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The scientific basis of acupuncture on mesenchymal stem cells (MSCs) for treating ischemic stroke (IS) is discussed. MSCs transplantation has great potential for the treatment of tissue damage caused by early stage inflammatory cascade reactions of IS, but its actual transformation is limited by various factors. How to improve the homing efficiency of MSCs is the primary issue to enhance its efficacy. As such, the possible mechanisms of acupuncture and MSCs transplantation in inhibiting inflammatory cascade reactions induced by IS are explored by reviewing literature, and a hypothesis that acupuncture could promote the secretion of stromal cell-derived factor-1α (SDF-1α) from ischemic foci to regulate SDF-1α/CXC chemokine receptor 4 (CXCR4) axis, thereby improving the homing efficiency of MSCs transplantation, exerting its neuroprotective function, and improving the bed transformation ability, is proposed.
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Humans , Ischemic Stroke , Chemokine CXCL12 , Acupuncture Therapy , Mesenchymal Stem Cells , InflammationABSTRACT
OBJECTIVE To investigate the effects and mechanism of atractylodin on inflammatory injury of periodontal tissue and alveolar bone loss in periodontitis rats. METHODS A total of 144 SD rats were divided into control group （intragastric and intraperitoneal injection of normal saline）， model group （intragastric and intraperitoneal injection of normal saline）， atractylodin low-dose， medium-dose and high-dose groups （intraperitoneal injection of 6.665， 13.33， and 26.66 mg/kg atractylodin）， metronidazole group （positive control group， intragastric injection of 0.05 g/kg metronidazole， intraperitoneal injection of normal saline）， AMD3100 [stromal cell-derived factor-1 （SDF-1）/CXC chemokine receptor-4 （CXCR4） pathway inhibitor] group （intragastric injection of 1 mg/kg AMD3100， intraperitoneal injection of normal saline）， atractylodin high-dose+AMD 3100 group （intraperitoneal injection of 26.66 mg/kg atractylodin， intragastric injection of 1 mg/kg AMD3100）， with 18 rats in each group. Except for the control group， all other groups of rats were inoculated with Porphyromonas gingivalis to construct a periodontitis model. After successful modeling， they were given relevant medicine or normal saline， once a day， for 4 consecutive weeks. The gingival index of rats was detected； the levels of interleukin-6 （IL-6） and tumor necrosis factor α （TNF-α） in rat serum were also determined； alveolar bone resorption， periodontal histopathologic changes and the number of osteoclasts were detected by methylene blue staining， HE staining and TRAP staining， respectively. The expressions of osteoprotegerin （OPG）， receptor activator of NF-κB ligand （RANKL）， SDF-1 and CXCR4 proteins were determined. RESULTS Compared with the control group， serious pathological injury of periodontal tissue was found in the model group， the gingival index， the levels of IL-6 and TNF- α， alveolar bone absorption value， the number of osteoclasts， and the expression of RANKL protein were all increased significantly （P＜0.05）， while the expressions of OPG， SDF-1 and CXCR4 proteins were decreased significantly （P＜0.05）. Compared with the model group， pathological injury of periodontal tissue in rats was reduced； the gingival index， the levels of IL-6 and TNF-α， alveolar bone resorption value， osteoclast number and RANKL protein expression were decreased significantly， while protein expressions of OPG， SDF-1 and CXCR4 were increased significantly in atractylodin low-dose， medium-dose and high-dose groups and metronidazole group （P＜0.05）. The change trend of corresponding indexes in the AMD3100 group was opposite to the above （P＜0.05）. AMD3100 attenuated the inhibitory effect of high-dose atractylodin on inflammatory response and alveolar bone loss in rats with periodontitis （P＜0.05）. CONCLUSIONS Atractylodin may improve the inflammatory response and alveolar bone loss in periodontitis rats by activating the SDF-1/CXCR4 signaling pathway.
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OBJECTIVE@#To explore the improvement effect of CXC chemokine receptor 4 (Cxcr4) gene-modified bone marrow mesenchymal stem cell (BMSC)-derived exosomes on aplastic anemia (AA), and make a preliminary exploration of the mechanism.@*METHODS@#Mouse BMSCs were isolated and cultured, then infected by recombinant lentivirus carrying Cxcr4 gene. The expression of green fluorescence was observed through fluorescence microscope, the expression of Cxcr4 mRNA was detected by real-time fluorescence quantitative PCR, and the BMSC-derived exosomes modified with Cxcr4 gene were extracted. Mouse models of AA were constructed, and control group, model group (AA), AA+BMSC group, AA+NC-BMSC group, AA+Cxcr4-BMSC group were set up. Except control group and model group, the other three groups of mice were injected 400 μl exosomes from different sources via the tail vein, after 2 weeks, the routine blood indices and the number of bone marrow nucleated cells were detected, the pathological changes of bone marrow were observed by HE staining, and the expression level of Treg cells was detected by flow cytometry.@*RESULTS@#Mouse BMSCs were successfully isolated, and BMSCs with high expression of Cxcr4 and their exosomes were obtained. Compared with the control group, the number of red blood cell (RBC), white blood cell (WBC), and platelet (PLT), the hemoglobin (Hb) content and proportion of Treg cells in the peripheral blood of mice in the model group significantly decreased (P<0.01), as well as the number of bone marrow nucleated cells (P<0.01). The proliferation level of nucleated cells was low, and the medullary cavity was filled with a large number of fat cells. Compared with the model group, the number of RBC, WBC, PLT, the Hb content and proportion of Treg cells in the peripheral blood of mice in the AA+BMSC group, AA+NC-BMSC group, and AA+Cxcr4-BMSC group significantly increased (P<0.01), as well as the number of bone marrow nucleated cells (P<0.01), and pathological changes of bone marrow were improved. In addition, the number of RBC, WBC, PLT, the Hb content and proportion of Treg cells in the peripheral blood of mice in the AA+Cxcr4-BMSC group were significantly higher than those in the AA+BMSC group (P<0.01), as well as the number of bone marrow nucleated cells (P<0.01).@*CONCLUSION@#Injection of Cxcr4 gene-modified BMSC-derived exosomes has a certain improvement effect on AA mice, and the mechanism may be related to an increase of the proportion of Treg cells.
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Animals , Humans , Mice , Anemia, Aplastic/metabolism , Bone Marrow Cells , Exosomes/metabolism , Mesenchymal Stem Cells , Receptors, CXCR4ABSTRACT
<p><b>OBJECTIVE</b>To evaluate whether the berberine treatment can improve endothelial repair capacity of early endothelial progenitor cells (EPCs) from prehypertensive subjects through increasing CXC chemokine receptor 4 (CXCR4) signaling.</p><p><b>METHODS</b>EPCs were isolated from prehypertensive and healthy subjects and cultured. In vivo reendothelialization capacity of EPCs from prehypertensive patients with or without in vitro berberine treatment was examined in a nude mouse model of carotid artery injury. The protein expressions of CXCR4/Janus kinase-2 (JAK-2) signaling of in vitro EPCs were detected by Western blot analysis.</p><p><b>RESULTS</b>CXCR4 signaling and alteration in migration and adhesion functions of EPCs were evaluated. Basal CXCR4 expression was significantly reduced in EPCs from prehypertensive patients compared with normal subjects (P<0.01). Also, the phosphorylation of JAK-2 of EPCs, a CXCR4 downstream signaling, was significantly decreased (P<0.01). Berberine promoted CXCR4/JAK-2 signaling expression of in vitro EPCs (P<0.01). Transplantation of EPCs pretreated with berberine markedly accelerated in vivo reendothelialization (P<0.01). The increased in vitro function and in vivo reendothelialization capacity of EPCs were inhibited by CXCR4 neutralizing antibody or pretreatment with JAK-2 inhibitor AG490, respectively (P<0.01).</p><p><b>CONCLUSION</b>Berberinemodified EPCs via up-regulation of CXCR4 signaling contributes to enhanced endothelial repair capacity in prehypertension, indicating that berberine may be used as a novel potential primary prevention means against prehypertension-related atherosclerotic cardiovascular disease.</p>
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AIM:To investigate the role of Buyanghuanwu decoction(BYHWD) in promoting endothelial pro-genitor cells(EPCs)-induced recovery of damaged vascular endothelium. METHODS:The endothelial damaged rats were lavaged with BYHWD and injected with EPCs through vena caudalis. The repaired situation of damaged endothelium was observed. RESULTS:Compared with EPCs group and BYHWD group,the endothelial thickness was reduced, the levels of calcium,triglycerides and total cholesterol were decreased,but the high density lipoprotein levels were increased. In ad-dition,the protein expression of vascular endothelial nitric oxide synthase and vascular stromal cell-drived factor-1 was sig-nificantly increased,but the expression of CXC chemokine receptor-4 was significantly reduced in BYHWD+EPC group. CONCLUSION:BYHWD promotes EPCs repairing damaged endothelium,the mechanism may be related to improve the internal environment and promotes the EPCs homing.
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AIM:To compare the effects of atorvastatin at different doses on the function of endothelial proge-nitor cells (EPCs) in the patients with ST-segment elevation myocardial infarction (STEMI).METHODS:The patients of STEMI (n=40) were chosen.According to treatment with different doses of atorvastatin calcium tablet, they were randomly divided into a group of 20 mg and a group of 40 mg (20 cases in each group).The EPCs isolated from the patients were identified and quantitatively analyzed at different time points (before the treatment and on days 5, 10, 15, 20, 30, 60, 90 and 120 after the treatment) by flow cytometry.The surface markers of the EPCs, CXC chemokine receptor 4 (CXCR4), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and silent information regulator 1 (SIRT1), were also detected.RESULTS:On the 5th day, the group of 40 mg demonstrated stronger cell proliferation capability and higher expression levels of CXCR4, VEGF and bFGF than the group of 20 mg (P<0.05).From the 10th day to 120th day, the group of 20 mg revealed stronger cell proliferation capability and higher expression levels of CXCR4, VEGF and bFGF than the group of 40 mg (P<0.05).Within 30 d, the expression of SIRT1 showed no significant diffe-rence between the 2 groups, yet it witnessed a marked change after that and peaked on the 60th day with a drop afterwards.At each time point, the SIRT1 expression level in the group 20 mg was observed higher than that in the group of 40 mg (P<0.05).CONCLUSION:In the acute phase, the repair function of the body treated with atorvastatin at dose of 40 mg is better than that with 20 mg.However, in a long term the low concentration of statin therapy works better in improving the vascular intima and promoting the angiogenesis than high concentration.
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Objective To investigate the expression of CXC chemokine receptor 4 (CXCR4) in clear cell renal cell carcinoma (ccRCC) and its relationship with the clinical pathological parameters of ccRCC.Methods The expression of CXCR4 was detected by immuno-histochemistry method in 63 cases of ccRCCs,20 cases of para-carcinoma tissues and 20 cases of normal renal tissues.The correlation between expression level of CXCR4 and clinical pathological parameters of ccRCC patients were analyzed,and the clinical significance of its expression in ccRCC was evaluated.Results The positive expression rate of CXCR4(49.2％) in ccRCCs was significantly higher than that in para-carcinoma tissues (15％) and normal renal tissue (10％),and the difference was statistically significant (P ＜ 0.05).The expression level of CXCR4 and the clinical stage and pathological grade of ccRCC were correlated (P ＜ 0.05),and was associated with lymph node transfer (P ＜ 0.05).The CXCR4 negative group overall survival rate [55.2％ (16/29)] and the average survival time(46 months) was significantly better than the positive group [38.5％ (10/26),32 months;P ＜ 0.05].Conclusions The expression level of CXCR4 in ccRCC is correlated with the clinicopathological parameters and prognosis.CXCR4 is expected to be an important marker for diagnosis and prognosis evaluation of renal cell carcinoma.
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Objective To observe the effects of mesenchymal stem cells (MSCs) surface CXC chemokine receptor 4 over-expression on the repair of kidney after ischemia reperfusion (I/R) injury.Methods The MSCs were co-cultured with I/R injured renal cell homogenate supernatant.The MSCs surface CXCR4 and stromal cells derived factor-1 (SDF-1α) protein levels were detected by Western blot, chemotactic ability of MSCs to SDF-1 was investigated by transwell test.The I/R injured renal model was made and pathological changes were observed in control group, I/R group, MSCs injection group and CXCR4 neutralize antibody group.Renal CXCR4 protein expression was measured by immunofluorescence histochemistry, SDF-1α、 CXCR4、 hepatocyte growth factor (HGF) and epidermal growth factor (EGF) mRNA were detected by Real-time quantitative polymerase chain reaction (RT-PCR).Comparisons among multiple groups were performed using One-way analysis of variance, and comparisons between groups were carried out using independent-sample t-test.Results In vitro, the SDF-1α protein expression markedly increased in I/R injured renal tissue homogenate, but the difference was not significant between I/R group and CXCR4 antibody group (t =0.862, P =0.403).MSCs surface CXCR4 protein expression increased significantly after co-cultured with I/R injured renal tissue homogenate (F =95.957, t =10.166, P ＜ 0.01), and the chemotactic ability of MSCs to SDF-1 increased at the same time (F =82.459, t =6.826, P ＜ 0.01), the CXCR4 protein expression (t =13.657, P ＜ 0.01) and the chemotactic ability (t =12.662, P ＜0.01) could be decreased by CXCR4 neutralize antibody.In vivo, renal tubular structure was destroyed in I/R group.After MSCs injection, the renal pathological injury improved rapidly, but the improvement could be inhibited by CXCR4 antibody.The expression of SDF-1α mRNA and level of SDF-1a protein increased in I/R group, but there was no significant difference among different groups (F =1.909,P =0.173).MSCs injection markedly up-regulated the CXCR4 protein and mRNA expression (F =6.663, P =0.006).Following the increase in CXCR4 expression, the expressions of HGF mRNA (F =11.898,P ＜ 0.01) and EGF mRNA (F =5.309, P ＜ 0.05) increased gradually which could be restrained by CXCR4 antibody (t =5.312, t =4.310, P ＜ 0.01).Conclusions I/R injured renal microenvironment markedly increased the mesenchymal stem cells surface CXCR4 expression, and increased CXCR4 expression can induce MSCs chemotaxis and stimulate the secretion of renal protective growth factors paracrine promoting the repair of the kidney.
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Objective To investigate the expressions of CXCR4 in Barrett esophagus (BE), esophageal adenocarcinoma (EADC) and esophageal squamous cell carcinoma (ESCC), and its relationship with pathology, clinical staging and lymph node metastasis. Methods The expressions of CXCR4 in 56 cases of normal esophageal mucosa, 80 BE (including 22 BE with multifocal dysplasia), 25 EADC and 48 ESCC were examined with immunohistochemical method. Results CXCR4 was expressed in most samples of BE (80. 8% ), EADC (68. 0% ) and ESCC (78.4%) without significant difference ( P ＞ 0. 05 ), which was significantly higher than that in normal esophageal mucosa (39. 3%, P ＜0. 01 ). The level of CXCR4 expression in BE, EADC or ESCC were not related with gender, age, or location of the foci ( P ＞ 0. 05). There was no significant difference in CXCR4 expression between BE without dysplasia or BE with multifocal dysplasia ( P ＞ 0. 05 ). CXCR4 expression level in well-differentiated EADC was significantly higher than that of mild or poorly differentiated (P ＜ 0. 05 ). CXCR4 expression level was higher in EADC with lymph node metastasis than those without ( P ＜ 0. 05 ). CXCR4 level in ESCC with TNM staging grades Ⅲ -Ⅳ was higher than that of grades Ⅰ - Ⅱ, and this variable was also higher in cases with lymph node metastasis than those without (P ＜ 0. 05), so was the case of well and poorly differentiated ESCC (P ＜ 0. 01 ). Conclusion Increased expression level of CXCR4 may be a common feature of EADC and ESCC, which is irrelevant to pathological types. CXCR4 level rises at the stage of BE, which is associated with the degree of tumor differentiation, lymph node metastasis and TNM staging. CXCR4 expression is of guiding significance in the diagnosis of BE, EADC and ESCC, and is the potential drug target.
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he activity of MMP-2 and MMP-9 via ERK1/2 signaling pathway.
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Objective:To investigate the relationship of CXCR4,VEGF-C and SDF-1 in human laryngeal carcinoma and discuss the significance of the three indexs in lymph node metastasis.Methods:The expression of CXCR4,VEGF-C and SDF-1 was detected by reverse transcription polymerase chain reaction(RT-PCR)and immuno-histochemical SP in 10 cases of adjacent normal tissue,45 cases of laryngeal carcinoma tissue and cervical lymph node tissue.Results:Not in the mRNA but the level of proteins,The positive rate of the expression of CXCR4 and VEGF-C were 78%,67%and 78%,71%in primary tumor cells,were altogether higher than that in adjacent normal tissue(P
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Background and purpose:It was reported that chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1(SDF-1)were involved in the proliferation,differentiation,and metastasis of tumor.This study was designed to observe the expression of chemokine receptor CXCR4 in hypopharyngeal squamous cell carcinoma tissue and study the relationship between the expression of chemokine receptor CXCR4 and different clinicopathlogical characteristics,and further to explore the clinical significance.Methods:For the detection of the expression of chemokine receptor CXCR4,43 primary hypopharyngeal squamous cell carcinoma tissues,27 normal hypopharyngeal tissues,34 lymph node metastastatic lesions and 9 normal lymph node lesions were detected by immunohistochemical method using rabbit anti-human CXCR4 polyclonal antibody.Results:The positive expression rates of CXCR4 in 43 hypopharyngeal carcinoma tissues and normal tissues were 95.3% and 22.2%,respectively(P
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Objective:To investigate the expression of CXCL12-CXCR4 and VEGF-C in pancreatic cancer and relation to clinical pathology.Methods:The tissue samples including PAC,the cancerous peripheral tissues,the normal pancreatic tissues and peripheral lympho nodes were obtained from 30 patients with PAC.The expressions of CXCL12,CXCR4and VEGF-C proteins in these tissues were assayed by immunohistochemical staining.The expressions of CXCL12,CXCR4 and VEGF-C mRNA in PAC were also investigated by fluorescence quantitative real-time PCR.Results:In all the samples,the positive rates of CXCL12 protein in PAC,the cancerous peripheral tissues,the normal pancreatic tissues and peripheral lympho nodes were respectively 13.3%(4/30),46.7%(14/30),56.7%(17/30) and 50.0%(15/30).The positive rates of CXCR4 protein in PAC,the cancerous peripheral tissues,the normal pancreatic tissues and peripheral lympho nodes were respectively 80.0%(24/30),70.0%(21/30),26.7%(8/30) and 73.3%(22/30).The expression levels of CXCR4 mRNA in PAC tissues,the cancerous peripheral tissues and peripheral lympho nodes were higher than that in the normal pancreatic tissues(P
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AIM:To investigate the role of SDF-1? in migrating of bone marrow stromal cells to the injured areas. METHODS:Ischemic brain lesion model was created in rats by permanent middle cerebral artery occlusion (MCAO). 48 SD rats were divided randomly into 2 groups. Group 1:phosphate buffered saline (PBS 1 mL) for control (n=25); Group 2:BMSCs (2?106) were injected intravenously at 24 h after MCAO (n=24). After propagated in BMSCs,Ad5/F35 GFP (green fluorescent protein) was infected to BMSCs. The expression of SDF-1? (stromal cell-derived factor-1?) mRNA in the penrumbral tissue was assayed by real-time quantitative PCR. The expression of CXCR4 on MSCs was detected by flow cytometry. Confocal microscopy was used to detect the GFP-labeled MSCs migration. RESULTS:Ad5/F35 GFP signals was observed in almost infected BMSCs. The expressions of SDF-1? mRNA in the thalamus and hippocampus of the ischemic brains were peaked at 3rd day after stroke,followed by a decrease at 14th day post-ischemia. The expression of SDF-1? mRNA in the cortex of the ischemic brains was peaked at 7th day post-ischemia,still at high level at 14th day post-ischemia. The median percentage of surface CXCR4 expression in BMSCs was 14%. GFP labeled BMSCs were detected in the origination of the middle cerebral artery (olfactory area) at 6 h,after 3 days in the prenumbra tissue such as thalamus,and in the cortex more labeled cells were found after 14 d post-ischemia.CONCLUSION:BMSCs can pass through the blood brain barrier of ischemic rats. Its mechanism might be associated with the expression of SDF-1? in the ischemic brain.