Objective To introduce the inflammatory microenvironment and epithelial-mesenchymal transition process of hepatocellular carcinoma, and review the relationship between them. Methods Domestic and international literatures were collected to summary the relationship between epithelial-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma. Result Many inflammatory factors and viral gene encoding proteins in the inflammatory microenvironment play an important role in the process of epithelial-mesenchymal transition in hepatocellular carcinoma. Conclusions The inflammatory microenvironment of hepatocellular carcinoma is an indispensable role in the process of epithelial-mesenchymal transition. The inhibition and treatment of inflammatory microenvironment may play a more active role in the control of tumor invasion and metastasis.
Glioma is one of the most common primary tumors in the human brain with poor prognosis. The local and systemic immunosuppressive environment created by glioma cells enables them to evade immunosurveillance. Myeloid-derived suppressor cells (MDSCs) are a critical component of the immunosuppression system. They are a heterogeneous cell population composed of early myeloid progenitor cells and precursor cells. Although the cells are diverse in phenotypes and functions, they all have strong immunosuppressive functions. MDSCs are extensively infiltrated into tumor tissues and play an important role in the glioma immunosuppressive microenvironment, which also hinders the immunotherapeutic effects of glioma. This article will review the phenotypic characteristics of MDSCs in the glioma microenvironment and their role in the progression of glioma. It is of positive significance to better understand the pathogenesis of glioma and explore effective comprehensive treatments.
背景: 在容易暴露于大量微生物的环境( 如传统的农场) 中成长的儿童, 不易患儿童哮喘和特应性体质。在既往的研究中, 微生物暴露的标志物与这些疾病呈负相关关系。方法: 在两项横断面研究中, 我们比较了居住于农场的儿童与参照组儿童哮喘和特应性体质的患病率以及微生物暴露的多样性。在一项PARSIFAL研究[ 变态反应的预防-与农业及特别信仰( Anthroposophic) 生活方式相关的儿童致敏作用的危险因素] 中, 研究者采用单链构型多态性( SSCP) 分析筛查了床垫灰尘样本的细菌DNA, 以检测出培养技术无法检测到的环境细菌。在另一项GABRIELA 研究[ 鉴定欧共体中哮喘的遗传和环境原因的多学科研究( GABRIEL) 高级研究] 中, 研究者采用培养技术对儿童房间落尘样本的细菌和真菌的分类进行了评估。结果: 在这两项研究中, 居住于农场的儿童哮喘与特应性体质的患病率较低, 并且他们比对照组儿童暴露于更多种类的环境微生物中。相反, 微生物暴露的多样性与哮喘发生危险呈负相关[ PARSIFAL 研究的比值比为0. 62; 95% 可信区间( CI) 为0. 44 ～0. 89; GABRIELA 研究的比值比为0. 86; 95% CI 为0. 75 ～0. 99] 。此外, 存在某种更为局限的暴露也与哮喘发生危险呈负相关; 这包括暴露于真菌中曲菌属中的某些物种( 经校正的比值比为0. 37; 95% CI 为0. 18 ～0. 76) , 以及暴露于多种细菌物种, 包括单核细胞增生李斯特菌、芽孢杆菌属物种、棒杆菌属物种和其他细菌( 经校正的比值比为0. 57,95% CI 为0. 38 ～0. 86) 。结论: 居住于农场的儿童比参照组儿童有更大范围的微生物暴露, 这种暴露解释了哮喘与成长在农场之间呈负相关关系的本质部分。【述评】哮喘发病机制的卫生学说认为在儿童时期接触大量的抗原能减少成年后哮喘的发病率, 主要机制是在人体免疫系统发育的过程中接触抗原可诱导免疫耐受, 此学说主要基于流行病学调查得出的结论。本研究采用分子生物学的方法研究儿童时期微生物暴露对哮喘发病率的影响, 结果证实微生物暴露的程度与哮喘发病呈负相关, 进一步证实了哮喘发病的卫生学说, 同时表明环境因素在哮喘发病中具有重要意义, 并提示儿童在发育过程中尽量接触多种抗原对减少成人过敏性疾病具有一定意义。
Objective To summarize the research progress on the regulation of hepatic sinusoidal microenvironment to promote liver regeneration based on liver sinusoidal endothelial cells (LSECs), aiming to further clarify the mechanism of liver regeneration and provide new ideas and methods for clinical promotion of liver regeneration and prevention of liver failure. Method The basic and clinical research studies on LSECs and liver regeneration at home and abroad in recent years were searched and reviewed. Results Differentiated LSECs played an important role in liver regeneration, regulated the homeostasis of hepatic sinusoid microenvironment by paracrine and autocrine, and participated in the whole process of promoting liver regeneration, such as hepatocyte proliferation and neovascularization after acute and chronic liver injury. Conclusion In the process of liver regeneration after all kinds of acute and chronic liver injury, LSECs promote liver regeneration by regulating hepatic sinusoid microenvironment, which will provide new strategies and methods for clinical promotion of liver regeneration and prevention of liver failure after hepatectomy.
ObjectiveTo investigate the effect of simulated in vivo physiological environment severed limb fostering system applying remote ischemic conditioning (RIC) perfusion on preserving severed limb. MethodEighteen adult Bama mini pigs (24-30 kg in weight) were randomly divided into 3 groups (n=6) . No ischemic treatment was given in group A as normal control group; the right lower limbs were completely amputated and preserved at room temperature for 3 hours to make ischemic models in groups B and C, and then the severed limbs were put into the simulated in vivo physiological environment severed limb fostering system. Continuous blood perfusion was performed in group B, and continuous blood perfusion was performed after RIC perfusion in group C. After 8 hours of perfusion, the skeletal muscle samples were harvested for the morphology observation by transmission electron microscopy. The protein levels of B-cell lymphoma-2(Bcl-2) and Caspase-3 were detected by Western blot. The content of cytochrome C in both mitochondria and cytoplasm was determined by ELISA. ResultsTransmission electron microscopy results illustrated that the muscle fibers arranged more orderly and the mitochondria swelling was slighter in group C than group B. Western blot analysis showed that the protein levels of Bcl-2 and Caspase-3 were significantly higher in groups B and C than group A (P<0.05) ; the protein level of Bcl-2 significantly increased and the protein level of Caspase-3 significantly decreased in group C when compared with those in group B (P<0.05) . ELISA detection implicated that mitochondrial cytochrome C significantly reduced and cytosolic cytochrome C significantly increased in group B when compared with those in groups A and C (P<0.05) , but no significant difference was found between group A and group C (P>0.05) . ConclusionsThe ischemia/reperfusion-induced injury to skeletal muscle could be considerably inhibited by RIC perfusion. The simulated in vivo physiological environment severed limb fostering system applying RIC perfusion can significantly prolong the severed limb preserving time.
Objective To investigate relationship between hypoxia microenvironment and occurrence and development of hepatocellular carcinoma (HCC). Method The relevant literatures on researches of the relationship between the hypoxic microenvironment and the HCC were review and analyzed. Results The hypoxia microenvironment played an important role in inducing the drug resistance and angiogenesis of the HCC cells, and it was an important factor of affecting the ability of tumor metabolism, invasion, and migration. The hypoxia microenvironment could up-regulate the expression of hypoxia-inducible factors (HIFs) and promote its transcriptional activity, promote the expression of the vascular endothelial growth factor gene, and regulate the neovascularization in the tumor. Among them, the HIF-1α played a major role in regulating the angiogenesis, immune escape, tumor invasion and metastasis-related gene expression, participating in the glycolysis, regulating lysyl oxidase 2 and thus regulated epithelial-mesenchymal transition, then promoted the invasion and metastasis of the HCC; HIF-2α was a key regulator of the malignant phenotype involving in the cell proliferation, angiogenesis, apoptosis, metabolism, metastasis, and resistance to chemotherapy. The hypoxia microenvironment posed some difficulties for the treatment of HCC, but it was also a potential therapeutic breakthrough. Conclusion Hypoxia microenvironment can promote invasion and metastasis of HCC through various mechanisms, which provides new targets and strategies for clinical treatment of HCC.
ObjectiveTo explore the effects of hypoxia inducible factor-1 alpha (HIF-1α) on the reverse differentiation of hepatocellular carcinoma cells into liver cancer stem cells, and the maintenance of malignant biological behavior in hypoxic environment.MethodsCD133-negative cells in HepG2 cells were separated by immunomagnetic beads and divided into two groups. The cells of siRNA group were transfected with siRNA-HIF-1α to silence the expression of HIF-1α gene, while cells of the blank control group did not transfect any siRNA fragments. The two groups of cells were cultured under normal and hypoxic conditions respectively. MTT, cloning and Transwell chamber experiments were used to detect the proliferation and invasion ability of cells. Western blot and real-time PCR (RT-PCR) were used to detect the expressions of HIF-1α, CD133, CD90, and CD44 protein and mRNA in cells.ResultsMTT results showed that the cell proliferation rate increased with the prolongation of hypoxia in four groups. Compared with the blank control group at 24, 32, 40, and 48 hours, the cell proliferation rate decreased significantly after siRNA-HIF-1a transfection, on both two kinds of cultured conditions (P<0.05). The results of plate cloning experiment showed that the number of cell-forming clones increased significantly after hypoxic culture (there were significant differences between the transfected normoxic group and transfected hypoxic group, blank control normoxic group and blank control hypoxic group, P<0.05); and the formation of transfected hypoxic condition group at the same time of hypoxia was also significant (P<0.05). The number of clones were significantly less than that of the blank control group at the hypoxic condition (P<0.05). Transwell lab experiment showed that after hypoxic culture, the number of cells migrated to the inferior chamber in the transfection group was significantly reduced compared with that of the blank control group (P<0.05). Western blot and RT-PCR results showed that the expression levels of HIF-1α protein and tumor stem cell markers (CD133, CD90, and CD44 protein) in the blank control hypoxic condition group were significantly higher than those in the other three groups (P<0.05); after siRNA-HIF-1a transfection, HIF-1α mRNA and tumor stem cell markers mRNA (CD133, CD90, and CD44 mRNA) in the transfected hypoxic condition group were significantly lower than those in the transfected normal condition group and the blank control normal condition group (P<0.05).ConclusionsIn hypoxia environment, HIF-1α can promote hepatocellular carcinoma cells to differentiate into liver cancer stem cells and enhance their malignant biological behavior.
ObjectiveTo analyze the correlation between the molecular biological information of SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC) and its clinical prognosis, and to explore the spatial features and molecular mechanisms of interactions between cells in the tumor microenvironment (TME) of SMARCA4-dNSCLC. MethodsUsing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), this study conducted functional enrichment analysis on differentially expressed genes (DEGs) in SMARCA4-dNSCLC and depicted its genomic variation landscape. Through weighted gene co-expression network analysis (WGCNA) and a combination of 10 different machine learning algorithms, patients in the training group were divided into a low-risk group and a high-risk group based on a median risk score (RiskScore). A corresponding prognostic prediction model was established, and on this basis, a nomogram was constructed to predict the 1, 3, and 5-year survival rates of patients. K-M survival curves, receiver operating characteristic (ROC) curves, and time-dependent ROC curves were drawn to evaluate the predictive ability of the model. External datasets from GEO further validated the prognostic value of the prediction model. In addition, we also evaluated the immunological characteristics of the TME of the prognostic model. Finally, using single-cell RNA sequencing (scRNA-seq) and spatial transcriptome (ST), we explored the spatial features of interactions between cells in the TME of SMARCA4-dNSCLC, intercellular communication, and molecular mechanisms. ResultsA total of 56 patients were included in the training group, including 38 males and 18 females, with a median age of 62 (56-70) years. There were 28 patients in both the low-risk and high-risk groups. A total of 474 patients were included in the training group, including 265 males and 209 females, with a median age of 65 (58-70) years. A risk score model composed of 8 prognostic feature genes (ELANE, FSIP2, GFI1B, GPR37, KRT81, RHOV, RP1, SPIC) was established. Compared with patients in the low-risk group, those in the high-risk group showed a more unfavorable prognostic outcome. Immunological feature analysis revealed differences in the infiltration of various immune cells between the low-risk and high-risk groups. ScRNA-seq and ST analyses found that interactions between cells were mainly through macrophage migration inhibitory factor (MIF) signaling pathways (MIF-CD74+CXCR4 and MIF-CD74+CD44) via ligand-receptor pairs, while also describing the niche interactions of the MIF signaling pathway in tissue regions. ConclusionThe 8-gene prognostic model constructed in this study has certain predictive accuracy in predicting the survival of SMARCA4-dNSCLC. Combining the ScRNA-seq and ST analyses, cell-to-cell crosstalk and spatial niche interaction may occur between cells in the TME via the MIF signaling pathway (MIF-CD74+CXCR4 and MIF-CD74+CD44).
ObjectiveTo investigate the effects of three-dimensional (3D) printed Ti6Al4V-4Cu alloy on inflammation and osteogenic gene expression in mouse bone marrow mesenchymal stem cells (BMSCs) and mouse mononuclear macrophage line RAW264.7.MethodsTi6Al4V and Ti6Al4V-4Cu alloys were prepared by selective laser melting, and the extracts of the two materials were prepared according to the biological evaluation standard of medical devices. The effects of two kinds of extracts on the proliferation of mouse BMSCs and mouse RAW264.7 cells were detected by cell counting kit 8 method. After co-cultured with mouse BMSCs for 3 days, the expression of osteogenesis- related genes [collagen type Ⅰ (Col-Ⅰ), alkaline phosphatase (ALP), Runx family transcription factor 2 (Runx-2), osteoprotegerin (OPG), and osteopontin (OPN)] were detected by real-time fluorescence quantitative PCR. After co-cultured with mouse RAW264.7 cells for 1 day, the expressions of inflammation-related genes [interleukin 4 (IL-4) and nitric oxide synthase 2 (iNOS)] were detected by real-time fluorescence quantitative PCR, and the supernatants of the two groups were collected to detect the secretion of vascular endothelial growth factor a (VEGF-a) and bone morphogenetic protein 2 (BMP-2) by ELISA. The osteogenic conditioned medium were prepared with the supernatants of the two groups and co-cultured with BMSCs for 3 days. The expressions of osteogenesis-related genes (Col-Ⅰ, ALP, Runx-2, OPG, and OPN) were detected by real-time fluorescence quantitative PCR.ResultsCompared with Ti6Al4V alloy extract, Ti6Al4V-4Cu alloy extract had no obvious effect on the proliferation of BMSCs and RAW264.7 cells, but it could promote the expression of OPG mRNA in BMSCs, reduce the expression of iNOS mRNA in RAW264.7 cells, and promote the expression of IL-4 mRNA. It could also promote the secretions of VEGF-a and BMP-2 in RAW264.7 cells. Ti6Al4V-4Cu osteogenic conditioned medium could promote the expressions of Col-Ⅰ, ALP, Runx-2, OPG, and OPN mRNAs in BMSCs. The differences were all significant (P<0.05).Conclusion3D printed Ti6Al4V-4Cu alloy can promote RAW264.7 cells to secret VEGF-a and BMP-2 by releasing copper ions, thus promoting osteogenesis through bone immune regulation, which lays a theoretical foundation for the application of metal prosthesis.