CXCL10 Research Articles

Modulating Th1/Th2 drift in asthma-related immune inflammation by enhancing bone mesenchymal stem cell homing through targeted inhibition of the Notch1/Jagged1 signaling pathway

Asthma, a disease intricately linked to immune inflammation, is significantly influenced by the immune regulatory effect of bone mesenchymal stem cells (BMSCs). This study aims to investigate changes in the homing of BMSCs in bronchial asthma, focusing on the Notch homolog (Notch)1/Jagged1 signaling pathway’s role in regulating T helper 1(Th1)/T helper 2(Th2) drift. Additionally, we further explore the effects and mechanisms of homologous BMSCs implantation in asthma-related immune inflammation. Following intervention with BMSCs, a significant improvement in the pathology of rats with asthma was observed. Simultaneously, a reduction in the expression of inflammatory cells and inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin(IL)-4, and IL-13 was observed in bronchoalveolar lavage fluid (BALF). Furthermore, there was an increase in the expression of Th1 cytokine Interferon-γ（IFN-γ）and the transcription factor T-box expressed in T cell (T-bet), while the expression of Th2 cytokine IL-13 and transcription factor GATA binding protein (GATA)-3 decreased in lung tissue. This indicates that the Th1/Th2 drift leans towards Th1, which a crucial in ameliorating asthma inflammation. Importantly, inhibition of the Notch1 signaling pathway led to an increased expression of the Stromal cell-derived factor-1(SDF-1)/C-X-C motif chemokine receptor (CXCR)4 chemokine axis. Consequently, the homing ability of bone marrow mesenchymal stem cells to asthma-affected lung tissue was significantly enhanced. BMSCs demonstrated heightened efficacy in regulating the cytokine/chemokine network and Th1/Th2 balance, thereby restoring a stable state during the immune response process in asthma. In conclusion, inhibiting the Notch signaling pathway enhances the expression of the SDF-1 and CXCR4 chemokine axis, facilitating the migration of allogeneic BMSCs to injured lung tissues. This, in turn, promotes immune regulation and improves the Th1/Th2 imbalance, thereby enhancing the therapeutic effect on asthmatic airway inflammation.

Precise Engineering of Growth Factor Presentation Using Extracellular Microenvironment-Mimicking Microfluidic Microparticles.

One of the main challenges in tissue engineering is finding a way to deliver specific growth factors (GFs) with precise spatiotemporal control over their presentation. Here, we report a novel strategy for generating microscale carriers with enhanced affinity for high content loading suitable for the sustained and localized delivery of GFs. Our developed microparticles can be injected locally and sustainably release encapsulated growth factors for up to 28 days. Fine-tuning of particles' size, affinity, microstructures, and release kinetics is achieved using a microfluidic system along with bioconjugation techniques. We also describe an innovative 3D micromixer platform to control the formation of core-shell particles based on superaffinity using a polymer-peptide conjugate for further tuning of release kinetics and delayed degradation. Chitosan shells block the burst release of encapsulated GFs and enable their sustained delivery for up to 10 days. The matched release profiles and degradation provide the local tissues with biomimetic, developmental-biologic-compatible signals to maximize regenerative effects. The versatility of this approach is verified using three different therapeutic proteins, including human bone morphogenetic protein-2 (rhBMP-2), vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1α). As in vivo morphogenesis is typically driven by the combined action of several growth factors, the proposed technique can be developed to generate a library of GF-loaded particles with designated release profiles.

Effects of electroacupuncture on repairing neurological damage following ischemic stroke based on miR-381-mediated SDF-1/CXCR4 signaling pathway.

To investigate the effects of electroacupuncture (EA) on the miR-381, leucine-rich repeat C4 protein (LRRC4), and downstream stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) signaling pathway in rat model of ischemic stroke, and to explore the mechanism by which EA improves neurological damage following ischemic stroke. Among 50 SPF male SD rats, 10 rats were randomly selected into a sham surgery group, and the remaining rats were used to establish the middle cerebral artery occlusion (MCAO) model. The 30 successfully modeled rats were randomly divided into a model group, an EA group, and an agonist group, with 10 rats in each group. The rats in the EA group received EA at "Baihui" (GV 20) and "Dazhui" (GV 14), with disperse-dense wave, a frequency of 2 Hz/10 Hz, and a current intensity of 1 mA, 30 min per session, once daily for a total of 14 days. The rats in the agonist group received miR-381 agonist injections into the lateral ventricle, with 10 μL per injection, every 7 days for a total of 2 injections. After intervention, ZeaLonga neurobehavioral deficit score was observed in each group. HE staining was performed to observe the morphological changes in the ischemic brain tissue of rats in each group. ELISA was used to measure the levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and nerve growth factor (NGF) in serum. Western blot was employed to detect the protein expression of LRRC4, SDF-1, CXCR4, and extracellular regulated protein kinase 1 (ERK1) in the ischemic brain tissue. Real-time PCR was utilized to assess the expression of miR-381 and LRRC4, SDF-1, CXCR4, ERK1 mRNA in the ischemic brain tissue. After intervention, the brain tissue showed disordered cell arrangement, reduced quantity, and significant interstitial edema, with numerous vacuoles in the model group. The pathological changes mentioned above were alleviated in the brain tissue of rats in the EA group and the agonist group. Compared with the sham surgery group, the rats in the model group exhibited increased ZeaLonga neurobehavioral deficit scores, elevated levels of serum TNF-α and IL-6 (P<0.01), and decreased serum NGF level (P<0.01)；the protein expression of SDF-1, CXCR4 and ERK1 in ischemic brain tissue was reduced (P<0.01), while LRRC4 protein expression was increased (P<0.01)；the expression of miR-381, as well as SDF-1, CXCR4 and ERK1 mRNA in ischemic brain tissue was decreased (P<0.01), while LRRC4 mRNA expression was increased (P<0.01). Compared with the model group, the rats in the EA group and the agonist group showed decreased ZeaLonga neurobehavioral deficit scores and reduced levels of serum TNF-α and IL-6 (P<0.05, P<0.01), and increased serum NGF levels (P<0.05, P<0.01); the protein expression of SDF-1, CXCR4 and ERK1 in ischemic brain tissue was increased (P<0.01), while LRRC4 protein expression was decreased (P<0.01)；the expression of miR-381, as well as SDF-1, CXCR4 and ERK1 mRNA in ischemic brain tissue was increased (P<0.05, P<0.01), while LRRC4 mRNA expression was decreased (P<0.01). EA at "Baihui" (GV 20) and "Dazhui" (GV 14) may promote the repair of neurological damage following ischemic stroke by up-regulating miR-381 to selectively inhibit LRRC4 expression, thereby activating the SDF-1/CXCR4 signaling pathway.

Unraveling the impact of cancer-associated fibroblasts on hypovascular pancreatic neuroendocrine tumors

BackgroundPancreatic neuroendocrine tumors (PNETs) with low microvessel density and fibrosis often exhibit clinical aggressiveness. Given the contribution of cancer-associated fibroblasts (CAFs) to the hypovascular fibrotic stroma in pancreatic ductal adenocarcinoma, investigating whether CAFs play a similar role in PNETs becomes imperative. In this study, we investigated the involvement of CAFs in PNETs and their effects on clinical outcomes.MethodsWe examined 79 clinical PNET specimens to evaluate the number and spatial distribution of α-smooth muscle actin (SMA)–positive cells, which are indicative of CAFs. Then, the findings were correlated with clinical outcomes. In vitro and in vivo experiments were conducted to assess the effects of CAFs (isolated from clinical specimens) on PNET metastasis and growth. Additionally, the role of the stromal-cell-derived factor 1 (SDF1)–AGR2 axis in mediating communication between CAFs and PNET cells was investigated.ResultsαSMA-positive and platelet-derived growth factor-α–positive CAFs were detected in the hypovascular stroma of PNET specimens. A higher abundance of α-SMA-positive CAFs within the PNET stroma was significantly associated with a higher level of clinical aggressiveness. Notably, conditioned medium from PNET cells induced an inflammatory phenotype in isolated CAFs. These CAFs promoted PNET growth and metastasis. Mechanistically, PNET cells secreted interleukin-1, which induced the secretion of SDF1 from CAFs. This cascade subsequently elevated AGR2 expression in PNETs, thereby promoting tumor growth and metastasis. The downregulation of AGR2 in PNET cells effectively suppressed the CAF-mediated promotion of PNET growth and metastasis.ConclusionCAFs drive the growth and metastasis of aggressive PNETs. The CXCR4–SDF1 axis may be a target for antistromal therapy in the treatment of PNET. This study clarifies mechanisms underlying PNET aggressiveness and may guide future therapeutic interventions targeting the tumor microenvironment.

Correlations of SDF-1ɑ and XRCC1 gene polymorphisms with the risk of renal cancer development and bioinformatics studies of SDF-1α and XRCC1 and the prognosis of renal cancer

To study the relationships between stromal cell-derived factor-1 (SDF-1ɑ) and renal cell carcinoma (RCC) susceptibility and the presence of single nucleotide polymorphisms in the human X-ray cross-complementary repair gene (XRCC1). Compare SDF-1 based on RCC related data in the TCGA database α, The expression difference of XRCC1 between RCC tissue and normal tissue; Collect 166 newly diagnosed RCC cases and 166 healthy individuals who underwent physical examinations during the same period, and detect genotype using iMLDR method. The results The rs1801157 locus (C:T) of the SDF-1α gene was not significantly associated with the pathohistological type, the rs1799782 locus (G:A) of the XRCC1 gene was associated with the pathohistological type of RCC, and there were interactions between rs1799782 and smoking, alcohol consumption, pesticide exposure, hair dye, and urine holding. The rs1799782 locus of the XRCC1 gene may be a key factor in the pathogenesis and pathological development of RCC. High SDF-1ɑ expression is a protective factor for the overall survival of patients with RCC, and SDF-1ɑ and XRCC1 may be important for the treatment of RCC.

Effects of sitagliptin activation of the stromal cell-derived factor-1/CXC chemokine receptor 4 signaling pathway on the proliferation, apoptosis, inflammation, and osteogenic differentiation of human periodontal ligament stem cells induced by lipopolysaccharide.

This study aimed to investigate the effects of sitagliptin on the proliferation, apoptosis, inflammation, and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) in lipopolysaccharide (LPS)-induced inflammatory microenvironment and its molecular mechanism. hPDLSCs were cultured in vitro and treated with different concentrations of sitagliptin to detect cell viability and subsequently determine the experimental concentration of sitagliptin. An hPDLSCs inflammation model was established after 24 h of stimulation with 1 µg/mL LPS and divided into blank, control, low-concentration sitagliptin (0.5 µmol/L), medium-concentration sitagliptin (1 µmol/L), and high-concentration sitagliptin (2 µmol/L), high-concentrationsitagliptin+stromal cell derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) pathway inhibitor (AMD3100) (2 µmol/L+10 µg/mL) groups. A cell-counting kit-8 was used to detect the proliferation activity of hPDLSCs after 24, 48, and 72 h culture. The apoptosis of hPDLSCs cultured for 72 h was detected by flow cytometry. After inducing osteogenic differentiation for 21 days, alizarin red staining was used to detect the osteogenic differentiation ability of hPDLSCs. The alkaline phosphatase (ALP) activity in hPDLSCs was determined using a kit. The levels of inflammatory factors [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6] in the supernatant of hPDLSCs culture were detected by enzyme-linked immunosorbent assay. The mRNA expressions of osteogenic differentiation genes [Runt-associated transcription factor 2 (RUNX2), osteocalcin (OCN), osteopontin (OPN)], SDF-1 and CXCR4 in hPDLSCs were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Western blot analysis was used to determine SDF-1 and CXCR4 protein expression in hPDLSCs. Compared with the blank group, the proliferative activity, number of mineralized nodules, staining intensity, ALP activity, and RUNX2, OCN, OPN mRNA, SDF-1, and CXCR4 mRNA and protein expression levels of hPDLSCs in the control group significantly decreased. The apoptosis rate and levels of TNF-α, IL-1β, and IL-6 significantly increased (P<0.05). Compared with the control group, the proliferative activity, number of mineralized nodule, staining intensity, ALP activity, and RUNX2, OCN, OPN mRNA, SDF-1, and CXCR4 mRNA and protein expression levels of hPDLSCs in low-, medium-, and high-concentration sitagliptin groups increased. The apoptosis rate and levels of TNF-α, IL-1β, and IL-6 decreased (P<0.05). AMD3100 partially reversed the effect of high-concentration sitagliptin on LPS-induced hPDLSCs (P<0.05). Sitagliptin may promote the proliferation and osteogenic differentiation of hPDLSCs in LPS-induced inflammatory microenvironment by activating the SDF-1/CXCR4 signaling pathway. Furthermore, it inhibited the apoptosis and inflammatory response of hPDLSCs.

Transplantation of induced pluripotent stem cells-derived cardiomyocytes combined with modified Taohong Siwu decoction improved heart repair after myocardial infarction

ObjectiveThis study aimed to study whether modified Taohong Siwu decoction (MTHSWD) combined with human induced pluripotent stem cells-derived cardiomyocytes (iPS-CMs) transplantation can promote cardiac function in myocardial infarction (MI) nude mouse model and explore its possible mechanism. MethodsThe MI mouse model was established by the ligation of left anterior descending coronary artery. After 4 weeks of gavage of MTHSWD combined with iPS-CMs transplantation, the changes in heart function of mice were examined by echocardiography. The histological changes were observed by Masson's trichrome staining. The survival and differentiation of transplanted cells were detected by double immunofluorescence staining of human nuclear antigen (HNA) and cardiac troponin T (cTnT). The number of c-kit-positive cells in the infarct area were evaluated by immunofluorescent staining. The levels of stromal cell-derived factor 1 (SDF-1), stem cell factor (SCF), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor in infarcted myocardium tissues were detected by ELISA. ResultsMTHSWD combined with iPS-CMs transplantation can improve the heart function of MI mice, reduce the infarct size and collagen deposition in infarct area. By immunofluorescence double-label detection of HNA and cTnT, it was found that MTHSWD combined with iPS-CMs transplantation can improve the survival and maturation of iPS-CMs. In addition, MTHSWD combined with iPS-CMs transplantation can activate more endogenous c-kit positive cardiac mesenchymal cells, and significantly increase the content of SDF-1, SCF and VEGF in myocardial tissues. ConclusionsThe combination of MTHSWD with iPS-CMs transplantation promoted cardiac function of nude mice with MI by improving the survival and maturation of iPS-CMs in the infarct area, activating the endogenous c-kit positive cardiac mesenchymal cells, and increasing paracrine.

Stromal cell-derived factor 1 alpha (SDF-1alfa) and cartilage oligomeric matrix protein (COMP): Two potential signature biomarkers of radiological detectable hemophilic arthropathy.

Hemophilia is a rare constitutional bleeding disorder due to a deficiency in Factor VIII or Factor IX. Recurrent hemarthroses, one of the major complications of the disease, lead to hemophilic arthropathy, a disabling condition that requires early diagnosis. Traditionally, clinical examination and plain film radiography have been used to diagnose hemophilic arthropathy. Magnetic resonance imaging (MRI) and ultrasound can be more useful for diagnosing soft-tissue changes. However, but each of these methods has limitations and diagnosis of arthropathy can be delayed. The aim of this project was to assess plasmatic biomolecules indicative of osteo-cartilaginous damage in patients with hemophilia with or without known arthropathy, in order to improve the diagnosis of this major complication of the disease. In this monocentric retrospective study, 40 patients with hemophilia A or B, for whom a plasma sample was available, provided informed consent for further analyses (multiplex immunoassays and ELISA) and collection of relevant clinical information in their medical files. Correlations were sought for between biomarkers of interest and the severity of joint lesions assessed according to Pettersson's radiologic score. Two biomarkers were identified, respectively SDF-1α and COMP. Their plasmatic levels were significantly increased in patients with arthropathy compared to controls and patients without arthropathy. These values correlated significantly with the Pettersson score in patients under regular prophylaxis. Two plasma biomarkers have been identified that could help assess the presence and severity of hemophilic arthropathy.

Causal association of rheumatoid arthritis with frailty and the mediation role of inflammatory cytokines: A Mendelian randomization study

BackgroundPrevious observational studies have suggested the association between rheumatoid arthritis (RA) and frailty. However, it remains obscure whether this association is causal. This study aims to investigate the causal association of RA with frailty and the mediation effect of inflammatory cytokines using Mendelian randomization (MR) design. MethodsSummary-level data for RA (N = 58,284), frailty index (FI) (N = 175,226), Fried frailty score (FFS) (N = 386,565), and 41 inflammatory cytokines (N = 8,293) were obtained from recent genome-wide association studies. Univariable and multivariable MR analyses were conducted to investigate and verify the causal association of RA with frailty. The potential mediation effects of inflammatory cytokines were estimated using two-step MR. ResultsUnivariable inverse variance weighted MR analysis suggested that genetically determined RA was associated with increased FI (beta=0.021; 95 % CI: 0.012, 0.03; p = 2.2 × 10−6) and FFS (beta=0.011; 95 %CI: 0.007, 0.015; p = 8.811 × 10−8). The consistent results were observed in multivariable MR analysis after adjustment for asthma, smoking, BMI, physical activity, telomere length, and depression. Mediation analysis showed evidence of an indirect effect of RA on FI through monokine induced by interferon-gamma (MIG) with a mediated proportion of 9.8 % (95 %CI: 4.76 %, 19.05 %), on FFS via MIG and stromal cell-derived factor-1 alpha with a mediated proportion of 9.6 % (95 %CI: 0 %, 18.18 %) and 8.44 % (95 %CI: 0 %, 18.18 %), respectively. ConclusionThis study provided credible evidence that genetically predicted RA was associated with a higher risk of frailty. Additionally, inflammatory cytokines were involved in the mechanism of RA-induced frailty.

Stromal Cell-Derived Factor 1α Inhibits Chondrocyte Apoptosis and Promotes Autophagy Through the Akt Signaling Pathway

To investigate the effects of stromal cell-derived factor 1α (SDF-1α) on the apoptosis and autophagy of chondrocytes and the underlying mechanisms. Chondrocytes were isolated from the knee joints of neonatal mice. The chondrocytes were then stimulated with 0 (the control group), 50, 100, and 200 ng/mL of SDF-1α. CCK-8 assay was performed to determine the effects of SDF-1α stimulation for 24 h, 48 h, and 72 h on the viability of the chondrocytes. Wound healing assay was conducted to determine the effects of SDF-1α stimulation for 12 h and 24 h on chondrocyte migration. The changes in the expression of Akt signaling pathway proteins in chondrocytes were determined by Western blot assay. Chondrocytes were stimulated with 0 (the control group) and 200 ng/mL of SDF-1α. Flow cytometry was performed to determine the effect of SDF-1α on the apoptosis of chondrocytes. Transmission electron microscope was used to examine the effect of SDF-1α on chondrocyte autophagy. Immunofluorescence staining assays were performed to visualize the differences in p-Akt expression and distribution in chondrocytes treated with SDF-1α. Compared with the control group, findings for the experimental groups showed that SDF-1α at the concentrations of 50, 100, and 200 ng/mL did not decrease chondrocyte activity at any time point (P<0.01) and it consistently promoted chondrocyte migration at 24 h (P<0.05). Western blot results revealed that, in comparison to the control group, SDF-1α at concentrations of 50, 100, and 200 ng/mL significantly up-regulated the protein expression of p-Akt in chondrocytes, while no significant difference in Akt expression was observed. Flow cytometry demonstrated that SDF-1α could inhibit chondrocyte apoptosis (P<0.05) and transmission electron microscopic observation showed that SDF-1α promoted chondrocyte autophagy (P<0.05). Immunofluorescence staining showed that the expression of p-Akt in chondrocytes was concentrated in the perinuclear area of the cells and this expression was further enhanced in the perinuclear area of the chondrocytes after treatment with SDF-1α. SDF-1α inhibits chondrocyte apoptosis and promotes chondrocyte migration and autophagy through activating the Akt signaling pathway.

Production of angiogenesis mediators and the structure of the vascular wall in the heart in ischemic cardiomyopathy

Background. In the pathogenesis of ischemic cardiomyopathy (ICMP), angiopoiesis remains unexplored.The aim. To describe the vasculature of the heart and the imbalance of angiogenesis mediators in the coronary circulation in association with the number of endothelial progenitor cells (EPC) and desquamated endothelial cells (DEC) in the blood of patients with coronary heart disease (CHD), suffering and not suffering from ICMP.Methods. Fifty-two patients with CHD (30 patients with ICMP, 22 patients without ICMP), 15 healthy donors were examined. The content of EPC (CD14+CD34+VEGFR2+) in the blood from the cubital vein and DEC (CD45–CD146+) in the blood from the coronary sinus and the cubital vein was determined by flow cytometry. The concentrations of VEGF-A (vascular endothelial growth factor A), PDGF (platelet-derived growth factor), and SDF-1 (stromal cell-derived factor 1) in blood plasma were recorded using immunofluorescence assay; the angiopoietin-2, MMP-9 (matrix metallopeptidase 9) were recorded using enzyme immunoassay. In myocardial biopsies the specific area of vessels and the expression of αSMA (smooth muscle alpha-actin) were determined by morphometric and immunohistochemical methods.Results. In the peripheral blood of patients with CHD, regardless of the presence of ICMP, the DEC content exceeded the physiological level, and the VEGF-A, PDGF, angiopoietin-2, and MMP-9 corresponded to the norm. In CHD patients without cardiomyopathy, there was an excess of SDF-1 and EPC in the blood from the cubital vein, and in ICMP, their physiological significance was noted. In the coronary blood flow in patients with CHD without cardiomyopathy, an increase in the concentration of PDGF was found, which was not determined in patients with ICMP, who had an increased content of DEC, angiopoietin-2 and MMP-9. The specific area of the vessels in the patients of the two groups was comparable; the expression of αSMA in ICMP was 6.2 times lower than in patients with CHD without cardiomyopathy.Conclusion. The development of ICMP is accompanied by impaired maturation of vessels in the myocardium, associated with the absence of a compensatory reaction of activation of cellular and humoral factors of angiogenesis.

Intra-ovarian inflammatory states and their associations with embryo quality in normal-BMI PCOS patients undergoing IVF treatment

BackgroundPolycystic ovary syndrome (PCOS) is the main cause of anovulatory infertility in women of reproductive age, and low-grade chronic inflammation plays a key role in the occurrence and development of PCOS. However, obesity, as a likely confounding factor, can affect the inflammatory state of PCOS patients.ObjectiveThe aim of this study was to comprehensively investigate intra-ovarian inflammatory states and their impact on embryo quality in PCOS patients with a normal BMI undergoing IVF treatment.MethodsDIA-mass spectrometry-based proteomics and bioinformatic analysis were combined to comprehensively profile the protein expression of granulosa cells (GCs) from 5 normal-BMI PCOS patients and 5 controls. Thirty-four cytokines were further systematically detected in follicular fluid (FF) from 32 age- and BMI-matched normal-BMI patients using Luminex liquid chip suspension technology. Next, the differentially expressed cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA) in 24 newly recruited subjects, and the relationship between these cytokines and embryo quality in PCOS patients was analysed. Finally, these cytokine levels were compared and evaluated in PCOS patients with different androgen levels.ResultsProteomic analysis showed that the suppression of substance metabolism and steroid biosynthesis, more interestingly, resulted in an enhanced immune and inflammatory response in the GCs of normal-BMI PCOS patients and prompted the involvement of cytokines in this process. Luminex analysis further showed that FF macrophage inflammatory protein-1 beta (MIP-1β) and stromal cell-derived factor-1 alpha (SDF-1α) levels were significantly increased in normal-BMI PCOS patients compared to controls (P = 0.005; P = 0.035, respectively), and the ELISA results were consistent with these findings. Besides, FF MIP-1β showed an inverse correlation with the number of D3 good-quality embryos and the good-quality blastocyst rate in patients with PCOS (P = 0.006; P = 0.003, respectively), which remained significant after correction for multiple comparisons. Moreover, SDF-1α levels had no relationship with embryo development in PCOS patients. Additionally, SDF-1α levels were significantly lower in PCOS patients with high androgen levels than in controls (P = 0.031).ConclusionsLocal ovarian inflammation was present in normal-BMI PCOS patients, affecting follicular development, and FF MIP-1β may be a potential biomarker associated with embryo quality in normal-BMI PCOS patients.Graphical abstract

OPTIMAL CONCENTRATION OF MESENCHYMAL STEM CELLS FOR FRACTURE HEALING IN A RAT MODEL WITH LONG BONE FRACTURE

There is still no consensus on which concentration of mesenchymal stem cells (MSCs) to use for promoting fracture healing in a rat model of long bone fracture.To assess the optimal concentration of MSCs for promoting fracture healing in a rat model.Wistar rats were divided into four groups according to MSC concentrations: Normal saline (C), 2.5 × 106 (L), 5.0 × 106 (M), and 10.0 × 106 (H) groups. The MSCs were injected directly into the fracture site. The rats were sacrificed at 2 and 6 자 post-fracture. New bone formation [bone volume (BV) and percentage BV (PBV)] was evaluated using micro-computed tomography (CT). Histological analysis was performed to evaluate fracture healing score. The protein expression of factors related to MSC migration [stromal cell-derived factor 1 (SDF-1), transforming growth factor-beta 1 (TGF-β1)] and angiogenesis [vascular endothelial growth factor (VEGF)] was evaluated using western blot analysis. The expression of cytokines associated with osteogenesis [bone morphogenetic protein-2 (BMP-2), TGF-β1 and VEGF] was evaluated using real-time polymerase chain reaction.Micro-CT showed that BV and PBV was significantly increased in groups M and H compared to that in group C at 6 wk post-fracture (P = 0.040, P = 0.009; P = 0.004, P = 0.001, respectively). Significantly more cartilaginous tissue and immature bone were formed in groups M and H than in group C at 2 and 6 wk post-fracture (P = 0.018, P = 0.010; P = 0.032, P = 0.050, respectively). At 2 wk post fracture, SDF-1, TGF-β1 and VEGF expression were significantly higher in groups M and H than in group L (P = 0.031, P = 0.014; P &lt; 0.001, P &lt; 0.001; P = 0.025, P &lt; 0.001, respectively). BMP-2 and VEGF expression were significantly higher in groups M and H than in group C at 6 wk postfracture (P = 0.037, P = 0.038; P = 0.021, P = 0.010). Compared to group L, TGF-β1 expression was significantly higher in groups H (P = 0.016). There were no significant differences in expression levels of chemokines related to MSC migration, angiogenesis and cytokines associated with osteogenesis between M and H groups at 2 and 6 wk post-fracture.The administration of at least 5.0 × 106 MSCs was optimal to promote fracture healing in a rat model of long bone fractures.

Correlations of Serum Retinol-Binding Protein and Stromal Cell-Derived Factor-1 with Renal Function in Patients with Diabetic Kidney Disease.

The aim is to investigate the correlations of serum retinol-binding protein (RBP) and stromal cell-derived factor-1 (SDF-1) with renal function in patients with diabetic kidney disease (DKD). A total of 438 patients with type 2 diabetes mellitus (T2DM) treated from October 2017 to October 2020 were enrolled in this prospective study and divided into simple T2DM and DKD groups. According to urinary albumin-to-creatinine ratio (UACR), DKD patients were divided into moderate, severe, and nephrotic groups. They were assigned to one of the following categories of estimated glomerular filtration rate (eGFR): G1, G2, G3a, G3b, G4, and G5 stages. The correlations of RBP and SDF-1 with renal function were analyzed. The DKD group had a longer T2DM course and higher RBP, uric acid (UA), blood urea nitrogen (BUN), β2-microglobulin (β2-MG), serum creatinine (Scr) levels and UACR, and lower SDF-1 level and eGFR than those of simple T2DM group (p < 0.05). The areas under the receiver operating characteristic curves of RBP and SDF-1 for identifying DKD were 0.903 and 0.868, and the optimal cutoff values were 70.71 mg/L and 5.69 ng/mL, respectively. With increasing urinary albumin and clinical stage, RBP, UA, BUN, β2-MG and Scr levels and UACR significantly rose, while SDF-1 level and eGFR declined (p < 0.05). In patients with DKD, RBP was correlated positively with UACR, UA, BUN, β2-MG, and Scr (r = 0.764/0.787/0.693/0.577/0.801, p < 0.0001), and negatively with eGFR (r = -0.782, p < 0.0001). SDF-1 was correlated negatively with UACR, UA, BUN, β2-MG and Scr (r = -0.744/-0.794/-0.666/-0.605/-0.820, p < 0.0001), and positively with eGFR (r = 0.767, p < 0.0001). The multiple linear regression equation was RBP = 29.852 + 0.007 x UACR + 0.101 x UA + 0.497 x BUN + 0.034 x Scr-0.083 x eGFR (p < 0.001). RBP and SDF-1 can identify DKD in patients with T2DM, and the degree of renal function damage is correlated positively with RBP and negatively with SDF-1. Elevated levels of UA, BUN, Scr and UACR as well as reduced eGFR are risk factors for evaluating RBP.

Value of four-dimensional computed tomography angiography combined with stromal cell-derived factor-1 for differentiating ruptured intracranial aneurysms and assessing risk of ruptures

Abstract Background: To analyze the value of four-dimensional computed tomography angiography (4D-CTA) combined with stromal cell-derived factor-1 (SDF-1) for differentiating ruptured intracranial aneurysms and assessing the risk of ruptures. Methods: Fifty patients with unruptured intracranial aneurysms and 50 patients with ruptured ones were included in non-rupture group 1 and rupture group 1, respectively. All patients underwent 4D-CTA and 3D-CTA, and the serum SDF-1 level was detected. Non-rupture group 1 was followed up for 12 months. On this basis, the patients with ruptured aneurysms were included in rupture group 2 and those without ruptured aneurysms were assigned to non-rupture group 2. Results: The AUC values of Wn, AR, L, SR, SDF-1 and their combination for the diagnosis of ruptured intracranial aneurysms were all &gt;0.70, especially their combination. Wn, AR, L, and SR were higher in rupture group 2 than those in non-rupture group 2 (P&lt;0.05). The level of SDF-1 in rupture group 2 [(142.48±11.23) μg/L] was higher than that in non-rupture group 2 [(128.03±10.28) μg/L] (P&lt;0.05). Wn, AR, L, SR, and SDF-1 and their combination all had the AUC values of &gt;0.70 for the prediction of ruptured intracranial aneurysms, especially their combination. The CT values of the internal carotid artery and middle cerebral artery and the CT value and noise of brain parenchyma in 4D-CTA were higher than those in 3D-CTA (P&lt;0.05). Conclusions: 4D-CTA combined with SDF-1 can effectively differentiate ruptured intracranial aneurysms and predict the risk of ruptures.

Silencing of transient receptor potential canonical channel 4 inhibits endothelial progenitor cell angiogenesis by suppressing VEGF and SDF-1.

Endothelial progenitor cells (EPCs) play a crucial role in acquired angiogenesis and endothelial injury repair. Transient receptor potential canonical channel 4 (TRPC4), a key component of store-operated calcium channels, is essential for EPC function. While the role of TRPCs has been clarified in vascular diseases, the relationship between TRPC4 and EPC function, along with the underlying molecular mechanisms, remains unclear and requires further elucidation. EPCs were isolated from canine bone marrow and identified by morphology and flow cytometry. TRPC4 was transfected into EPCs using lentivirus or negative control, and its expression was assessed using real-time polymerase chain reaction (RT-PCR). Proliferation, migration, and tube formation were evaluated using Cell Counting Kit-8 (CCK-8), Transwell, and Matrigel assays, respectively. Levels of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) were measured using enzyme-linked immunosorbent assay (ELISA). TRPC4 mRNA expression was significantly reduced in TRPC4-short hairpin RNA (shRNA) transfected EPCs compared to the normal control (NC)-shRNA groups. Migration and tube formation were significantly decreased after TRPC4 silencing, while proliferation showed no difference. Additionally, levels of SDF-1 and VEGF in EPCs were markedly reduced following TRPC4 silencing. TRPC4 plays a crucial role in regulating angiogenesis in EPCs. Silencing of TRPC4 can lead to decreased angiogenesis by inhibiting VEGF and SDF-1 expression, suggesting that TRPC4 knockdown might be a novel therapeutic strategy for vascular diseases.

Effect of SDF-1 and CXCR4 gene variants on the development of diabetic kidney disease.

Diabetic kidney disease (DKD) is the gradual loss of renal function occurring in patients with diabetes. Stromal cell-derived factor-1 (SDF-1, encoded by SDF-1 gene) is a chemokine that binds to its receptor, CXCR4, to mediate many aspects of renal biology. To test the potential impact of SDF-1/CXCR4 gene variations on the risk for DKD, single-nucleotide polymorphisms (SNPs) of SDF-1/CXCR4 genes were genotyped in 388 DKD patients and 335 DKD-free diabetic controls. Among 6 SNPs examined, we demonstrated that rs1801157 of SDF-1 gene was associated with an increased risk for DKD (GA vs GG, AOR=2.252, p=0.035; GA+AA vs GG, AOR=2.156, p=0.036). Further stratification revealed that the correlation of rs1801157 with DKD was particularly detected in diabetic patients with early CKD but not in those with severe renal impairment. Instead, another SNP of SDF-1 gene, rs266085, was found in association with the advanced form of DKD (TC vs TT, AOR=2.106, p=0.027; TC+CC vs TT, AOR=2.130, p=0.019), indicating differential impacts of SDF-1 gene polymorphisms on the progressive loss of renal function in diabetic patients. Moreover, preliminary survey of public gene expression datasets showed that rs1801157 and rs266085 modulated SDF-1 expression in many human tissues, and SDF-1/CXCR4 levels were elevated in renal tissues of DKD patients. These data suggest that allele-specific expression of SDF-1 gene may influence DKD progression.

Mechanism of Linagliptin on Stromal Cell-Derived Factor 1 and Vascular Endothelial Growth Factor Protein after Molar Pulp Revascularization in Rats

Mechanism of Linagliptin on Stromal Cell-Derived Factor 1 and Vascular Endothelial Growth Factor Protein after Molar Pulp Revascularization in Rats

Protection of stromal cell-derived factor-1 SDF-1/CXCL12 against proteases yields improved skin wound healing.

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.

CXCR4-Expressing Mesenchymal Stem Cells Derived Nanovesicles for Rheumatoid Arthritis Treatment.

Cell membrane camouflage technology, which a demonstrated value for the bionic replication of natural cell membrane properties, is an active area of ongoing research readily applicable to nanomedicine. How to realize immune evasion, slow down the clearance from the body, and improve targeting are still worth great efforts for this technology. Herein, novel cell membrane-mimicked nanovesicles from genetically engineered mesenchymal stem cells (MSCs) are presented as a potential anti-inflammatory platform for rheumatoid arthritis (RA) management. Utilizing the synthetic biology approach, the biomimetic nanoparticles are constructed by fusing C-X-C motif chemokine receptor4 (CXCR4)-anchored MSC membranes onto drug-loaded polymeric cores (MCPNs), which make them ideal decoys of stromal cell-derived factor-1 (SDF-1)-targeted arthritis. These resulting nanocomplexes function to escape from the immune system and enhance accumulation in the established inflamed joints via the CXCR4/SDF-1 chemotactic signal axis, thereby achieving an affinity to activated macrophages and synovial fibroblasts. It is further demonstrated that the MCPNs can significantly suppress synovial inflammation and relieve pathological conditions with favorable safety properties in collagen-induced arthritis mice. These findings indicate the clinical value of MCPNs as biomimetic nanodrugs for RA therapy and related diseases.