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Blood and lymphatic vessels in the body are central to molecular and cellular transport, tissue repair, and pathophysiology. Several approaches have been employed for engineering microfabricated blood and lymphatic vessels in vitro, yet traditionally these approaches require specialized equipment, facilities, and research training beyond the capabilities of many biomedical laboratories. Here we present xurography as an inexpensive, accessible, and versatile rapid prototyping technique for engineering cylindrical and lumenized microvessels. Using a benchtop xurographer, or a cutting plotter, we fabricated modular multi-layer poly(dimethylsiloxane) (PDMS)-based microphysiological systems (MPS) that house endothelial-lined microvessels approximately 260 μm in diameter embedded within a user-defined 3-D extracellular matrix (ECM). We validated the vascularized MPS (or vessel-on-a-chip) by quantifying changes in blood vessel permeability due to the pro-angiogenic chemokine CXCL12. Moreover, we demonstrated the reconfigurable versatility of this approach by engineering a total of four distinct vessel-ECM arrangements, which were obtained by only minor adjustments to a few steps of the fabrication process. Several of these arrangements, such as ones that incorporate close-ended vessel structures and spatially distinct ECM compartments along the same microvessel, have not been widely achieved with other microfabrication strategies. Therefore, we anticipate that our low-cost and easy-to-implement fabrication approach will facilitate broader adoption of MPS with customizable vascular architectures and ECM components while reducing the turnaround time required for iterative designs. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is characterized by low systemic bone mineral content and destruction of bone microarchitecture. Promoting bone regeneration and reversing its loss by infusion of exogenous bone marrow mesenchymal stem cells (BMSCs) is a potentially effective treatment for osteoporosis. However, their limited migration to target organs reduces the therapeutic effect of the cells. Stromal cell-derived factor 1 (SDF1) is a chemokine that induces targeted cell migration through the SDF1/CXCR4 (C-X-C chemokine receptor 4) axis and can induce migration of exogenous mesenchymal stem cells to sites of high SDF1 concentration. There are no studies on BMSCs overexpressing SDF1 (SDF1-BMSCs) in osteoporotic mice in vivo. We aimed to investigate if the increased SDF1 concentration facilitated cell migration to the bone. Methods: We used lentivirus to construct BMSCs overexpressing SDF1 or knocking down CXCR4. We verified the proliferation ability of the cells in vitro using Cell Counting Kit-8 (CCK8) and 5-Bromodeoxyuridinc (BrdU), the migration ability of the cells using Transwell, and the osteogenic and lipogenic ability of the cells using osteogenic and lipogenic induction solutions. In in vivo experiments, we induced osteoporosis in 72 female mice by ovariectomy and injected different groups of cells via the tail vein. Femoral tissue samples were collected for a fixed time, and the osteogenic and homing abilities of the cells were verified by MicroCT and tissue section staining. Results: We successfully demonstrated that high expression of SDF1 promoted cell proliferation and migration in vitro, without affecting their cell differentiation ability. In an ovariectomized mouse model, SDF1-BMSCs were more likely to be home to the femur than the BMSCs, had a better pro-osteogenic ability, and had higher expression of Wnt-1. Blocking the SDF1/CXCR4 axis reduced the homing of exogenous mesenchymal stem cells (MSCs) to the femur and their osteogenic capacity. Conclusions: SDF1-BMSCs can further promote bone formation by increasing the number of cells homing to the femur in osteoporotic mice. Our study shows that stem cells can promote their proliferation and home to the femur via the SDF1/CXCR4 axis and further help bone formation via Wnt-1 signaling. [ABSTRACT FROM AUTHOR]

Introduction: Acute lymphoblastic leukemia is characterized by a disturbed maturation of hematopoietic stem cells (HSCs) resulting in development of a malignant clone. Despite relatively positive outcome, there are still instances of disease relapse occurring due to ineffective disease eradication or primary leukemic clone alterations. Unclear significance of stem cells in the course of ALL led us to investigate and establish crucial changes in two stem cell populations - very small embryonic-like stem cells (VSELs) and HSCs during the induction phase of treatment. Methods: In a retrospective study selected stem cells in peripheral blood and bone marrow of 60 pediatric ALL subjects and 48 healthy controls were subjected to flow cytometric analysis at 4 different time points. Results: Both VSELs and HSCs were elevated at the moment of ALL diagnosis compared to healthy controls, but profoundly decline until day 15. Further observations revealed an increase in HSCs with a concomitant depletion of VSELs until week 12. ALL patients with high HSCs showed positive correlation with bone marrow blasts at diagnosis. Patients with lower VSELs or HSCs at diagnosis had slightly improved response to applied therapy. We observed higher initial bone marrow lymphoblast values in patients with lower VSELs or higher HSCs in the high-risk group. The significance of VSELs in predicting treatment outcome can be illustrated by lower day 15 MRD level of patients with lower VSELs at diagnosis. ȩ Discussion: We found HSCs and VSELs to be valid participants in pediatric ALL with possible contribution in the neoplastic process and prediction of initial treatment outcome. [ABSTRACT FROM AUTHOR]

This study aims to investigate the interplay between tumor-associated endothelial cells (TECs) and immune cells within the tumor microenvironment (TME) and its impact on tumor prognosis. We conducted single-cell RNA sequencing (scRNA-seq) of tumor, normal, and lymph node tissues obtained from intrahepatic cholangiocarcinoma (ICC) patients to reveal the role of TECs in tumor angiogenesis and their significant heterogeneity. Meanwhile, we identified genes highly expressed in TECs and constructed TEC signatures (TEC.Sig). Next, we calculated TEC scores of samples based on TEC.Sig. Patients with higher TEC scores exhibited a higher frequency of KRAS mutations, which was associated with increased infiltration of neutrophils and immature dendritic cells (iDCs), and decreased numbers of natural killer (NK), CD4 + T, and CD8 + T effector memory (Tem) cells, indicating an inflammation-dominated immunosuppressive phenotype. In contrast, BAP1 mutations and CXCL12 overexpression showed a contrasting trend. Spatial transcriptomics analysis and histological experiments further confirmed that TECs interacted with various tumor-killing immune cells through the CXCL12/CXCR4 axis. Multiple tumor immunotherapy datasets confirmed that the TEC.Sig could predict patient responses to immunotherapy. The TEC score is a promising and reliable biomarker for predicting genetic mutations and prognosis in ICC patients. Enhancing the regulation of the CXCL12/CXCR4 signaling pathway may represent a potential novel therapeutic target for ICC treatment. [ABSTRACT FROM AUTHOR]

Background: The release of extracellular vesicles (EVs) including exosomes from human mesenchymal stroma/stem-like cells (MSC) represents valuable cell-free carriers for the delivery of regenerative and medicinal compounds. Methods: EVs/exosomes were isolated by differential centrifugation from four individual MSC as controls and after treatment with a sub-lethal concentration of 10 mM taxol for 24 h, respectively. The isolated EVs/exosomes were characterized and quantified by nano-tracking-analysis and by Western blots. MicroRNAs (miRs) were isolated from the different EVs/exosome populations and expression levels were quantified by qPCR using 1246 miR templates. Cytotoxic effects of the different MSC-derived taxol-loaded EVs/exosomes were determined in five different GFP-transduced cancer cell lines and quantified by a fluoroscan assay with a GFP-detecting fluorimeter. The presence of stroma cell-derived factor 1 (SDF-1) in MSC-derived EVs/exosomes and its enhanced expression in the vesicles after taxol treatment of MSC was quantified by a specific ELISA. Results: EVs/exosomes isolated from four individual taxol-treated MSC displayed a larger size and higher yields as the control EVs/exosomes and were used as anti-tumor therapeutic vehicles. Application of each of the four MSC-derived taxol-loaded EVs/exosome populations revealed significant cytotoxic effects in cell lines of five different tumor entities (carcinomas of lung, breast, ovar, colon, astrocytoma) in a concentration-dependent manner. Expression analysis of 1246 miRs in these taxol-loaded EVs/exosomes as compared to the corresponding MSC-derived control EVs/exosomes unraveled a taxol-mediated up-regulation of 11 miRs with predominantly anti-tumorigenic properties. Moreover, various constitutively expressed protein levels were unanimously altered in the MSC cultures. Taxol treatment of the different MSC revealed an up-regulation of tetraspanins and a 2.2-fold to 5.4-fold increased expression of SDF-1 among others. Treatment of cancer cells with MSC-derived taxol-loaded EVs/exosomes in the presence of a neutralizing SDF-1 antibody significantly abolished the cytotoxic effects between 20.3% and 27%. Conclusions: These findings suggested a taxol-mediated increase of anti-cancer properties in MSC that enhance the tropism of derived EVs/exosomes to tumors, thereby specifically focusing the therapeutic effects of the delivered products. [ABSTRACT FROM AUTHOR]

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an anti‐aquaporin 4 (anti‐AQP4) autoantibodies‐mediated idiopathic inflammatory demyelinating disease of the central nervous system. While intravenous pulse methylprednisolone (IVMP) is the recommended initial treatment option for acute onset NMOSD, its therapeutic mechanism remains unclear. We hypothesized that IVMP would reduce the expression of pro‐inflammatory factors and increase the resolution of inflammation in patients with NMOSD. Methods: Mendelian randomization (MR) analysis was used to screen meaningful inflammatory and resolution factors for inclusion. Three MR methods with inverse variance weighting (IVW) were primarily used to identify positive results. Interleukin (IL)‐10, IL‐1β, IL‐6, C‐X‐C motif chemokine ligand 12 (CXCL12), and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) were screened from 41 inflammatory factors, and resolvin D1 (RvD1), maresin 1 (MaR1), and lipoxin A4 (LXA4) were screened from 6 resolution markers for inclusion. Subsequently, 12 patients with NMOSD were enrolled and treated with IVMP. Serum levels of the aforementioned inflammatory and resolution markers were measured by enzyme‐linked immunosorbent assay before and after IVMP treatment. Results: High levels of TRAIL, CXCL12, and IL‐1β were associated with an increased risk of NMOSD (TRAIL: odds ratio [OR], 1.582; 95% confidence interval [CI], 1.003–2.495; CXCL12: OR, 3.610; 95% CI, 1.011–12.889; IL‐1β: OR, 4.500; 95% CI, 1.129–17.927). High levels of RvD1, MaR1, and LXA4 were associated with a reduced risk of NMOSD (RvD1: OR, 0.725; 95% CI, 0.538–0.976; MaR1: OR, 0.985; 95% CI, 0.970–0.999; LXA4: OR, 0.849; 95% CI, 0.727–0.993). Among patients with NMOSD, serum levels of IL‐6, CXCL12, and TRAIL significantly decreased following IVMP treatment, compared with pretreatment levels, while levels of IL‐1β, LXA4, and MaR1 significantly increased after IVMP treatment (p < 0.05). A significant positive correlation was observed between CXCL12 levels and Expanded Disability Status Scale (EDSS) scores (r = 0.451, p < 0.05). Conclusion: Several systemic inflammatory regulators associated with the pathogenesis of NMOSD were identified. The protective roles of LXA4 and MaR1 may be indispensable components of glucocorticoid treatment. Therefore, the use of resolution markers may be a potential strategy for improving central nervous system injury in individuals with NMOSD. [ABSTRACT FROM AUTHOR]

Chronic stress is a common cause of hair loss, involving inflammatory responses and changes in cellular signaling pathways. This study explores the mechanism of action of the SDF-1/CXCR4 signaling axis in chronic stress-induced hair loss. The research indicates that SDF-1 promotes hair follicle growth through the PI3K/Akt and JAK/STAT signaling pathways. Transcriptome sequencing analysis was conducted to identify differentially expressed genes in the skin of normal and stressed mice, with key genes SDF-1/CXCR4 selected through machine learning and a protein-protein interaction network established. A chronic stress mouse model was created, with injections of SDF-1 and AMD3100 administered to observe hair growth, weight changes, and behavioral alterations and validate hair follicle activity. Skin SDF-1 concentrations were measured, differentially expressed genes were screened, and pathways were enriched. Activation of the PI3K/Akt and JAK/STAT signaling pathways was assessed, and siRNA technology was used in vitro to inhibit the expression of SDF-1 or CXCR4. SDF-1 promoted hair follicle activity, with the combined injection of SDF-1 and AMD3100 weakening this effect. The activation of the PI3K/Akt and JAK/STAT signaling pathways was observed in the SDF-1 injection group, confirmed by Western blot and immunofluorescence. Silencing SDF-1 through siRNA-mediated inhibition reduced cell proliferation and migration abilities. SDF-1 promotes hair growth in chronic stress mice by activating the PI3K/Akt and JAK/STAT pathways, an effect reversible by AMD3100. The SDF-1/CXCR4 axis may serve as a potential therapeutic target for stress-induced hair loss. [ABSTRACT FROM AUTHOR]

The ability to accurately measure drug‐target interaction is critical for the discovery of new therapeutics. Classical pharmacological bioassays such as radioligand or fluorescent ligand binding assays can define the affinity or Kd of a ligand for a receptor with the lower the Kd, the stronger the binding and the higher the affinity. However, in many drug discovery laboratories today, the target of interest if often artificially upregulated by means of transfection to modify the host cell's genetic makeup. This then potentially invalidates the assumptions of classical pharmacology affinity calculations as the receptor of interest is no longer at normal physiological densities. The CXCR4 receptor is expressed on many different cancer cell types and is associated with metastasis and poor prognosis. Therefore, the CXCR4 receptor is a desirable target for novel therapeutics. In this study, we explore the applicability of the newly developed fluorescently tagged CXCR4 antagonists, IS4‐FAM as an investigative tool to study CXCR4 affinity and competitive antagonism in native, non‐transfected cancer cells using confocal microscopy and flow cytometry. IS4‐FAM directly labels CXCR4 in several cell lines including high CXCR4 expressing SK‐MEL‐28 (malignant melanoma) and PC3 (metastatic prostate cancer) and lower CXCR4 expressing THP‐1 (acute monocytic leukemia) and was competitive with the established CXCR4 antagonist, AMD3100. This highlights the potential of IS4‐FAM as a pharmacological tool for drug discovery in native cells lines and tissues. [ABSTRACT FROM AUTHOR]

[Display omitted] Preventing breast cancer liver metastasis presents formidable challenges with multifaceted obstacles. In the case of acute and chronic liver injury, the disrupted liver microenvironment induced by activated hepatic stellate cells (aHSCs) would suppress immune surveillance and license the re-multiplication of disseminated tumor cells (DTCs). Herein, a cyclic peptide pPB modified nanovesicle with aHSCs targeting capability was constructed as CP-SB-siRNA to co-deliver hydrophobic SB431542 and nucleic acid drug CXCL12 siRNA. Due to the TGF-β signaling inhibition of SB431542, CP-SB-siRNA significantly suppressed the expression levels of genes coding the uppermost fibrosis-associated proteins including α-sma , Col-1 and Col-3 in aHSCs. On the other hand, the gene and protein expression level of metastasis-associated chemokine CXCL12 was significantly decreased. In addition, CP-SB-siRNA could regain the function of NK cells and attenuate the breast cancer proliferation through CXCL12-CXCR4 axis. On both breast cancer spontaneous metastasis with fibrosis mouse model and breast cancer via hematogenous metastasis with fibrosis mouse model, CP-SB-siRNA successfully reversed hepatic fibrosis by regressing aHSCs, and thereby restored the liver microenvironment, ultimately inhibiting breast cancer hepatic metastasis. This nanomaterial vector, featuring targeting and drug co-delivery functionalities, exhibited a great potential to restrain breast cancer hepatic metastasis based on the relationship among aHSCs, NK cells and DTCs. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) generally presents as an immunosuppressive microenvironment. The characteristics of cell‐to‐cell communication in the LUAD microenvironment has been unclear. In this study, the LUAD bulk RNA‐seq data and single‐cell RNA‐seq data were retrieved from public dataset. Differential expression genes (DEGs) between LUAD tumor and adjacent non‐tumor tissues were calculated by limma algorithm, and then detected by PPI, KEGG, and GO analysis. Cell–cell interactions were explored using the single‐cell RNA‐seq data. Finally, the first 15 CytoHubba genes were used to establish related pathways and these pathways were used to characterize the immune‐related ligands and their receptors in LUAD. Our analyses showed that monocytes or macrophages interact with tissue stem cells and NK cells via SPP1 signaling pathway and tissue stem cells interact with T and B cells via CXCL signaling pathway in different states. Hub genes of SPP1 participated in SPP1 signaling pathway, which was negatively correlated with CD4+ T cell and CD8+ T cell. The expression of SPP1 in LUAD tumor tissues was negatively correlated with the prognosis. While CXCL12 participated in CXCL signaling pathway, which was positively correlated with CD4+ T cell and CD8+ T cell. The role of CXCL12 in LUAD tumor tissues exhibits an opposite effect to that of SPP1. This study reveals that tumor‐associated monocytes or macrophages may affect tumor progression. Moreover, the SPP1 and CXCL12 may be the critic genes of cell‐to‐cell communication in LUAD, and targeting these pathways may provide a new molecular mechanism for the treatment of LUAD. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is a prevalent chronic disease marked by significant metabolic dysfunctions. Understanding its molecular mechanisms is vital for early diagnosis and treatment strategies. Methods: We used datasets GSE7014, GSE25724, and GSE156248 from the GEO database to build a diagnostic model for DM using Random Forest (RF) and LASSO regression models. GSE20966 served as a validation cohort. DM patients were classified into two subtypes for functional enrichment analysis. Expression levels of key diagnostic genes were validated using quantitative real‐time PCR (qRT‐PCR) on Peripheral Blood Mononuclear Cells (PBMCs) from DM patients and healthy controls, focusing on CXCL12 and PPP1R12B with GAPDH as the internal control. Results: After de‐batching the datasets, we identified 131 differentially expressed genes (DEGs) between DM and control groups, with 70 up‐regulated and 61 down‐regulated. Enrichment analysis revealed significant down‐regulation in the IL‐12 signaling pathway, JAK signaling post‐IL‐12 stimulation, and the ferroptosis pathway in DM. Five genes (CXCL12, MXRA5, UCHL1, PPP1R12B, and C7) were identified as having diagnostic value. The diagnostic model showed high accuracy in both the training and validation cohorts. The gene set also enabled the subclassification of DM patients into groups with distinct functional traits. qRT‐PCR results confirmed the bioinformatics findings, particularly the up‐regulation of CXCL12 and PPP1R12B in DM patients. Conclusion: Our study pinpointed seven energy metabolism‐related genes differentially expressed in DM and controls, with five holding diagnostic value. Our model accurately diagnosed DM and facilitated patient subclassification, offering new insights into DM pathogenesis. [ABSTRACT FROM AUTHOR]

Summary The lack of biomarkers for accurate diagnosis and prognosis is a major clinical challenge of primary immune thrombocytopaenia (ITP). Using an Olink proteomics platform with a 92 immune response‐related human protein panel, we analysed plasma samples from ITP patients (ITP, n = 40), patients with thrombocytopaenia secondary to other causes (Non‐ITP, n = 19) and healthy controls (NC, n = 18), of a discovery cohort as well as a validation cohort (ITP, n = 36; NC, n = 20). A total of 10 differentially expressed proteins (DEPs) were identified in the ITP group compared with the non‐ITP and NC groups of the discovery cohort. These include CXCL11, GZMH, ARG1, TGF‐β1, ANGPT1, CXCL12, CD40‐L, PDGF subunit B, IL4 and TNFSF14. Furthermore, least absolute shrinkage and selection operator regression analysis showed some of these DEPs, such as CXCL11, TGF‐β1, ARG1 and GZMH to be significant in differentiating between patients with ITP and healthy controls (validation area under the curve = 0.87). The analysis demonstrated that the ITP group has a specific proteomic profile relative to non‐ITP and NC groups. In summary, we report for the first time that Olink precision proteomics can specifically detect up‐regulated inflammatory proteins as potential diagnostic biomarkers for ITP. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between stromal cell-derived factor-1 (SDF-1), angiopoietin-like 4 (ANGPTL4), glucose-regulated protein 78 (GRP78) and postoperative macular edema (ME) in patients with type 2 diabetic cataract and their predictive efficacy analysis. Methods: 195 patients (195 eyes) with type 2 diabetic cataract who were admitted to our hospital from January 2020 to March 2023 were selected, all patients underwent phacoemulsification combined with foldable intraocular lens implantation, patients were divided into ME group (45 cases) and non-ME group (150 cases) according to whether ME occurred after operation. The levels of SDF-1, ANGPTL4 and GRP78 in aqueous humor were detected before operation, and clinical data were collected. The influencing factors of postoperative ME in patients with type 2 diabetic cataract were analyzed by multivariate Logistic regression analysis, the predictive value of preoperative aqueous humor SDF-1, ANGPTL4 and GRP78 levels in predicting postoperative ME in patients with type 2 diabetic cataract were analyzed by receiver operating characteristic (ROC) curve. Results: The levels of SDF-1, ANGPTL4 and GRP78 in aqueous humor before operation in ME group were higher than those in non-ME group (P<0.05). High glycated hemoglobin, high SDF-1, high ANGPTL4, and high GRP78 were risk factors for postoperative ME in patients with type 2 diabetic cataract (P<0.05). The area under the curve (AUC) of preoperative SDF-1, ANGPTL4 and GRP78 levels in aqueous humor to predict postoperative ME in patients with type 2 diabetic cataract was 0.809, 0.801 and 0.760 respectively, the area under the curve predicted by combined SDF-1, ANGPTL4 and GRP78 was 0.896, which was higher than that of single detection (P<0.05). Conclusion: The increase levels of SDF-1, ANGPTL4 and GRP78 in aqueous humor of patients with type 2 diabetic cataract before operation are relate to the occurrence of postoperative ME, the combination of SDF-1, ANGPTL4 and GRP78 has high application value in predicting the occurrence of ME. [ABSTRACT FROM AUTHOR]

Doublecortin-like kinase 1 (DCLK1) is a proposed driver of gastric cancer (GC) that phosphorylates serine and threonine residues. Here, we showed that the kinase activity of DCLK1 orchestrated cancer cell–intrinsic and–extrinsic processes that led to pro-invasive and pro-metastatic reprogramming of GC cells. Inhibition of the kinase activity of DCLK1 reduced the growth of subcutaneous xenograft tumors formed from MKN1 human gastric carcinoma cells in mice and decreased the abundance of the stromal markers α-Sma, vimentin, and collagen. Similar effects were seen in mice with xenograft tumors formed from MKN1 cells expressing a kinase-inactive DCLK1 mutant (MKN1D511N). MKN1D511N cells also had reduced in vitro migratory potential and stemness compared with control cells. Mice orthotopically grafted with MKN1 cells overexpressing DCLK1 (MKN1DCLK1) showed increased invasiveness and had a greater incidence of lung metastases compared with those grafted with control MKN1 cells. Mechanistically, we showed that the chemokine CXCL12 acted downstream of DCLK1 in cultured MKN1 cells and in mice subcutaneously implanted with gastric tumors formed by MKN1DCLK1 cells. Moreover, inhibition of the kinase activity of DCLK1 or the expression of DCLK1D511N reversed the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a broadly acting and potentially targetable promoter of GC. Editor's summary: The serine/threonine kinase DCLK1 is a putative cancer stem cell marker that is associated with the progression of gastric cancers. Afshar-Sterle et al. found that mutating the kinase domain of DCLK1 or inhibiting its kinase activity reduced tumor growth, abundance of markers of stromal remodeling, and induction of epithelial-to-mesenchymal transition (EMT). The tumor-intrinsic and -extrinsic effects of DCLK1 at least partially depended on increased amounts of CXCL12, which correlated with DCLK1 abundance and acted downstream of DCLK1. These results shed light on the mechanistic contribution of DCLK1 in shaping gastric cancer progression. —Amy E. Baek [ABSTRACT FROM AUTHOR]

Chemokine receptor CXCR4 is involved in diverse diseases. A comparative study was conducted on CXCR4 embedded in a POPC lipid bilayer binding with CXCL12 in full and truncated forms, hBD-3 in wildtype, analog, and mutant forms based on in total 63 µs all-atom MD simulations. The initial binding structures of CXCR4 with ligands were predicted using HADDOCK docking or random-seed method, then μs-long simulations were performed to refine the structures. CXCR4&ligand binding structures predicted agree with available literature data. Both kinds of ligands bind stably to the N-terminus, extracellular loop 2 (ECL2), and ECL3 regions of CXCR4; the C2-C3 (K32-R38) region and occasionally the head of hBD-3 bind stably with CXCR4. hBD-3 analogs with Cys11-Cys40 disulfide bond can activate CXCR4 based on the Helix3-Helix6 distance calculation, but not other analogs or mutant. The results provide insight into understanding the dynamics and activation mechanism of CXCR4 receptor binding with different ligands. The chemokine receptor CXCR4 is involved in cancers and diverse diseases, however, molecular details surrounding the binding of different ligands to this receptor remain incomplete. Here, the authors study the binding and interaction between CXCR4 with CXCL12 and hBD-3 in different forms, and find that both ligands can bind with CXCR4 at the same site, and analogs of hBD-3 with a Cys11-Cys40 disulfide bond can activate CXCR4. [ABSTRACT FROM AUTHOR]

This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α. [ABSTRACT FROM AUTHOR]

This document contains summaries of various research studies conducted in the field of veterinary medicine. The studies cover a wide range of topics, including the use of computed tomography in identifying surgical lesions in cats, injuries sustained by dogs in motor vehicle accidents, and the effects of mild hypothermia on fluid therapy in cats. The findings of these studies provide valuable insights into specific areas of veterinary emergency and critical care. The document also includes studies on topics such as the use of handheld ultrasound devices in dogs, the treatment of NSAID toxicosis in dogs, and the management of anemia in dogs using a rapid infuser device. These studies contribute to the understanding and improvement of veterinary medical practices. [Extracted from the article]

Atherosclerosis (As) is one of the major causes of high mortality and morbidity worldwide. Chemokines and their receptors are involved in the pathogenesis of As. CXC chemokine ligand 12 (CXCL12) is a member of the chemokine family, and macrophage migration inhibition factor (MIF) is a chemokine like functional chemokine, CXCL12 and MIF together play important roles in As through CXC chemokine receptor 4 (CXCR4). The CXCL12-CXCR4 bioaxis is an important chemokine/chemokine receptor axis that can regulate various biological behaviors such as cell proliferation, mobilization, differentiation, homing, and chemotaxis. Numerous studies have found that it widely affects various cells related to As and is closely related to the formation and development of As plaques. Therefore, the CXCL12/MIF-CXCR4 bioaxis is expected to become a more precise target for As treatment, and regulating the CXCL12/MIF-CXCR4 bioaxis strategy provides new ideas for the prevention and treatment of As. [ABSTRACT FROM AUTHOR]

Our study aimed to investigate the associations between CXCL12 rs1029153, rs1801157, and rs2297630 single-nucleotide polymorphisms (SNPs), CXCL12 protein levels, MS prevalence, and clinical parameters. This study included 250 individuals diagnosed with MS and 250 sex- and age-matched healthy control individuals from Lithuania. The SNPs were genotyped with real-time PCR-based assays. The CXCL12 protein concentration was evaluated in serum using the ELISA method. Of the studied CXCL12 SNPs, we found that the rs1801157 CT genotype in the males was associated with 2.3 times reduced MS odds when compared with the CC genotype according to the overdominant and codominant models (p = 0.011 and p = 0.012, respectively). There was a tendency, which did not reach adjusted statistical significance, for a lower CXCL12 protein concentration in the healthy individuals with the rs1801157 CT genotype (p = 0.028). Sensory symptoms were rarer in the women with the rs1801157 TT genotype (p = 0.004); however, this genotype was also associated with a shorter MS disease duration (p = 0.007). CXCL12 rs1801157 was associated with reduced odds of MS occurrence in the male individuals. In women, rs1801157 was associated with a sensory symptom prevalence. [ABSTRACT FROM AUTHOR]

Objective: Todetect the abnormal distribution of B-lymphocytes between peripheral and bone marrow (BM) compartments and explore the mechanism of abnormal chemotaxis of B-lymphocytes in lupus subjects. Methods: the proportions of CXC chemokine receptor (CXCR)4+ B cells and CFDA-labeled MRL/lpr-derived B cells were detected by flow cytometry. the levels of CXC chemokine ligand (CXCL)12in peripheral blood (PB)were measured by elisa. The migrated B cells to osteoblasts (OBs) was measured by transwell migration assay. The relative spatial position of B cells, OBs and CXCL12 was presented by immunofluorescence assay. Results: Firstly, we found that the percentage of CXCR4+ B cells was lower in PB and higher in the BM from both MRl/lpr mice and patientswith systemic lupus erythematosus (SLE). Secondly, OBs from MRl/lpr mice produced more CXCL12 than that from C57BL/6 mice. Besides, MRL/lpr-derived OBs demonstrated more potent chemotactic ability toward B-lymphocytes than control OBs by vitro an vivo. Additionally, more B-lymphocytes were found to co-localize with OBs within the periosteal zone of bone in MRl/lpr mice. Lastly, the percentages of CXCR4+B cells were found to be negatively correlated with serum immunoglobulin (IG) G concentration, moreover, BM CXCL12 levels were found to be positively correlated with SLE disease activity index score and negatively correlated with serum complement3 (C3) concentration. Conclusions: our results indicated that there is a shifted distribution of B-lymphocytes between BM and peripheral compartments in both sle patients and MRl/ lpr mice. Besides, the up-regulated levels of CXCL12 in OBs was indicated to contribute to the enhanced chemotactic migration and anchorage of B-lymphocytes to OBs. [ABSTRACT FROM AUTHOR]

Objective: To analyze the relationship between serum homocysteine (Hcy), superoxide dismutase (SOD), stromal cell-derived factor-1 (SDF-1) and distal symmetric polyneuropathy (DSPN) in patients with type 2 diabetes mellitus (T2DM). Methods:146 T2DM patients admitted to our hospital from January 2020 to January 2023 were selected as research objects, ccording to whether they were combined with DSPN, patients were divided into DSPN (DSPN group) and non-DSPN (NDSPN group), 65 cases and 81 cases respectively. The general clinical data (drinking history, smoking history, age, duration of diabetes mellitus, body mass index, baseline blood pressure, gender, etc.) and biochemical indexes such as blood glucose and blood lipid were collected. The levels of Hcy, SOD and SDF-1 in serum were detected by enzyme-linked immunosorbent assay, the levels of serum Hcy, SOD and SDF-1 were compared between two groups, the levels of serum Hcy, SOD and SDF-1 in patients with different severity of disease were analyzed, the correlation between the three and the severity of DSPN was analyzed, and the predictive value of the three in the clinical diagnosis of DSPN were analyzed by receiver operating curve (ROC). Results: The age, duration of diabetes mellitus and DBP in DSPN group were higher than those in NDSPN group (P＜0.05). The serum SOD and SDF-1 levels in DSPN group were significantly lower than those in NDSPN group,while the Hcy level was significantly higher than that in NDSPN group (P＜0.05). The level of serum Hcy increased with the severity of DSPN neuropathy, while the levels of SOD and SDF-1 decreased with the severity of DSPN neuropathy (P＜0.05). Multivariate Logistic regression analysis showed that, age, duration of diabetes mellitus and serum levels of SOD, Hcy and SDF-1 were independent influencing factors of DSPN (P＜0.05). The area under the curve (AUC) of serum Hcy, SOD and SDF-1 levels for predicting DSPN in T2DM patients was 0.793, 0.801 and 0.840 respectively, the AUC value of the combined prediction of the three (0.877) was higher than that of the three alone. Conclusion: Serum Hcy, SOD and SDF-1 may be involve in the occurrence and development of DSPN, which are independent influencing factors of DSPN, and joint testing have high predictive value for the clinical diagnosis of DSPN. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide, and cancer-associated fibroblasts (CAFs) play a major role in the tumor microenvironment (TME), which facilitates the progression of CRC. It is critical to understand how CAFs promote the progression of CRC for the development of novel therapeutic approaches. The purpose of this study was to understand how CAF-derived stromal-derived factor-1 (SDF-1) and its interactions with the corresponding C-X-C motif chemokine receptor 4 (CXCR4) promote CRC progression. Our study focused on their roles in promoting tumor cell migration and invasion and their effects on the characteristics of cancer stem cells (CSCs), which ultimately impact patient outcomes. Here, using in vivo approaches and clinical histological samples, we analyzed the influence of secreted SDF-1 on CRC progression, especially in terms of tumor cell behavior and stemness. We demonstrated that CAF-secreted SDF-1 significantly enhanced CRC cell migration and invasion through paracrine signaling. In addition, the overexpression of SDF-1 in CRC cell lines HT29 and HCT-116 triggered these cells to generate autocrine SDF-1 signaling, which further enhanced their CSC characteristics, including those of migration, invasion, and spheroid formation. An immunohistochemical study showed a close relationship between SDF-1 and CXCR4 expression in CRC tissue, and this significantly affected patient outcomes. The administration of AMD3100, an inhibitor of CXCR4, reversed the entire phenomenon. Our results strongly suggest that targeting this signaling axis in CRC is a feasible approach to attenuating tumor progression, and it may, therefore, serve as an alternative treatment method to improve the prognosis of patients with CRC, especially those with advanced, recurrent, or metastatic CRC following standard therapy. [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 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]

Background: Chronic kidney disease presents global health challenges, with hemodialysis as a common treatment. However, non-dialyzable uremic toxins demand further investigation for new therapeutic approaches. Renal tubular cells require scrutiny due to their vulnerability to uremic toxins. Methods: In this study, a systems biology approach utilized transcriptomics data from healthy renal tubular cells exposed to healthy and post-dialysis uremic plasma. Results: Differential gene expression analysis identified 983 up-regulated genes, including 70 essential proteins in the protein–protein interaction network. Modularity-based clustering revealed six clusters of essential proteins associated with 11 pathological pathways activated in response to non-dialyzable uremic toxins. Conclusions: Notably, WNT1/11, AGT, FGF4/17/22, LMX1B, GATA4, and CXCL12 emerged as promising targets for further exploration in renal tubular pathology related to non-dialyzable uremic toxins. Understanding the molecular players and pathways linked to renal tubular dysfunction opens avenues for novel therapeutic interventions and improved clinical management of chronic kidney disease and its complications. [ABSTRACT FROM AUTHOR]

Objective: We compared peripheral blood (PBL) chemokine ligand/receptor profiles in children and adolescents with type 1 diabetes mellitus (T1D) or obesity (OB) (both involving inflammation and vascular complications) to identify their associations with cardiometabolic risk factors. Materials and methods: PBL samples from children and adolescents (12-18 years) included: healthy controls (n=29), patients with T1D (n=31) and OB subjects (n=34). Frequency of mononuclear cell populations and chemokine receptor expression (CCR2, CCR4, CXCR3, CXCR4) were determined by flow cytometry. Chemokine levels of CCL2, CCL5, CXCL10 and CXCL11 were measured by bead-based assay and CXCL12 by ELISA. Data were correlated with cardiovascular, metabolic and inflammatory parameters. Results: The proportion of CD14+ monocytes was higher in T1D, whereas the proportion of CD19+ B lymphocytes was higher and CD3+ T lymphocytes was lower in OB. The level of CCL2 was higher in T1D (241.0 (IQR 189.6-295.3) pg/mL in T1D vs 191.5 (IQR 158.0-254.7) pg/mL in control, p=0.033), CXCL11 was lower in OB (6.6 (IQR 4.9-7.7) pg/mL in OB vs 8.2 (IQR 6.9-11.3) pg/mL in control, p=0.018) and CXCL12 was lower in both diseases (2.0 (IQR 1.8-2.5) ng/mL in T1D, 2.1 (IQR 1.9-2.4) ng/mL in OB vs 2.4 (IQR 2.2-2.5) ng/mL in control, p=0.016). Numerous significant associations were found for chemokine ligand/receptor profiles and clinical data. Among these, we are suggesting the most important indicators of cardiometabolic risk in T1D: positive associations of CCR2+ monocytes with blood pressure and CCL12 levels with urine albuminto-creatinine ratio (ACR), inverse association of CXCR3+ B lymphocytes with AST but positive with triglycerides; and OB: positive associations of CXCL12 levels with triglycerides and AST/ALT, inverse association of CCR4+ and CXCR3+ monocytes with ACR. Both diseases share positive associations for CCR4+ T lymphocytes and blood pressure, inverse associations of CXCR4+ subsets with ACR and CXCR3+ T lymphocytes with lipid profile. Conclusion: Significantly changed chemokine ligand/receptor profiles were found in both T1D and OB even at a young age. Although different associations with cardiometabolic risk factors indicate disease-specific changes, overlapping pattern was found for the associations between CCR4+ T lymphocytes and vascular inflammation, CXCR4+ subsets and albuminuria as well as CXCR3+ T lymphocytes and dyslipidemia. Thus, chemokine axes might present potential therapeutic targets for disease-related morbidity. [ABSTRACT FROM AUTHOR]

Background/Objectives: People living with HIV (PLWH) treated with combined antiretroviral therapy (cART) show a greater predisposition to metabolic and inflammatory disturbances compared to the general population. This study aimed to assess the effect of five years of cART use on the level of selected parameters related to carbohydrate and lipid metabolism and inflammation in PLWH compared to the uninfected. Methods: The levels of sirtuins (-1, -3, -6); irisin (IRS); myostatin (MSTN); peptide YY (PYY); glucagon-like peptide-1 (GLP-1); dipeptidyl peptidase IV (DPP-4); fetuin-A (FETU-A); pentraxin 3 (PTX3); chemokine stromal cell-derived factor 1 (SDF-1); regulated on activation, normal T cell expressed and presumably secreted (RANTES); and interleukins (-4, -7, -15) in the plasma of PLWH and a control group were evaluated by immunoassay methods. The results obtained after five years of antiretroviral therapy were compared with the levels obtained before and one year after cART. Results: Analysis of the parameters after five years of cART showed significantly higher levels in PLWH compared to the control group for SIRT-6, IRS, and IL-4 and significantly lower levels for RANTES and IL-7. There were significantly higher levels of SIRT-6, PYY, GLP-1, and PTX3 obtained after five years of cART compared to the results before therapy and after one year of cART. Conclusions: The results indicated changes occur in the expression of selected parameters during cART use in PLWH. Further research on the clinical usefulness of selected parameters and obtaining new information on the development of HIV-related comorbidities needs to be conducted. [ABSTRACT FROM AUTHOR]

Addressing inflammation, demyelination, and associated neurodegeneration in inflammatory demyelinating diseases like multiple sclerosis (MS) remains challenging. ACT-1004-1239, a first-in-class and potent ACKR3 antagonist, currently undergoing clinical development, showed promise in preclinical MS models, reducing neuroinflammation and demyelination. However, its effectiveness in treating established disease and impact on remyelination after the occurrence of demyelinated lesions remain unexplored. This study assessed the therapeutic effect of ACT-1004-1239 in two demyelinating disease models. In the proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) model, ACT-1004-1239 administered upon the detection of the first signs of paralysis, resulted in a dose-dependent reduction in EAE disease severity, concomitant with diminished immune cell infiltrates in the CNS and reduced demyelination. Notably, efficacy correlated with elevated plasma concentrations of CXCL11 and CXCL12, two pharmacodynamic biomarkers of ACKR3 antagonism. Combining ACT-1004-1239 with siponimod, an approved immunomodulatory treatment for MS, synergistically reduced EAE severity. In the cuprizone-induced demyelination model, ACT-1004-1239 administered after 5 weeks of cuprizone exposure, significantly accelerated remyelination, already quantifiable one week after cuprizone withdrawal. Additionally, ACT-1004-1239 penetrated the CNS, elevating brain CXCL12 concentrations. These results demonstrate that ACKR3 antagonism significantly reduces the severity of experimental demyelinating diseases, even when treatment is initiated therapeutically, after the occurrence of lesions. It confirms the dual mode of action of ACT-1004-1239, exhibiting both immunomodulatory effects by reducing neuroinflammation and promyelinating effects by accelerating myelin repair. The results further strengthen the rationale for evaluating ACT-1004-1239 in clinical trials for patients with demyelinating diseases. [ABSTRACT FROM AUTHOR]

This article discusses the importance of circulating tumor cells (CTCs) in both clinical studies and basic research on metastasis. CTCs have been proposed as new blood biomarkers that could be more reliable and prognostic than traditional biomarkers for diagnosing, staging, and treating cancer. The article also explores the heterogeneity of CTCs and the challenges in detecting and isolating them for molecular analysis. The research focuses on breast cancer but also mentions other types of cancer and alternative approaches to CTC detection. Overall, CTC research is advancing and has the potential to improve diagnostics and personalized treatments in the future. [Extracted from the article]

We investigated the association between the SDF-1-3′ (c801G > A) variant and the development of diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR) in a Hungarian cohort. SDF-1-3′ (c801G > A) was genotyped in 103 patients with diabetic retinopathy and 31 age- and sex-matched non-diabetic controls. Central retinal and choroidal thickness was measured by swept-source optical coherence tomography. The distribution of heterozygous and homozygous SDF-1-3′ (c801G > A) genotypes was similar in diabetic and control subjects. The SDF-3′(c801AA) genotype was associated with DME (n = 94 eyes, allele distribution p = 0.006, genotype distribution p = 0.01 OR: 2.48, 95% CL: 1.21–5.08) in both univariable and multivariable modelling, independent of duration and type of diabetes, HbA1C, hypertension and microalbuminuria (p = 0.03). DME occurred earlier in patients carrying the SDF-1 (c801A) allele (Kaplan–Meier analysis, log-rank test p = 0.02). A marginally significant association was found between the presence of the SDF-1 (c801A) allele and the development of PDR (n = 89 eyes, p = 0.06). The SDF-1-3′ (c801A) allele also showed a correlation with central retinal (p = 0.006) and choroidal (p = 0.08) thickness. SDF-1-3′ (c801G > A) is involved in the development of macular complications in DM independent of critical clinical factors, suggesting that SDF-1 may be a future therapeutic target for high-risk patients, especially those carrying the SDF-1 (c801A) allele. [ABSTRACT FROM AUTHOR]

Introduction: Salivary gland dysfunction, often resulting from salivary gland obstruction-induced inflammation, is a prevalent condition. Corticosteroid, known for its anti-inflammatory and immunomodulatory properties, is commonly prescribed in clinics. This study investigates the therapeutic implications and potential side effects of dexamethasone on obstructive sialadenitis recovery using duct ligation mice and salivary gland organoid models. Methods: Functional and pathological changes were assessed after administering dexamethasone to the duct following deligation 2 weeks after maintaining ligation of the mouse submandibular duct. Additionally, lipopolysaccharide- and tumor necrosis factor-induced salivary gland organoid inflammation models were established to investigate the effects and underlying mechanisms of action of dexamethasone. Results: Dexamethasone administration facilitated SG function restoration, by increasing salivary gland weight and saliva volume while reducing saliva lag time. Histological evaluation revealed, reduced acinar cell atrophy and fibrosis with dexamethasone treatment. Additionally, dexamethasone suppressed proinflammatory cytokines IL-1β and TNF expression. In a model of inflammation in salivary gland organoids induced by inflammatory substances, dexamethasone restored acinar markers such as AQP5 gene expression levels, while inhibiting pro-inflammatory cytokines TNF and IL6, as well as chemokines CCL2, CXCL5, and CXCL12 induction. Macrophages cultured in inflammatory substancetreated media from salivary gland organoid cultures exhibited proinflammatory polarization. However, treatment with dexamethasone shifted them towards an anti-inflammatory phenotype by reducing M1 markers (Tnf, Il6, Il1b, and Cd86) and elevating M2 markers (Ym1, Il10, Cd163, and Klf4). However, high-dose or prolonged dexamethasone treatment induced acinoductal metaplasia and had side effects in both in vivo and in vitro models. Conclusions: Our findings suggest the effectiveness of corticosteroids in treating obstructive sialadenitis-induced salivary gland dysfunction by regulating pro-inflammatory cytokines. [ABSTRACT FROM AUTHOR]

A key step in platelet production is the migration of megakaryocytes to the vascular sinusoids within the bone marrow. This homing is mediated by the chemokine CXCL12 and its receptor CXCR4. CXCR4 is also a positive regulator of platelet activation and thrombosis. Pim-1 kinase has been shown to regulate CXCR4 signalling in other cell types, and we have previously described how Pim kinase inhibitors attenuate platelet aggregation to CXCL12. However, the mechanism by which Pim-1 regulates CXCR4 signalling in platelets and megakaryocytes has yet to be elucidated. Using human platelets, murine bone marrow-derived megakaryocytes, and the megakaryocyte cell line MEG-01, we demonstrate that pharmacological Pim kinase inhibition leads to reduced megakaryocyte and platelet function responses to CXCL12, including reduced megakaryocyte migration and platelet granule secretion. Attenuation of CXCL12 signalling was found to be attributed to the reduced surface expression of CXCR4. The decrease in CXCR4 surface levels was found to be mediated by rapid receptor internalisation, in the absence of agonist stimulation. We demonstrate that pharmacological Pim kinase inhibition disrupts megakaryocyte and platelet function by reducing constitutive CXCR4 surface expression, decreasing the number of receptors available for agonist stimulation and signalling. These findings have implications for the development and use of Pim kinase inhibitors for the treatment of conditions associated with elevated circulating levels of CXCL12/SDF1α and increased thrombotic risk. [ABSTRACT FROM AUTHOR]

Objective: To investigate the mechanism by cryptotanshinone regulates the signaling pathway of stromal cell derived factor 1 (SDF-1)/C-X-C chemokine receptor 4 (CXCR4) and inhibits hydrogen peroxide induced cell apoptosis of human bone marrow mesenchymal stem cells (BMSCs). Methods: Cultivated human bone marrow mesenchymal stem cells (HBMSCs) in vitro and established an oxidative stress model by H2O2. Divided HBMSC cells into control group (without oxidative stress induction) and model group (500 μmol/L H2O2 induction for 24 hours), low-dose group of cryptotanshinone(10 μmol/L), medium dose group of cryptotanshinone (20 μmol/L), high-dose group of cryptotanshinone(40 μmol/L). Cell activity was detected by Cell Count Kit (CCK-8). Cell apoptosis was detected by flow cytometry detection. Cellular glucose uptake and lactate levels was detected by enzyme linked immunosorbent assay(Elisa) testing. The content of glutathione (GSH), superoxide dismutase (SOD) and malondialdehyde (MDA) in cells were detected by micro method. Cysteine aspartate protease 3(caspase-3), B-lymphoblastoma-2 associated X protein (Bax), B-lymphoblastoma-2 (Bcl-2), expression of SDF-1 and CXCR4 proteins was detected by western blot detection (Western blot). Results: Compared with the control group, the glucose uptake and lactate levels, GSH, SOD activity, Bcl-2 protein expression, and SDF-1/CXCR4 signaling pathway protein expression of HBMSC cells in the model group decreased, while the cell apoptosis rate, expression of apoptotic protein caspase-3, Bax, and MDA content increased(P<0.05). Compared with the model group, the low, medium, and high dose groups of cryptotanshinone showed an increase in glucose uptake and lactate levels, GSH, SOD activity, Bcl-2 protein expression, and SDF-1/CXCR4 signaling pathway protein expression in HBMSC cells, while the cell apoptosis rate, expression of apoptotic proteins caspase-3, Bax, and MDA content decreased (P<0.05). The differences in various indicators among the low, medium, and high dose groups of cryptotanshinone were statistically significant(P<0.05). Conclusion: Cryptotanshinone may inhibit oxidative stress damage and apoptosis of BMSC induced by hydrogen peroxide by promoting SDF-1/CXCR4 signaling pathway transduction, with high-dose cryptotanshinone having the best effect. [ABSTRACT FROM AUTHOR]

Heterozygous autosomal dominant mutations in the CXCR4 gene cause WHIM syndrome, a severe combined immunodeficiency disorder. The mutations primarily affect the C-terminal region of the CXCR4 chemokine receptor, specifically several potential phosphorylation sites critical for agonist (CXCL12)- mediated receptor internalization and desensitization. Mutant receptors have a prolonged residence time on the cell surface, leading to hyperactive signaling that is responsible for some of the symptoms of WHIM syndrome. Recent studies have shown that the situation is more complex than originally thought, as mutant WHIM receptors and CXCR4 exhibit different dynamics at the cell membrane, which also influences their respective cellular functions. This review examines the functional mechanisms of CXCR4 and the impact of WHIM mutations in both physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

BACKGROUND: In recent years, some scholars in the field of tendon bone injury have attached stromal cell-derived factor 1 to tissue engineering scaffolds to promote tendon bone healing, and achieved good results. However, whether stromal cell-derived factor 1 promotes tendon bone healing mechanisms and participates in the repair of natural healing has not yet been defined. OBJECTIVE: To study the expression of stroma-cell derived factor 1 during tendon bone healing after rupture of the whole supraspinatus muscle of the rabbit rotator cuff and its migration effect and optimal in vitro migration promoting concentration on stem cells during tendon bone injury. METHODS: Totally 18 adult New Zealand rabbits were randomly selected to establish rotator cuff injury models, and an additional 3 rabbits were selected as blank controls. At 3, 5, 7, 14, 21, and 28 days after modeling, three rabbits were executed separately and the rabbits in the blank group were sacrificed. The tissues of tendon bone junction were taken and stored in a -80 ℃ refrigerator. The expression of stromal cell-derived factor 1 was detected by ELISA at each time point after injury. Mesenchymal stem cells were isolated from the bone marrow of young rabbit femur, cultured, and identified. Transwell assay was performed to verify the migration-promoting effect of stromal cell-derived factor 1 on stem cells and the optimal migration-promoting concentration in vitro. The stem cells cultured to P3 were co-cultured with BrdU and injected into the rabbit ear marginal vein, and immunohistochemical staining was used to verify whether the stem cells migrated to the injury site. RESULTS AND CONCLUSION: (1) Stromal cell-derived factor 1 gene expression was bimodal during rotator cuff tendon bone healing. Stromal cell-derived factor 1 gene expression increased significantly at 3 days post-injury (P < 0.01) and then decreased, reaching a minimum at 5 days post-injury. It increased again and reached a peak 14 days after injury (P < 0.01) and then decreased. (2) Cell immunohistochemical staining displayed that stem cells labeled with BrdU did migrate to the injury site. (3) The results of the transwell experiment exhibited that 60-80 ng/mL stromal cell-derived factor 1 had the best effect on promoting migration of stem cells, while a concentration of 200 ng/mL inhibited migration. (4) Stromal cell-derived factor 1 is involved in the healing of rotator cuff tendon bone during the inflammatory response phase and the proliferation phase. The mechanism of action may be to promote the migration of stem cells to the injury and their differentiation into various types of cells to promote repair. In addition, the pro-migration effect of stromal cell-derived factor 1 exists at a range of concentrations, beyond which it may act as an inhibitor. [ABSTRACT FROM AUTHOR]

Chemokines are small, secreted cytokines crucial in the regulation of a variety of cell functions. The binding of chemokine C-X-C motif chemokine ligand 12 (CXCL12) (stromal cell-derived factor 1) to a G-protein-coupled receptor C-X-C chemokine receptor type 4 (CXCR4) triggers downstream signaling pathways with effects on cell survival, proliferation, chemotaxis, migration, and gene expression. Intensive and extensive investigations have provided evidence suggesting that the CXCL12-CXCR4 axis plays a pivotal role in tumor development, survival, angiogenesis, metastasis, as well as in creating tumor microenvironment, thus implying that this axis is a potential target for the development of cancer therapies. The structures of CXCL12 and CXCR4 have been resolved with experimental methods such as X-ray crystallography, NMR, or cryo-EM. Therefore, it is possible to apply structure-based computational approaches to discover, design, and modify therapeutic molecules for cancer treatments. Here, we summarize the current understanding of the roles played by the CXCL12-CXCR4 signaling axis in cellular functions linking to cancer progression and metastasis. This review also provides an introduction to protein structures of CXCL12 and CXCR4 and the application of computer simulation and analysis in understanding CXCR4 activation and antagonist binding. Furthermore, examples of strategies and current progress in CXCL12-CXCR4 axis-targeted development of therapeutic anticancer inhibitors are discussed. [ABSTRACT FROM AUTHOR]

Glioblastoma recruits various nontransformed cells from distant tissues. Although bone marrow‐derived mesenchymal stem cells (MSCs) have been observed migrating to glioblastoma, the underlying mechanism driving MSC migration toward glioblastoma remains unclear. Tumor vascularity is critical in the context of recurrent glioblastoma and is closely linked to the expression of stromal cell‐derived factor‐1 (SDF‐1). We demonstrated that cadherin‐6 mediated MSC migration both toward SDF‐1 and toward glioblastoma cells. Cadherin‐6 knockdown resulted in the downregulation of MSCs capacity to migrate in response to SDF‐1. Furthermore, MSCs with cadherin‐6 knockdown exhibited impaired migration in response to conditioned media derived from glioblastoma cell lines (U87 and U373) expressing SDF‐1, thus simulating the glioblastoma microenvironment. Moreover, MSCs enhanced the vasculogenic capacity of U87 cells without increasing the proliferation, cancer stem cell characteristics, or migration of U87. These results suggest that the current strategy of utilizing MSCs as carriers for antiglioblastoma drugs requires careful examination. Furthermore, cadherin‐6 may represent a novel potential target for controlling the recruitment of MSCs toward glioblastoma. [ABSTRACT FROM AUTHOR]

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Spermatogonial stem cells (SSCs) undergo self-renewal division to sustain spermatogenesis. Although it is possible to derive SSC cultures in most mouse strains, SSCs from a 129 background never proliferate under the same culture conditions, suggesting they have distinct self-renewal requirements. Here, we established long-term culture conditions for SSCs from mice of the 129 background (129 mice). An analysis of 129 testes showed significant reduction of GDNF and CXCL12, whereas FGF2, INHBA and INHBB were higher than in testes of C57BL/6 mice. An analysis of undifferentiated spermatogonia in 129 mice showed higher expression of Chrna4, which encodes an acetylcholine (Ach) receptor component. By supplementing medium with INHBA and Ach, SSC cultures were derived from 129 mice. Following lentivirus transduction for marking donor cells, transplanted cells re-initiated spermatogenesis in infertile mouse testes and produced transgenic offspring. These results suggest that the requirements of SSC self-renewal in mice are diverse, which has important implications for understanding selfrenewal mechanisms in various animal species. [ABSTRACT FROM AUTHOR]

The reciprocal modulation between the CXCL12/CXCR4/ACKR3 axis and the STAT3 signaling pathway plays a crucial role in the progression of various diseases and neoplasms. Activation of the CXCL12/CXCR4/ACKR3 axis triggers the STAT3 pathway through multiple mechanisms, while the STAT3 pathway also regulates the expression of CXCL12. This review offers a thorough and systematic analysis of the reciprocal regulatory mechanisms between the CXCL12/CXCR4/ACKR3 signaling axis and the STAT3 signaling pathway in the context of diseases, particularly tumors. It explores the potential clinical applications in tumor treatment, highlighting possible therapeutic targets and novel strategies for targeted tumor therapy. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSC) from adult bone marrow are the most commonly used cells in clinical trials. MSCs from single donors are the preferred starting material but suffer from a major setback of being heterogeneous that results in unpredictable and inconsistent clinical outcomes. To overcome this, we developed a method of pooling MSCs from different donors and created cell banks to cater clinical needs. Initially, the master cell banks (MCBs) were created at passage 1 (P1) from the bone marrow MSCs isolated from of nine different donors. At this stage, MCBs from three different donors were mixed in equal proportion and expanded till P3 to create working cell banks. Further, the pooled cells and individual donor MSCs were expanded till P5 and cryopreserved and extensively characterised. There was a large heterogeneity among the individual donor MSCs in terms of growth kinetics (90% Coefficient of variation (CV) for cell yield and 44% CV for population doubling time at P5), immunosuppressive ability (30% CV at 1:1 and 300% CV at 1:10 ratio), and the angiogenic factor secretion potential (20% CV for VEGF and71% CV for SDF-1). Comparatively, the pooled cells have more stable profiles (60% CV for cell yield and 7% CV for population doubling time at P5) and exhibit better immunosuppressive ability (15% CV at 1:1 and 32% CV at 1:10 ratio) and consistent secretion of angiogenic factors (16% CV for VEGF and 51% CV for SDF-1). Further pooling does not compromise the trilineage differentiation capacity or phenotypic marker expression of the MSCs. The senescence and in vitro tumourigenicity characteristics of the pooled cells are also similar to those of individual donor MSCs. We conclude that pooling of MSCs from three different donors reduces heterogeneity among individual donors and produces MSCs with a consistent secretion and higher immunosuppressive profile. [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]

Keloids are pathological scar tissue resulting from skin trauma or spontaneous formation, often accompanied by itching and pain. Although GNAS antisense RNA 1 (GNAS‐AS1) shows abnormal upregulation in keloids, the underlying molecular mechanism is unclear. The levels of genes and proteins in clinical tissues from patients with keloids and human keloid fibroblasts (HKFs) were measured using quantitative reverse transcription PCR, western blot and enzyme‐linked immunosorbent assay. The features of HKFs, including proliferation and migration, were evaluated using cell counting kit 8 and a wound healing assay. The colocalization of GNAS‐AS1 and miR‐196a‐5p in HKFs was measured using fluorescence in situ hybridization. The relationships among GNAS‐AS1, miR‐196a‐5p and C‐X‐C motif chemokine ligand 12 (CXCL12) in samples from patients with keloids were analysed by Pearson correlation analysis. Gene interactions were validated by chromatin immunoprecipitation and luciferase reporter assays. GNAS‐AS1 and CXCL12 expression were upregulated and miR‐196a‐5p expression was downregulated in clinical tissues from patients with keloids. GNAS‐AS1 knockdown inhibited proliferation, migration, and extracellular matrix (ECM) accumulation of HKFs, all of which were reversed by miR‐196a‐5p downregulation. Signal transducer and activator of transcription 3 (STAT3) induced GNAS‐AS1 transcription through GNAS‐AS1 promoter interaction, and niclosamide, a STAT3 inhibitor, decreased GNAS‐AS1 expression. GNAS‐AS1 positively regulated CXCL12 by sponging miR‐196‐5p. Furthermore, CXCL12 knockdown restrained STAT3 phosphorylation in HKFs. Our findings revealed a feedback loop of STAT3/GNAS‐AS1/miR‐196a‐5p/CXCL12/STAT3 that promoted HKF proliferation, migration and ECM accumulation and affected keloid progression. [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]

(1) Background: Peptides are appealing as pharmacological materials because they are easily produced, safe, and tolerable. Despite increasing gum-care awareness, periodontitis is still prevalent and is influenced by factors like high sugar consumption, smoking, and aging. Porphyromonas gingivalis is considered a major etiologic agent of periodontitis and activates the NLR family pyrin domain containing 3 (NLRP3) but is absent in melanoma 2 (AIM2) inflammasomes, resulting in pro-inflammatory cytokine release. (2) Methods: We examined the anti-inflammatory effects of 18 peptides derived from human stromal cell-derived factor-1 (SDF-1) on THP-1 macrophages. Inflammation was induced by P. gingivalis, and the anti-inflammatory effects were analyzed using molecular biological techniques. In a mouse periodontitis model, alveolar bone resorption was assessed using micro-CT. (3) Results: Of the 18 SDF-1-derived peptides, S10 notably reduced IL-1β and TNF-α secretion. S10 also diminished the P. gingivalis-induced expression of NLRP3, AIM2, ASC (apoptosis-associated speck-like protein), caspase-1, and IL-1β. Furthermore, S10 attenuated the enhanced TLR (toll-like receptor) signaling pathway and decreased the phosphorylation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). In addition, S10 mitigated alveolar bone loss in our P. gingivalis-induced mouse model of periodontitis. (4) Conclusions: S10 suppressed TLR/NF-κB/NLRP3 inflammasome signaling and the AIM2 inflammasome in our P. gingivalis-induced murine periodontitis model, which suggests that it has potential use as a therapeutic treatment for periodontitis. [ABSTRACT FROM AUTHOR]

IntroductionAcute lymphoblastic leukemia is characterized by a disturbed maturation of hematopoietic stem cells (HSCs) resulting in development of a malignant clone. Despite relatively positive outcome, there are still instances of disease relapse occurring due to ineffective disease eradication or primary leukemic clone alterations. Unclear significance of stem cells in the course of ALL led us to investigate and establish crucial changes in two stem cell populations - very small embryonic-like stem cells (VSELs) and HSCs during the induction phase of treatment.MethodsIn a retrospective study selected stem cells in peripheral blood and bone marrow of 60 pediatric ALL subjects and 48 healthy controls were subjected to flow cytometric analysis at 4 different time points.ResultsBoth VSELs and HSCs were elevated at the moment of ALL diagnosis compared to healthy controls, but profoundly decline until day 15. Further observations revealed an increase in HSCs with a concomitant depletion of VSELs until week 12. ALL patients with high HSCs showed positive correlation with bone marrow blasts at diagnosis. Patients with lower VSELs or HSCs at diagnosis had slightly improved response to applied therapy. We observed higher initial bone marrow lymphoblast values in patients with lower VSELs or higher HSCs in the high-risk group. The significance of VSELs in predicting treatment outcome can be illustrated by lower day 15 MRD level of patients with lower VSELs at diagnosis.DiscussionWe found HSCs and VSELs to be valid participants in pediatric ALL with possible contribution in the neoplastic process and prediction of initial treatment outcome.

Bone regeneration and mineralization can be achieved by means of distraction osteogenesis (DO). In the present study, we investigated the effect of stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) on the new bone formation during DO in rats. Forty-eight Sprague–Dawley rats were randomized into four groups of 12 rats each. We established the left femoral DO model in rats and performed a mid-femoral osteotomy, which was fixed with an external fixator. DO was performed at 0.25 mm/12 h after an incubation period of 5 days. Distraction was continued for 10 days, resulting in a total of 5 mm of lengthening. After distraction, the solution was locally injected into the osteotomy site, once a day 1 ml for 1 week. One group received the solvent alone and served as the control, and the other three groups were treated with SDF-1, VEGF, and SDF-1with VEGF in an aqueous. Sequential X-ray radiographs were taken two weekly. The regeneration was monitored with the use of micro-CT analysis, mechanical testing, and histology. Radiographs showed accelerated regenerate ossification in the SDF-1, VEGF, and SDF-1 with the VEGF group, with a larger amount of new bone compared with the control group, especially SDF-1 with the VEGF group. Micro-CT analysis and biomechanical tests showed Continuous injection of the SDF-1, VEGF, and SDF-1 with VEGF during the consolidation period significantly increased bone mineral density bone volume, mechanical maximum loading, and bone mineralization of the regenerate. Similarly, the expression of osteogenic-specific genes, as determined by real-time polymerase chain reaction , was significantly higher in SDF-1 with the VEGF group than in the other groups. Histological examination revealed more new trabeculae in the distraction gap and more mature bone tissue for the SDF-1 with the VEGF group. SDF-1 and VEGF promote bone regeneration and mineralization during DO, and there is a synergistic effect between the SDF-1 and VEGF. It is possible to provide a new and feasible method to shorten the period of treatment of DO.

During inflammation and tissue regeneration, the alarmin High Mobility Group Box 1 (HMGB1), in its reduced isoform, enhances the activity of the chemokine CXCL12, forming a heterocomplex that acts via the chemokine receptor CXCR4. Despite the established roles of both HMGB1 and CXCL12 in tumor progression and metastatic spread to distal sites, the role of the CXCL12/HMGB1 heterocomplex in cancer has never been investigated. By employing a newly established mass spectrometry protocol that allows an unambiguous distinction between reduced (red-HMGB1) and oxidized (ox-HMGB1) HMGB1 isoforms in cell lysates, we demonstrate that human epithelial cells derived from breast (MCF-7 and MDA-MB-231) and prostate (PC-3) cancer predominantly express red-HMGB1, while primary CD3+ T lymphocytes from peripheral blood express both HMGB1 isoforms. All these cancer cells release HMGB1 in the extracellular microenvironment together with varying concentrations of thioredoxin and thioredoxin reductase. The CXCL12/HMGB1 heterocomplex enhances, via CXCR4, the directional migration and invasiveness of cancer cells characterized by high metastatic potential that possess a fully active thioredoxin system, contributing to maintain red-HMGB1. On the contrary, cancer cells with low metastatic potential, lack thioredoxin reductase, promptly uptake CXCL12 and fail to respond to the heterocomplex. Our study demonstrates that the responsiveness of cancer cells to the CXCL12/HMGB1 heterocomplex, resulting in enhanced cell migration and invasiveness, depends on the maintenance of HMGB1 in its reduced isoform, and suggests disruption of the heterocomplex as a potential therapeutic target to inhibit invasion and metastatic spread in cancer therapies. [ABSTRACT FROM AUTHOR]

The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation. Recent studies show that targeting CXCL12 can improve the effect of radiotherapy (RT) in preclinical models of glioblastoma (GBM). Here, the authors report the safety and preliminary efficacy of a phase I/II clinical trial investigating an L-RNA aptamer-based CXCL12 inhibitor (NOX-A12) in combination with RT in patients with newly-diagnosed GBM. [ABSTRACT FROM AUTHOR]

Malignant insulinoma is an extremely rare type of functioning pancreatic neuroendocrine tumour with a high degree of malignancy and a high incidence of metastasis. However, it is still unclear how malignant insulinomas develop and metastasize. Serum amyloid P component (SAP), a member of the pentraxin protein family, is an acute‐phase protein secreted by liver cells. The role of SAP in insulinoma and the related mechanism are still unknown. To determine the effect of SAP on insulinoma, we crossed Rip1‐Tag2 mice, which spontaneously develop insulinoma, and SAP knockout (KO) mice to generate Rip1‐Tag2;SAP−/− mice. We found that SAP deletion significantly promoted the growth, invasion and metastasis of malignant insulinoma through C‐X‐C motif chemokine ligand 12 (CXCL12) secreted by cancer‐associated fibroblasts (CAFs). Further study showed that SAP deletion promoted CXCL12 secretion by CAFs through the CXCR4/p38/ERK signalling pathway. These findings reveal a novel role and mechanism of SAP in malignant insulinoma and provide direct evidence that SAP may be a therapeutic agent for this disease. [ABSTRACT FROM AUTHOR]

Introduction: Low energy availability due to excessive exercise lowers bone mass and impairs various physiological functions, including immunity and hematopoiesis. We focused on Cxcl12 abundant reticular (CAR) cells, which are bone marrow mesenchymal stem cells and are essential for the maintenance of hematopoietic and immune cells in bone marrow. We examine the functional changes in CAR cells resulting from dietary restriction combined with exercise. Materials and methods: Five-week-old wild-type female mice were divided into an ad libitum group (CON), a 60% dietary restriction group (DR), an ad libitum with exercise group (CON + ex), and a 60% dietary restriction with exercise group (DR + ex). Blood parameters, bone structure parameters, and bone marrow fat volume were evaluated after 5 weeks. In addition, bone marrow CAR cells were isolated by cell sorting and analyzed for gene expression by RT-qPCR. Results: Bone mineral density (BMD) was significantly decreased in DR and DR + ex compared to CON and CON + ex. Especially, cortical bone mass and thickness were significantly decreased in DR and DR + ex groups, whereas trabecular bone mass was significantly increased. Bone marrow fat volume was significantly increased in DR and DR + ex groups compared to CON and CON + ex. The number of leukocytes in the blood was significantly decreased in the DR + ex group compared to the other three groups. RT-qPCR showed a significant decrease in gene expression of both Foxc1 and Runx2 in CAR cells of the DR + ex group compared to CON. Conclusion: Dietary restriction combined with exercise promotes CAR cell differentiation into bone marrow adipocyte and suppresses osteoblast differentiation. [ABSTRACT FROM AUTHOR]