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SDF-1/CXCL12 is a unique chemotactic factor with multiple functions on various types of precursor cells, all carrying the cognate receptor CXCR4. Whereas individual biological functions of SDF-1/CXCL12 have been well documented, practical applications in medicine are insufficiently studied. This is explained by the complex multifunctional biology of SDF-1 with systemic and local effects, critical dependence of SDF-1 activity on aminoterminal proteolytic processing and limited knowledge of applicable modulators of its activity. We here present new insights into modulation of SDF-1 activity in vitro and in vivo by a macromolecular compound, chlorite-oxidized oxyamylose (COAM). COAM prevented the proteolytic inactivation of SDF-1 by two inflammationassociated proteases: matrix met a lloproteinase-9/MMP-9 and dipeptidylpeptidase IV/DPPIV/CD26. The inhibition of proteolytic inactivation was functionally measured by receptor-mediated effects, including intracellular calcium mobilization, ERK1/2 phosphorylation, receptor internalization and chemotaxis of CXCR4-positive cells. Protection of SDF-1/CXCL12 against proteolysis was dependent on electrostatic COAM-SDF-1 interactions. By in vivo experiments in mice, we showed that the combination of COAM with SDF-1 delivered through physiological fibrin hydrogel had beneficial effect for the healing of skin wounds. Collectively, we show that COAM protects SDF-1 from proteolytic inactivation, maintaining SDF-1 biological activities. Thus, protection from proteolysis by COAM represents a therapeutic strategy to prolong SDF-1 bioavailability for wound healing applications. [ABSTRACT FROM AUTHOR]

Abstract Introduction Stromal cell-derived factor-1 (SDF-1) is a newly discovered small molecule adipocytokine, and research has shown that it is closely related to the occurrence and development of obesity. However, there are currently few research reports on SDF-1 in childhood obesity and nonalcoholic fatty liver disease (NAFLD), and this study aims to explore the relationship between SDF-1 and obesity related indicators in obese children. Methods Serum SDF-1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Clinical and biochemical data were collected, such as body mass index (BMI), waist and hip circumference, blood pressure, liver enzymes, cholesterol, and fasting insulin. Children with NAFLD or not were evaluated through Color Doppler Ultrasound. Results Serum SDF-1 concentrations were significantly higher in obese subjects than in non-obese subjects (P

To investigate the relationship between aqueous humor semaphorin-3A (Sema3A), Klotho, stromal cell-derived factor-1 (SDF-1) and postoperative neovascular glaucoma (NVG) in patients with proliferative diabetic retinopathy (PDR). 145 patients admitted to Chengdu Sixth People's Hospital from January 2021 to January 2022 who underwent vitrectomy PDR were selected, and according to whether occurrence of NVG at 1 year after surgery, patients were divided into the NVG group and the non-NVG group. Enzyme-linked immunosorbent assay was used to detect the levels of aqueous humor Sema3A, Klotho and SDF-1. Multivariate Logistic regression analysis was used to analyze the factors affecting postoperative NVG in patients with PDR, and the predictive value of aqueous humor Sema3A, Klotho and SDF-1 on postoperative NVG in patients with PDR was analyzed by receiver operating characteristic (ROC) curve. PDR patients were followed up for 1 year, and the incidence rate of postoperative NVG was 17.24%.Compared with the non-NVG group, the levels of aqueous humor Sema3A and SDF-1 in the NVG group were increased, and the level of Klotho was decreased(P＜0.05). Multivariate Logistic regression analysis showed that preoperative iris neovascularization and elevated Sema3A and SDF-1 were independent risk factors affecting postoperative NVG in patients with PDR, and elevated Klotho was an independent protective factor(P＜0.05). ROC curve analysis showed that the area under curve (AUC) of aqueous humor Sema3A, Klotho and SDF-1 predicted postoperative NVG in patients with PDR was 0.913, which was greater than the 0.796, 0.794, and 0.800 predicted by aqueous humor Sema3A, Klotho and SDF-1 individually. Elevated aqueous humor Sema3A, SDF-1 and reduced Klotho are closely related to the occurrence of postoperative NVG in patients with PDR, and the combined detection of aqueous humor Sema3A, Klotho and SDF-1 has a high predictive value for postoperative NVG in patients with PDR. [ABSTRACT FROM AUTHOR]

This study aims to investigate the diagnostic efficacy of combined detection of serum C-C Motif Chemokine 18 (CCL-18), p185 and Stromal cell derived factor 1 (SDF-1) in breast cancer. 88 breast cancer patients admitted to our hospital were selected as study subjects. 88 healthy women who visited for a physical examination during the same period were selected as controls. Serum CCL-18, p185 and SDF-1 levels were measured. Combined detection and single detection in breast cancer diagnosis were compared in terms of sensitivity, specificity, accuracy, positive predictive value and negative predictive value. ROC (receiver operating characteristic) curves were drawn to further compare the differences between combined detection and single detection methods. CCL-18, p185 and SDF-1 in the cancer group were significantly higher than in the control group (p < 0.05). The area under the ROC curve of CCL-18, p185, SDF-1 and combined detection were 0.786 (95% Confidence Interval (CI): 0.717-0.854), 0.852 (95% CI: 0.788-0.916), 0.921 (95% CI: 0.883-0.958) and 0.962 (95% CI: 0.925-0.999), respectively. Sensitivity of combined detection was significantly higher than CCL-18 and p185 (p < 0.05). Specificity, accuracy and positive predictive value of combined detection were significantly higher than CCL-18, p185 and SDF-1 (p < 0.05). Compared with CCL-18 and p185, combined detection had a higher negative predictive value, which was statistically significant (p<0.05). Combined detection of serum CCL-18, p185 and SDF-1 is more effective at diagnosing breast cancer and is worth clinical application. [ABSTRACT FROM AUTHOR]

Numerous studies have tried to evaluate the potential role of thrombophilia-related genes in retinal vein occlusion (RVO); however, there is limited research on genes related to different pathophysiological mechanisms involved in RVO. In view of the strong contribution of oxidative stress and inflammation to the pathogenesis of RVO, the purpose of the present study was to investigate the association of inflammation- and oxidative-stress-related polymorphisms from three different genes [apolipoprotein E (APOE), paraoxonase 1 (PON1) and stromal cell-derived factor 1 (SDF-1)] and the risk of RVO in a Greek population. Participants in this case-control study were 50 RVO patients (RVO group) and 50 healthy volunteers (control group). Blood samples were collected on EDTA tubes and genomic DNA was extracted. Genotyping of rs854560 (L55M) and rs662 (Q192R) for the PON1 gene, rs429358 and rs7412 for the APOE gene and rs1801157 [SDF1-3′G(801)A] for SDF-1 gene was performed using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. Multiple genetic models (codominant, dominant, recessive, overdominant and log-additive) and haplotype analyses were performed using the SNPStats web tool to assess the correlation between the genetic polymorphisms and the risk of RVO. Binary logistic regression analysis was used for the association analysis between APOE gene variants and RVO. Given the multifactorial nature of the disease, our statistical analysis was adjusted for the most important systemic risk factors (age, hypertension and diabetes mellitus). The dominant genetic model for the PON1 Q192R single nucleotide polymorphism (SNP) of the association analysis revealed that there was a statistically significant difference between the RVO group and the control group. Specifically, after adjusting for age and hypertension, the PON1 192 R allele (QR + RR) was found to be associated with a statistically significantly higher risk of RVO compared to the QQ genotype (OR = 2.51; 95% CI = 1.02–6.14, p = 0.04). The statistically significant results were maintained after including diabetes in the multivariate model in addition to age and hypertension (OR = 2.83; 95% CI = 1.01–7.97, p = 0.042). No statistically significant association was revealed between the other studied polymorphisms and the risk of RVO. Haplotype analysis for PON1 SNPs, L55M and Q192R, revealed no statistically significant correlation. In conclusion, PON1 192 R allele carriers (QR + RR) were associated with a statistically significantly increased risk of RVO compared to the QQ homozygotes. These findings suggest that the R allele of the PON1 Q192R is likely to play a role as a risk factor for retinal vein occlusion. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) is the leading cause of cancer-associated deaths worldwide, among which non-small-cell lung cancer (NSCLC) accounts for 80%. Stromal cell-derived factor-1 (SDF-1) inhibition results in a significant depletion of NSCLC metastasis. Additionally, SDF-1 is the only natural chemokine known to bind and activate the receptor CXCR4. Thus, we attempted to clarify the molecular mechanism of SDF-1 underlying NSCLC progression. Transwell migration, adhesion, and G-LISA assays were used to assess megakaryocytic chemotaxis in vitro and in vivo in terms of megakaryocytic migration, adherence, and RhoA activation, respectively. Western blotting was used to assess PI3K/Akt-associated protein abundances in MEG-01 cells and primary megakaryocytes under the indicated treatment. A hematology analyzer and flow cytometry were used to assess platelet counts in peripheral blood and newly formed platelet counts in Lewis LC mice under different treatments. Immunochemistry and flow cytometry were used to measure CD41+ megakaryocyte numbers in Lewis LC mouse tissue under different treatments. ELISA was used to measure serum TPO levels, and H&E staining was used to detect NSCLC metastasis. SDF-1 receptor knockdown suppressed megakaryocytic chemotaxis in Lewis LC mice. SDF-1 receptor inhibition suppressed megakaryocytic chemotaxis via the PI3K/Akt pathway. SDF-1 receptor knockdown suppressed CD41+ megakaryocyte numbers in vivo through PI3K/Akt signaling. SDF-1 receptor inhibition suppressed CD41+ megakaryocytes to hinder NSCLC metastasis. SDF-1 facilitates NSCLC metastasis by enhancing the chemoattraction of megakaryocytes via the PI3K/Akt signaling pathway, which may provide a potential new direction for seeking therapeutic plans for NSCLC. [ABSTRACT FROM AUTHOR]

Background. The impact of cysteine-rich angiogenic inducer 61 (Cyr61, also called CCN1) on endothelial progenitor cells (EPCs) from diabetic-rat-derived whole peripheral and bone marrow remains poorly understood. Therefore, the expression levels of CCN1, CCN1-induced C-X-C chemokine receptor type 4 (CXCR4), and stromal-cell-derived factor-1 (SDF-1) were explored under high glucose (HG) conditions. Objectives. The aim of the study was to explore the effects of high CCN1 levels on EPC activity in diabetic rats through mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway modulation. Materials and methods: Primary EPCs were isolated from bone marrow and whole peripheral blood of streptozocin (STZ)-induced diabetic Sprague-Dawley rats and controls. Cell migration, tube formation ability and viability were determined using transwell, Cell Counting Kit-8 (CCK-8), and Matrigel®-based capillary-like tube formation assays. Protein and gene expression levels were measured by western blot and real-time quantitative polymerase chain reaction (RT-qPCR). Results: The study findings showed that EPC migration, viability and tube formation ability were significantly lower under HG conditions. High CCN1 expression levels restored EPC function by inducing SDF-1 and CXCR4 in EPCs under HG conditions. Furthermore, HG suppressed MEK/ERK phosphorylation, while an ERK1/2 agonist rescued EPC CCN1-SDF-1/CXCR4 expression under HG conditions through the activation of the MEK/ERK pathway. Conclusions. This study demonstrates that high CCN1 expression levels restored EPC functions, partly by modulating MEK/ERK signaling. These findings provide a basis for developing novel therapeutic methods for diabetic vascular neogenesis and vascular injury repair. [ABSTRACT FROM AUTHOR]

Introduction: Stromal cell-derived factor-1 (SDF-1) is a newly discovered small molecule adipocytokine, and research has shown that it is closely related to the occurrence and development of obesity. However, there are currently few research reports on SDF-1 in childhood obesity and nonalcoholic fatty liver disease (NAFLD), and this study aims to explore the relationship between SDF-1 and obesity related indicators in obese children. Methods: Serum SDF-1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Clinical and biochemical data were collected, such as body mass index (BMI), waist and hip circumference, blood pressure, liver enzymes, cholesterol, and fasting insulin. Children with NAFLD or not were evaluated through Color Doppler Ultrasound. Results: Serum SDF-1 concentrations were significantly higher in obese subjects than in non-obese subjects (P < 0.05), and were elevated in the NAFLD obese subjects than in the non-NAFLD obese subjects (P < 0.05). SDF-1 was positively correlated with BMI, waist-to-hip ratio, systolic blood pressure, body fat percentage (BFP), basal metabolic rate (BMR), alanine transaminase (ALT), aspartate transaminase (AST), glutyltranspeptidase (GT), and homoeostasis model of HOMA-IR, independent of their uric acid (UA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), gender and age. BFP and BMR were associated with the serum SDF-1 concentrations in multivariable linear regression analysis. Conclusion: These results suggest that SDF-1 levels are elevated in obese children and are associated with NAFLD, indicating that SDF-1 may play a role in the development of childhood obesity and metabolic disorders. [ABSTRACT FROM AUTHOR]

Background: The invasion of trophoblast cells into the maternal uterine decidua is crucial for the formation of the placenta and establishment of pregnancy. Stromal cell-derived factor-1 (SDF-1) regulates cellular functions such as migration, adhesion, and proliferation. During pregnancy, both SDF-1 and its receptor CXCR4 are expressed in the placenta. Abnormal expression of the SDF-1 system has been linked to pregnancy disorders such as pre-eclampsia. Objective: The purpose of this study was to investigate the effect of SDF-1/CXCR4 signaling on trophoblast cells and the related molecular mechanism(s). Results: The invasiveness of HTR8/SVneo human trophoblast cells was stimulated by extracellular SDF-1. SDF-1 activated the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) signaling pathways. The ability of SDF-1 to stimulate HTR8/SVneo cell invasion was blocked in the presence of a PI3K inhibitor (wortmannin), an ERK1/2 MAPK inhibitor (U0126), or a P38 MAPK inhibitor (SB203580). The expression of the matrix metalloproteinase (MMP)-2 and MMP-9 genes increased in SDF-1-treated HTR8/SVneo cells, and the up-regulation of MMPs expression was inhibited by blocking the SDF-1 receptor. Additionally, SDF-1 treatment increased MMP-2 and MMP-9 protein levels in HTR8/SVneo cells, and the increase of MMP-2 and MMP-9 was reduced by inhibiting the PI3K and/or MAPK intracellular signaling pathway. Conclusion: These findings provide evidence that appropriate SDF-1-mediated signaling pathways contribute to the regulation of trophoblast invasiveness into the endometrium. [ABSTRACT FROM AUTHOR]

SDF-1/CXCL12 is a unique chemotactic factor with multiple functions on various types of precursor cells, all carrying the cognate receptor CXCR4. Whereas individual biological functions of SDF-1/CXCL12 have been well documented, practical applications in medicine are insufficiently studied. This is explained by the complex multifunctional biology of SDF-1 with systemic and local effects, critical dependence of SDF-1 activity on aminoterminal proteolytic processing and limited knowledge of applicable modulators of its activity. We here present new insights into modulation of SDF-1 activity in vitro and in vivo by a macromolecular compound, chlorite-oxidized oxyamylose (COAM). COAM prevented the proteolytic inactivation of SDF-1 by two inflammation-associated proteases: matrix metalloproteinase-9/MMP-9 and dipeptidylpeptidase IV/DPPIV/CD26. The inhibition of proteolytic inactivation was functionally measured by receptor-mediated effects, including intracellular calcium mobilization, ERK1/2 phosphorylation, receptor internalization and chemotaxis of CXCR4-positive cells. Protection of SDF-1/CXCL12 against proteolysis was dependent on electrostatic COAM-SDF-1 interactions. By in vivo experiments in mice, we showed that the combination of COAM with SDF-1 delivered through physiological fibrin hydrogel had beneficial effect for the healing of skin wounds. Collectively, we show that COAM protects SDF-1 from proteolytic inactivation, maintaining SDF-1 biological activities. Thus, protection from proteolysis by COAM represents a therapeutic strategy to prolong SDF-1 bioavailability for wound healing applications.

Purpose of Review: Intervertebral disc degeneration is the primary etiology of low back pain and radicular pain. This review examines the roles of crucial chemokines in different stages of degenerative disc disease, along with interventions targeting chemokine function to mitigate disc degeneration. Recent Findings: The release of chemokines from degenerated discs facilitates the infiltration and activation of immune cells, thereby intensifying the inflammatory cascade response. The migration of immune cells into the venous lumen is concomitant with the emergence of microvascular tissue and nerve fibers. Furthermore, the presence of neurogenic factors secreted by disc cells and immune cells stimulates the activation of pain-related cation channels in the dorsal root ganglion, potentially exacerbating discogenic and neurogenic pain and intensifying the degenerative cascade response mediated by chemokines. Summary: Gaining a deeper comprehension of the functions of chemokines and immune cells in these processes involving catabolism, angiogenesis, and injury detection could offer novel therapeutic avenues for managing symptomatic disc disease. [ABSTRACT FROM AUTHOR]

In vertebrates, the lateral body wall muscle formation is thought to be initiated by direct outgrowth of the dermomyotomes resulting in the elongation of the hypaxial myotomes. This contrasts with the formation of the muscles of the girdle, limbs and intrinsic tongue muscles, which originate from long-range migrating progenitors. Previous work shows that the migration of these progenitors requires CXCR4 which is specifically expressed in the migrating cells, but not in the dermomyotome. Here, we show that cells in the ventrolateral-lip (VLL) of the dermomyotome at the flank level express CXCR4 in a pattern consistent with that of Pax3 and MyoR. In ovo gain-of-function experiments using electroporation of SDF-1 constructs into the VLL resulted in increased expression of c-Met, Pax3 and MyoD. In contrast, a loss-of-function approach by implantation of CXCR4-inhibitor beads into the VLL of the flank region caused a reduction in the expression of these markers. These data show that CXCR4 is expressed in the VLL, and by experimentally manipulating the CXCR4/SDF-1 signaling, we demonstrate the importance of this axis in body wall muscle development. [Display omitted] • CXCR4 is expressed in the VLL at interlimb level. • CXCR4 is critical for the development of thoracic and abdominal muscles. • CXCR4 is co-expressed with MyoR and Pax3 in the VLL. [ABSTRACT FROM AUTHOR]

Periodontitis is an inflammatory disease characterized by the destruction of periodontal tissues, and the promotion of bone tissue regeneration is the key to curing periodontitis. Psoralen is the main component of Psoralea corylifolia Linn, and has multiple biological effects, including anti-osteoporosis and osteogenesis. We constructed a novel hydrogel loaded with psoralen (PSO) and stromal cell-derived factor-1 (SDF-1) for direct endogenous cell homing. This study aimed to evaluate the synergistic effects of PSO/SDF-1 on periodontal bone regeneration in patients with periodontitis. The results of CCK8, alkaline phosphatase (ALP) activity assay, and Alizarin Red staining showed that PSO/SDF-1 combination treatment promoted cell proliferation, chemotaxis ability, and ALP activity of PDLSCs. qRT-PCR and western blotting showed that the expression levels of alkaline phosphatase (ALP), dwarf-associated transcription factor 2 (RUNX2), and osteocalcin (OCN) gene were upregulated. Rat periodontal models were established to observe the effect of local application of the composite hydrogel on bone regeneration. These results proved that the PSO/SDF-1 combination treatment significantly promoted new bone formation. The immunohistochemical (IHC) results confirmed the elevated expression of ALP, RUNX2, and OCN osteogenic genes. PSO/SDF-1 composite hydrogel can synergistically regulate the biological function and promote periodontal bone formation. Thus, this study provides a novel strategy for periodontal bone regeneration.

Stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine 4 (CXCR4) have been demonstrated to play critical roles in diabetic retinopathy (DR). This study investigated whether single-nucleotide polymorphisms (SNPs) of SDF-1 and its receptor CXCR4 are correlated with diabetic retinopathy (DR). Three SDF-1 SNPs, namely, rs1801157 (G/A), rs2297630 (G/A), and rs266085 (T/C), and two CXCR4 SNPs, namely, rs2228014 (C/T) and rs6430612 (C/T), were chosen and genotyped via the TaqMan allelic discrimination for 454 non-DR subjects and 276 DR individuals. Our results revealed that subjects carrying SDF-1 SNP rs2297630 GA (AOR: 2.962, 95% CI: 1.279-6.861, p = 0.011) and SDF-1 SNP rs2297630 GA + AA (AOR: 3.095, 95% CI: 1.394-6.872, p = 0.006) had significantly higher risk in the non-proliferative diabetic retinopathy (NPDR) groups than in the non-DR group. Further analyses using the datasets from the Genotype-Tissue Expression (GTEx) Portal revealed that SDF-1 SNP rs2297630 GA and AA genotypic variants have higher SDF-1 expression than the GG wild-type alleles (p = 0.000016). In conclusion, our findings revealed that SDF-1 SNP rs2297630 was associated with NPDR. [ABSTRACT FROM AUTHOR]

FLT3 mutations are very frequent in AML and utilization of FLT3 inhibitors as approved treatment options are very common. Despite the initial success of inhibitor treatment, the development of resistances against this treatment is a major challenge in AML therapy. One of the mechanisms causing resistance is the homing of the leukemic cells in the protective niche of the bone marrow microenvironment (BMM). A pathway mediating homing to the BMM and leukemic cell survival is the CXCL12/CXCR4 axis. The analysis of patient samples in several independent studies indicated that FLT3-ITD expression led to higher CXCR4 surface expression. However, several in vitro studies reported contradictory findings, suggesting that FLT3-ITD signaling negatively influenced CXCR4 expression. In this commentary, we provide an overview summarizing the studies dealing with the relationship of FLT3 and CXCR4. Taken together, the current research status is not sufficient to answer the question whether FLT3 and CXCR4 act together or independently in leukemia progression. Systematic analyses in model cell systems are needed to understand the interplay between FLT3 and CXCR4, since this knowledge could lead to the development of more effective treatment strategies for AML patients. [ABSTRACT FROM AUTHOR]

Glucocorticoids are common anti-inflammatory factors; however, they have been reported to have side effects that delay the wound healing process. In a previous study, we found that mesenchymal stem cells isolated from the adipose tissue of patients with long-term glucocorticoid treatment (sAT-MSC) showed impaired wound healing ability due to the downregulation of SDF-1. In this study, we aimed to clarify the mechanisms by which SDF-1 is regulated in sAT-MSC by focusing on the roles of hypoxia-inducible factors (HIFs). Our data suggested that sAT-MSC showed impairment of HIF-1α and the upregulation of HIF-2α. Notably, HIF-2α impairment resulted in the compensatory overexpression of HIF-1α and its target gene SDF-1, which improved the wound healing ability of sAT-MSC. In addition, using knockdown/knockout heterozygous HIF-2α kd/null mice (kd/null), the functions of HIF-2α in the ischemic wound healing process were clarified. With a 50% reduction in the expression of HIF-2α, kd/null mice showed significantly induced wound healing effects, which are involved in the promotion of the inflammatory phase. Specifically, kd/null mice showed the compensatory overexpression of HIF-1α, which upregulated the expression of SDF-1 and enhanced the recruitment of inflammatory cells, such as neutrophils. Our study highlighted the novel function of HIF-2α in the inflammation phase of the wound healing process through the HIF-1α/SDF-1 axis, suggesting that the physiological state of the impaired expression of HIF-2α is a new concept for wound therapy. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most critical cancers; thus, novel therapeutical regimens are of great need. In this study, we investigated the effects of umbilical cord mesenchymal stem cells (UC-MSCs) derived exosomes on HepG2 cell line, and the underlying mechanism to control HCC proliferation, to identify the potential clinical role of exosomes as a novel molecular therapeutic target. Proliferation, apoptosis, and angiogenesis effects were assessed together with the cell viability evaluation by MTT assay in HepG2 cells at 24/48 h. with or without UC-MSCs-derived exosomes. Gene expressions of TNF-α, caspase-3, VEGF, stromal cell-derived factor-1 (SDF-1), and CX chemokine receptor-4 (CXCR-4) were measured by quantitative real-time PCR technique. Expression of sirtuin-1 (SIRT-1) protein was detected by western blot. Treatment of HepG2 cells with UC-MSCs-derived exosomes for 24 and 48 h. demonstrated a significant reduction of cells survival compared to the control group (p < 0.05). The SIRT-1 protein, and VEGF, SDF-1, CXCR-4 expression levels were significantly lower, TNF-α and caspase-3 expression levels were significantly higher in exosomal-treated HepG2 cells for 24 and 48 h. than those in the control group. Moreover, our findings documented that the anti-proliferative, apoptotic, and anti-angiogenic effects were achieved in a time-dependent manner in which more effects were determined after 48 h supplementation compared to 24 h (p < 0.05). UC-MSCs-derived exosomes exert anticarcinogenic molecular effects on HepG2 cells through the involvement of SIRT-1, SDF-1, and CXCR-4. Hence, exosomes would be a potential novel therapy regimen against HCC. Large-scale studies are recommended to verify this conclusion. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovarian syndrome (PCOS) is a multifactorial condition with metabolic-related complications, such as diabetic nephropathy and chronic renal disorder, which are the leading cause of renal transplant globally. Protective effects of histone deacetylase (HDAC) inhibitors (HDACi) have been documented in metabolic-linked pathologies. Nonetheless, the current study investigated the restorative role of HDACi, butyrate in experimental PCOS-induced renal disorder. Materials and methods: Female Wistar rats (8-week-old) were divided into groups; control, butyrate-treated, letrozole and letrozole + butyrate-treated groups. To induce PCOS, 1 mg/kg of letrozole was given (oral gavage) for 21 days. After confirmation of PCOS, 200 mg/kg of butyrate (oral gavage) was administered for 6 weeks. Results: Rats with PCOS revealed disruption in glucose homeostasis (hyperinsulinemia and impaired glucose tolerance and insulin resistance) and presented with the phenotypes of PCOS (hyperandrogenism, multiple ovarian cysts and elevated LH/FSH ratio). Increased plasma and renal triglycerides and inflammatory (TNF-α/SDF-1/NF-κB) markers were observed with elevated levels of TGFβ-1, renal lipid peroxidation and redox imbalance (GGT, GSH, HIF-1α). Interestingly, animals with PCOS reported increased body weight as well as renal mass. Whereas, heightened levels of plasma urea, creatinine and creatine kinase indicating renal dysfunction, characterized by renal apoptosis (Caspase-6) and increased HDAC2 levels. Notwithstanding, administration of butyrate averted the alterations. Conclusion: The present investigation demonstrates that PCOS declines renal function, which is accompanied by renal inflammation, apoptosis and fibrosis. The study further suggests that butyrate, an HDAC2i restores renal function by suppressing renal SDF-1 with subsequent attenuation of renal inflammation, apoptosis and fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Background The key to the success of endogenous regeneration is to improve the homing rate of stem cells, and low-energy laser is an effective auxiliary means to promote cell migration and proliferation. The purpose of this study was to observe whether low-energy neodymium (Nd: YAG) laser with appropriate parameters can affect the proliferation and migration of periodontal ligament stem cells (PDLSCs) through SDF-1/CXCR4 pathway. Methods h PDLSCs were cultured and identified. CCK8 assay was used to detect the proliferation of h PDLSCs after different power (0, 0.25, 0.5, 1, and 1.5 W) Nd: YAG laser (MSP, 10 Hz, 30 s, 300 μ m) irradiation at 2th, 3rd,5th, and 7th days, and the optimal laser irradiation parameters were selected for subsequent experiments. Then, the cells were categorized into five groups: control group (C), SDF-1 group (S), AMD3100 group (A), Nd: YAG laser irradiation group (N), and Nd: YAG laser irradiation + AMD3100 group (N + A). the migration of h PDLSCs was observed using Transwell, and the SDF-1 expression was evaluated using ELISA andRT-PCR. The SPSS Statistics 21.0 software was used for statistical analysis. Results The fibroblasts cultured were identified as h PDLSCs. Compared with the C, when the power was 1 W, the proliferation rate of h PDLSCs was accelerated (P 0.05). The number of cell perforations values as follows: C (956.5 ± 51.74), A (981.5 ± 21.15), S (1253 ± 87.21), N (1336 ± 48.54), and N + A (1044 ± 22.13), that increased significantly in group N (P

Abstract Background Islet transplantation is used therapeutically in a minority of patients with type 1 diabetes (T1D). However, successful outcomes are hampered by early islet β-cell loss caused by immune rejection and autoimmunity. Recent studies have demonstrated that mesenchymal stromal cells can enhance islet function both in vitro and in vivo by secreting ligands that activate islet G-protein coupled receptors (GPCRs). Stromal cell-derived factor 1 (SDF-1) is an MSC-secreted GPCR ligand, whereas the suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of STAT3-activating cytokines. Here, we determined whether improvement in islet function mediated by exogenous SDF-1 is impaired by SOCS3 in experimental models of T1D. Methods Isolated islets were cultured for 48 h with SDF-1. Cytokine-induced apoptosis was measured immediately. Islets from Socs3 −/− mice were pre-cultured with exogenous SDF-1 and transplanted underneath the kidney capsule of C57BL/6 mice with streptozotocin-induced diabetes. Blood glucose levels were monitored for 28 days. AMD3100, an antagonist of the SDF-1 ligand CXCR4, was administered subcutaneously to islet transplanted mice to inhibit CXCR4 before and after transplantation. Results SDF-1 protected islet cells from cytokine-induced apoptosis in vitro. SOCS3-knockout (KO) islets pretreated with SDF-1 were effective in reducing blood glucose in non-obese diabetic mice in vivo. We found that SDF-1 elicits localized immunosuppression in transplanted SOCS3-KO islets. Immunomodulation was observed when SOCS-KO islets were preconditioned with SDF-1. Gene expression and flow cytometric analyses revealed significantly decreased immune cell infiltration, inflammatory cytokines, and concomitant increases in FOXP3+ regulatory T cells, alternatively activated M2 macrophages, and dendritic cell phenotypes. Administration of AMD3100 impaired the SDF-1-mediated improvement in SOCS3-KO islet function and local immune suppression. Conclusion SDF-1 improves the function of islet grafts in autoimmune diabetes through regulation by CXCR4; however, the presence of SOCS3 reverses the protective effect of SDF-1 on islet grafts. These data reveal a molecular pathway that can elicit localized immunosuppression and delay graft destruction in transplanted islets.

Numerous studies have tried to evaluate the potential role of thrombophilia-related genes in retinal vein occlusion (RVO); however, there is limited research on genes related to different pathophysiological mechanisms involved in RVO. In view of the strong contribution of oxidative stress and inflammation to the pathogenesis of RVO, the purpose of the present study was to investigate the association of inflammation- and oxidative-stress-related polymorphisms from three different genes [apolipoprotein E (APOE), paraoxonase 1 (PON1) and stromal cell-derived factor 1 (SDF-1)] and the risk of RVO in a Greek population. Participants in this case-control study were 50 RVO patients (RVO group) and 50 healthy volunteers (control group). Blood samples were collected on EDTA tubes and genomic DNA was extracted. Genotyping of rs854560 (L55M) and rs662 (Q192R) for the PON1 gene, rs429358 and rs7412 for the APOE gene and rs1801157 [SDF1-3′G(801)A] for SDF-1 gene was performed using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. Multiple genetic models (codominant, dominant, recessive, overdominant and log-additive) and haplotype analyses were performed using the SNPStats web tool to assess the correlation between the genetic polymorphisms and the risk of RVO. Binary logistic regression analysis was used for the association analysis between APOE gene variants and RVO. Given the multifactorial nature of the disease, our statistical analysis was adjusted for the most important systemic risk factors (age, hypertension and diabetes mellitus). The dominant genetic model for the PON1 Q192R single nucleotide polymorphism (SNP) of the association analysis revealed that there was a statistically significant difference between the RVO group and the control group. Specifically, after adjusting for age and hypertension, the PON1 192 R allele (QR + RR) was found to be associated with a statistically significantly higher risk of RVO compared to the QQ genotype (OR = 2.51; 95% CI = 1.02–6.14, p = 0.04). The statistically significant results were maintained after including diabetes in the multivariate model in addition to age and hypertension (OR = 2.83; 95% CI = 1.01–7.97, p = 0.042). No statistically significant association was revealed between the other studied polymorphisms and the risk of RVO. Haplotype analysis for PON1 SNPs, L55M and Q192R, revealed no statistically significant correlation. In conclusion, PON1 192 R allele carriers (QR + RR) were associated with a statistically significantly increased risk of RVO compared to the QQ homozygotes. These findings suggest that the R allele of the PON1 Q192R is likely to play a role as a risk factor for retinal vein occlusion.

Background: The key to the success of endogenous regeneration is to improve the homing rate of stem cells, and low-energy laser is an effective auxiliary means to promote cell migration and proliferation. The purpose of this study was to observe whether low-energy neodymium (Nd: YAG) laser with appropriate parameters can affect the proliferation and migration of periodontal ligament stem cells (PDLSCs) through SDF-1/CXCR4 pathway. Methods: h PDLSCs were cultured and identified. CCK8 assay was used to detect the proliferation of h PDLSCs after different power (0, 0.25, 0.5, 1, and 1.5 W) Nd: YAG laser (MSP, 10 Hz, 30 s, 300 μ m) irradiation at 2th, 3rd,5th, and 7th days, and the optimal laser irradiation parameters were selected for subsequent experiments. Then, the cells were categorized into five groups: control group (C), SDF-1 group (S), AMD3100 group (A), Nd: YAG laser irradiation group (N), and Nd: YAG laser irradiation + AMD3100 group (N + A). the migration of h PDLSCs was observed using Transwell, and the SDF-1 expression was evaluated using ELISA andRT-PCR. The SPSS Statistics 21.0 software was used for statistical analysis. Results: The fibroblasts cultured were identified as h PDLSCs. Compared with the C, when the power was 1 W, the proliferation rate of h PDLSCs was accelerated (P < 0.05). When the power was 1.5 W, the proliferation rate decreased (P < 0.05). When the power was 0.25 and 0.5 W, no statistically significant difference in the proliferation rate was observed (P > 0.05). The number of cell perforations values as follows: C (956.5 ± 51.74), A (981.5 ± 21.15), S (1253 ± 87.21), N (1336 ± 48.54), and N + A (1044 ± 22.13), that increased significantly in group N (P < 0.05), but decreased in group N + A (P < 0.05). The level of SDF-1 and the expression level of SDF-1 mRNA in groups N and N + A was higher than that in group C (P < 0.05) but lower than that in group A (P < 0.05). Conclusions: Nd: YAG laser irradiation with appropriate parameters provides a new method for endogenous regeneration of periodontal tissue. SDF-1/CXCR4 signaling pathway may be the mechanism of LLLT promoting periodontal regeneration. [ABSTRACT FROM AUTHOR]

Background: Islet transplantation is used therapeutically in a minority of patients with type 1 diabetes (T1D). However, successful outcomes are hampered by early islet β-cell loss caused by immune rejection and autoimmunity. Recent studies have demonstrated that mesenchymal stromal cells can enhance islet function both in vitro and in vivo by secreting ligands that activate islet G-protein coupled receptors (GPCRs). Stromal cell-derived factor 1 (SDF-1) is an MSC-secreted GPCR ligand, whereas the suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of STAT3-activating cytokines. Here, we determined whether improvement in islet function mediated by exogenous SDF-1 is impaired by SOCS3 in experimental models of T1D. Methods: Isolated islets were cultured for 48 h with SDF-1. Cytokine-induced apoptosis was measured immediately. Islets from Socs3−/− mice were pre-cultured with exogenous SDF-1 and transplanted underneath the kidney capsule of C57BL/6 mice with streptozotocin-induced diabetes. Blood glucose levels were monitored for 28 days. AMD3100, an antagonist of the SDF-1 ligand CXCR4, was administered subcutaneously to islet transplanted mice to inhibit CXCR4 before and after transplantation. Results: SDF-1 protected islet cells from cytokine-induced apoptosis in vitro. SOCS3-knockout (KO) islets pretreated with SDF-1 were effective in reducing blood glucose in non-obese diabetic mice in vivo. We found that SDF-1 elicits localized immunosuppression in transplanted SOCS3-KO islets. Immunomodulation was observed when SOCS-KO islets were preconditioned with SDF-1. Gene expression and flow cytometric analyses revealed significantly decreased immune cell infiltration, inflammatory cytokines, and concomitant increases in FOXP3+ regulatory T cells, alternatively activated M2 macrophages, and dendritic cell phenotypes. Administration of AMD3100 impaired the SDF-1-mediated improvement in SOCS3-KO islet function and local immune suppression. Conclusion: SDF-1 improves the function of islet grafts in autoimmune diabetes through regulation by CXCR4; however, the presence of SOCS3 reverses the protective effect of SDF-1 on islet grafts. These data reveal a molecular pathway that can elicit localized immunosuppression and delay graft destruction in transplanted islets. [ABSTRACT FROM AUTHOR]

Activated fibroblasts and M2-polarized macrophages may contribute to the progression of pulmonary fibrosis by forming a positive feedback loop. This study was aimed to investigate whether fibroblasts and macrophages form this loop by secreting SDF-1 and TGF-β and the impacts of neotuberostemonine (NTS) and tuberostemonine (TS). Mice were intratracheally injected with 3 U·kg−1 bleomycin and orally administered with 30 mg·kg−1 NTS or TS. Primary pulmonary fibroblasts (PFBs) and MH-S cells (alveolar macrophages) were used in vitro. The animal experiments showed that NTS and TS improved fibrosis related indicators, inhibited fibroblast activation and macrophage M2 polarization, and reduced the levels of TGF-β and SDF-1 in alveolar lavage fluid. Cell experiments showed that TGF-β1 may activated fibroblasts into myofibroblasts secreting SDF-1 by activating the PI3K/AKT/HIF-1α and PI3K/PAK/RAF/ERK/HIF-1α pathways. It was also found for the first time that SDF-1 was able to directly polarize macrophages into M2 phenotype secreting TGF-β through the same pathways as mentioned above. Moreover, the results of the cell coculture confirmed that fibroblasts and macrophages actually developed a feedback loop to promote fibrosis, and the secretion of TGF-β and SDF-1 was crucial for maintaining this loop. NTS and TS may disturb this loop through inhibiting both the PI3K/AKT/HIF-1α and PI3K/PAK/RAF/ERK/HIF-1α pathways to improve pulmonary fibrosis. NTS and TS are stereoisomeric alkaloids with pyrrole[1,2-a]azapine skeleton, and their effect on improving pulmonary fibrosis may be largely attributed to their parent nucleus. Moreover, this study found that inhibition of both the AKT and ERK pathways is essential for maximizing the improvement of pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Background Transglutaminase 2 (TGM2) is a gene previously reported to be associated with the differentiation of bone marrow mesenchymal stem cells (BMSCs). The study was developed to reveal the impact of TGM2 on the migration and differentiation of BMSCs. Methods Cells were isolated from bone marrow of mice and then the surface antigens were identified by flow cytometry. Wound healing assays were conducted to assess the migratory ability of BMSCs. The mRNA levels of TGM2 and osteoblast-associated genes (ALP, OCN, and RUNX2) were subjected to RT-qPCR analysis, and protein levels of these genes as well as β-catenin were quantitated by western blotting. Alizarin red staining was conducted for detection of osteogenic ability. The activation of Wnt signaling was assessed by TOP/FOP flash assays. Results Surface antigens were positively identified in MSCs, indicating good multidirectional differentiation ability of cells. TGM2 silencing suppressed BMSC migration while weakening mRNA and protein levels of osteoblast-associated genes. While TGM2 overexpression exerts the opposite impact on cell migration and expression levels of osteoblast-associated genes. Additionally, overexpressed TGM2 promotes the mineralization of BMSCs according to results of Alizarin red staining. Moreover, TGM2 activated the Wnt/β-catenin signaling, and DKK1 (an inhibitor of Wnt signaling) reversed the promoting influence of TGM2 on cell migration and differentiation. Conclusion TGM2 promotes the migration and differentiation of BMSCs via activation of the Wnt/β-catenin signaling.

Neovascularization is a key therapeutic target for cancer treatment. However, anti-angiogenic therapies have shown modest success, as tumors develop rapid resistance to treatment owing to activation of redundant pathways that aid vascularization. We hypothesized that simultaneously targeting different pathways of neovascularization will circumvent the current issue of drug resistance and offer enhanced therapeutic benefits. To test this hypothesis, we made use of two distinct models of tumor-neovascularization, which exhibit equally dense microvasculature but show disparate sensitivity to anti-SDF-1 treatment. Lewis lung carcinoma (LLC) is primarily a vasculogenic-tumor that is associated with HSC functioning as a hemangioblast to generate circulating Endothelial Progenitor Cells contributing to formation of new blood vessels, and responds to anti-SDF-1 treatment. B16F0 melanoma is an angiogenic-tumor that derives new blood vessels from existing vasculature and is resistant to anti-SDF-1 therapy. In this study, we observed increased expression of the angiogenic-factor, Robo1 predominantly expressed on the blood vessels of B16F0 tumor. Blockade of Robo1 by the decoy receptor, RoboN, resulted in reduced microvascular-density and tumor-growth. However, this was associated with mobilization of BM-cells into the B16F0 tumor, thus switching the mode of neovascularization from angiogenic to vasculogenic. The use of a combinatorial treatment of RoboN and the monoclonal anti-SDF-1 antibody effectively attenuated tumor-growth and inhibited both angiogenic and BM-derived microvessels. [ABSTRACT FROM AUTHOR]

Abstract Background Tumor infiltration with cytotoxic CD8+ T-cells is associated with a favorable outcome in several neoplasms, including thyroid cancer. The chemokine axis CXCR4/SDF-1 correlates with more aggressive tumors, but little is known concerning the prognostic relevance in relation to the tumor immune microenvironment of differentiated thyroid cancer (DTC). Methods A tissue microarray (TMA) of 37 tumor specimens of primary DTC was analyzed by immunohistochemistry (IHC) for the expression of CD8+, CXCR4, phosphorylated CXCR4 and SDF-1. A survival analysis was performed on a larger collective (n = 456) at RNA level using data from The Cancer Genome Atlas (TCGA) papillary thyroid cancer cohort. Results Among the 37 patients in the TMA-cohort, the density of CD8+ was higher in patients with less advanced primary tumors (median cells/TMA-punch: 12.5 (IQR: 6.5, 12.5) in T1–2 tumors vs. 5 (IQR: 3, 8) in T3–4 tumors, p = 0.05). In the TCGA-cohort, CXCR4 expression was higher in patients with cervical lymph node metastasis compared to N0 or Nx stage (CXCR4high/low 116/78 vs. 97/116 vs. 14/35, respectively, p = 0.001). Spearman’s correlation analysis of the TMA-cohort demonstrated that SDF-1 was significantly correlated with CXCR4 (r = 0.4, p = 0.01) and pCXCR4 (r = 0.5, p = 0.002). In the TCGA-cohort, density of CD8+ correlated with CXCR4 and SDF-1 expression (r = 0.58, p

Background: Transglutaminase 2 (TGM2) is a gene previously reported to be associated with the differentiation of bone marrow mesenchymal stem cells (BMSCs). The study was developed to reveal the impact of TGM2 on the migration and differentiation of BMSCs. Methods: Cells were isolated from bone marrow of mice and then the surface antigens were identified by flow cytometry. Wound healing assays were conducted to assess the migratory ability of BMSCs. The mRNA levels of TGM2 and osteoblast-associated genes (ALP, OCN, and RUNX2) were subjected to RT-qPCR analysis, and protein levels of these genes as well as β-catenin were quantitated by western blotting. Alizarin red staining was conducted for detection of osteogenic ability. The activation of Wnt signaling was assessed by TOP/FOP flash assays. Results: Surface antigens were positively identified in MSCs, indicating good multidirectional differentiation ability of cells. TGM2 silencing suppressed BMSC migration while weakening mRNA and protein levels of osteoblast-associated genes. While TGM2 overexpression exerts the opposite impact on cell migration and expression levels of osteoblast-associated genes. Additionally, overexpressed TGM2 promotes the mineralization of BMSCs according to results of Alizarin red staining. Moreover, TGM2 activated the Wnt/β-catenin signaling, and DKK1 (an inhibitor of Wnt signaling) reversed the promoting influence of TGM2 on cell migration and differentiation. Conclusion: TGM2 promotes the migration and differentiation of BMSCs via activation of the Wnt/β-catenin signaling. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a major health problem, characterized by progressive cartilage degeneration. Previous works have shown that mechanical loading can alleviate OA symptoms by suppressing catabolic activities. This study evaluated whether mechanical loading can enhance anabolic activities by facilitating the recruitment of stem cells for chondrogenesis. We evaluated cartilage degradation in a mouse model of OA through histology with H&E and safranin O staining. We also evaluated the migration and chondrogenic ability of stem cells using in vitro assays, including immunohistochemistry, immunofluorescence, and Western blot analysis. The result showed that the OA mice that received mechanical loading exhibited resilience to cartilage damage. Compared to the OA group, mechanical loading promoted the expression of Piezo1 and the migration of stem cells was promoted via the SDF-1/CXCR4 axis. Also, the chondrogenic differentiation was enhanced by the upregulation of SOX9, a transcription factor important for chondrogenesis. Collectively, the results revealed that mechanical loading facilitated cartilage repair by promoting the migration and chondrogenic differentiation of endogenous stem cells. This study provided new insights into the loading-driven engagement of endogenous stem cells and the enhancement of anabolic responses for the treatment of OA. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus-induced erectile dysfunction (DMED) is one of the complications of diabetes and has a poor response to phosphodiesterase type 5 inhibitor, the first-line treatment for ED. Saxagliptin (Sax), a dipeptidyl peptidase-4 inhibitor (DPP-4i), has been officially used in the treatment of type 2 diabetes. Stromal cell-derived factor-1 (SDF-1) is one of the important substrates of DPP-4, and has been proven to be beneficial for several DMcomplications. However, it is unknownwhether Sax contributes to the management of DMED. Objectives: To explore the effect and possible underlying mechanisms of Sax in the treatment of DMED. Methods: The model of DMwas established by intraperitoneal injection of streptozotocin. All rats were divided into three groups (n = 8 per group): control group, DMED group and DMED+Sax group. In cellular experiments, the corpus cavernosum smooth muscle cells (CCSMCs) were exposed to high glucose (HG), and treated with Sax and AMD3100 (SDF-1 receptor inhibitor). The penile tissue and CCSMCs were harvested for detection. Results: We found that erectile function was impaired in DMED rats compared with the control group, which was partially relieved by Sax. Decreased expression of DPP-4 and increased level of SDF-1 were also observed in DMED+Sax group, together with elevation of PI3K/AKT pathway and inhibition of endothelial dysfunction, oxidative stress and apoptosis in corpus cavernosum. Moreover, Sax could also regulate oxidative stress and apoptosis in CCSMCs underHGcondition, which was blocked in part by AMD3100. Conclusion: Sax could alleviate DMED through increasing SDF-1 and PI3K/AKT pathway, in company with moderation of endothelial dysfunction, oxidative stress and apoptosis. Our findings indicated that DPP-4 is may be beneficial to the management of DMED. [ABSTRACT FROM AUTHOR]

Pathway involving insulin-like growth factor 1 (IGF-1) plays significant role in growth and development. Crucial role of IGF-1 was discovered inter alia through studies involving deficient patients with short stature, including Laron syndrome individuals. Noteworthy, despite disturbances in proper growth, elevated values for selected stem cell populations were found in IGF-1 deficient patients. Therefore, here we focused on investigating role of these cells—very small embryonic-like (VSEL) and hematopoietic stem cells (HSC), in the pathology. For the first time we performed long-term observation of these populations in response to rhIGF-1 (mecasermin) therapy. Enrolled pediatric subjects with IGF-1 deficiency syndrome were monitored for 4–5 years of rhIGF-1 treatment. Selected stem cells were analyzed in peripheral blood flow cytometrically, together with chemoattractant SDF-1 using immunoenzymatic method. Patients' data were collected for correlation of experimental results with clinical outcome. IGF-1 deficient patients were found to demonstrate initially higher levels of VSEL and HSC compared to healthy controls, with their gradual decrease in response to therapy. These changes were significantly associated with SDF-1 plasma levels. Correlations of VSEL and HSC were also reported in reference to growth-related parameters, and IGF-1 and IGFBP3 values. Noteworthy, rhIGF-1 was shown to efficiently induce development of Laron patients achieving at least proper rate of growth (compared to healthy group) in 80% of subjects. In conclusion, here we provided novel insight into stem cells participation in IGF-1 deficiency in patients. Thus, we demonstrated basis for future studies in context of stem cells and IGF-1 role in growth disturbances. [ABSTRACT FROM AUTHOR]

Simple Summary: Feline idiopathic cystitis is a common disease in domestic cats. The pathogenesis of the illness is not completely understood, but the role of various stress factors and the concomitant release of stress hormones, such as norepinephrine, is strongly suggested. Therefore, the examination of this hormone is essential to gain a deeper knowledge of the development of the disease. In the present study, a novel cell culture of uroepithelial cells from a feline urinary bladder was established to serve as a proper model for studying the effects of a norepinephrine triggered stress reaction. Acute, 1 h norepinephrine exposure affected uroepithelial cells by increasing metabolic activity, inducing a proinflammatory response, triggering oxidative stress, and decreasing the barrier integrity of the cultured cells. The results of this study underline that stress-associated norepinephrine release has a direct molecular effect on the uroepithelial cells; the reaction of these cells may play an important mediatory role in the pathogenesis of the disease. The established cell culture model can be a good tool for further in vitro investigations related to urinary disorders of cats. Feline idiopathic cystitis (FIC) is one of the most common urinary tract disorders in domestic cats. As stress is suggested to play a key role in the pathogenesis of FIC, the effects of norepinephrine (NE) as a stress mediator were investigated on a novel feline primary uroepithelial cell culture, serving as an in vitro model of the disease. The uroepithelial cells gained from the mucosa of the bladder of a euthanized cat were cultured for 6 days and were acutely exposed to NE (10, 100, and 1000 µM) for 1 h. NE increased the metabolic activity of the cultured cells and elevated the extracellular concentrations of the pro-inflammatory mediators interleukin-6 (IL-6) and stromal cell derived factor 1 (SDF-1), confirming that NE can trigger an inflammatory response in the uroepithelium. Cellular protein carbonyl levels were increased by NE exposure, while malondialdehyde and glucose regulated protein 78 concentrations remained unchanged, indicating that NE may provoke the oxidative damage of proteins without inducing lipid peroxidation or endoplasmic reticulum stress. Further, it can be strongly suggested that an acute NE challenge might diminish the barrier function of uroepithelial cells, as reflected by the decreased glycosaminoglycan concentration, claudin-4 protein expression, and reduced TER values of the NE-treated cell cultures. Based on these results, short-term NE exposure mimicking acute stress can provoke an inflammatory response and decrease the barrier integrity of cultured feline uroepithelial cells. Hence, it is highly expected that stress-associated NE release may play an important mediatory role in the pathogenesis of FIC. [ABSTRACT FROM AUTHOR]

Filgrastim, a recombinant type of granulocyte-colony stimulating factor (G-CSF), has a high potential to manage chemotherapy-induced leukopenia. It can increase stromal cell-derived factor 1 (SDF-1) which may stimulate C-X-C chemokine receptor type 4 (CXCR4) to migrate bone marrow-derived stem/progenitor cells to the bloodstream. Here, we aimed to investigate in vitro and in vivo effects of filgrastim on cell migration, invasion, and metastasis. A lentivirus vector of the anti-CXCR4 receptor was first used for the CXCR4 knockout. Effects of filgrastim on cell proliferation and migration were then investigated on 4T1 cells by Transwell migration and wound healing assay. At last, the effects of filgrastim on cell metastasis and the possible involved mechanisms have been investigated in a metastatic murine breast tumor. The knockout of the CXCR4 receptor could lead to a decrease in cell proliferation, migration, and invasion of the 4T1 cells. Filgrastim could directly target SDF-1 and upregulate the expression of the CXCR4 receptor. The knockout of the CXCR4 receptor reduced cell metastasis in an animal model of breast cancer. CXCR4 receptor stimulation by the filgrastim-affected pathways is a conserved evolutionary response that could increase cancer cell proliferation and consequent cell metastasis. Our results suggest that the activation of the CXCR4 receptor is a conserved evolutionary response that can increase cell proliferation, migration, and consequent metastasis. It seems that filgrastim may increase the chance of cancer cell metastasis in people continuously receiving it to increase the number of neutrophils. Filgrastim induces the SDF-1/CXCR4 axis on tumor cell growth. SDF-1 and its receptor CXCR4 are vital targets for filgrastim. The CXCR4 can stimulate the PI3K/AKT, NF-κB, and JAK/STAT signaling pathways. The SDF-1/CXCR4 pathway promotes cell chemotaxis and proliferation via MAPKs signaling. It also enhances cell survival, proliferation, and angiogenesis, increasing tumor cell metastasis. The STAT3-mediated inflammation is essential for tumorigenesis processes, and Akt, Wnt, STAT3, and CXCR4 signaling pathways are all correlated. CXCR4 = C-X-C chemokine receptor type 4, SDF-1 = stromal-derived-factor-1, MAPK = mitogen activated protein kinase; NF-κB = nuclear factor-κB, PI3K = phosphoinositide 3-kinase, JAK = Janus kinase, STAT = signal transducer and activator of transcription, PLC = phospholipase C, PKC = Protein kinase C, GRK = G protein-coupled receptor kinase [ABSTRACT FROM AUTHOR]

While supplemental angiopoietin-1 (Ang1) improves hematopoiesis, excessive Ang1 induces bone marrow (BM) impairment, hematopoietic stem cell (HSC) senescence, and erythropoietic defect. Here, we examined how excessive Ang1 disturbs hematopoiesis and explored whether hematopoietic defects were related to its level using K14-Cre;c-Ang1 and Col2.3-Cre;c-Ang1 transgenic mice that systemically and locally overexpress cartilage oligomeric matrix protein-Ang1, respectively. We also investigated the impacts of Tie2 inhibitor and AMD3100 on hematopoietic development. Transgenic mice exhibited excessive angiogenic phenotypes, but K14-Cre;c-Ang1 mice showed more severe defects in growth and life span with higher presence of Ang1 compared with Col2.3-Cre;c-Ang1 mice. Dissimilar to K14-Cre;c-Ang1 mice, Col2.3-Cre;c-Ang1 mice did not show impaired BM retention or senescence of HSCs, erythropoietic defect, or disruption of the stromal cell-derived factor 1 (SDF-1)/CXCR4 axis. However, these mice exhibited a defect in platelet production depending on the expression of Tie2 and globin transcription factor 1 (GATA-1), but not GATA-2, in megakaryocyte progenitor (MP) cells. Treatment with Tie2 inhibitor recovered GATA-1 expression in MP cells and platelet production without changes in circulating RBC in transgenic mice. Consecutive AMD3100 administration not only induced irrecoverable senescence of HSCs but also suppressed formation of RBC, but not platelets, via correlated decreases in number of erythroblasts and their GATA-1 expression in B6 mice. Our results indicate that genetic overexpression of Ang1 impairs hematopoietic development depending on its level, in which megakaryopoiesis is preferentially impaired via activation of Ang1/Tie2 signaling, whereas erythropoietic defect is orchestrated by HSC senescence, inflammation, and disruption of the SDF-1/CXCR4 axis. Graphical Abstract Genetic overexpression of COMP-Ang1 impairs BM microenvironment, induces HSC senescence, and leads to anemic and thrombocytopenic disorders depending on its systemic and local overexpression through a dysregulated activation of the Ang1/Tie2 signaling and/or SDF-1/CXCR4 retention axis. [ABSTRACT FROM AUTHOR]

Stromal cell-derived factor 1 (SDF-1, also known as CXCL12) and its receptor CXCR4 have shown to play a role in the homing and engraftment of hematopoietic stem and progenitor cells. SDF-1 is highly expressed in platelets and involved in thrombosis formation. However, the exact roles of platelet-derived SDF-1 and CXCR4 in platelet activation and mitochondrial function have not been revealed yet. Deletion of Sdf-1 and Cxcr4 specifically in platelets decreased agonist-induced platelet aggregation and dramatically impaired thrombin-induced glucose uptake. In SDF-1-deficient and CXCR4-deficient platelets, intracellular ATP secretions were reduced when activated by the addition of thrombin. SDF-1 deficiency in platelets can impair the routine respiration during resting state and maximal capacity of the electron transfer system (ETS) during activated state. Mitochondrial respiration measurements in permeabilized platelets indicated an impaired function of the oxidative phosphorylation system in -SDF-1 or CXCR4-deficient platelets. These results suggested a novel role of the SDF-1/CXCR4 axis in modulating platelet energy metabolism and activation by regulating mitochondrial respiration, glucose uptake, and ATP production.

Abstract Background The effect of bevacizumab combined with chemotherapy on the expression of stromal cell-derived factor-1 (SDF-1) and receptor CXCR4 in epithelial ovarian cancer tumor cells and its prognosis are unknown. Our work aimed to investigate the effect of chemotherapy +/− bevacizumab on these markers and the impact of this treatment modality in clinical outcomes. Methods Altogether 68 patients with epithelial ovarian cancer who were treated with chemotherapy in our hospital from June 2018 to June 2019 were selected. It was an open-labeled and controlled clinical trial (ethical approval no. 20180435). The patients were grouped according to their admission order. Patients treated with paclitaxel and carboplatin were included in group A, while patients treated with bevacizumab, paclitaxel, and carboplatin were included in group B. qRT-PCR was used to detect the changes of SDF-1 and CXCR4 before and after chemotherapy. Various clinical indicators of patients in the two groups were recorded to analyze the clinical efficacy, and safety of different treatment modalities and the prognosis of the two groups was analyzed. Results The relative expression of SDF-1 and CXCR4 was positively correlated with epithelial ovarian cancer stages (P0.05), but the recurrence rate after 1 year was lower in group B than in group A (P

We aimed to explore the effects of alteplase on neurological function and expression of stromal cell-derived factor-1 (SDF-1) and Claudin-5 in rats with acute cerebral infarction (ACI). 120 Sprague–Dawley rats were divided into sham operation group (SOG), model group (MG), and thrombolysis group (TG) with 40 rats in each group. Rats in the TG were injected with alteplase via the femoral vein, whereas those in the MG and SOG were injected with the same volume of normal saline. Ten rats from each group were sacrificed to measure the lesion area with hematoxylin–eosin staining, whereas another 10 rats from each group were sacrificed to determine the water content of brain tissues. The remaining 20 rats were tested for the expressions of serum SDF-1 and Claudin-5 by enzyme-linked immunosorbent assay. The expression of SDF-1 in the TG was lower than that in the MG but higher than that in the SOG, whereas the expression of Claudin-5 showed the opposite outcome. The general conditions, behavioral expression, neurological behaviors, and nerve injury degree in the TG were better than those in the MG but worse than those in the SOG. The lesion area and water content in the TG were lower than those in the MG, and the contents of IL-6 and IL-1β in the TG were lower than those in the MG but higher than those in the SOG. Alteplase can improve the neurological function, downregulate SDF-1, and upregulate Claudin-5 in the treatment of ACI. [ABSTRACT FROM AUTHOR]

Background: Tumor infiltration with cytotoxic CD8+ T-cells is associated with a favorable outcome in several neoplasms, including thyroid cancer. The chemokine axis CXCR4/SDF-1 correlates with more aggressive tumors, but little is known concerning the prognostic relevance in relation to the tumor immune microenvironment of differentiated thyroid cancer (DTC). Methods: A tissue microarray (TMA) of 37 tumor specimens of primary DTC was analyzed by immunohistochemistry (IHC) for the expression of CD8+, CXCR4, phosphorylated CXCR4 and SDF-1. A survival analysis was performed on a larger collective (n = 456) at RNA level using data from The Cancer Genome Atlas (TCGA) papillary thyroid cancer cohort. Results: Among the 37 patients in the TMA-cohort, the density of CD8+ was higher in patients with less advanced primary tumors (median cells/TMA-punch: 12.5 (IQR: 6.5, 12.5) in T1–2 tumors vs. 5 (IQR: 3, 8) in T3–4 tumors, p = 0.05). In the TCGA-cohort, CXCR4 expression was higher in patients with cervical lymph node metastasis compared to N0 or Nx stage (CXCR4high/low 116/78 vs. 97/116 vs. 14/35, respectively, p = 0.001). Spearman's correlation analysis of the TMA-cohort demonstrated that SDF-1 was significantly correlated with CXCR4 (r = 0.4, p = 0.01) and pCXCR4 (r = 0.5, p = 0.002). In the TCGA-cohort, density of CD8+ correlated with CXCR4 and SDF-1 expression (r = 0.58, p < 0.001; r = 0.4, p < 0.001). The combined marker analysis of the TCGA cohort demonstrated that high expression of both, CXCR4 and SDF-1 was associated with reduced overall survival in the CD8 negative TCGA cohort (p = 0.004). Conclusion: These findings suggest that the prognostic significance of CXCR4 and SDF-1 in differentiated thyroid cancer depends on the density of CD8 positive T-lymphocytes. Further studies with larger sample sizes are needed to support our findings and inform future investigations of new treatment and diagnostic options for a more personalized approach for patients with differentiated thyroid cancer. [ABSTRACT FROM AUTHOR]

Background: Bone marrow-derived mesenchymal stem cells (MSCs), which possess immunomodulatory characteristic, are promising candidates for the treatment of acute myocardial infarction (AMI). However, the low retention and survival rate of MSCs in the ischemic heart limit their therapeutic efficacy. Strategies either modifying MSCs or alleviating the inflammatory environment, which facilitates the recruitment and survival of the engrafted MSCs, may solve the problem. Thus, we aimed to explore the therapeutic efficacy of sequential transplantation of exosomes and combinatorial pretreated MSCs in the treatment of AMI. Methods: Exosomes derived from MSCs were delivered to infarcted hearts through intramyocardial injection followed by the intravenous infusion of differentially pretreated MSCs on Day 3 post-AMI. Enzyme linked immunosorbent assay (ELISA) was performed to evaluate the inflammation level as well as the SDF-1 levels in the infarcted border zone of the heart. Echocardiography and histological analysis were performed to assess cardiac function, infarct size, collagen area and angiogenesis. Results: Sequential transplantation of exosomes and the combinatorial pretreated MSCs significantly facilitated cardiac repair compared to AMI rats treated with exosomes alone. Notably, compared to the other three methods of cotransplantation, combinatorial pretreatment with hypoxia and Tongxinluo (TXL) markedly enhanced the CXCR4 level of MSCs and promoted recruitment, which resulted in better cardiac function, smaller infarct size and enhanced angiogenesis. We further demonstrated that exosomes effectively reduced apoptosis in MSCs in vitro. Conclusion: Sequential delivery of exosomes and pretreated MSCs facilitated cardiac repair post-AMI, and combined pretreatment with hypoxia and TXL better enhanced the cardioprotective effects. This method provides new insight into the clinical translation of stem cell-based therapy for AMI. [ABSTRACT FROM AUTHOR]

Background: In this study, we investigated the prediction and prognostic value of SDF-1 for triple-negative breast cancer (TNBC) patients who underwent neoadjuvant chemotherapy (NAC) following standard radical surgery. Methods: A total of 303 TNBC patients were included in this study. The NAC regimen was weekly paclitaxel plus carboplatin (PC) for all patients. SDF-1 and CXCR4 expression were measured at baseline and surgery via enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC), respectively. Correlations between variables and treatment response were studied, and Cox proportional hazards regression analysis was implemented for prognostic evaluation. Results: Of the 303 patients, 103 (34.0%) experienced pathological complete response (pCR) after completion of NAC. Serum SDF-1 expression before NAC was significantly correlated with the abundance of TILs. A higher pCR rate was more likely to be observed in patients with lower serum SDF-1 levels before NAC (P=0.001, OR=0.997, 95% CI: 0.996-0.999) and higher levels of TILs (P=0.005). In the multivariate survival model for nonpCR patients, serum SDF-1 expression at surgery served as an independent prognostic value for survival (high level, HR=1.980, 95% CI: 1.170-3.350, low level was used as a reference; P=0.011). Additionally, the predictive and prognostic value of serum SDF-1 expression was significant in patients with high abundance of TILs but not in patients with low abundance of TILs. Conclusions: This study contributes to the clarification of the value of serum SDF-1 to predict pCR and survival for TNBC patients who underwent NAC. This new serum marker, together with TILs, might help identify clinical subtypes of TNBC with different treatment responses and survival and play an important role in tailoring and modifying the NAC strategy for advanced TNBCs in the future. [ABSTRACT FROM AUTHOR]

Abstract Background Bone marrow-derived mesenchymal stem cells (MSCs), which possess immunomodulatory characteristic, are promising candidates for the treatment of acute myocardial infarction (AMI). However, the low retention and survival rate of MSCs in the ischemic heart limit their therapeutic efficacy. Strategies either modifying MSCs or alleviating the inflammatory environment, which facilitates the recruitment and survival of the engrafted MSCs, may solve the problem. Thus, we aimed to explore the therapeutic efficacy of sequential transplantation of exosomes and combinatorial pretreated MSCs in the treatment of AMI. Methods Exosomes derived from MSCs were delivered to infarcted hearts through intramyocardial injection followed by the intravenous infusion of differentially pretreated MSCs on Day 3 post-AMI. Enzyme linked immunosorbent assay (ELISA) was performed to evaluate the inflammation level as well as the SDF-1 levels in the infarcted border zone of the heart. Echocardiography and histological analysis were performed to assess cardiac function, infarct size, collagen area and angiogenesis. Results Sequential transplantation of exosomes and the combinatorial pretreated MSCs significantly facilitated cardiac repair compared to AMI rats treated with exosomes alone. Notably, compared to the other three methods of cotransplantation, combinatorial pretreatment with hypoxia and Tongxinluo (TXL) markedly enhanced the CXCR4 level of MSCs and promoted recruitment, which resulted in better cardiac function, smaller infarct size and enhanced angiogenesis. We further demonstrated that exosomes effectively reduced apoptosis in MSCs in vitro. Conclusion Sequential delivery of exosomes and pretreated MSCs facilitated cardiac repair post-AMI, and combined pretreatment with hypoxia and TXL better enhanced the cardioprotective effects. This method provides new insight into the clinical translation of stem cell-based therapy for AMI.

Stromal cell-derived factor 1 (SDF-1) is known to influence bone marrow stromal cell (BMSC) migration, osteogenic differentiation, and fracture healing. We hypothesize that SDF-1 mediates some of its effects on BMSCs through epigenetic regulation, specifically via microRNAs (miRNAs). MiRNAs are small non-coding RNAs that target specific mRNA and prevent their translation. We performed global miRNA analysis and determined several miRNAs were differentially expressed in response to SDF-1 treatment. Gene Expression Omnibus (GEO) dataset analysis showed that these miRNAs play an important role in osteogenic differentiation and fracture healing. KEGG and GO analysis indicated that SDF-1 dependent miRNAs changes affect multiple cellular pathways, including fatty acid biosynthesis, thyroid hormone signaling, and mucin-type O-glycan biosynthesis pathways. Furthermore, bioinformatics analysis showed several miRNAs target genes related to stem cell migration and differentiation. This study's findings indicated that SDF-1 induces some of its effects on BMSCs function through miRNA regulation.

BackgroundIn this study, we investigated the prediction and prognostic value of SDF-1 for triple-negative breast cancer (TNBC) patients who underwent neoadjuvant chemotherapy (NAC) following standard radical surgery.MethodsA total of 303 TNBC patients were included in this study. The NAC regimen was weekly paclitaxel plus carboplatin (PC) for all patients. SDF-1 and CXCR4 expression were measured at baseline and surgery via enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC), respectively. Correlations between variables and treatment response were studied, and Cox proportional hazards regression analysis was implemented for prognostic evaluation.ResultsOf the 303 patients, 103 (34.0%) experienced pathological complete response (pCR) after completion of NAC. Serum SDF-1 expression before NAC was significantly correlated with the abundance of TILs. A higher pCR rate was more likely to be observed in patients with lower serum SDF-1 levels before NAC (P=0.001, OR=0.997, 95% CI: 0.996-0.999) and higher levels of TILs (P=0.005). In the multivariate survival model for nonpCR patients, serum SDF-1 expression at surgery served as an independent prognostic value for survival (high level, HR=1.980, 95% CI: 1.170-3.350, low level was used as a reference; P=0.011). Additionally, the predictive and prognostic value of serum SDF-1 expression was significant in patients with high abundance of TILs but not in patients with low abundance of TILs.ConclusionsThis study contributes to the clarification of the value of serum SDF-1 to predict pCR and survival for TNBC patients who underwent NAC. This new serum marker, together with TILs, might help identify clinical subtypes of TNBC with different treatment responses and survival and play an important role in tailoring and modifying the NAC strategy for advanced TNBCs in the future.

Background: Bone marrow stromal cells (BMSCs) form a perivascular cell population in the bone marrow. These cells do not present naïve myogenic potential. However, their myogenic identity could be induced experimentally in vitro or in vivo. In vivo, after transplantation into injured muscle, BMSCs rarely fused with myofibers. However, BMSC participation in myofiber reconstruction increased if they were modified by NICD or PAX3 overexpression. Nevertheless, BMSCs paracrine function could play a positive role in skeletal muscle regeneration. Previously, we showed that SDF-1 treatment and coculture with myofibers increased BMSC ability to reconstruct myofibers. We also noticed that SDF-1 treatment changed selected miRNAs expression, including miR151 and miR5100. Methods: Mouse BMSCs were transfected with miR151 and miR5100 mimics and their proliferation, myogenic differentiation, and fusion with myoblasts were analyzed. Results: We showed that miR151 and miR5100 played an important role in the regulation of BMSC proliferation and migration. Moreover, the presence of miR151 and miR5100 transfected BMSCs in co-cultures with human myoblasts increased their fusion. This effect was achieved in an IGFBP2 dependent manner. Conclusions: Mouse BMSCs did not present naïve myogenic potential but secreted proteins could impact myogenic cell differentiation. miR151 and miR5100 transfection changed BMSC migration and IGFBP2 and MMP12 expression in BMSCs. miR151 and miR5100 transfected BMSCs increased myoblast fusion in vitro. [ABSTRACT FROM AUTHOR]

Although stem cells have extensively been studied as a novel vehicle for tissue repair, their sustained efficacy remains controversial. In this study, we aimed to investigate the angiogenic potency over time of stromal cell‐derived factor‐1 (SDF‐1) gene‐edited amniotic mesenchymal stem cells (AMM/S) in a hindlimb ischaemia model. An SDF‐1 transgene was inserted into the AMM cell genome via transcription activator‐like effector nuclease (TALEN) mediated knock‐in, and cell migration, Matrigel tube formation, and in vivo Matrigel plug assays were performed. AMM/S were also transplanted into hindlimb ischaemia model mice. Blood perfusion, therapeutic potential, histology, capillary density and in vivo angiogenic assays were performed. AMM/S exhibited high expression of the SDF‐1 gene, and robustly promoted migration, proliferation and microvascular formation. AMM/S transplantation significantly increased blood perfusion and limb loss prevention compared with AMM. AMM/S also significantly inhibited increased capillary density and expression of angiogenic factors in the ischaemic hindlimb. Our study demonstrated that AMM/S provides a significant therapeutic effect in ischaemic hindlimbs by enhancing angiogenesis. [ABSTRACT FROM AUTHOR]

Oncolytic adenoviruses have emerged as a promising therapeutic approach for cancer therapy. However, systemic delivery of the viruses to metastatic tumors remains a major challenge. Mesenchymal stem cells (MSCs) possess tumor tropism property and can be used as cellular vehicles for delivering oncolytic adenoviruses to tumor sites. Since telomerase activity is found in ~90% of human carcinomas, but undetected in normal adult cells, the human telomerase reverse transcriptase gene (TERT) promoter can be exploited for regulating the replication of oncolytic adenoviruses. Here, we evaluated the antitumor effects of syngeneic murine MSCs loaded with the luciferase-expressing, telomerase-dependent oncolytic adenovirus Ad.GS2 (MSC-Ad.GS2) and Ad.GS2 alone on metastatic MBT-2 bladder tumors. MSCs supported a low degree of Ad.GS2 replication, which could be augmented by coculture with MBT-2 cells or tumor-conditioned medium (TCM), suggesting that viral replication is increased when MSC-Ad.GS2 migrates to tumor sites. MBT-2 cells and TCM enhanced viral replication in Ad.GS2-infected MSCs. SDF-1 is a stem cell homing factor. Our results suggest that the SDF-1/STAT3/TERT signaling axis in MSCs in response to the tumor microenvironment may contribute to the enhanced replication of Ad.GS2 carried by MSCs. Notably, we demonstrate the potent therapeutic efficacy of systemically delivered MSC-Ad.GS2 in pleural disseminated tumor and experimental metastasis models using intrapleural and tail vein injection of MBT-2 cells, respectively. Treatment with MSC-Ad.GS2 significantly reduced tumor growth and prolonged the survival of mice bearing metastatic bladder tumors. Since telomerase is expressed in a broad spectrum of cancers, this therapeutic strategy may be broadly applicable., (© The Author(s) 2024. Published by Oxford University Press.)

SDF-1/CXCL12 is a unique chemotactic factor with multiple functions on various types of precursor cells, all carrying the cognate receptor CXCR4. Whereas individual biological functions of SDF-1/CXCL12 have been well documented, practical applications in medicine are insufficiently studied. This is explained by the complex multifunctional biology of SDF-1 with systemic and local effects, critical dependence of SDF-1 activity on aminoterminal proteolytic processing and limited knowledge of applicable modulators of its activity. We here present new insights into modulation of SDF-1 activity in vitro and in vivo by a macromolecular compound, chlorite-oxidized oxyamylose (COAM). COAM prevented the proteolytic inactivation of SDF-1 by two inflammation-associated proteases: matrix metalloproteinase-9/MMP-9 and dipeptidylpeptidase IV/DPPIV/CD26. The inhibition of proteolytic inactivation was functionally measured by receptor-mediated effects, including intracellular calcium mobilization, ERK1/2 phosphorylation, receptor internalization and chemotaxis of CXCR4-positive cells. Protection of SDF-1/CXCL12 against proteolysis was dependent on electrostatic COAM-SDF-1 interactions. By in vivo experiments in mice, we showed that the combination of COAM with SDF-1 delivered through physiological fibrin hydrogel had beneficial effect for the healing of skin wounds. Collectively, we show that COAM protects SDF-1 from proteolytic inactivation, maintaining SDF-1 biological activities. Thus, protection from proteolysis by COAM represents a therapeutic strategy to prolong SDF-1 bioavailability for wound healing applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Pereira, EzEldeen, Ugarte-Berzal, Vandooren, Martens, Gouwy, Ganseman, Van Damme, Matthys, Vranckx, Proost and Opdenakker.)

Stromal cell-derived factor 1 (SDF-1, also known as CXCL12) and its receptor CXCR4 have shown to play a role in the homing and engraftment of hematopoietic stem and progenitor cells. SDF-1 is highly expressed in platelets and involved in thrombosis formation. However, the exact roles of platelet-derived SDF-1 and CXCR4 in platelet activation and mitochondrial function have not been revealed yet. Deletion of Sdf-1 and Cxcr4 specifically in platelets decreased agonist-induced platelet aggregation and dramatically impaired thrombin-induced glucose uptake. In SDF-1-deficient and CXCR4-deficient platelets, intracellular ATP secretions were reduced when activated by the addition of thrombin. SDF-1 deficiency in platelets can impair the routine respiration during resting state and maximal capacity of the electron transfer system (ETS) during activated state. Mitochondrial respiration measurements in permeabilized platelets indicated an impaired function of the oxidative phosphorylation system in -SDF-1 or CXCR4-deficient platelets. These results suggested a novel role of the SDF-1/CXCR4 axis in modulating platelet energy metabolism and activation by regulating mitochondrial respiration, glucose uptake, and ATP production. [ABSTRACT FROM AUTHOR]

Background: Despite the importance of immune response and environmental stress on head and neck cancer (HNC) outcomes, no current pre‐clinical stress model includes a humanized immune system. Methods: We investigated the effects of chronic stress induced by social isolation on tumor growth and human immune response in subcutaneous HNC tumors grown in NSG‐SGM3 mice engrafted with a human immune system. Results: Tumor growth (p < 0.0001) and lung metastases (p = 0.035) were increased in socially isolated versus control animals. Chronic stress increased intra‐tumoral CD4+ T‐cell infiltrate (p = 0.005), plasma SDF‐1 (p < 0.0001) expression, and led to tumor cell dedifferentiation toward a cancer stem cell phenotype (CD44+/ALDHhigh, p = 0.025). Conclusions: Chronic stress induced immunophenotypic changes, increased tumor growth, and metastasis in HNC in a murine model with a humanized immune system. This model system may provide further insight into the immunologic and oncologic impact of chronic stress on patients with HNC. [ABSTRACT FROM AUTHOR]