocytes/physiology , Arthritis, Rheumatoid/genetics , Case-Control Studies , Cell Movement/physiology , Flow Cytometry , Humans , Interleukin-6/metabolism , Osteoarthritis/genetics , Osteoarthritis/physiopathology , Receptors, CCR5/metabolism , Receptors, CXCR3/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
To analyze the hydrochemical characteristics of river water and snow meltwater during snow-melting period in the Kayiertesi River, the headwaters of the Ertis River, samples of river water and meltwater were collected every day during March and April, 2014. Furthermore, the combination of descriptive statistics, Gibbs Figure and Piper Triangular diagrams of anions and cations were used for hydrochemical analyses. The results showed that the major ion compositions and hydrochemical types were significantly different between river water and snow meltwater. The total dissolved solid (TDS) in the river water ranged from 24.9 to 50.3 mg · L⻹. The major cations of river water were Ca²âº and Naâº, accounting for 61% and 17% of the total cation equivalent concentration, respectively. Meanwhile, HCO3â» constituted about 95% of the total anions concentration. The hydrochemical type of river water was HCO3â»-Ca²âº. The chemical composition of river water samples located in the middle with a deviation to left of Gibbs model, indicating that the major chemical process of river water was controlled by rock weath ring and precipitation but rock weathering played a more important role.
Subject(s)
Environmental Monitoring , Rivers/chemistry , Snow/chemistry , Bicarbonates/analysis , Calcium/analysis , China , Sodium/analysisABSTRACT
To analyze the major ion chemistry of water in the upper reach of the Shule River Basin and possible controls, samples of river water, groundwater, precipitation, melt water were collected and methods including descriptive statistics, Gibbs Figure, Piper Triangular diagrams of anions and cations were comprehensive used. Results showed that the major ion compositions and hydrochemical types were significantly different in different waters such as stream water, groundwater and precipitation. The total dissolved solid (TDS) in the river water ranges between 51.7 to 432. 3 mgL-1 with an average of 177.7 mgL-1. The major cations of river water are Ca2+ and Mg2+, accounting for 45% and 31% of the cations respectively. Meanwhile, HCO(3)- constituted about 75% of the anions. The hydrochemical type of river water is HCO(-)(3)-Ca2+-Mg2+. Owing to the interaction between the river and layer, the concentration of SO(2-)4 is relatively higher. Comparing major ion concentrations of the river water with local groundwater and precipitation, concentrations of the river water ranged between precipitation and groundwater but were much closer to the concentration of groundwater, indicating that the surface water was recharged by a mixture of precipitation and groundwater while groundwater is dominant. The chemical composition of surface water samples located in the middle and a bit upper of Gibbs model, which indicates that the major chemical process of river water is controlled by rock weathering and evaporation-crystallization but rock weathering plays a much more important role.