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| 1 | Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis显示文摘Iron has been shown to trigger oxidative stress by elevating reactive oxygen species (ROS) and to participate in different modes of cell death,such as ferroptosis,apoptosis and necroptosis. However,whether iron-elevated ROS is also linked to pyroptosis has not been reported. Here,we demonstrate that iron-activated ROS can induce pyroptosis via a Tom20-Bax-caspase-GSDME pathway. In melanoma cells,iron enhanced ROS signaling initiated by CCCP,causing the oxidation and oligomerization of the mitochondrial outer membrane protein Tom20. Bax is recruited to mitochondria by oxidized Tom20,which facilitates cytochrome c release to cytosol to activate caspase-3;eventually triggering pyroptotic death by inducing GSDME cleavage. Therefore,ROS acts as a causative factor and Tom20 senses ROS signaling for iron-driven pyroptotic death of melanoma cells. Since iron activates ROS for GSDME-dependent pyroptosis induction and melanoma cells specifically express a high level of GSDME,iron may be a potential candidate for melanoma therapy. Based on the functional mechanism of iron shown above,we further demonstrate that iron supplementation at a dosage used in iron-deficient patients is sufficient to maximize the anti-tumor effect of clinical ROS-inducing drugs to inhibit xenograft tumor growth and metastasis of melanoma cells through GSDME-dependent pyroptosis. Moreover,no obvious side effects are observed in the normal tissues and organs of mice during the combined treatment of clinical drugs and iron. This study not only identifies iron as a sensitizer amplifying ROS signaling to drive pyroptosis,but also implicates a novel iron-based intervention strategy for melanoma therapy. | Bo Zhou Jia-yuan Zhang Xian-shuo Liu Hang-zi Chen Yuan-li Ai Kang Cheng Ru-yue Sun Dawang Zhou Jiahuai Han Qiao Wu | 2018 | Cell Research2018，28，12： | 52 |
| 2 | Magnesium deficiency in plants:An urgent problem显示文摘Although magnesium(Mg) is one of the most important nutrients, involved in many enzyme activities and the structural stabilization of tissues, its importance as a macronutrient ion has been overlooked in recent decades by botanists and agriculturists, who did not regard Mg deficiency(MGD) in plants as a severe health problem. However, recent studies have shown,surprisingly, that Mg contents in historical cereal seeds have markedly declined over time, and two thirds of people surveyed in developed countries received less than their minimum daily Mg requirement. Thus, the mechanisms of response to MGD and ways to increase Mg contents in plants are two urgent practical problems. In this review, we discuss several aspects of MGD in plants, including phenotypic and physiological changes, cell Mg2+homeostasis control by Mg2+transporters, MGD signaling, interactions between Mg2+and other ions, and roles of Mg2+in plant secondary metabolism. Our aim is to improve understanding of the influence of MGD on plant growth and development and to advance crop breeding for Mg enrichment. | Wanli Guo Hussain Nazim Zongsuo Liang Dongfeng Yang | 2016 | The Crop Journal2016，4，2： | 39 |
| 3 | Regulation of Toll-like receptor signaling in innate immunity显示文摘Toll-like receptors sense invading pathogens by recognizing a wide variety of conserved pathogen-associated molecular patterns(PAMPs).The members of the TLR family selectively utilize adaptor proteins MyD88,TRIF,TIRAP and TRAM to activate overlapping but distinct signal transduction pathways which trigger production of different panels of mediators such as proinflammatory cytokines and type I interferon.These mediators not only control innate immunity but also direct subsequently developed adaptive immunity.TLR activation is strictly and finely regulated at multiple levels of the signal transduction pathways. | AN HuaZhang,QIAN Cheng & CAO XueTao National Key Laboratory of Medical Immunology & Institute of Immunology,Second Military Medical University,Shanghai 200433,China | 2010 | Science China(Life Sciences)2010，53，1： | 29 |
| 4 | Taxus chinensis ameliorates diabetic nephropathy through down-regulating TGF-β1/Smad pathway显示文摘Diabetic nephropathy(DN) is one of the common microvascular complications of diabetes mellitus. Renal fibrosis is closely related to the deterioration of renal function. The present study aimed to investigate protective effect of Taxus chinensis on high-fat diet/streptozotocin-induced DN in rats and explore the underlying mechanism of action. The rat DN model was established via feeding high fat diet for 4 weeks and subsequently injecting streptozotocin(30 mg·kg^(-1) body weight) intraperitoneally. The rats with blood glucose levels higher than 16.8 mmol·L^(-1) were selected for experiments. The DN rats were treated with Taxus chinensis orally(0.32, 0.64, and 1.28 g·kg^(-1)) once a day for 8 weeks. Taxus chinensis significantly improved the renal damage, which was indicated by the decreases in 24-h urinary albumin excretion rate, blood serum creatinine, and blood urea nitrogen. Histopathological examination confirmed the protective effect of Taxus chinensis. The thickness of glomerular basement membrane was reduced, and proliferation of mesangial cells and podocytes cells and increase in mesangial matrix were attenuated. Further experiments showed that Taxus chinensis treatment down-regulated the expression of TGF-β1 and α-SMA, inhibited phosphorylation of Smad2 and Smad3. These results demonstrated that Taxus chinensis alleviated renal injuries in DN rats, which may be associated with suppressing TGF-β1/Smad signaling pathway. | WENG Hong-Bo HAN Wen-Ke XIONG Yan-Wen JIN Zhou-Hui LAN Zhen LIU Cheng ZHANG Xue-Mei PENG Wen | 2018 | Chinese Journal of Natural Medicines2018，16，2： | 28 |
| 5 | Epithelial-mesenchymal transition- activating transcription factors- multifunctional regulators in cancer显示文摘The process of epithelial to mesenchymal transition(EMT), first noted during embryogenesis, has also been reported in tumor formation and leads to the development of metastatic growth. It is a naturally occurring process that drives the transformation of adhesive,non-mobile epithelial like cells into mobile cells with a mesenchymal phenotype that have ability to migrate to distant anatomical sites. Activating complex network of embryonic signaling pathways, including Wnt, Notch,hedgehog and transforming growth factor-β pathways,lead to the upregulation of EMT activating transcription factors, crucial for normal tissue development and maintenance. However, deregulation of tightly regulated pathways affecting the process of EMT has been recently investigated in various human cancers. Given the critical role of EMT in metastatic tumor formation,better understanding of the mechanistic regulation provides new opportunities for the development of potential therapeutic targets of clinical importance. | Minal Garg | 2013 | World Journal of Stem Cells2013，5，4： | 26 |
| 6 | Pilose antler aqueous extract promotes the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells by stimulating the BMP-2/Smad1, 5/Runx2 signaling pathway显示文摘Peptides from Pilose antler aqueous extract(PAAE) have been shown to stimulate the proliferation and differentiation of bone marrow mesenchymal stem cells(BMSCs). However, the underlying molecular mechanisms are not well understood. Here, PAAE was isolated and purified to explore the molecular mechanisms underlying PAAE’s effects on BMSCs as well as its osteoprotective effects in ovariectomized rats. Our results showed that PAAE promoted proliferation and differentiation of BMSCs to become osteoblasts by enhancing ALP activity and increasing extracellular matrix mineralization. The trabecular microarchitecture of ovariectomized rats was also found to be protected by PAAE. Quantitative reverse transcription-polymerase chain reaction(Quantitative RT-PCR) results suggest that PAAE also increased the expression of osteogenic markers including, alkaline phosphatase(ALP), runt-related transcription factor 2(Runx2), osteocalcin(OCN), bone morphogenetic protein-2(BMP-2), and collagen I(COL-I). Immunoblotting results indicated that PAAE upregulated the levels of BMP-2 and Runx2 and was associated with Smad1/5 phosphorylation. PAAE A at the concentration of 200μg·mL^-1 showed the strongest effect on proliferation and osteogenic differentiation of BMSCs after 48 h. Using matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF MS), we identified the molecular weight of PAAE A and found that it is less than 3000 Da and showed several significant peaks. In conclusion, PAAE activates the BMP-2/Smad1, 5/Runx2 pathway to induce osteoblastic differentiation and mineralization in BMSCs and can inhibit OVX-induced bone loss. These mechanisms are likely responsible for its therapeutic effect on postmenopausal osteoporosis. | REN Cong GONG Wei LI Feng XIE Ming | 2019 | Chinese Journal of Natural Medicines2019，17，10： | 25 |
| 7 | Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma显示文摘Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc . Based on the investigated mechanisms,some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC. | Bo Zhai Xue-Ying Sun | 2013 | World Journal of Hepatology2013，5，7： | 24 |
| 8 | Molecular mechanisms of insulin resistance in type 2 diabetes mellitus显示文摘Free fatty acids are known to play a key role in promoting loss of insulin sensitivity in type 2 diabetes mellitus but the underlying mechanism is still unclear.It has been postulated that an increase in the intracellular concentration of fatty acid metabolites activates a serine kinase cascade,which leads to defects in insu-lin signaling downstream to the insulin receptor.In addition,the complex network of adipokines released from adipose tissue modulates the response of tissues to insulin.Among the many molecules involved in the intracellular processing of the signal provided by insulin,the insulin receptor substrate-2,the protein kinase B and the forkhead transcription factor Foxo 1a are of particular interest,as recent data has provided strong evidence that dysfunction of these proteins results in insulin resistance in vivo.Recently,studies have revealed that phosphoinositidedependent kinase 1-independent phosphorylation of protein kinase Cε causes a reduction in insulin receptor gene expression.Additionally,it has been suggested that mitochondrial dysfunction triggers activation of several serine kinases,and weakens insulin signal transduction.Thus,in this review,the current developments in understanding the pathophysiological processes of insulin resistance in type 2 diabetes have been summarized.In addition,this study provides potential new targets for the treatment and prevention of type 2 diabetes. | Vandana Saini | 2010 | World Journal of Diabetes2010，1，3： | 23 |
| 9 | Effects of interventions on oxidative stress and inflammation of cardiovascular diseases显示文摘Excessive oxidative stress and low-grade chronic inflammation are major pathophysiological factors contributing to the development of cardiovascular diseases (CVD) such as hypertension, diabetes and atherosclerosis. Accumulating evidence suggests that a compromised antioxidant system can lead to excessive oxidative stress in cardiovascular related organs, resulting in cell damage and death. In addition, increased circulating levels of pro-inflammatory cytokines, such as tumor necrosis factor α, interleukin-6 and C-reactive protein, are closely related to morbidity and mortality of cardiovascular complications. Emerging evidence suggests that interventions including nutrition, pharmacology and exercise may activate expression of cellular anti-oxidant systems via the nuclear factor erythroid 2-related factor 2-Kelchlike ECH-associated protein 1 signaling pathway and play a role in preventing inflammatory processes in CVD. The focus of the present review is to summarize recent evidence showing the role of these anti-oxidant and anti-inflammatory interventions in cardiovascular disease. We believe that these findings may prompt new effective pathogenesis-oriented interventions, based on the exercise-induced protection from disease in the cardiovascular system, aimed at targeting oxidant stress and inflammation. | Sewon Lee Yoonjung Park Mozow Yusof Zuidema Mark Hannink | 2011 | World Journal of Cardiology2011，3，1： | 23 |
| 10 | Impaired PI3K/Akt signal pathway and hepatocellular injury in high-fat fed rats显示文摘AIM:To determine whether mitochondrial dysfunction resulting from high-fat diet is related to impairment of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt,also known as PKB) pathway. METHODS:Rat models of nonalcoholic fatty liver were established by high-fat diet feeding. The expression of total and phosphorylated P13K and Akt proteins in hepatocytes was determined by Western blotting. Degree of fat accumulation in liver was measured by hepatic triglyceride. Mitochondrial number and size were determined using quantitative morphometric analysis under transmission electron microscope. The permeability of the outer mitochondrial membrane was assessed by determining the potential gradient across this membrane.RESULTS:After Wistar rats were fed with high-fat diet for 16 wk,their hepatocytes displayed an accumulation of fat (103.1 ± 12.6 vs 421.5 ± 19.7,P < 0.01),deformed mitochondria (9.0% ± 4.3% vs 83.0% ± 10.9%,P < 0.05),and a reduction in the mitochondrial membrane potential (389.385% ± 18.612% vs 249.121% ± 13.526%,P < 0.05). In addition,the expression of the phosphorylated P13K and Akt proteins in hepatocytes was reduced,as was the expression of the anti-apoptotic protein Bcl-2,while expression of the pro-apoptotic protein caspase-3 was increased. When animals were treated with pharmacological inhibitors of P13K or Akt,instead of high-fat diet,a similar pattern of hepatocellular fat accumulation,mitochondrial impairment,and change in the levels of PI3K,Akt,Bcl-2 was observed. CONCLUSION:High-fat diet appears to inhibit the PI3K/Akt signaling pathway,which may lead to hepa-tocellular injury through activation of the mitochondrial membrane pathway of apoptosis. | Ji-Wu Han,Department of Gastroenterology,The 4th Hospital of Harbin Medical University,Harbin 150001,Heilongjiang Province,China Xiao-Rong Zhan,Xin-Yu Li,Bing Xia,Yue-Ying Wang,Jing Zhang,Department of Endocrinology,First Hospital of Harbin Medical University,Harbin 150001,Heilongjiang Province,China Bao-Xin Li,Department of Pharmacology,State Key Laboratory of Biomedicine and Pharmacology,Harbin Medical University,Harbin 150001,Heilongjiang Province,China | 2010 | World Journal of Gastroenterology2010，16，48： | 22 |
| 11 | Effects of Fufang Biejia Ruangan Pills on hepatic fibrosis in vivo and in vitro显示文摘AIM:To explore the protective effect and the relevant mechanisms of Fufang Biejia Ruangan Pills(FFBJRGP)on hepatic fibrosis in vivo and in vitro.METHODS:Hepatic fibrosis was induced by carbon tetrachloride composite factors.Adult Wistar rats were randomly divided into four groups:normal control group;hepatic fibrosis model group;FFBJRGP-treated group at a daily dose of 0.55 g/kg;and colchicinetreated group at a daily dose of 0.1 g/kg.The effects of FFBJRGP on liver function,serum levels of hyaluronic acid(HA),typeⅣcollagen(CⅣ),typeⅢprocollagen(PCⅢ),laminin(LN),histopathology,and expression of transforming growth factor(TGF-β1)and Smad3 in hepatic fibrosis were evaluated in vivo.The effects of FFBJRGP on survival rate,hydroxyproline content and cell cycle distribution were further detected in vitro.RESULTS:Compared with the hepatic fibrosis model group,rats treated with FFBJRGP showed a reduction in hepatic collagen deposition and improvement in hepatic lesions.Compared with those of the model group,the activities of alanine aminotransferase(62.0±23.7 U/L)and aspartate aminotransferase(98.8±40.0 U/L)in the FFBJRGP-treated group were decreased(50.02±3.7 U/L and 57.2±30.0 U/L,respectively,P<0.01).Compared with those in the model group,the levels of PCⅢ(35.73±17.90 g/mL),HA(563.82±335.54 ng/mL),LN(89.57±7.59 ng/mL)and CⅣ(29.20±6.17ng/mL)were decreased to 30.18±9.41,456.18±410.83,85.46±7.51 and 28.02±9.45 ng/mL,respectively.Reverse-transcriptase polymerase chain reaction and Western blotting also revealed that expression of TGF-β1 and Smad3 were down-regulated in vivo.Cell proliferation was inhibited,the level of hydroxyproline was decreased compared with the control group(P<0.01),and the cell cycle was redistributed when exposed to FFBJRGP in vitro.CONCLUSION:FFBJRGP inhibits hepatic fibrosis in vivo and in vitro,which is probably associated with downregulation of fibrogenic signal transduction of the TGF-β-Smad pathway. | Feng-Rui Yang Bu-Wu Fang Jian-Shi Lou | 2013 | World Journal of Gastroenterology2013，19，32： | 22 |
| 12 | Acacetin protects against cerebral ischemia-reperfusion injury via the NLRP3 signaling pathway显示文摘Acacetin(5,7-dihydroxy-4′-methoxyflavone), a potential neuroprotective agent, has an inhibitory effect on lipopolysaccharide-induced neuroinflammatory reactions. However, whether acacetin has an effect on inflammatory corpuscle 3(NLRP3) after cerebral ischemia-reperfusion injury has not been fully determined. This study used an improved suture method to establish a cerebral ischemia-reperfusion injury model in C57BL/6 mice. After ischemia with middle cerebral artery occlusion for 1 hour, reperfusion with intraperitoneal injection of 25 mg/kg of acacetin(acacetin group) or an equal volume of saline(0.1 mL/10 g, middle cerebral artery occlusion group) was used to investigate the effect of acacetin on cerebral ischemia-reperfusion injury. Infarct volume and neurological function scores were determined by 2,3,5-triphenyltetrazolium chloride staining and the Zea-Longa scoring method. Compared with the middle cerebral artery occlusion group, neurological function scores and cerebral infarction volumes were significantly reduced in the acacetin group. To understand the effect of acacetin on microglia-mediated inflammatory response after cerebral ischemia-reperfusion injury, immunohistochemistry for the microglia marker calcium adapter protein ionized calcium-binding adaptor molecule 1(Iba1) was examined in the hippocampus of ischemic brain tissue. In addition, tumor necrosis factor-α, interleukin-1β, and interleukin-6 expression in ischemic brain tissue of mice was quantified by enzyme-linked immunosorbent assay. Expression of Iba1, tumor necrosis factor-α, interleukin-1β and interleukin-6 was significantly lower in the acacetin group compared with the middle cerebral artery occlusion group. Western blot assay results showed that expression of Toll-like receptor 4, nuclear factor kappa B, NLRP3, procaspase-1, caspase-1, pro-interleukin-1β, and interleukin-1β were significantly lower in the acacetin group compared with the middle cerebral artery occlusion group. Our findings indicate that acacetin has a protective effect on cerebral ischemia-reperfusion injury, and its mechanism of action is associated with inhibition of microglia-mediated inflammation and the NLRP3 signaling pathway. | Juan Bu Shen Shi Hui-Qin Wang Xiao-Shan Niu Zong-Feng Zhao Wei-Dong Wu Xiao-Ling Zhang Zhi Ma Yan-Jun Zhang Hui Zhang Yi Zhu | 2019 | Neural Regeneration Research2019，14，4： | 22 |
| 13 | Progress in neural plasticity显示文摘One of the properties of the nervous system is the use-dependent plasticity of neural circuits.The structure and function of neural circuits are susceptible to changes induced by prior neuronal activity,as reflected by short-and long-term modifications of synaptic efficacy and neuronal excitability.Regarded as the most attractive cellular mechanism underlying higher cognitive functions such as learning and memory,activity-dependent synaptic plasticity has been in the spotlight of modern neuroscience since 1973 when activity-induced long-term potentiation(LTP) of hippocampal synapses was first discovered.Over the last 10 years,Chinese neuroscientists have made notable contributions to the study of the cellular and molecular mechanisms of synaptic plasticity,as well as of the plasticity beyond synapses,including activity-dependent changes in intrinsic neuronal excitability,dendritic integration functions,neuron-glia signaling,and neural network activity.This work highlight some of these significant findings. | POO Mu-Ming | 2010 | Science China(Life Sciences)2010，53，3： | 21 |
| 14 | Human urokinase-type plasminogen activator gene-modifiedbone marrow-derived mesenchymal stem cells attenuateliver fibrosis in rats by down-regulating the Wnt signalingpathway显示文摘AIM: To evaluate the therapeutic effects of bone marrow-derived mesenchymal stem cells(BMSCs) with human urokinase-type plasminogen activator(u PA) on liver fibrosis, and to investigate the mechanism of gene therapy.METHODS: BMSCs transfected with adenovirusmediated human urokinase plasminogen activator(Adu PA) were transplanted into rats with CCl4-induced liver fibrosis. All rats were sacrificed after 8 wk, and their serum and liver tissue were collected for biochemical, histopathologic, and molecular analyzes. The degree of liver fibrosis was assessed by hematoxylin and eosin or Masson's staining. Western blot and quantitative reverse transcription-polymerase chain reaction were used to determine protein and m RNA expression levels.RESULTS: Serum levels of alanine aminotransferase, aminotransferase, total bilirubin, hyaluronic acid, laminin, and procollagen type Ⅲ were markedly decreased, whereas the levels of serum albumin were increased by u PA gene modified BMSCs treatment. Histopathology revealed that chronic CCl4-treatment resulted in significant fibrosis while u PA gene modified BMSCs treatment significantly reversed fibrosis. By quantitatively analysing the fibrosis area of liver tissue using Masson staining in different groups of animals, we found that model animals with CCl4-induced liver fibrosis had the largest fibrotic area(16.69% ± 1.30%), while fibrotic area was significantly decreased by BMSCs treatment(12.38% ± 2.27%) and was further reduced by u PA-BMSCs treatment(8.31% ± 1.21%). Both protein and m RNA expression of β-catenin, Wnt4 and Wnt5 a was down-regulated in liver tissues following u PA gene modified BMSCs treatment when compared with the model animals.CONCLUSION: Transplantation of u PA gene modified BMSCs suppressed liver fibrosis and ameliorated liver function and may be a new approach to treating liver fibrosis. Furthermore, treatment with u PA gene modified BMSCs also resulted in a decrease in expression of molecules of the Wnt signaling pathway. | Zhi-Gang Ma Xiao-Dan Lv Ling-Ling Zhan Lan Chen Qi-Yuan Zou Ji-Qiao Xiang Jiao-Li Qin Wei-Wei Zhang Zhao-Jing Zeng Hui Jin Hai-Xing Jiang Xiao-Ping Lv | 2016 | World Journal of Gastroenterology2016，22，6： | 21 |
| 15 | Long noncoding RNA LINC00520 prevents the progression of cutaneous squamous cell carcinoma through the inactivation of the PI3K/Akt signaling pathway by downregulating EGFR显示文摘Background: Long noncoding RNAs (lncRNAs) play pivotal roles in various malignant tumors. Epidermal growth factor receptor (EGFR) signaling is associated with the pathogenesis of cutaneous squamous cell carcinoma (cSCC). This study aimed to explore the role of LINC00520 in the development of cSCC via EGFR and phosphoinositide 3-kinase-protein kinase B (PI3K/Akt) signaling pathways. Methods: A microarray analysis was applied to screen differentially expressed lncRNAs in cSCC samples. The A431 cSCC cell line was transfected and assigned different groups. The expression patterns of LINC00520, EGFR, and intermediates in the PI3K/Akt pathway were characterized using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting analysis. Cell proliferation, migration, and invasion were detected using the MTT assay, scratch test, and Transwell assay, respectively. Cell-based experiments and a tumorigenicity assay were conducted to assess the effect of LINC00520 on cSCC progression. This study was ended in September 2017. Comparisons between two groups were analyzed with t-test and comparisons among multiple groups were analyzed using one-way analysis of variance. The nonparametric Wilcoxon rank sum test was used to analyze skewed data. The enumerated data were analyzed using the chi-square test or Fisher exact test. Results: Data from chip GSE66359 revealed depletion of LINC00520 in cSCC. Cells transfected with LINC00520 vector and LINC00520 vector + si-EGFR showed elevated LINC00520 level but decreased levels of the EGFR, PI3K, AKT, VEGF, MMP-2 and MMP-9 mRNAs and proteins, and inhibition of the growth, migration and adhesion of cSCC cells, while the si-LINC00520 group showed opposite trends (all P < 0.05). Compared with the LINC00520 vector group, the LINC00520 vector + si-EGFR group showed decreased levels of the EGFR, PI3K, AKT, VEGF, MMP-2 and MMP-9 mRNAs and proteins, and inhibition of the growth, migration and adhesion of cSCC cells, while the LINC00520 vector+ EGFR vector group showed opposite results (all P < 0.05). Conclusion: Based on our results, LINC00520-targeted EGFR inhibition might result in the inactivation of the PI3K/Akt pathway, thus inhibiting cSCC development. | Xue-Ling Mei Shah Zhong | 2019 | Chinese Medical Journal2019，，4： | 20 |
| 16 | Molecular regulation of vasculogenic mimicry in tumors and potential tumor-target therapy显示文摘'Vasculogenic mimicry(VM)',is a term that describes the unique ability of highly aggressive tumor cells to express a multipotent,stem cell-like phenotype,and form a pattern of vasculogenic-like networks in threedimensional culture.As an angiogenesis-independent pathway,VM and/or periodic acid-schiff-positive patterns are associated with poor prognosis in tumor patients.Moreover,VM is resistant to angiogenesis inhibitors.Here,we will review the advances in research on biochemical and molecular signaling pathways of VM in tumors and on potential anti-VM therapy strategy. | Yue-Zu Fan Wei Sun | 2010 | World Journal of Gastrointestinal Surgery2010，2，4： | 19 |
| 17 | Dissecting the molecular pathophysiology of drug-induced liver injury显示文摘Drug-induced liver injury(DILI) has become a major topic in the field of Hepatology and Gastroenterology. DILI can be clinically divided into three phenotypes: hepatocytic, cholestatic and mixed. Although the clinical manifestations of DILI are variable and the pathogenesis complicated, recent insights using improved preclinical models, have allowed a better understanding of the mechanisms that trigger liver damage. In this review, we will discuss the pathophysiological mechanisms underlying DILI. The toxicity of the drug eventually induces hepatocellular damage through multiple molecular pathways, including direct hepatic toxicity and innate and adaptive immune responses. Drugs or their metabolites, such as the common analgesic, acetaminophen, can cause direct hepatic toxicity through accumulation of reactive oxygen species and mitochondrial dysfunction. The innate and adaptive immune responses play also a very important role in the occurrence of idiosyncratic DILI. Furthermore, we examine common forms of hepatocyte death and their association with the activation of specific signaling pathways. | Hui Ye Leonard J Nelson Manuel Gómez del Moral Eduardo Martínez-Naves Francisco Javier Cubero | 2018 | World Journal of Gastroenterology2018，24，13： | 19 |
| 18 | Oxidative stress and inflammatory signaling in cerulein pancreatitis显示文摘Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis.Reactive oxygen species(ROS)regulate the activation of inflammatory cascades,the recruitment of inflammatory cells and tissue damage in acute pancreatitis.A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression,which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB(NF-κB)and activator protein-1(AP-1),signal transducer and activator of transcription 3(STAT3),and mitogen-activated protein kinases(MAPKs).Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB,AP-1,STAT3,and MAPKs;this crosstalk amplifies the inflammatory cascade in acute pancreatitis.Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis.Since oxidative stress may activate inflammatory signaling pathways and contribute to thedevelopment of pancreatitis,antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis.Since chronic administration of high doses of antioxidants may have deleterious effects,dosage levels and duration of antioxidant treatment should be carefully determined. | Ji Hoon Yu Hyeyoung Kim | 2014 | World Journal of Gastroenterology2014，20，46： | 19 |
| 19 | The molecular mechanism underlying angiogenesis in hepatocellular carcinoma: the imbalance activation of signaling pathways显示文摘OBJECTIVE: To explore the effect of two dominating signaling pathways, VEGF/KDR andangiopoietins/Tie2, on the formation of new blood vessel in hepatocellular carcinoma (HCC) growth andmetastasis.METHODS: RT-PCR and Western blot were employed to evaluate the VEGF/KDR andangiopoietins/Tie2 expression in samples from 23 patients with HCC. Meanwhile, microvessel density(MVD) was determined as a marker of angiogenesis by counting CD34 positive cells with the method ofimmunohistochemistry.RESULTS: The two pathways were activated in all HCC samples. The expressions of vascular endothelialgrowth factor (VEGF) and angiopoietin-2 (Ang2) were significantly higher (P<0.05) in hepatocellularcarcinoma tissues and the margin of the tumor than those in control groups, and so did CD34 positivecells. Although significant difference in the expression of kinase insert domain containing receptor (KDR)and Ang1/Tie2 was not observed in all groups, their distinct high levels were seen in hepatoma and itsmargin compared with normal and cirrhotic liver. VEGF and Ang2 expressions were seen up-regulated inHCC with vascular invasion and satellite lesion.CONCLUSIONS: The two signaling pathways, VEGF/KDR and angiopoietins/Tie2 are activated in theprocess of angiogenesis in HCC and modulate the formation of new blood vessels. The imparity of the twosignaling pathways’ activation is to benefit HCC metastasis. In the two pathways, VEGF and Ang2 mayplay an important role in the process of angiogenesis, and are necessary indicators for the prognosis andmetastasis of HCC. This study provides another clue for the exploration of anti-angiogenic agents. | Zhi-Cheng Zhao Shu-Sen Zheng Yun-Le Wan Chang-Ku Jia Hai-Yang Xie the Department of Hepatobiliary Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China | 2003 | Hepatobiliary & Pancreatic Diseases International2003，2，4： | 19 |
| 20 | Xinfuli Granule improves post-myocardial infarction ventricular remodelingand myocardial fibrosis in rats by regulating TGF-β/Smads signaling pathway显示文摘Background Recent clinical and experimental studies have confirmed the effects of Xinfuli Granule (XG), a compound Chinesemedicine in the prevention and treatment of heart failure (HF). This study aimed to investigate the effects and the mechanisms of XG onventricular reconstruction in rats with acute myocardial infarction (AMI). Methods Sprague-Dawley rats were subjected to left anteriordescending branch ligation. The rats that survived 24 h were randomly assigned to five groups: medium-dose of XG group (MI+XGM),high-dose of XG group (MI+XGH), carvedilol group (MI+C), medium-dose of XG + carvedilol group (MI+C+XGM). Fourteen rats under-went identical surgical procedures without artery ligation, serving as sham controls. At 28 days, left ventricular weight to body weight(LVW/BW) and heart weight to body weight (HW/BW) were calculated; left ventricular ejection fraction (LVEF), left ventricular shorteningfraction (LVFS), left ventricular internal diameter at systole (LVIDS) were measured by ultrasound; HE staining, Masson staining, and Siriusred staining were used to assess the myocardial pathological and physiological changes as well as myocardial fibrosis area and non-infarctzone Ⅰ/Ⅲ collagen ratio. Expression of Smad3 were detected and analyzed by Western blot, immunohistochemistry and immunofluorescenceP-Smad3, Smad2 and Smad7 in the TGF-13/Smads signaling pathway were also analyzed by Western blot. Results The LVIDS (P 〈 0.01),HW/BW (P 〈 0.05), type UIII collagen ratio (P 〈 0.01) and myocardial collagen (P 〈 0.01) decreased significantly while the LVW/BW,LVFS (P 〈 0.05) increased significantly in MI+XGM group as compared with those in other groups. The expression of key signal moleculesof the TGF-β/Smads signaling pathway, including Smad3, P-Smad3 and Smad2 protein were decreased, while the expression of Smad7 in-creased in both XG and carvedilol treatment groups as compared to those of the MI group (all P 〈 0.01). Immunohistochemistry and im-munofluorescence further confirmed the down-regulated Smad3 expression. Conclusion XG can improve ventricular reconstruction andinhibit myocardial fibrosis in rats with AMI by regulating TGF-β/Smads signaling pathway. | Jie MA Zhi-Yuan LI Xiao-Peng LIANG Cai-Xia GUO Pei-Pei LU Li-Hong MA | 2017 | Journal of Geriatric Cardiology2017，14，5： | 19 |
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