Evaluation of C-X-C chemokine receptor type 4 (CXCR4) and Peroxisome proliferator-activated receptor gamma (PPAR-?) expression in colorectal carcinoma: Relation to the available clinicopathological parameters

Background: Colorectal carcinoma (CRC) is the most common malignancy of the gastrointestinal tract, representing an incredible health problem. It is essential to develop drugs against novel targets––involved in CRC tumorigenesis and progression––to improve the management of the disease. The aim of this study was to evaluate C-X-C chemokine receptor type 4 (CXCR4) and Peroxisome proliferator-activated receptor gamma (PPAR-?) expression in CRC, and to associate their expression with the available clinicopathological parameters. Materials and Methods: This study included 50 cases of primary CRC. All cases were stained by CXCR4 and PPAR-? antibodies to assess their immunohistochemical expression. The relations between their expression and clinicopathological variables were assessed. Results: CXCR4 expression was detected in 76% of studied cases. High CXCR4 expression showed significant associations with the depth of tumor invasion (P = 0.024), lymph node metastasis (P = 0.009), advanced tumor stage (P = 0.001) and the presence of vascular invasion (P = 0.035). PPAR-? expression was detected in 78% of studied cases. PPAR-? expression showed a statistically significant inverse relation with histologic types (P = 0.001), tumor grade (P = 0.005), depth of tumor invasion (P = 0.001), lymph node status (P = 0.001), TNM stage (P = 0.002), and vascular invasion (P = 0.001). Conclusions: High CXCR4 and decreased PPAR-? expressions are related to high tumor grade, advanced stage, and vascular invasion in colorectal carcinoma.

Advances in the study on cytokines related to dental pulp regeneration / 口腔医学

@#With the development of molecular biology, biomaterials and tissue engineering, regenerative treatment of pulpal and periradicular diseases is facing new opportunities. At present, a large number of studies on dental pulp regeneration reveal that cytokines are essential for promoting migration, proliferation and osteogenic differentiation of dental pulp stem cells. In this paper, we review several kinds of cytokines related to dental pulp regeneration, and analyze their roles and regulatory mechanisms in dental pulp regeneration.

Reversing the PAI-1-induced fibrotic immune exclusion of solid tumor by multivalent CXCR4 antagonistic nano-permeator

Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8+ T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.

Scientific basis of acupuncture on mesenchymal stem cells for treating ischemic stroke / 中国针灸

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.

Bushen Jianpi Jiedu Liyan Formula Regulates Homing-associated Cell Adhesion Molecules in Rat Model of IgA Nephropathy / 中国实验方剂学杂志

ObjectiveTo investigate the effect of Bushen Jianpi Jiedu Liyan formula on the expression of integrin alpha 4 beta 1 （α4 β1）， vascular cell adhesion molecule-1 （VCAM-1）， stromal-derived factor-1 （SDF-1）， and chemokine receptor-4 （CXCR4） in the small intestine and bone marrow of the rat model of immunoglobulin A（IgA） nephropathy. MethodA total of 120 male SD rats were used to establish the IgA nephropathy model by intragastric administration of bovine serum albumin （BSA）， subcutaneous injection of CCl4， and tail vein injection of lipopolysaccharide （LPS）. The successfully modeled rats were randomized into blank， model， lotensin （63 mg·kg-1）， and low-， medium-， and high-dose （10.4， 20.81， 41.62 g·kg-1， respectively） Bushen Jianpi Jiedu Liyan formula groups （n=16）. The rats were treated with corresponding drugs according to their body weight. After 7 weeks of administration， the rats were sacrificed for the collection of samples， and the protein and mRNA levels of α4 β1， VCAM-1， SDF-1， and CXCR4 in the small intestine and bone marrow were determined by immunohistochemistry and real-time fluorescence quantitative polymerase chain reaction， respectively. ResultCompared with the blank group， the model group showed increased red blood cell count in the urine at the 10th， 12th， 14th， 16th weeks （P<0.01）， and such increases were reduced in the drug intervention groups （P<0.05）， especially in the medium-dose Bushen Jianpi Jiedu Liyan formula group （P<0.05）. Compared with those in the blank group， the protein levels of α4 β1， VCAM-1， SDF-1， and CXCR4 in the intestinal lamina propria in the model group were up-regulated （P<0.05）， and such un-regulations were inhibited in the drug intervention groups （P<0.05）. Compared with the model group， medium-dose Bushen Jianpi Jiedu Liyan formula down-regulated the protein levels of SDF-1 and CXCR4 in the intestinal lamina propria （P<0.05）. Compared with the blank group， the model group showed down-regulated mRNA levels of α4 β1 and SDF-1 and up-regulated mRNA levels of VCAM-1 and CXCR4 （P<0.05）. Compared with the model group， the drug intervention groups showed down-regulated mRNA levels of SDF-1 and CXCR4 （P<0.05）. ConclusionBushen Jianpi Jiedu Liyan formula regulates the expression of α4 β1， VCAM-1， SDF-1， and CXCR4 in the intestinal lamina propria to inhibit the homing effect of plasma cells， which may be associated with the Toll-like receptor-mediated activation of immune response. Bushen Jianpi Jiedu Liyan formula can down-regulate the expression of adhesion molecules to inhibit the proliferation of plasmocytes in circulation， so as to reduce the renal injury of IgA nephropathy.

Expansion of cord blood stem cells in fibronectin-coated microfluidic bioreactor

ABSTRACT Background: Hematopoietic stem/progenitor cell transplantation is the main treatment option for hematological malignancies and disorders. One strategy to solve the problem of low stem cell doses used in transplantation is pre-transplant expansion. We hypothesized that using fibronectin-coated microfluidic channels would expand HSPCs and keep self-renewal potential in a three-dimensional environment, compared to the conventional method. We also compared stem cell homing factors expression in microfluidic to conventional cultures. Materials and methods: A microfluidic device was created and characterized by scanning electron microscopy. The CD133+ cells were collected from cord blood and purified. They were subsequently cultured in 24-well plates and microfluidic bioreactor systems using the StemSpan serum-free medium. Eventually, we analyzed cell surface expression levels of the CXCR4 molecule and CXCR4 mRNA expression in CD133+ cells cultured in different systems. Results: The expansion results showed significant improvement in CD133+ cell expansion in the microfluidic system than the conventional method. The median expression of the CXCR4 in the expanded cell was lower in the conventional system than in the microfluidic system. The CXCR4 gene expression up-regulated in the microfluidic system. Conclusion: Utilizing microfluidic systems to expand desired cells effectively is the next step in cell culture. Comparative gene expression profiling provides a glimpse of the effects of culture microenvironments on the genetic program of HSCs grown in different systems.

Self-assembling protein nanocarrier for selective delivery of cytotoxic polypeptides to CXCR4+ head and neck squamous cell carcinoma tumors

Loco-regional recurrences and distant metastases represent the main cause of head and neck squamous cell carcinoma (HNSCC) mortality. The overexpression of chemokine receptor 4 (CXCR4) in HNSCC primary tumors associates with higher risk of developing loco-regional recurrences and distant metastases, thus making CXCR4 an ideal entry pathway for targeted drug delivery. In this context, our group has generated the self-assembling protein nanocarrier T22-GFP-H6, displaying multiple T22 peptidic ligands that specifically target CXCR4. This study aimed to validate T22-GFP-H6 as a suitable nanocarrier to selectively deliver cytotoxic agents to CXCR4+ tumors in a HNSCC model. Here we demonstrate that T22-GFP-H6 selectively internalizes in CXCR4+ HNSCC cells, achieving a high accumulation in CXCR4+ tumors in vivo, while showing negligible nanocarrier distribution in non-tumor bearing organs. Moreover, this T22-empowered nanocarrier can incorporate bacterial toxin domains to generate therapeutic nanotoxins that induce cell death in CXCR4-overexpressing tumors in the absence of histological alterations in normal organs. Altogether, these results show the potential use of this T22-empowered nanocarrier platform to incorporate polypeptidic domains of choice to selectively eliminate CXCR4+ cells in HNSCC. Remarkably, to our knowledge, this is the first study testing targeted protein-only nanoparticles in this cancer type, which may represent a novel treatment approach for HNSCC patients.

Effect of CXCR4 on the Treatment Response and Prognosis of Carfilzomib in Multiple Myeloma / 中国实验血液学杂志

OBJECTIVE@#To explore the effect of CXCR4 on the treatment response and prognosis of Carfilzomib (CFZ) in multiple myeloma.@*METHODS@#Dataset GSE69078 based on microarray data from two CFZ-resistant MM cell lines and their corresponding parental cell lines (KMS11-KMS11/CFZ and KMS34-KMS34/CFZ) were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified, and Protein-protein interaction (PPI) network was established to identify the key genes involved in CFZ resistance acquisition. Finally, the prognostic roles of the CFZ risistance key genes in MM using MMRF-CoMMpass data study was verified.@*RESULTS@#44 up-regulated and 46 down-regulated DEGs were identified. Top 10 hub genes (CCND1, CXCR4, HGF, PECAM1, ID1, HEY1, TCF4, HIST1H4J, HIST1H2BD and HIST1H2BH) were identified via Protein-protein interaction (PPI) network analysis. The CoMMpass data showed that high CXCR4 expression showed correlation to relative higher relapse and progress rates and the overall survival was significant decreased in high CXCR4 patients (P=0.013).@*CONCLUSION@#CXCR4 perhaps plays a crucial role in CFZ acquired resistance, which might help identifying potential CFZ-sensitive patients before treatment and providing a new therapeutic target in CFZ-resistant MM.

Correlation of c-MET and CXCR4 proteins and microvessel density with liver metastasis in colorectal cancer / 肿瘤研究与临床

Objective:To explore the correlation of c-MET and CXCR4 proteins and microvessel density (MVD) with liver metastasis in colorectal cancer tissues.Methods:A total of 40 colorectal cancer tissue samples and 10 paracancerous (5 cm from the edge of the tumor) normal colorectal tissue samples were collected from March 2015 to December 2020 in Shanxi Traditional Chinese Medical Hospital. Among 40 patients with colorectal cancer, 15 patients had liver metastasis. Immunohistochemistry was used to detect c-MET protein, CXCR4 protein and CD34-labeled MVD in various tissues, and the relationships between them and liver metastasis and between the three were analyzed.Results:The positive rates of c-MET protein [72.5% (29/40) vs. 30.0% (3/10)], CXCR4 protein [47.5% (19/40) vs. 10.0% (1/10)] and MVD (20.1±5.2 vs. 11.5±4.3) in colorectal cancer tissues were higher than those in paracancerous tissues, and the differences were statistically significant (all P < 0.05). The positive rates of c-MET protein [86.7% (13/15) vs. 64.0% (16/25)] and CXCR4 protein [66.7% (10/15) vs. 36.0% (9/25)] in colorectal cancer liver metastasis group were significantly higher than those in non-liver metastasis group, and the differences were statistically significant (both P < 0.05). MVD in colorectal cancer liver metastasis group was significantly higher than that in non-liver metastasis group (21.5±5.3 vs. 12.4±5.7), and the difference was statistically significant ( P < 0.05). In colorectal cancer tissues, c-MET protein expression was positively correlated with CXCR4 protein expression ( r = 0.568, P < 0.05), and MVD in c-MET-positive patients or CXCR4-positive patients was higher than that in negative ones (both P < 0.05). Conclusions:The c-MET protein, CXCR4 protein and MVD may play important roles in the liver metastasis of colorectal cancer. The three indicators can provide a certain reference for the early diagnosis and prognosis prediction of liver metastasis of colorectal cancer.

Effect of Astragali Radix-Curcumae Rhizoma on SDF-1/CXCR4/NF-κB Signaling Pathway of Orthotopic Transplantation Model of Colon Cancer in Mice / 中国实验方剂学杂志

Objective:To explore the possible mechanism of Astragali Radix-Curcumae Rhizoma （AC） in inhibiting tumor growth in the orthotopic transplantation model of colon cancer in mice. Method:The molecular docking technology was used to predict the intermolecular interaction between the main active components of AC and the pathway target proteins， such as stromal cell-derived factor-1 （SDF-1）， C-X-C motif chemokine receptor 4 （CXCR4）， and nuclear factor kappa-B p65 （NF-<italic>κ</italic>B p65）. The orthotopic transplantation model of CT26.WT colon cancer was established in mice for <italic>in vivo</italic> experimental verification. Sixty BALB/c male mice were randomly divided into a sham operation group， a model group， a 5-fluorouracil （5-Fu， 30 mg·kg^-1） group，and low- （0.32 g·kg^-1）， medium- （0.64 g·kg^-1）， and high-dose （1.28 g·kg^-1） AC groups， with 10 mice in each group. The sham operation group and the model group received normal saline by gavage. The corresponding drugs were administered by gavage in the 5-Fu group and by intraperitoneal injection in the AC groups. After intervention for 15 days， the tumor <italic>in situ</italic> was completely stripped， and the colon tissues 5-6 cm in length adjacent to the tumor were taken. The tumor volume was measured and calculated. The pathological changes of tumor tissues and colon tissues were observed by Hematoxylin-Eosin （HE） staining. Western blot was used to detect the protein expression of SDF-1， CXCR4， p-NF-<italic>κ</italic>B p65 in colon tissues. Western blot and Real-time quantitative polymerase chain reaction （Real-time PCR） were used to detect SDF-1， CXCR4， NF-<italic>κ</italic>B p65， Cyclin D₁， oncogene c-Myc protein and mRNA expression in tumor tissues. Result:Compared with the model group， 5-Fu and AC groups showed reduced tumor volumes <italic>in situ</italic> （<italic>P</italic><0.05， <italic>P</italic><0.01）， with the tumor inhibition rate in the 5-Fu group as high as （61.38±2.34）%. The tumor-inhibiting effect was optimal in the medium-dose AC group， with the tumor inhibition rate of （43.43±3.71）%. Compared with the model group， 5-Fu and AC groups showed relieved pathological changes of tumor and colon tissues. Specifically， AC down-regulated the protein expression levels of SDF-1， CXCR4， and p-NF-<italic>κ</italic>B p65 in colon tissues （<italic>P</italic><0.01）， and down-regulated the protein and mRNA expression levels of SDF-1， CXCR4， NF-<italic>κ</italic>B p65， Cyclin D₁， and c-Myc in tumor tissues （<italic>P</italic><0.05， <italic>P</italic><0.01）. Conclusion:AC can inhibit the growth of orthotopic transplantation tumor of colon cancer， and its intervention mechanism may be related to the regulation of related protein and mRNA expression in the SDF-1/CXCR4/NF-<italic>κ</italic>B signaling pathway.

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation

Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases. A natural fragment of serum albumin, named EPI-X4, has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases. To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4. Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4. The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100. EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model. Moreover, topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis. Thus, rationally designed EPI-X4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis. Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis, asthma and other CXCR4-associated diseases is highly warranted.

Cell membrane-derived vesicles for delivery of therapeutic agents

Cell membranes have recently emerged as a new source of materials for molecular delivery systems. Cell membranes have been extruded or sonicated to make nanoscale vesicles. Unlike synthetic lipid or polymeric nanoparticles, cell membrane-derived vesicles have a unique multicomponent feature, comprising lipids, proteins, and carbohydrates. Because cell membrane-derived vesicles contain the intrinsic functionalities and signaling networks of their parent cells, they can overcome various obstacles encountered

Expression and significance of stromal cell-derived factor-1 and its receptor CXCR4 in patients with pterygium / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To investigate the expression and significance of stromal cell-derived factor(SDF-1)and its receptor CXC chemokine receptor 4(CXCR4)in patients with pterygium of different ages.<p>METHODS: From January 2018 to October 2018, surgical specimens of 60 patients with primary pterygium and 60 eyes(including 30 eyes younger than 50 years old and 30 eyes older than 50 years old)were collected from the No.474 Hospital of Chinese PLA, at the same time collect age matched strabismus diorthosis and normal conjunctiva tissues of 30 patients with retinal detachment repairs(including 15 eyes younger than 50 years, older than 50 years of age 15 eyes).The expression and localization of SDF-1/CXCR4 in pterygium tissue specimens were detected by HE staining and immunohistochemistry, and the relationship between the expression of SDF-1/CXCR4 and the clinical characteristics of patients was analyzed. The mean optical density of SDF-1 /CXCR4 was measured by IPP 6.0 software.<p>RESULTS: SDF-1/CXCR4 showed slightly positive or no positive expression in normal conjunctival basal cells, but positive expression in both full-layer conjunctival epithelial cells and vascular endothelial cells in pterygium, with significant difference in expression level, and more obvious expression in basal cells, showing obvious polarity. The expression levels of SDF-1 and CXCR4 in pterygium tissues were higher than those in normal conjunctival tissues, and the difference was statistically significant(<i>P</i><0.05). The expression of CXCR4 in patients younger than 50 years old was greater than that in patients older than 50 years old, and the difference was statistically significant(<i>P</i><0.05).<p>CONCLUSION: SDF-1 and CXCR4 expression is up-regulated in pterygium, suggesting that SDF-1 and CXCR4 participates in the formation of pterygium and inhibits the SDF-1/CXCR4 signaling pathway, which may inhibit the occurrence of pterygium, and may also become a drug therapeutic target for pterygium, and become a new research direction. The higher expression of CXCR4 in young pterygium patients suggests that individualized drug administration may be realized in the future to reduce the waste of medical resources.

Effect of Duhuo Xuduan Tang for Oral Administration and Iontophoresis on SDF-1/CXCR4 Signaling Pathway and Relevant Factors of Cartilage Degradation in Knee Joint Fluid of Patients with Knee Osteoarthritis with Liver and Kidney Deficiency / 中国实验方剂学杂志

Objective::To observe the clinical efficacy of Duhuo Xuduan Tang for oral administration and iontophoresis in the treatment of knee osteoarthritis (KOA) with liver and kidney deficiency and its effect on stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling pathway. Method::Totally 150 KOA patients with deficiency of liver and kidney diagnosed in the Teaching Hospital of Tianjin University of Traditional Chinese Medicine(TCM) were randomly divided into control group, oral TCM group and iontophoresis group, with 50 cases in each group. The control group was given glucosamine sulfate capsule, 0.5 g/time, twice a day, while the oral TCM group was given Duhuo Xuduan Tang, 150 mL/time, twice a day. In the iontophoresis group, Duhuo Xuduan Tang was administered at Kuangu acupoint, Xiguan acupoint, Xiyan acupoint and Dubi acupoint for iontophoresis for 30 minutes, once a day. All of the three groups were treated for 4 weeks. The swelling degree and the pain degree of knee joint before and after treatment were observed, and the clinical efficacy was recorded. The protein contents of SDF-1, CXCR4, matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-13 (MMP-13) in knee joint fluid before and after treatment were detected by enzyme-linked immunosorbent assay (ELISA). Result::The efficacy of oral TCM group was better than that of iontophoresis group and control group, and the recurrence rate was the lowest (P<0.05). Compared with before treatment, the tenderness increased, whereas visual analogue scale(VAS) score, knee swelling score, The Western Ontario and McMaste Universities (WOMAC) score and SDF-1, CXCR4, MMP-3 and MMP-13 protein content in knee joint fluid decreased in oral TCM group after treatment, which were better than those in iontophoresis group and control group (P<0.05). Conclusion::Duhuo Xuduan Tang for oral administration and iontophoresis has an obvious effect on KOA with liver and kidney deficiency, with the best effect through oral administration. Its mechanism may be related to the inhibition of SDF-1/CXCR4 inflammatory signaling pathway and cartilage decomposition.

Effect of Ru′ai Shuhou Prescription on Proliferation and Metastasis of Breast Cancer MDA-MB-453 Cells Through SDF-1/CXCR4 Biological Axis / 中国实验方剂学杂志

Objective:To investigate the effect of Ru′ai Shuhou prescription （RSR） drug-containing serum on the proliferation and invasion ability of breast cancer cells MDA-MB-453 based on the biological axis of stromal cell-derived factor-1（SDF-1）/chemokine receptor 4 （CXCR4）. Method:A model of MDA-MB-453 cells with SDF-1-induced high expression of CXCR4 was established， and the rat drug-serum containing RSR and blank rat serum were prepared respectively. The cells were divided into fetal bovine serum control group （Blank）， blank rat serum group， SDF-1+blank rat serum group， SDF-1+RSR group， AMD3100+ SDF-1+blank rat serum group， and AMD3100+ SDF-1+RSR group. After intervention for 48 h， cell proliferation was detected by cell counting kit-8 （CCK-8） assay， cell invasion ability was detected by transwell assay， and mRNA and protein expressions of CXCR4， matrix metalloproteinase-2 （MMP-2） and MMP-9 were detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. Result:As compared with the blank serum group， the proliferation of MDA-MB-453 cells was promoted and expression of CXCR4 mRNA was increased significantly when SDF-1 was 100 μg·L-1 （P<0.05）. As compared with SDF-1+blank rat serum group， RSR inhibited the proliferation and invasion of MDA-MB-453 cells induced by SDF-1， and at the same time， down-regulated the mRNA and protein expressions of CXCR4， MMP-2 and MMP-9 （P<0.05）. After pre-treatment with AMD3100 for 24 h， the inhibitory effect of RSR to cell proliferation was significantly increased （P<0.05）， and meanwhile， the decreases in mRNA and protein expression of CXCR4， MMP-2 and MMP-9 were more obvious， with statistically significant differences （P<0.05）. Conclusion:Through SDF-1/CXCR4 biological axis， RSR could down-regulate the expression of MMP-2 and MMP-9， reduce the degradation of extracellular matrix （ECM）， and then inhibit the metastasis of MDA-MB-453 cells. In addition， it has a synergistic effect with CXCR4 inhibitor AMD3100.

CXCR4/SDF-1 axis regulates the effect of human lung adenocarcinoma PC-9 cells on function of in vitro blood-brain barrier model formed by Bends cells / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the influences of human lung adenocarcinoma PC-9 cells on tight junction proteins of blood brain barrier (BBB) under CXCR4/SDF-1 axis by establishing a model of BBB in vitro. Methods: The immortalized mouse brain microvascular endothelial Bends cells were used to establish a model of BBB in vitro by monolayer culture; Subsequently, transendothelial electric resistance (TEER) and fluorescein sodium permeability experiment were used to detect the function of in vitro BBB model and observe the effect of PC-9 cells on the function of BBB model, respectively. Western blotting was used to detect the effect of PC-9 cells on function of BBB model and expressions of endothelial tight junction proteins under the treatment of single or combined AMD3100 and SDF-1 (1 μg/ml AMD3100,100 ng/ml SDF-1, AMD3100+SDF-1). Transwell assay was used to detect the influence of CXCR4/SDF-1 axis on the ability of PC-9 cells transmigrating the cell layer of BBB model. Results: Monolayer culture of Bends cells can form tightly connected BBB withhighTEER,which reached (182.13±5.19) Ω.cm2 at the 96 h; in the meanwhile, fluorescein sodium permeability experiment showed that BBB had significantly lower permeability than that of control group ([40.31±2.43]% vs [150.10±3.17]%, P<0.05). The TEER of BBB decreased to (46.7±4.35) Ω·cm2 after coculture with PC-9 cells for 24 h, and at the same time the sodium fluorescein permeability of BBB significantly increased than that of pre-treatment ([136.32±4.93]% vs [50.24±6.21]%, P<0.05). PC-9 cells up-regulated the expressions of tight junction proteins of Bends cells under the treatment of AMD3100 (P<0.05). The number of PC-9 cells transmigrating the BBB inAMD3100 treatment group was significantly lower than that of CON group (43±2 vs 81±2, P<0.05). Conclusion: AMD3100 can reduce the ability of PC-9 cells destroying the tight junction of the BBB model established in vitro by Bends cells.

Effect of chronic emotional stress induced by empty bottle stimulation on inflammatory factors in rats with acute myocardial infarction: analysis of the CXCL12/CXCR4 axis / 南方医科大学学报

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.

68Ga-NOTA-NFB PET/CT imaging in breast cancer: clinical study of a new targeted agent for chemokine receptor 4 / 中华核医学与分子影像杂志

Objective To investigate the clinical application of chemokine receptor 4 (CXCR4)-targeted PET/CT imaging in breast cancer using 68Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid-TN14003 (NOTA-NFB) and the correlation between 68Ga-NOTA-NFB uptake and pathology.Methods From June 2014 to December 2014,11 female patients (age range:38-68 years) with non-specific invasive breast cancer were recruited in this study.All patients underwent neoadjuvant chemotherapy before surgery.68GaNOTA-NFB and 18F-fluorodeoxyglucose (FDG) PET/CT imaging were performed before the chemotherapy.Three patients also underwent 68Ga-NOTA-NFB PET/CT imaging after the fourth cycle of chemotherapy.The region of interest (ROI) method was used to measure the maximum standardized value (SUVmax) and tumor/non-tumor (T/NT) ratio was calculated.Paired t test and Spearman correlation analysis were used for statistical analysis.Results The SUVmax values of primary lesions were 3.78±2.03 and 8.11±5.14 (t=-3.01,P＜0.05) respectively in 68Ga-NOTA-NFB imaging and 18F-FDG imaging.The T/NT ratios for primary lesions were not significantly different between the two imaging methods (9.36±7.81 vs 15.62±14.51;t=-1.63,P＞0.05).In the metastatic lymph nodes,SUVmax values were not significantly different between 68Ga-NOTA-NFB imaging and 18F-FDG imaging (t=-2.02,P＞0.05),but T/NT ratios were significantly different (t=-2.43,P＜0.05).After neoadjuvant chemotherapy,T/NT ratios were decreased in the 3 patients.Correlation was not found between T/NT in 68Ga-NOTA-NFB imaging and Ki-67,but the P value was close to 0.05 (rs =0.600,P=0.051).Conclusion 68Ga-NOTA-NFB PET/CT can be used as a new CXCR4-targered imaging in diagnosis of breast cancer,and it may be beneficial to evaluate the effect of neoadjuvant chemotherapy.

Effect of triptolide in improving platelet activation in patients with ankylosing spondylitis by regulating VEGFA,SDF-1,CXCR4 pathway / 中国中药杂志

The effect of triptolide( TP) on VEGFA,SDF-1,CXCR4 pathway were investigated in vitro to explore the mechanism in improving platelet activation in patients with ankylosing spondylitis( AS). Peripheral blood mononuclear cells( PBMC) were used for the experiment and divided into 4 groups: normal group( NC),model group( MC),triptolide group( TP),and AMD3100 group. The optimal concentration of TP was measured by the MTT method. The expressions of TNF-α,IL-1β,IL-4,IL-10,VEGFA and VEGFR were detected by ELISA. The expressions of SDF-1,CXCR4 and VEGFA were detected by real-time quantitative PCR( RT-qPCR).The expressions of SDF-1,CXCR4,VEGFA and VEGFR were detected by Western blot. The expression levels of CD62 p,CD40 L and PDGFA were detected by immunofluorescence. MTT results showed that medium-dose TP had the strongest inhibitory effect on cells at24 h. The results of ELISA and PCR showed that TP inhibited mRNA expressions of IL-1β,TNF-α,VEGFA,VEGFR and SDF-1,CXCR4 and VEGFA. The results of Western blot indicated that TP inhibited SDF-1,CXCR4 and VEGFA,VEGFR protein expressions; immunofluorescence results indicate that TP can inhibit the expressions of CD62 p,CD40 L,PDGFA. TP may regulate platelet activation by down-regulating SDF-1,CXCR4,VEGFA and VEGFR mRNA expressions,thereby down-regulating IL-1β and TNF-αexpressions,and up-regulating the expressions of IL-4 and IL-10 cytokines.

A CXCL12/CXCR4 axis in regulation of tumor behaviors by ionizing radiation / 中华放射医学与防护杂志

In addition to induce cell death in tumor cells, ionizing radiation (IR) regulates many biological behaviors of malignant tumors, such as intrinsic radiosensitivity, invasion and metastasis, angiogenesis, as well as immune response of tumor cells. The C-X-C motif chemokine ligand 12 (CXCL12) and its receptor CXCR4 are highly expressed in a variety of malignant tumors, and are involved in the process of remote metastasis, blood vessel formation, immune regulation, and therapeutic resistance of malignant tumors. Recent studies have found that the CXCL12/CXCR4 signal axis plays critical roles in the IR-regulated biological behavior of malignant tumors. This paper reviews the roles of CXCL12/CXCR4 signal axis in the biological behavior changes of irradiated malignant tumors.