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Abstract Although accumulating evidence has linked mesenchymal stem cells (MSCs) with tumor growth, the underlying mechanisms are poorly understood. Here, we demonstrated for the first time that human umbilical cord MSCs (hUCMSCs) dramatically increased the growth of lung adenocarcinoma (LUAD) cancer cells in a xenograft tumor model. Then, we observed that hUCMSC-derived extracellular vesicles (hUCMSC-EVs) contribute to the hUCMSC-promoted LUAD cell growth through a direct effect on LUAD cells. Furthermore, we showed that hUCMSC-EV-mediated LUAD growth is associated with increased proliferation and decreased apoptosis in LUAD cells, concomitant with reduced PTEN expression mediated by the hUCMSC-EV-transmitted miR-410. Our findings provide novel insights into the intercellular communications between cancer cells and MSCs through MSC-EV-miRNA and suggest that modification of hUCMSC-EVs might be an attractive therapeutic option for the clinical application of hUCMSC-EVs that would reduce unwanted side effects.
Schistosomiasis is a neglected tropical disease of public health concern. The most devastating pathology in schistosomiasis japonica and mansoni is mainly attributed to the egg-induced granulomatous response and secondary fibrosis in host liver, which may lead to portal hypertension or even death of the host. Schistosome eggs induce M2 macrophages-rich granulomas and these M2 macrophages play critical roles in the maintenance of granuloma and subsequent fibrosis. Reactive oxygen species (ROS), which are highly produced by stimulated macrophages during infection and necessary for the differentiation of M2 macrophages, are massively distributed around deposited eggs in the liver. However, whether ROS are induced by schistosome eggs to subsequently promote M2 macrophage differentiation, and the possible underlying mechanisms as well, remain to be clarified during S. japonicum infection. Herein, we observed that extensive expression of ROS in the liver of S. japonicum-infected mice. Injection of ROS inhibitor in infected mice resulted in reduced hepatic granulomatous responses and fibrosis. Further investigations revealed that inhibition of ROS production in S. japonicum-infected mice reduces the differentiation of M2, accompanied by increased M1 macrophage differentiation. Finally, we proved that S. japonicum egg antigens (SEA) induce a high level of ROS production via both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and mitochondria in macrophages. Our study may help to better understand the mechanism of schistosomiasis japonica-induced hepatic pathology and contribute to the development of potential therapeutic strategies by interfering with ROS production.
The pathology associated with Schistosoma japonicum (S. japonicum) infection in humans is attributed to parasite egg-induced granulomatous inflammation and fibrosis in the host liver. Currently, a marker that is reliable, cheap, less device-dependent, and can be easily and repeatedly used on a large scale to monitor the progression of liver pathology in schistosomiasis japonica endemic areas is lacking. The levels of serum S. japonicum heat shock protein 60 (SjHSP60)-specific IgG and its subtype antibodies in animals (mice and rabbits) or patients with schistosomiasis were measured by ELISA. Liver pathologies in mice and rabbits were evaluated by gross pathology and histopathology, and hepatic fibrosis in patients was examined with ultrasound imaging. The results revealed that the titers of the total IgG and subtype IgG1 anti-SjHSP60 antibodies were positively correlated with the severity of liver pathology after S. japonicum infection. Our findings indicate that the SjHSP60 IgG and IgG1 antibody levels can be used as potential candidate biomarkers for evaluation of liver pathology in schistosomiasis; however, validation remains to be explored in further work.
BACKGROUND:No definitive conclusions have been drawn from the available data about the utilization of extracorporeal membrane oxygenation (ECMO) to treat severe acute respiratory distress syndrome (ARDS). The aim of this study was to review our center's experience with ECMO and determine predictors of outcome from our Chinese center. MATERIAL AND METHODS:We retrospectively analyzed a total of 23 consecutive candidates who fulfilled the study entry criteria between January 2009 and December 2015. Detailed clinical data, ECMO flow, and respiratory parameters before and after the introduction of ECMO were compared among in-hospital survivors and nonsurvivors; factors associated with mortality were investigated. RESULTS:Hemodynamics and oxygenation parameters were significantly improved after ECMO initiation. Thirteen patients survived to hospital discharge. Univariate correlation analysis demonstrated that APACHE II score (r=–0.463, p=0.03), acute kidney injury (r=–0.574, p=0.005), membrane oxygenator replacement (r=–0.516, p=0.014) and total length of hospital stay (r=0.526, p=0.012) were significantly correlated with survival to hospital discharge, and that the evolution of the levels of urea nitrogen, platelet, and fibrinogen may help to determine patient prognosis. Sixteen patients referred for ECMO from an outside hospital were successfully transported to our institution by ambulance, including seven transported under ECMO support. The survival rate of the ECMO-transport group was comparable to the conventional transport or the non-transport group (both p=1.000). CONCLUSIONS:ECMO is an effective alternative option for severe ARDS. APACHE II score on admission, onset of acute kidney injury, and membrane oxygenator replacement, and the evolution of levels of urea nitrogen, platelet, and fibrinogen during hospitalization may help to determine the in-hospital patient prognosis. By establishing a well-trained mobile ECMO team, a long-distance, inter-hospital transport can be administered safely.
Abstract Severe infection commonly results in immunosuppression, which leads to impaired pathogen clearance or increased secondary infection in both humans and animals. However, the exact mechanisms remain poorly understood. Here, we demonstrate that IL-33 results in immunosuppression by inducing thymic involution-associated naive T cell dysfunction with aberrant expression of aging-associated genes and impairs host control of infection in mouse disease models of schistosomiasis or sepsis. Furthermore, we illustrate that IL-33 triggers the excessive generation of medullary thymic epithelial cell (mTEC) IV (thymic tuft cells) in a Pou2f3-dependent manner, as a consequence, disturbs mTEC/cortical TEC (cTEC) compartment and causes thymic involution during severe infection. More importantly, IL-33 deficiency, the anti-IL-33 neutralizing antibody treatment, or IL-33 receptor ST2 deficient thymus transplantation rescues T cell immunity to better control infection in mice. Our findings not only uncover a link between severe infection-induced IL-33 and thymic involution-mediated naive T cell aging, but also suggest that targeting IL-33 or ST2 is a promising strategy to rejuvenate T cell immunity to better control severe infection.
Glioblastoma (GBM) stem cells (GSCs) possess multilineage differentiation potential, which is responsible for cancer progression. Glycoprotein M6B (GPM6B) is a pivotal enzyme in regulating intracranial cell differentiation and neuronal myelination, and is widely studied in several cancers. However, research on GPM6B in glioma is limited. In this study, we analyzed the clinical and molecular characteristics of GPM6B using RNA sequencing data of glioma samples from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets. Quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC) were performed for further validation. Moreover, a neurosphere formation assay, extreme limiting dilution assay, and bioluminescent imaging were employed to validate the therapeutic effects targeted on GPM6B in vitro and in vivo. We found lower expression of GPM6B in aggressive glioma. Receiver operating characteristic (ROC) analysis suggested that GPM6B is an indicator of mesenchymal subtype. Kaplan-Meier analysis also revealed that patients with glioma with high GPM6B expression levels had a tendency toward prolonged survival. The GPM6B expression level could predict favorable prognosis of patients independent of age, grade, IDH status, and 1p/19q status. Additionally, targeting GPM6B impaired the self-renewal and tumorgenicity of mesenchymal GSCs by inhibiting the activation of the Wnt pathway in vitro and in vivo. Our results demonstrated that GPM6B is a crucial predictor in glioma prognosis and represents an underlying therapeutic target in GSC therapy.
Regulation of the oxidative stress response is crucial for the management and prognosis of traumatic brain injury (TBI). The copper chaperone Antioxidant 1 (Atox1) plays a crucial role in regulating intracellular copper ion balance and impacting the antioxidant capacity of mitochondria, as well as the oxidative stress state of cells. However, it remains unknown whether Atox1 is involved in modulating oxidative stress following TBI. Here, we investigated the regulatory role of Atox1 in oxidative stress on neurons both in vivo and in vitro, and elucidated the underlying mechanism through culturing hippocampal HT-22 cells with Atox1 mutation. The expression of Atox1 was significantly diminished following TBI, while mice with overexpressed Atox1 exhibited a more preserved hippocampal structure and reduced levels of oxidative stress post-TBI. Furthermore, the mice displayed notable impairments in learning and memory functions after TBI, which were ameliorated by the overexpression of Atox1. In the stretch injury model of HT-22 cells, overexpression of Atox1 mitigated oxidative stress by preserving the normal morphology and network connectivity of mitochondria, as well as facilitating the elimination of damaged mitochondria. Mechanistically, co-immunoprecipitation and mass spectrometry revealed the binding of Atox1 to DJ-1. Knockdown of DJ-1 in HT-22 cells significantly impaired the antioxidant capacity of Atox1. Mutations in the copper-binding motif or sequestration of free copper led to a substantial decrease in the interaction between Atox1 and DJ-1, with overexpression of DJ-1 failing to restore the antioxidant capacity of Atox1 mutants. The findings suggest that DJ-1 mediates the ability of Atox1 to withstand oxidative stress. And targeting Atox1 could be a potential therapeutic approach for addressing post-traumatic neurological dysfunction.
To assess the influence of glycolytic pathway on the proportion and numbers of regulatory T cells during Schistosoma japonicum infection.A S. japonicum -infected mouse model was established, and C57/BL6 male mice infected with S. japonicum were subjected to intraperitoneal injections of with the glycolytic inhibitor 2-Deoxy-D-glucose (2DG) or PBS for 6 times, and then the cells from spleen or mesenteric lymph nodes (LNs) were isolated and analyzed by flow cytometry (FCM) to detect the percentage of Glut1+CD4+ T cells and Treg cells.The proportions of Glut1+CD4+ T cells in the spleen (43.58%±2.50% vs. 21.15%±0.96%; t = 8.834, P < 0.01) and mesenteric LNs (38.97%±1.97% vs. 28.40%±2.11%; t = 3.662, P < 0.05) were higher in the normal mice than those in the infected mice, and the percentages of Treg cells in the spleen (6.83%±0.21% vs. 13.30%±0.35%; t = 15.65, P < 0.01) and LNs (8.26%±0.15% vs. 14.37%±0.44%; t = 13.14, P < 0.01) were lower in the normal mice than those in the infected mice. In addition, the proportions of Treg cells in the spleen (15.50%±0.76% vs. 13.07%±0.15%; t = 3.130, P < 0.05) and LNs (17.00% ±0.41% vs. 13.83%±0.18%; t = 6.947, P < 0.01) were higher in the infected mice injected intraperitoneally with 2DG than those in the infected mice injected intraperitoneally with PBS.Glycolytic pathway inhibits Treg differentiation in the spleen and mesenteric LNs of S. japonicum-infected mice.[摘要] 目的 探索日本血吸虫感染过程中糖酵解途径对小鼠调节性T (Treg) 细胞数量和功能的影响。方法 建立日 本血吸虫感染小鼠模型, 用糖酵解抑制剂2-Deoxy-D-glucose (2DG) 或PBS对日本血吸虫感染小鼠进行6次腹腔注射后, 分离脾脏细胞和肠系膜淋巴结, 采用流式细胞术 (FCM) 检测分离得到的细胞中Glut1+CD4+ T细胞以及Treg细胞比例。结 果 未感染组小鼠脾脏 (43.58%±2.50% vs. 21.15%±0.96%; t = 8.834, P < 0.01) 和肠系膜淋巴结中Glut1+CD4+ T细胞比例 (38.97%±1.97% vs. 28.40%±2.11%; t = 3.662, P < 0.05) 均显著高于感染日本血吸虫8 周小鼠, 但未感染组小鼠脾脏 (6.83%±0.21% vs. 13.30%±0.35%; t = 15.65, P < 0.01) 和肠系膜淋巴结中Treg细胞比例 (8.26%±0.15% vs. 14.37%±0.44%; t = 13.14, P < 0.01) 均显著低于感染组小鼠。感染小鼠给与2DG腹腔注射后, 脾脏 (15.50%±0.76% vs. 13.07%±0.15%; t = 3.130, P < 0.05) 和肠系膜淋巴结中Treg细胞比例 (17.00%±0.41% vs. 13.83%±0.18%; t = 6.947, P < 0.01) 显著高于给与 PBS注射小鼠。结论 糖酵解途径抑制了日本血吸虫感染小鼠Treg细胞分化。.
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