ABSTRACT
OBJECTIVE@#To investigate the effect of chronic emotional stimulation induced by empty bottle stimulation on CXCL12/CXCR4-mediated inflammatory response in rats with acute myocardial infarction (AMI).@*METHODS@#Rat models of anxiety were established by a 21-day stimulation with uncertain empty bottle drinking water, and myocardial infarction was induced by ligating the left anterior descending branch of the coronary artery; compound models were established by performing myocardial infarction operation on the 15th day of anxiety modeling. The rats were randomly divided into 4 groups: shamoperated group (=6), myocardial infarction group (=6), compound model group (with myocardial infarcted and anxiety; = 6), and inhibitor group (compound models treated daily with 1 mg/kg AMD3100 for 6 days; =7). Echocardiography was used to examine the LVEF and LVFS to evaluate the cardiac function of the rats. Elevated maze test and open field test were used to evaluate the behaviors of the rats. The expressions of CXCL12, CXCR4, IL-1β, IL-18 and neutrophil active protease (NE) in the myocardial tissues and blood samples were detected with ELISA and immunohistochemistry.@*RESULTS@#The LVEF and LVFS were lower in the compound model group than in the sham group and myocardial infarction group ( < 0.05), and were higher in inhibitor group than in the compound model group ( < 0.05). LVID; d and LVID; s were lower in the inhibitor group than in the compound model group ( < 0.05). Compared to those in the sham group and myocardial infarction group, the rats in the compound model group more obviously preferred to stay in the closed arm ( < 0.05) in EPM; the rats in the inhibitor group had more times of entering and staying in the open arm than the compound model rats ( < 0.05); the horizontal and vertical movements were less in the compound model rats than in those in the sham group and the myocardial infarction group ( < 0.05) in OFT, and the vertical movement of the rats in inhibitor group was higher than those in the compound model group ( < 0.05). The expression of CXCR4 in the marginal zone of myocardial infarction was significantly higher in the compound model group than in the sham-operated group, myocardial infarction group and inhibitor group ( < 0.05). The expressions of IL-1β, IL-18 and NE in the inhibitor group were significantly lower than those in the compound model group ( < 0.05). Compared with at in the sham-operated group, the number of Nissl bodies in the compound model group decreased significantly ( < 0.01).@*CONCLUSIONS@#Chronic emotional stress induced by empty bottle stimulation can lead to dysfunction of the CXCL12/CXCR4 axis, which causes inflammatory cascade after myocardial infarction to worsen myocardial cell necrosis, cardiac function and hippocampal neuronal damage after the infarction.
Subject(s)
Animals , Rats , Chemokine CXCL12 , Coronary Vessels , Emotions , Myocardial Infarction , Myocardium , Psychological Distress , Receptors, CXCR4 , Signal TransductionABSTRACT
Objective: To investigate the effect of CXCL12/CXCR4/CXCR7 axis on the metastasis and invasion in pancreatic cancer so as to provide new evidence for research on pancreatic cancer metastasis treatment. Methods: MiaPaCa-2 cells were transfected with CXCR4 shRNA and CXCR7 shRNA, and the Transwell assay was used to determine the effects of CXCL12/CXCR4/CXCR7 axis on cell invasion and migration. Quantitative RT-PCR and Western blotting were used to explore the effects of CXCL12/CXCR4/CXCR7 axis on the expressions of invasion-related genes (MMP-2 and uPA) and EMT-related genes (E-cadherin and Vimentin). Results: CXCL12 significantly increased the metastasis and invasion of pancreatic cancer cells. The enhancement of tumor cell invasion was effectively countered by CXCR4 shRNA or CXCR7 shRNA. CXCL12/CXCR4 axis in cancer cells increased the expressions of invasion-related genes (MMP-2 and uPA) and EMT-related genes (E-cadherin and Vimentin). CXCL12/CXCR7 axis only increased the expressions of MMP-2 and uPA. Compared to blocking CXCR4 or CXCR7 alone, the inhibitory effects on invasion-related genes and EMT-related genes were more effective when both CXCR4 and CXCR7 were blocked. Conclusion: CXCL12/CXCR4/CXCR7 axis regulates the EMT, metastasis, and invasion of pancreatic cancer cells.
ABSTRACT
Chemokine 12 (CXCL12), also known as stromal cell derived factor-1 (SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand for the transmembrane G protein-coupled receptors CXCR4 and CXCR7. The CXCL12/CXCR4 axis takes part in a series of physiological, biochemical, and pathological process, such as inflammation and leukocyte trafficking, cancer-induced bone pain, and postsurgical pain, and also is a key factor in the cross-talking between tumor cells and their microenvironment. Aberrant overexpression of CXCR4 is critical for tumor survival, proliferation, angiogenesis, homing and metastasis. In this review, we summarized the role of CXCL12/CXCR4 in cancer, CXCR4 inhibitors under clinical study, and natural product CXCR4 antagonists. In conclusion, the CXCL12/CXCR4 signaling is important for tumor development and targeting the pathway might represent an effective approach to developing novel therapy in cancer treatment.
Subject(s)
Animals , Humans , Antineoplastic Agents , Chemistry , Pharmacology , Biological Products , Chemistry , Pharmacology , Chemokine CXCL12 , Genetics , Metabolism , Molecular Targeted Therapy , Neoplasms , Drug Therapy , Genetics , Metabolism , Receptors, CXCR4 , Genetics , MetabolismABSTRACT
Chemokine 12 (CXCL12), also known as stromal cell derived factor-1 (SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand for the transmembrane G protein-coupled receptors CXCR4 and CXCR7. The CXCL12/CXCR4 axis takes part in a series of physiological, biochemical, and pathological process, such as inflammation and leukocyte trafficking, cancer-induced bone pain, and postsurgical pain, and also is a key factor in the cross-talking between tumor cells and their microenvironment. Aberrant overexpression of CXCR4 is critical for tumor survival, proliferation, angiogenesis, homing and metastasis. In this review, we summarized the role of CXCL12/CXCR4 in cancer, CXCR4 inhibitors under clinical study, and natural product CXCR4 antagonists. In conclusion, the CXCL12/CXCR4 signaling is important for tumor development and targeting the pathway might represent an effective approach to developing novel therapy in cancer treatment.
Subject(s)
Animals , Humans , Antineoplastic Agents , Chemistry , Pharmacology , Biological Products , Chemistry , Pharmacology , Chemokine CXCL12 , Genetics , Metabolism , Molecular Targeted Therapy , Neoplasms , Drug Therapy , Genetics , Metabolism , Receptors, CXCR4 , Genetics , MetabolismABSTRACT
Numerous studies of colitis in IBD (inflammatory bowel diseases) patients and in animal models have demonstrated that both inflammatory cytokines and chemokines are up-regulated in settings of active inflammation. Blockade or absence of various cytokines and chemokines attenuates the disease in murine models of IBD. Therefore, identifying cytokines and chemokines involved in intestinal inflammation provide promising targets for the development of new drugs in the treatment of IBD. In general, chemokines have been implicated in many fundamental immune processes including lymphoid organogenesis, immune cell differentiation, development and positioning. Many chemokines are markedly increased in intestinal tissue from patients with IBD. In this study, we focused on the role of CXCL12-CXCR4 and CXCL16. CXCL12-CXCR4 axis plays a crucial role in the pathophysiology of IBD, especially UC, while SR-PSOX/CXCL16 plays a significant role in the pathophysiology of CD. Our present data suggest new insights into the etiology of IBD and we hope that the manipulation of these chemokines may have therapeutic value.
Subject(s)
Humans , Axis, Cervical Vertebra , Cell Differentiation , Chemokines , Colitis , Cytokines , Inflammation , Inflammatory Bowel Diseases , Models, Animal , OrganogenesisABSTRACT
Idiopathic pulmonary fibrosis(IPF), with unknown pathogeny, is an interstitial lung disease.The pathological features are diffuse epithelial-cell lesion, fibroblast proliferation, myofibroblast differentiation and excessive extracellular matrix deposition.CXCR4 is the predominant chemokine receptor on fibrocytes;CXCL12 is the only ligand of CXCR4.A large number of studies have shown that CXCL12/CXCR4 biological axis plays an important role in the pathogenesis of idiopathic pulmonary fibrosis.Under the regulation of hypoxia, HIF-1α and PI3K-Akt-mTOR path, CXCL12/CXCR4 biological axis promotes lung fibroblast proliferation, myofibroblast differentiation and extracellular matrix deposition, resulting in development and progression of IPF.
ABSTRACT
Colorectal cancer(CRC) is kind of the common malignant tumor worldwide.Bad prognosis is always due to distal metastasis.In recent years,the research on chemokines targeted on cancer metastasis and directing on the movement of the tumor cells have been more and more deeply taken into consideration.Chemokine CXCL12 and its specific chemokine receptor CXCR4 play important roles in CRC cell's targeted cancer metastasis and directing movement by signal transduction mechanism.Researches showed that it can inhibit the migration and invasion of the tumor through interception chemokine receptor CXCR4 by many ways.The studies of this signal may be a potential target sit for gene therapy.The aim of this review was to summarize the current knowledge of these researches.