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Background: The interactions between fibroblasts and bronchial epithelial cells play important roles in the development of chronic obstructive pulmonary disease (COPD). Interleukin (IL)-17A triggers the activation of fibroblasts and secretion of inflammatory mediators, which promotes epithelial mesenchymal transition (EMT) in bronchial epithelial cells. Fibroblasts secrete C-X-C motif chemokine ligand 12 (CXCL12), which specifically binds to its receptor, C-X-C motif chemokine receptor 4 (CXCR4) to mediate inflammatory responses. This study aims to investigate IL-17A- and CXCL12-induced airway remodeling. Methods: Primary lung fibroblasts were isolated from human and murine lung tissue for the in vitro experiments, and a mouse model of cigarette smoke (CS)-induced COPD was established for the in vivo experiments. The results were analyzed using one-way ANOVA and Tukey's test or Bonferroni's test for post-hoc test. A p-value < 0.05 was considered statistically significant. Results: Through in vitro experiments, we found that IL-17A-activated primary lung fibroblasts secreted CXCL12 and stimulated EMT in bronchial epithelial cells. However, these effects could be blocked by neutralizing IL-17A or CXCL12. In vivo, an anti-IL-17A antibody or a CXCR4 antagonist (AMD3100) could reverse the degree of EMT in lungs of the COPD mouse model. The IL-17A-induced EMT and increased CXCL12 expression occurred via extracellular signal-regulated kinase (ERK)/phosphorylated (p-)ERK pathways. Conclusion: This study showed that exposure of mice to CS and IL-17A stimulation upregulated CXCL12 expression and induced EMT by activating the ERK signaling pathway. These data offer a novel perspective regarding the molecular mechanism of CXCL12/CXCR4 signaling in IL-17A-induced EMT related to airway remodeling.

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Replacement of insulin-producing pancreatic beta-cells by islet transplantation offers a functional cure for type-1 diabetes (T1D). We recently demonstrated that a clinical grade alginate micro-encapsulant incorporating the immune-repellent chemokine and pro-survival factor CXCL12 could protect and sustain the integrity and function of autologous islets in healthy non-human primates (NHPs) without systemic immune suppression. In this pilot study, we examined the impact of the CXCL12 micro encapsulant on the function and inflammatory and immune responses of xenogeneic islets transplanted into the omental tissue bilayer sac (OB; n = 4) and diabetic (n = 1) NHPs. Changes in the expression of cytokines after implantation were limited to 2-6-fold changes in blood, most of which did not persist over the first 4 weeks after implantation. Flow cytometry of PBMCs following transplantation showed minimal changes in IFNγ or TNFα expression on xenoantigen-specific CD4+  or CD8+  T cells compared to unstimulated cells, and these occurred mainly in the first 4 weeks. Microbeads were readily retrievable for assessment at day 90 and day 180 and at retrieval were without microscopic signs of degradation or foreign body responses (FBR). In vitro and immunohistochemistry studies of explanted microbeads indicated the presence of functional xenogeneic islets at day 30 post transplantation in all biopsied NHPs. These results from a small pilot study revealed that CXCL12-microencapsulated xenogeneic islets abrogate inflammatory and adaptive immune responses to the xenograft. This work paves the way toward future larger scale studies of the transplantation of alginate microbeads with CXCL12 and porcine or human stem cell-derived beta cells or allogeneic islets into diabetic NHPs without systemic immunosuppression.

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SUMMARY OBJECTIVE: This study aimed to evaluate the expression of C-X-C motif chemokine ligand 12 and its C-X-C chemokine receptor type 4, and the tumor-stroma ratio using collagen stromal content of breast cancer samples, correlating it with clinicopathological data. METHODS: Through a retrospective cohort study, samples were obtained from female patients, over 18 years of age, with the disease in stages 1-4, who underwent mastectomy or lumpectomy. The biopsies were provided by the Oncology sector of the Hospital das Clínicas of Universidade Federal de Pernambuco, Recife city, in 2011-2014, including samples of invasive ductal carcinoma, ductal carcinoma in situ, or benign changes (fibroadenoma and hypertrophy), which were analyzed between 2020 and 2022 by immunohistochemistry for the expression of stromal cell characteristics. Collagen content was tested by Gomori staining and digital analysis of images. RESULTS: Absence of stromal expression of C-X-C motif chemokine ligand 12 was associated with longer disease-free survival (disease-free survival=0.481), and expression of C-X-C chemokine receptor type 4 was associated with lower disease-free survival. An association was observed between clinicopathological variables and stromal expression of chemokines, that is, an association of stromal C-X-C motif chemokine ligand 12 with histological grade, angiolymphatic invasion, and an association between C-X-C chemokine receptor type 4 expression and histological grade. Analyses of digital pixels images of collagen and tumor cells showed a lower percentage of collagen in the invasive ductal carcinoma samples (39%), unlike samples without neoplasms (78%). CONCLUSION: Low expression of C-X-C motif chemokine ligand 12 may be associated with a worse prognosis for breast cancer. Collagen staining analyzed using digital images represents an opportunity for clinical application and is indicative of the prognosis of the tumor microenvironment in breast carcinoma.

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Cancer is a multi-step disease caused by the accumulation of genetic mutations and/or epigenetic changes, and is the biggest challenge around the world. Cytokines, including chemokines, exhibit expression changes and disorders in all human cancers. These cytokine abnormalities can disrupt homeostasis and immune function, and make outstanding contributions to various stages of cancer development such as invasion, metastasis, and angiogenesis. Chemokines are a superfamily of small molecule chemoattractive cytokines that mediate a variety of cellular functions. Importantly, the interactions of chemokine members CXCL12 and its receptors CXCR4 and CXCR7 have a broad impact on tumor cell proliferation, survival, angiogenesis, metastasis, and tumor microenvironment, and thus participate in the onset and development of many cancers including leukemia, breast cancer, lung cancer, prostate cancer and multiple myeloma. Therefore, this review aims to summarize the latest research progress and future challenges regarding the role of CXCL12-CXCR4/CXCR7 signaling axis in cancer, and highlights the potential of CXCL12-CXCR4/CXCR7 as a biomarker or therapeutic target for cancer, providing essential strategies for the development of novel targeted cancer therapies.

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BACKGROUND/AIM: The complex of C-X-C motif chemokine receptor 4 (CXCR4) and its ligand, C-X-C motif chemokine ligand 12 (CXCL12), plays an essential role in cancer cell proliferation, invasion, and metastasis. These are emerging therapeutic targets, and recent studies have reported that inhibition of CXCL12-CXCR4 signaling pathway enhances the effects of immune checkpoint inhibitors. Thus, we aimed to investigate tissue expression of CXCL12 and CXCR4 in high-grade serous ovarian carcinoma (HGSOC) and to determine their potential as prognostic markers. PATIENTS AND METHODS: We used chemotherapy-naïve, formalin-fixed paraffin-embedded primary ovarian cancer tissues obtained from patients with advanced-stage HGSOC at the time of primary cytoreductive surgery. After histological reassessment, we constructed a tissue microarray and performed immunohistochemical staining for CXCL12 and CXCR4. Thereafter, clinicopathological characteristics and survival outcomes were compared between the high- and low-expression groups. RESULTS: A total of 97 patients with FIGO stage IIIC-IV HGSOC were included: 15 (15.5%), 66 (68.0%), and 13 (13.4%) patients showed high expression of CXCL12, CXCR4, and both, respectively. The expression level of each protein was not associated with germline BRCA1/2 mutational status, FIGO stage, or residual tumor after primary cytoreductive surgery. In multivariate analysis adjusted for confounders, high CXCL12 expression was identified as an independent poor prognostic biomarker for progression-free survival (adjusted hazards ratio, 1.990; 95% confidence interval=1.090-3.633; p=0.025). However, CXCR4 expression was not associated with patient survival outcomes. CONCLUSION: The CXCL12 expression level may represent a prognostic biomarker for HGSOC. Proteins related to the CXCL12/CXCR4 complex may serve as therapeutic targets in HGSOC treatment.

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BACKGROUND: Complex networks of chemokines are part of the immune reaction targeted against tumor cells. Chemokines influence cancer growth. It is unclear whether the concentrations of chemokines at the time of NSCLC (non-small cell lung cancer) diagnosis differ from healthy controls and reflect the extent of NSCLC. AIMS: To compare chemokine concentrations (CCL2, CCL8, CXCL12) in the plasma of patients with resectable NSCLC to those without cancer. To determine whether the chemokine concentrations differ relative to the stage of disease. METHODS: Sixty-nine patients undergoing surgery for proven/suspected NSCLC were enrolled. They underwent standard diagnostic and staging procedures to determine resectability, surgery was performed. Forty-two patients were diagnosed with NSCLC, while 27patients had benign lung lesions and functioned as the control group. Chemokine concentrations in peripheral blood were assessed using ELISA. Parametric statistics were used for the analysis of results. RESULTS: There were no differences in plasma chemokine concentrations in NSCLC patients compared to controls. CXCL12 concentrations correlated positively with tumor extent expressed as clinical stage, (mean values: stage I 5.08 ng/mL, SEM 0.59; stage II and IIIA 7.82 ng/mL; SEM 1.06; P=0.022). Patients with NSCLC stages II+IIIA had significantly higher CXCL12 concentrations than controls (mean values: stage II+IIIA 7.82 ng/mL; SEM 1.06; controls 5.3 ng/mL; SEM 0.46; P=0.017). CONCLUSION: CXCL12 was related to tumor growth and could potentially be used as a biomarker of advanced disease.

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Objective To explore the improvement effect of myricitrin on bone defect in rats with bacterial osteomyelitis(OM)through vascular endothelial growth factor A(VEGFA)/stromal cell-derived factor(SDF-1)/C-X-C chemokine receptor 4(CXCR4)pathway.Methods Rats were randomly divided into the sham operation group,the OM group,the myricitrin group[50 mg/(kg·d)],PX-478 group[25 mg/(kg·d)VEGFA/SDF-1/CXCR4 signaling pathway inhibitor PX-478],and the myricitrin+PX-478 group[50 mg/(kg·d)myricitrin and 25 mg/(kg·d)PX-478],18 mice per group.Bilateral proximal tibia bone defects were used to construct bacterial OM rat model.After 12 weeks of continuous treatment,the wound healing degree of rats was observed,and anal temperature of rats was measured.The serum inflammatory factors interleukin(IL)-6,IL-1β,IL-17 and bone metabolism indexes bone alkaline phosphatase(BALP),osteocalcin(BGP)and C-terminal telopeptide of type Ⅰ collagen(CTX-Ⅰ)were measured by enzyma-linked immunosorbent assay(ELISA).The bacterial load of tissue around the lesion was detected.HE staining was used to detect the pathological changes of the tissue around lesions.The expression of CD31 was detected by immunofluorescence staining.Western blot assay was used to detect the expression of VEGFA/SDF-1/CXCR4 signal pathway related proteins.Results Compared with the sham operation group,the number of rats with grade A wound healing,BALP and BGP levels,CD31 positive area,VEGFA,SDF-1 and CXCR4 protein levels were decreased in the OM group(P＜0.005 or P＜0.05),and the anal temperature,bacterial load,IL-6,IL-1β,IL-17 and CTX-Ⅰlevels were increased(P＜0.05).Compared with the OM group,the BALP and BGP levels,CD31 positive area,VEGFA,SDF-1 and CXCR4 protein levels were increased,and the anal temperature,bacterial load,IL-6,IL-1β,IL-17 and CTX-Ⅰlevels were decreased in the myricitrin group(P＜0.05).Results of PX-478 group showed the opposite trend.PX-478 reversed the effect of myricitrin on the improvement of bone defects in bacterial OM rats.Conclusion Myricitrin may improve bone defect of OM rats by activating the VEGFA/SDF-1/CXCR4 signal pathway.

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OBJECTIVE: The purpose of this study was to investigate the differential expression of long noncoding RNAs (lncRNAs) in dental pulp stem cells (DPSCs) after stromal cell-derived factor-1α (SDF-1α) induction and to explore the lncRNAs that regulate the odontogenic differentiation and migration of DPSCs. DESIGN: We examined the altered expression of lncRNAs in DPSCs after SDF-1α induction by performing lncRNA microarray and qRT-PCR analyses. Moreover, a bioinformatics analysis was conducted to predict the interactions of lncRNAs and identify core regulatory factors. A small interfering RNA (siRNA) was used to knock down lncRNA AC080037.1 expression in DPSCs. Cell transmigration assays, alizarin red staining, qRT-PCR and Western blotting were performed to detect the expression of osteo/dentinogenic differentiation markers or Rho GTPase after lncRNA knockdown in DPSCs. RESULTS: The microarray analysis identified 206 differentially expressed lncRNAs at 7 days after treatment. One lncRNA, AC080037.1, was shown to regulate the odontogenic differentiation of DPSCs. An siRNA targeting lncRNA AC080037.1 suppressed DPSCs migration and the expression of Rho GTPase induced by SDF-1α. Moreover, AC080037.1 knockdown significantly affected mineralized nodule formation and substantially suppressed runt-related factor-2 (RUNX-2), dentin matrix protein-1 (DMP-1) and dentin sialophosphoprotein (DSPP) expression in DPSCs. CONCLUSIONS: Our results revealed the differential expression of lncRNAs in DPSCs before and after SDF-1α induction. Furthermore, we highlighted the significant involvement of one lncRNA, AC080037.1, in the positive regulation of the osteo/odontogenic differentiation of DPSCs and indicated that this lncRNA might be a potential target in regenerative endodontics. These findings may further advance translational studies of pulp engineering.

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C-X-C motif chemokine 12 (CXCL12), also known as stromal cell-derived factor-1 (SDF-1), is produced by the bone marrow microenvironment. This chemokine binds and activates its cognate receptors C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine receptor type 7 (CXCR7) to widely regulate cell proliferation, survival, differentiation, as well as homing and mobilization of hematopoietic stem cells (HSCs) in specialized niches within the bone marrow. Given this key role in hematopoiesis, it comes as no surprise that any aberrancies in CXCL12/CXCR4 or CXCL12/CXCR7 pathways might lead to excessive proliferation of HSCs, an event that leads to the development of leukemia. So far, numerous therapeutic interventions have been developed to harness CXCL12/CXCR4 and CXCL12/CXCR7 axes in leukemic cells. Plerixafor, BKT140, LY2510924, PF-06747143, ulocuplumab, and NOX-A12 are among the most well-known CXCR4 and CXCL12 modulators that their therapeutic efficacies have been evaluated in different pre-clinical and clinical studies of hematologic malignancies. To have an overview of the importance of CXCL12/CXCR4 and CXCL12/CXCR7 axes in the pathogenesis of leukemia and to gather information about the latest advances as well as challenges in targeting these axes in clinical settings, the present review has begun with a discussion about how aberrant expression of CXCL12/CXCR4 and CXCL12/CXCR7 pathways might regulate leukemogenesis and ended by outlining the key news of preclinical and clinical investigations in leukemia treatment.

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Objective:To investigate the correlation between serum CXCL12 and the outcomes after intravenous thrombolytic therapy in patients with acute ischemic stroke.Methods:Consecutve patients with acute ischemic stroke treated with intravenous thrombolytic therapy in the Department of Neurology, the First Affiliated Hospital of Soochow University from January 1, 2020 to August 31, 2021 were enrolled retrospectively. Serum CXCL12 was measured by enzyme-linked immunosorbent assay within 24 h of onset. No improvement in early neurological function was defined as the National Institutes of Health Stroke Scale (NIHSS) 24 h after thrombolysis decreased by <4 compared with the baseline. The clinical outcome was evaluated by the modified Rankin Scale at 90 d after onset, and >2 were defined as a poor outcome. Multivariate logistic regression analysis was used to evaluate the correlation between serum CXCL12 and the outcome after intravenous thrombolysis, and the predictive value of serum CXCL12 for no improvement of early neurological function and poor short-term outcome was analyzed by the receiver operating characteristic (ROC) curve. Results:A total of 66 patients were enrolled, and the serum CXCL12 was 15.72±6.52 g/L. Twenty-seven patients (40.9%) had poor outcomes, and 34 (51.5%) had no improvement in early neurological function. Multivariate logistic regression analysis showed that higher serum CXCL12 was an independent predictor of poor outcome (odds ratio [ OR] 1.245, 95% confidence interval [ CI] 1.093-1.419; P=0.001) and no improvement in early neurological function ( OR 1.250, 95% CI 1.100-1.420; P=0.001). ROC curve analysis showed that the area under the curve of serum CXCL12 for predicting poor outcome was 0.793 (95% CI 0.679-0.908), the best cut-off value was 15.38 μg/L, and the corresponding sensitivity and specificity were 81.5% and 76.9%, respectively. The area under the curve of serum CXCL12 for predicting no improvement of early neurological function was 0.849 (95% CI 0.748-0.951), and the best cut-off value was 15.68 μg/L, and the corresponding sensitivity and specificity were 76.5% and 87.5%, respectively. Conclusion:Serum CXCL12 had a better predictive value for the outcomes of patients with acute ischemic stroke after intravenous thrombolytic therapy.

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Atherosclerosis, in the ultimate stage of cardiovascular diseases, causes an obstruction of vessels leading to ischemia and finally to necrosis. To restore vascularization and tissue regeneration, stimulation of angiogenesis is necessary. Chemokines and microRNAs (miR) were studied as pro-angiogenic agents. We analysed the miR-126/CXCL12 axis and compared impacts of both miR-126-3p and miR-126-5p strands effects in CXCL12-induced angiogenesis. Indeed, the two strands of miR-126 were previously shown to be active but were never compared together in the same experimental conditions regarding their differential functions in angiogenesis. In this study, we analysed the 2D-angiogenesis and the migration assays in HUVEC in vitro and in rat's aortic rings ex vivo, both transfected with premiR-126-3p/-5p or antimiR-126-3p/-5p strands and stimulated with CXCL12. First, we showed that CXCL12 had pro-angiogenic effects in vitro and ex vivo associated with overexpression of miR-126-3p in HUVEC and rat's aortas. Second, we showed that 2D-angiogenesis and migration induced by CXCL12 was abolished in vitro and ex vivo after miR-126-3p inhibition. Finally, we observed that SPRED-1 (one of miR-126-3p targets) was inhibited after CXCL12 treatment in HUVEC leading to improvement of CXCL12 pro-angiogenic potential in vitro. Our results proved for the first time: 1-the role of CXCL12 in modulation of miR-126 expression; 2-the involvement of miR-126 in CXCL12 pro-angiogenic effects; 3-the involvement of SPRED-1 in angiogenesis induced by miR-126/CXCL12 axis.

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Background: Chronic tubulointerstitial fibrosis is a common final pathway leading to end stage kidney disease in cats and has no effective treatment. The use of cell-based molecules to treat kidney fibrosis may be a promising approach. The objectives were to test the effects of intra-renal chemokine CXCL12 injection in a pre-clinical cat model of unilateral ischemia/reperfusion (I/R)-induced kidney fibrosis and then, within a clinical pilot study, test the safety/feasibility of CXCL12 injection in cats that might have early chronic kidney disease (CKD). Methods: Pre-clinical: Thirty cats received intra-renal injection of 100, 200, or 400 ng of recombinant human CXCL12, or sterile saline, into the I/R kidney 70 days post-injury, or were non-injured, non-injected controls (n = 6/group). Kidney collagen content was quantified 4 months post-treatment using Masson's Trichrome and Picrosirius Red (PSR) stained tissues. In a separate study (n = 2) exploring short-term effects of CXCL12, 200 ng CXCL12 was injected into I/R kidneys and then harvested either 30 min (n = 1) or 1 month (n = 1) post-injection. Kidney concentrations of CXCL12, matrix metalloproteinase 1 (MMP-1), and lysyl oxidase-like enzyme 2 (LOXL-2) were quantified via ELISA. Clinical Pilot: 14 client-owned cats with potential early kidney disease received a single-treatment, bilateral intra-renal injection of 200 ng CXCL12 (n = 7), or received no injection (n = 7). Blood/urine samples were collected monthly for 9 months to assess renal function and CKD staging. Results: Pre-clinical: I/R increased the affected kidney collagen content, which both mid and high doses of CXCL12 restored to normal (ps < 0.05 vs. untreated). I/R increased collagen fiber width, which both mid and high doses of CXCL12 restored to normal (p < 0.001 vs. untreated). Early changes in kidney MMP-1, associated with collagen breakdown, and subsequent decreases in LOXL-2, associated with collagen cross-linking, in response to CXCL12 treatment may contribute to these findings. Clinical Pilot: Bilateral intra-renal injection of CXCL12 using ultrasound guidance in cats with CKD was feasible and safe in a general practice clinical setting with no obvious side effects noted during the 9-month follow-up period. Conclusions: Intra-renal injection of CXCL12 may prove to be an effective treatment for kidney fibrosis in cats with CKD. Additional mechanistic and clinical evaluations are needed.

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AIM: To explore whether Agkistrodon Halys venom antitumor component-I (AHVAC-I) affects the migration of gastric cancer cells by human primary gastric cancer-associated fibroblast (GCAFs). METHODS: Tissue block culture and trypsin digestion were used to separate and culture human primary gastric cancer-associated fibroblasts (GCAFs); the GCAFs-CM

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Objective: To observe the expression, correlation and significance of chemokine (C-X-C motif) ligand 12 (CXCL12) and chemokine (C-X-C motif) receptor 4 (CXCR4) in endometrium and myometrium of adenomyosis. Methods: Totally 38 patients were selected in this study, who underwent hysterectomy for adenomyosis at Beijing Obstetrics and Gynecology Hospital from October 2017 to December 2018 as the adenomyosis group, and, in the same period, selected 31 patients with cervical intraepithelial neoplasia Ⅲ or cervical cancer undergoing hysterectomy served as control group. The expression levels of mRNA and protein for CXCL12, CXCR4 in the endometrium and myometrium of the two groups were detected by immunohistochemistry and real-time PCR. Results: (1) The protein levels of CXCL12 and CXCR4 in endometrium in uterus with adenomyosis (0.229±0.025 and 0.226±0.016) were significantly higher than those in endometrium in uterus without adenomyosis (0.153±0.018 and 0.178±0.026); compared with each other, the differences were statistically significant (all P<0.05). And the expressions of CXCL12 and CXCR4 proteins in uterine myometrium of adenomyosis were 0.222±0.045 and 0.126±0.058, respectively, which were higher than those in the control group (0.091±0.029 and 0.099±0.020); compared with each other, the differences were statistically significant (all P<0.05). (2) The expression levels of CXCL12 and CXCR4 mRNA in endometrium of patients with adenomyosis were 6.31±0.12 and 8.49±0.21, respectively, which were higher than those in the control group (1.23±0.10 and 1.36±0.13); compared with each other, the differences were statistically significant (all P<0.05). Moreover, the expression levels of CXCL12 and CXCR4 mRNA in myometrium of patients with adenomyosis were 9.11±0.12 and 8.45±0.16, respectively, which were higher than those in the control group (1.18±0.08 and 1.46±0.13); compared with each other, the differences were statistically significant (all P<0.05). (3) In endometrium and myometrium of uterus with adenomyosis, CXCL12 and CXCR4 mRNA expression levels were positively associated (r=0.478, 0.542, all P<0.05). Conclusions: The levels of CXCL12 and CXCR4 in the endometrium and myometrium of adenomyosis are increased and positively correlated. The two chemokine may be involved in the development of adenomyosis.

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Chemokine CXCL12 and its receptors CXCR4/CXCR7 play a pivotal role in many physiological and pathological situations, while the expression and function in human term trophoblast cells remain largely unknown. In the study, the expression and function of CXCL12 and its receptors CXCR4/CXCR7 in human term trophoblast cells were investigated. Immunocytochemistry and flow cytometry showed that the expression of CXCL12/CXCR4/CXCR7 could be detected in term trophoblast cells while expression level differed. The secretion of CXCL12 in human term trophoblast cells was confirmed by enzyme-linked immunosorbent assay (ELISA). In order to reveal the function of CXCL12, exogenetic recombinant human CXCL12 protein (rhCXCL12) was added to the cultured term trophoblast cells; results showed that cell proliferation ability was increased while cell apoptosis rate was decreased. Moreover, the effects of rhCXCL12 on term trophoblast cells could be diminished or attenuated by antibodies against CXCL12, CXCR4, or CXCR7, respectively. Therefore, these results revealed the important role of CXCL12 on human term trophoblast cells. Our study will provide new insights into understanding the role of CXCL12 on human term trophoblast cells.

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INTRODUCTION AND HYPOTHESIS: SDF-1 chemokine enhances tissue regeneration through stem cell chemotaxis, neovascularization and neuronal regeneration. We hypothesized that non-viral delivery of human plasmids that express SDF-1 (pSDF-1) may represent a novel regenerative therapy for stress urinary incontinence (SUI). METHODS: Seventy-six female rats underwent vaginal distention (VD). They were then divided into four groups according to treatment: pSDF-1 (n = 42), sham (n = 30), PBS (n = 1) and luciferase-tagged pSDF-1 (n = 3). Immediately after VD, the pSDF-1 group underwent immediate periurethral injection of pSDF-1, and the sham group received a vehicle injection followed by leak point pressure (LPP) measurement at the 4th, 7th and 14th days. Urogenital tissues were collected for histology. H&E and trichrome slides were analyzed for vascularity and collagen/muscle components of the sphincter. For the luciferase-tagged pSDF-1 group, bioluminescence scans (BLIs) were obtained on the 3rd, 7th and 14th days following injections. Statistical analysis was conducted using ANOVA with post hoc LSD tests. The Mann-Whitney U test was employed to make pair-wise comparisons between the treated and sham groups. We used IBM SPSS, version 22, for statistical analyses. RESULTS: BLI showed high expression of luciferase-tagged pSDF-1 in the pelvic area over time. VD resulted in a decline of LPP at the 4th day in both groups. The pSDF1-treated group demonstrated accelerated recovery that was significantly higher than that of the sham-treated group at the 7th day (22.64 cmH2O versus 13.99 cmH2O, p < 0.001). Functional improvement persisted until the 14th day (30.51 cmH2O versus 24.11 cmH2O, p = 0.067). Vascularity density in the pSDF-1-treated group was higher than in the sham group at the 7th and 14th days (p < 0.05). The muscle density/sphincter area increased significantly from the 4th to 14th day only in the pSDF-1 group. CONCLUSIONS: Periurethral injection of pSDF-1 after simulated childbirth accelerated the recovery of continence and regeneration of the urethral sphincter in a rat SUI model. This intervention can potentially be translated to the treatment of post-partum urinary incontinence.

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The CXCL12 gene produces a series of transcript variants through alternative splicing at the 3' end of its pre-mRNA. This study explores the biological activities of these alternative transcripts and the mechanisms involved in the regulation of CXCL12 transcription and RNA splicing. We identified a "GA" insertion mutation in the region of CXCL12α DNA encoding the conserved 3'UTR. This variant transcript was named CXCL12-3'GA+. The mutation occurred at a frequency of 13.2% in healthy Chinese individuals. However, its frequency in healthy Caucasians was 22.6%, significantly higher than what was observed in the Chinese. Genomic analysis indicated that the GA+ mutation likely encodes a G-quadruplex structure in close proximity to a cluster of important AU-rich elements (AREs) that are well-established regulators of mRNA stability at the 3'UTR. Experiments using molecular constructs encoding the 3'UTR of CXCL12 revealed that the GA+ allele can significantly increase gene expression compared to the WT allele. Further studies uncovered that the WT allele was associated with the production of a 225-bp minor transcript isoform (MTI) through alternative splicing resulting in the deletion of exon 2. ARMS-PCR using samples collected from cultured PBMCs of WT/GA+ genotype carriers indicated that the GA+ allele was preferentially transcribed compared to the WT allele. In summary, the study demonstrates that a GA insertion in the region encoding the 3'UTR of CXCL12α may affect gene expression through alternative mRNA splicing. This finding provides a basis for understanding how multiple elements in the sequence encoding the 3'UTR of the CXCL12 gene regulates its transcription and may lead to insights about diseases involving abnormal CXCL12α expression.

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BACKGROUND: Nowadays, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) signal axis has been used extensively because of its biological effects and particularly a great progress has been achieved in the mechanism of SDF-1/CXCR4 signal axis as well as in its use for tissue regeneration. OBJECTIVE: To summarize the factors affecting the regulation of SDF-1 and CXCR4 and to review the research progress in the biological characteristics of SDF-1/CXCR4 signal axis. METHODS: The first author searched the PubMed, CNKI, WanFang and VIP databases for relevant articles published from January 1990 to August 2018. The keywords were "tissue engineering; cell homing; chemokine; regeneration; pulp regeneration; HIF-1; SDF-1; CXCL12; CXCR4; NOX-A12" in both Chinese and English. RESULTS AND CONCLUSION: Hypoxia-inducible factor-1 plays a key role in the regulation of SDF-1, and there are multiple factors which can affect the expression of CXCR4. SDF-1/CXCR4 signal axis formed by the combination of SDF-1 and CXCR4 plays an important biological role in various physiological and pathological processes. Blocking SDF-1 is used to inhibit the pathogenic effect of the SDF-1/CXCR4 signal axis for therapeutic purposes, while increasing SDF-1 can strengthen the SDF-1/CXCR4 signal axis and enhance the ability of chemotactic endogenous cell homing for tissue regeneration. To further illustrate the mechanism of the SDF-1/CXCR4 signal axis, we upregulate or downregulate the expression of SDF-1 or CXCR4 by exogenous means to influence the biological function of the signal axis, and thus provide theoretical basis for optimizing clinical treatment strategies, and developing the biological function of the signal axis for human health benefits.

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Objective To detect the expression and clinical significance of stro-mal cell derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) in peripheral blood of patients with hepatitis C cirrhosis.Methods From January 2015 to January 2018,120 patients with hepatitis C cirrhosis in our hospital were selected as the subjects,including 60 patients with compensated hepatitis C cirrhosis and 60 patients with decompensated hepatitis C cirrhosis,and 60 hepatitis C patients without cirrhosis in the same period were selected as the control group.Enzyme linked immunosorbent assay (ELISA) was used to detect the expression levels of SDF-1 and CXCR4 in peripheral blood;the correlation between SDF-1 and CXCR4 expressions in compensated cirrhosis and decompensated cirrhosis patients was analyzed.Results The expression levels of SDF-1 and CXCR4 in peripheral blood samples of patients with decompensated cirrhosis of hepatitis C were significantly higher than those of patients with compensated cirrhosis of hepatitis C (P ＜ 0.05);the expression levels of SDF-1 and CXCR4 in peripheral blood samples of patients with compensated and decompensated cirrhosis of hepatitis C were significantly higher than those of control group (P ＜ 0.05);the expressions of SDF-1 and CXCR4 in peripheral blood of patients with compensated and decompensated cirrhosis of hepatitis C were positively correlated (r =0.684,P ＜ 0.05,r =0.765,P ＜ 0.05).Albumin (AlB) level in peripheral blood of cirrhosis group was significantly lower than that of control group (P ＜ 0.05);alanine aminotransferase (ALT),aspartate aminotransferase (AST),total bilirubin (TBIL),while fasting insulin (FINs) and interleukin (IL)-6 in cirrhosis group were higher than those of control group (P ＜ 0.05);SDF-1 level and CXCR4 level were positively correlated with AlB,FINs and IL-6 (P ＜ 0.05);multiple regression analysis showed that FINs,IL-6,SDF-1 and CXCR4 were risk factors for hepatitis C cirrhosis.Conclusions The levels of SDF-1 and CXCR4 in peripheral blood of patients with hepatitis C cirrhosis increased,and the levels of SDF-1 and CXCR4 in peripheral blood were positively correlated,suggesting that they may be involved in the regulation of the occurrence and development of hepatitis C cirrhosis.

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Chemokines and their receptors play an important role in the occurance and development of hepatocellular carcinoma(HCC).The effects of chemokines and their receptors in HCC are different,chemokines and their receptors associated with HCC are mostly expressed in promoting tumor cell proliferation,angiogenesis and invasion,but some chemokines and their receptors play an anti-tumor role.This reviews focus on the role of chemokines and their receptors in HCC.