Stromal Cell-derived Factor-1alpha Research Articles

Injectable Self-Oxygenating Cardio-Protective and Tissue Adhesive Silk-Based Hydrogel for Alleviating Ischemia After Mi Injury.

Myocardial infarction (MI) is a significant cardiovascular disease that restricts blood flow, resulting in massive cell death and leading to stiff and noncontractile fibrotic scar tissue formation. Recently, sustained oxygen release in the MI area has shown regeneration ability; however, improving its therapeutic efficiency for regenerative medicine remains challenging. Here, a combinatorial strategy for cardiac repair by developing cardioprotective and oxygenating hybrid hydrogels that locally sustain the release of stromal cell-derived factor-1 alpha (SDF) and oxygen for simultaneous activation of neovascularization at the infarct area is presented. A sustained release of oxygen and SDF from injectable, mechanically robust, and tissue-adhesive silk-based hybrid hydrogels is achieved. Enhanced endothelialization under normoxia and anoxia is observed. Furthermore, there is a marked improvement in vascularization that leads to an increment in cardiomyocyte survival by ≈30% and a reduction of the fibrotic scar formation in an MI animal rodent model. Improved left ventricular systolic and diastolic functions by ≈10% and 20%, respectively, with a ≈25% higher ejection fraction on day 7 are also observed. Therefore, local delivery of therapeutic oxygenating and cardioprotective hydrogels demonstrates beneficial effects on cardiac functional recovery for reparative therapy.

Effect of coffee, tea and alcohol intake on circulating inflammatory cytokines: a two sample-Mendelian randomization study.

Despite the abundance of research examining the effects of coffee, tea, and alcohol on inflammatory diseases, there is a notable absence of conclusive evidence regarding their direct causal influence on circulating inflammatory cytokines. Previous studies have primarily concentrated on established cytokines, neglecting the potential impact of beverage consumption on lesser-studied but equally important cytokines. Information regarding the consumption of coffee, tea, and alcohol was collected from the UK Biobank, with sample sizes of 428,860, 447,485, and 462,346 individuals, respectively. Data on 41 inflammatory cytokines were obtained from summary statistics of 8293 healthy participants from Finnish cohorts. The consumption of coffee was found to be potentially associated with decreased levels of Macrophage colony-stimulating factor (β = -0.57, 95% CI -1.06 ~ -0.08; p = 0.022) and Stem cell growth factor beta (β = -0.64, 95% CI -1.16 ~ -0.12; p = 0.016), as well as an increase in TNF-related apoptosis-inducing ligand (β = 0.43, 95% CI 0.06 ~ 0.8; p = 0.023) levels. Conversely, tea intake was potentially correlated with a reduction in Interleukin-8 (β = -0.45, 95% CI -0.9 ~ 0; p = 0.045) levels. Moreover, our results indicated an association between alcohol consumption and decreased levels of Regulated on Activation, Normal T Cell Expressed and Secreted (β = -0.24, 95% CI -0.48 ~ 0; p = 0.047), as well as an increase in Stem cell factor (β = 0.17, 95% CI 0.02 ~ 0.31; p = 0.023) and Stromal cell-derived factor-1 alpha (β = 0.20, 95% CI 0.04 ~ 0.36; p = 0.013). Revealing the interactions between beverage consumption and various inflammatory cytokines may lead to the discovery of novel therapeutic targets, thereby facilitating dietary interventions to complement clinical disease treatments.

Repressing miR-23a promotes the transdifferentiation of pancreatic α cells to β cells via negatively regulating the expression of SDF-1α.

Pancreatic β-cell failure is a pathological feature in type 1 diabetes. One promising approach involves inducing transdifferentiation of related pancreatic cell types, specifically α cells that produce glucagon. The chemokine stromal cell-derived factor-1 alpha (SDF-1α) is implicated in pancreatic α-to-β like cell transition. Here, the serum level of SDF-1α was lower in T1D with C-peptide loss, the miR-23a was negatively correlated with SDF-1α. We discovered that exosomal miR-23a, secreted from β cells, functionally downregulates the expression of SDF-1α, leading to increased Pax4 expression and decreased Arx expression in vivo. Adenovirus-vectored miR-23a sponge and mimic were constructed to further explored the miR-23a on pancreatic α-to-β like cell transition in vitro, which yielded results consistent with our cell-based assays. Suppression of miR-23a upregulated insulin level and downregulated glucagon level in STZ-induced diabetes mice models, effectively promoting α-to-β like cell transition. Our findings highlight miR-23a as a new therapeutic target for regenerating pancreatic β cells from α cells.

Diagnostic Challenges in Inflammatory Choroidal Neovascularization.

Inflammation plays a key role in the induction of choroidal neovascularization (CNV). Inflammatory choroidal neovascularization (iCNV) is a severe but uncommon complication of both infectious and non-infectious uveitides. It is hypothesized that its pathogenesis is similar to that of wet age-related macular degeneration (AMD), and involves hypoxia as well as the release of vascular endothelial growth factor, stromal cell-derived factor 1-alpha, and other mediators. Inflammatory CNV develops when inflammation or infection directly involves the retinal pigment epithelium (RPE)-Bruch's membrane complex. Inflammation itself can compromise perfusion, generating a gradient of retinal-choroidal hypoxia that additionally promotes the formation of choroidal neovascularization in the course of uveitis. The development of choroidal neovascularization may be a complication, especially in conditions such as punctate inner choroidopathy, multifocal choroiditis, serpiginous choroiditis, and presumed ocular histoplasmosis syndrome. Although the majority of iCNV cases are well defined and appear as the "classic" type (type 2 lesion) on fluorescein angiography, the diagnosis of iCNV is challenging due to difficulties in differentiating between inflammatory choroiditis lesions and choroidal neovascularization. Modern multimodal imaging, particularly the recently introduced technology of optical coherence tomography (OCT) and OCT angiography (noninvasive and rapid imaging modalities), can reveal additional features that aid the diagnosis of iCNV. However, more studies are needed to establish their role in the diagnosis and evaluation of iCNV activity.

Potential inhibition of CXCL12/SDF-1 by small molecule Hesperetin in management of tobacco associated oral cancer

Goal of the perspective: Stromal cell-derived factor-1 alpha CXCL12/SDF-1 has a substantial impact on the tumorigenicity in tobacco related oral cancer. Inhibition could help derive preventive and therapeutic approaches. DiscussionBinding energy score between CXCL12/SDF-1 and small molecule Hesperetin is indicative of a strong and stable interaction, significative of a high affinity for the chemokine. The specific molecular interactions, including hydrogen bonding and van der Waals interactions further contribute to the stable complex formation. ConclusionTargeting molecular components of the NF-κB signaling pathway through inhibition of CXCL12/SDF-1 could serve as a vital therapeutic adjunct in management of tobacco associated oral cancer. Also topical drug delivery systems with Hesperetin can be planned in oral potentially malignant disorders.

Stromal cell-derived factor-1 alpha improves cardiac function in a novel diet-induced coronary atherosclerosis model, the SR-B1ΔCT/LDLR KO mouse

Background and aimsThere are a limited number of pharmacologic therapies for coronary artery disease, and few rodent models of occlusive coronary atherosclerosis and consequent myocardial infarction with which one can rapidly test new therapeutic approaches. Here, we characterize a novel, fertile, and easy-to-use HDL receptor (SR-B1)-based model of atherogenic diet-inducible, fatal coronary atherosclerosis, the SR-B1ΔCT/LDLR KO mouse. Additionally, we test intramyocardial injection of Stromal Cell-Derived Factor-1 alpha (SDF-1α), a potent angiogenic cytokine, as a possible therapy to rescue cardiac function in this mouse. MethodsSR-B1ΔCT/LDLR KO mice were fed the Paigen diet or standard chow diet, and we determined the effects of the diets on cardiac function, histology, and survival. After two weeks of feeding either the Paigen diet (n = 24) or standard chow diet (n = 20), the mice received an intramyocardial injection of either SDF-1α or phosphate buffered saline (PBS). Cardiac function and angiogenesis were assessed two weeks later. ResultsWhen six-week-old mice were fed the Paigen diet, they began to die as early as 19 days later and 50% had died by 38 days. None of the mice maintained on the standard chow diet died by day 72. Hearts from mice on the Paigen diet showed evidence of cardiomegaly, myocardial infarction, and occlusive coronary artery disease.For the five mice that survived until day 28 that underwent an intramyocardial injection of PBS on day 15, the average ejection fraction (EF) decreased significantly from day 14 (the day before injection, 52.1 ± 4.3%) to day 28 (13 days after the injection, 30.6 ± 6.8%) (paired t-test, n = 5, p = 0.0008). Of the 11 mice fed the Paigen diet and injected with SDF-1α on day 15, 8 (72.7%) survived to day 28. The average EF for these 8 mice increased significantly from 48.2 ± 7.2% on day 14 to63.6 ± 6.9% on day 28 (Paired t-test, n = 8, p = 0.003). ConclusionsThis new mouse model and treatment with the promising angiogenic cytokine SDF-1α may lead to new therapeutic approaches for ischemic heart disease.

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.

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

Implantable SDF-1α-loaded silk fibroin hyaluronic acid aerogel sponges as an instructive component of the glioblastoma ecosystem: Between chemoattraction and tumor shaping into resection cavities

In view of inevitable recurrences despite resection, glioblastoma (GB) is still an unmet clinical need. Dealing with the stromal-cell derived factor 1-alpha (SDF-1α)/CXCR4 axis as a hallmark of infiltrative GB tumors and with the resection cavity situation, the present study described the effects and relevance of a new engineered micro-nanostructured SF-HA-Hep aerogel sponges, made of silk fibroin (SF), hyaluronic acid (HA) and heparin (Hep) and loaded with SDF-1α, to interfere with the GB ecosystem and residual GB cells, attracting and confining them in a controlled area before elimination. 70 µm-pore sponges were designed as an implantable scaffold to trap GB cells. They presented shape memory and fit brain cavities. Histological results after implantation in brain immunocompetent Fischer rats revealed that SF-HA-Hep sponges are well tolerated for more than 3 months while moderately and reversibly colonized by immuno-inflammatory cells. The use of human U87MG GB cells overexpressing the CXCR4 receptor (U87MG-CXCR4+) and responding to SDF-1α allowed demonstrating directional GB cell attraction and colonization of the device in vitro and in vivo in orthotopic resection cavities in Nude rats. Not modifying global survival, aerogel sponge implantation strongly shaped U87MG-CXCR4+ tumors in cavities in contrast to random infiltrative growth in controls. Overall, those results support the interest of SF-HA-Hep sponges as modifiers of the GB ecosystem dynamics acting as “cell meeting rooms” and biocompatible niches whose properties deserve to be considered toward the development of new clinical procedures. Statement of SignificanceBrain tumor glioblastoma (GB) is one of the worst unmet clinical needs. To prevent the relapse in the resection cavity situation, new implantable biopolymer aerogel sponges loaded with a chemoattractant molecule were designed and preclinically tested as a prototype targeting the interaction between the initial tumor location and its attraction by the peritumoral environment. While not modifying global survival, biocompatible SDF1-loaded hyaluronic acid and silk fibroin sponges induce directional GB cell attraction and colonization in vitro and in rats in vivo. Interestingly, they strongly shaped GB tumors in contrast to random infiltrative growth in controls. These results provide original findings on application of exogenous engineered niches that shape tumors and serve as cell meeting rooms for further clinical developments.

Inflammation biomarkers in acute ischemic stroke according to different etiologies.

High throughput technologies provide new opportunities to further investigate the pathophysiology of ischemic strokes. The present cross-sectional study aimed to evaluate potential associations between the etiologic subtypes of ischemic stroke and blood-based proteins. We investigated the associations between ischemic stroke subtypes and a panel of circulating inflammation biomarkers in 364 patients included in the Stroke Cohort Augsburg (SCHANA). Stroke etiologies were categorized according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Serum concentrations of 52 biomarkers were measured using the Bio-Plex Pro™ Human Cytokine Screening Panel, ICAM-1 set and VCAM-1 set, plus the Pro™ Human TH17 cytokine sCD40L set and IL31 set (all Bio-Rad, USA). Multivariable linear regression models were used to examine associations. Point estimates were calculated as the mean difference in -standardized cytokine levels on the log2 -scale. Stromal-cell-derived-factor 1 alpha (SDF-1a) showed significantly higher serum levels in cardioembolic compared with large vessel atherosclerotic stroke (β = 0.48; 95% CI 0.22; 0.75; Padj = 0.036). Significantly lower levels of interleukin-6 (IL-6) (β = -0.53; 95% CI -0.84; -0.23; Padj = 0.036) and macrophage migration inhibitory factor (MIF) (β = -0.52; 95% CI -0.84; -0.21; Padj = 0.043) were found in the small vessel versus large vessel stroke subtype. Immune dysregulations observed in different stroke subtypes might help uncover pathophysiological mechanisms of the disease. Further studies are needed to validate identified biomarkers in diverse study populations before they can potentially be used in clinical practice to further improve stroke management and patient outcomes.

Accelerate wound healing by microscale gel array patch encapsulating defined SDF-1α gradient.

Recruiting endogenous stem cells to deliver signaling molecules is an attractive therapeutic strategy for the treatment of skin injuries. Although various signaling molecule delivery techniques have been developed, they are limited in their ability to accurately mimic the natural physiological process in which stem cells are recruited via signaling molecule concentration gradients. Hence, herein, we developed an approach to generate persistent signaling molecule concentration gradients in microscale gel arrays. Signaling molecule concentration gradients were established in each microscale gel via chemical conjugation and were maintained for >12days. Moreover, the microscale gel provided a suitable environment for bone mesenchymal stem cells (BMSCs) growth, with many BMSCs migrating toward the stromal cell-derived factor-1 alpha (SDF-1α) gradient in vitro. Subsequently, a patch was formulated by mounting a microscale gel array on an adhesive layer and designated as the SDF-1α gradient microscale gel array patch. In a murine full-thickness skin defect model, this patch effectively increased the recruitment of endogenous BMSCs, accelerated wound healing, and enhanced neovascularization. Moreover, the regenerated tissue was more similar to normal skin tissue, as evidenced by histological analysis. The SDF-1α gradient microscale gel array patch also proved its efficacy in a diabetic animal model. Taken together, our findings indicate that the microscale gel array system developed in this study provides an innovative strategy for accelerating wound healing by creating well-defined and localized SDF-1α gradients in vivo. Furthermore, the patch-like design will facilitate on-demand use, thereby further aiding with wound healing.

Abstract 1448: The YAP1/TEAD and NF-Kappa B transcription factors may cooperate to mediate prostate cancer progression

Abstract Metastatic castration-resistant prostate cancer is morbid and lethal. The transcriptional coregulator YAP1 (Yes-associated protein 1) is a nuclear effector of the Hippo pathway. The Hippo pathway regulates cell growth, motility, and carcinogenesis. Here, we investigated biochemical and functional interactions between YAP1 and the nuclear factor (NF) kappa B/RELA subunit in prostate cancer cell models. We demonstrated that endogenous YAP1 and RELA form protein complexes in the cell, as revealed by co-immunoprecipitation and western blotting. Compared with control, we found that combined treatment of cells with androgen and SDF1a (stromal cell-derived factor-1 alpha) or RANKL (receptor activator of NF-kappa Β ligand) enhanced the protein-protein interaction between YAP1 and RELA, as showed by proximity ligation assay. Our confocal microscopy experiment further showed that combined SDF1a and androgen treatment augmented the YAP1 and RELA colocalization relative to single-agent. Moreover, our promoter-reporter and RNAi experiments showed that genetic silencing YAP1 or TEAD protein, a key mediator of the YAP1 transcription, significantly reduced the NF-Kappa B promoter-reporter gene activity. Also, disruption of YAP1 activity by genetic and small molecule attenuated endogenous protein-protein interaction between TEAD and RELA. Furthermore, controlled expression of MST1/STK4, a potent inhibitor of YAP1, suppressed the NF-Kappa B-promoter reporter activity. Additionally, our unbiased bioinformatics analysis of the exiting ChIP-seq (chromatin immunoprecipitation-sequencing) data identified several genes likely co-regulated by the TEAD1-4 and NF-Kappa B transcription factors. Besides, our computational analysis of the TCGA and Stand Up To Cancer (SU2C) prostate cancer data sets indicated that expression of YAP/TEAD and NF-kappa B/RELA correlates in clinical cases. These findings suggest that cooperative androgen and cytokine signaling regulates Hippo/YAP and NF-Kappa B interaction and their functions. These may have critical roles in advanced prostate cancer downstream of the Hippo pathway. Citation Format: Bekir Cinar, Marwah M. Al-Mathkour, Abdulrahman M. Dwead, Ava M. Boston, Michael S. Lewis, Carlos S. Moreno. The YAP1/TEAD and NF-Kappa B transcription factors may cooperate to mediate prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1448.

Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study.

Increasing evidence shows that systemic inflammation is an embedded mechanism of proliferative diabetic retinopathy (PDR). However, the specific systemic inflammatory factors involved in this process remained obscure. The study aimed to identify the upstream and downstream systemic regulators of PDR by using Mendelian randomization (MR) analyses. We performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and PDR from FinnGen consortium (2,025 cases vs. 284,826 controls) and eight cohorts of European ancestry (398 cases vs. 2,848 controls), respectively. The inverse-variance-weighted method was adopted as the main MR method, and four additional MR methods (MR-Egger, weighted-median, MR-pleiotropy residual sum and outlier (MR-PRESSO), and MR-Steiger filtering methods) were used for the sensitivity analyses. Results from FinnGen and eight cohorts were pooled into a meta-analysis. Our results showed that genetically predicted higher stem cell growth factor-β (SCGFb) and interleukin-8 were positively associated with an elevated risk of PDR, with a combined effect of one standard deviation (SD) increase in SCGFb and interleukin-8 causing 11.8% [95% confidence interval (CI): 0.6%, 24.2%]) and 21.4% [95% CI: 3.8%, 41.9%]) higher risk of PDR, respectively. In contrast, genetically predisposition to PDR showed a positive association with the increased levels of growth-regulated oncogene-α (GROa), stromal cell-derived factor-1 alpha (SDF1a), monocyte chemotactic protein-3 (MCP3), granulocyte colony-stimulating factor (GCSF), interleukin-12p70, and interleukin-2 receptor subunit alpha (IL-2ra). Our MR study identified two upstream regulators and six downstream effectors of PDR, providing opportunities for new therapeutic exploitation of PDR onset. Nonetheless, these nominal associations of systemic inflammatory regulators and PDR require validation in larger cohorts.

Megrment the Level of SDF1-Α in the Serum of Patients with Urinary Tract Infection and Patients with Vaginal Infection

Urinary tract infection, Bacterial vaginosis as one of the global threats affecting millions of women and causing some time deaths around the world. Objective: This study aims to assess levels of SDF1 and IgA in patients with Urinary tract infection, Bacterial vaginosis, and people enjoying good health as a control group. Methods: Collecting medical information from (180) participants in the Imam Al-Sadiq General Teaching Hospital in Iraq-Babylon, the Gynecology Consultant, according to specific criteria, the subjects were divided into three groups: the control group, the patients (UTI, BV), while the demographic study included age, education, Jobs, and living Laboratory results, signs and symptoms, SDF1-α and IgA levels were assessed by the enzyme-linked immunosorbent assay (ELISA) technique. Results: The results revealed that there were significant variations in SDF1 and IgA between the UTI group, BV group, and control groups. SDF1 level with the UTI group was (1.206522 ±.0927277 pg/ml) and for patients with BV was(1.213735 ±.0661389 pg/ml) whereas the control group appear was (1.130013±.0496400 pg/ml), IgA level in the UTI patients was (64.252983 ± 7.5946759pg/ml) and patients with BV was (60.441928±6.1457661pg/ml) whereas the control group appears was (48.011745 ±4.7938613 pg/ml) Conclusion: They can be considered good indicators to give knowledge about the diagnosis of urinary tract infection and bacterial vaginosis, and help doctors to give appropriate medications. Keywords: Urinary tract infection, bacterial vaginosis, stromal cell-derived factor 1-alpha, Immunoglobulin A.

DEL-1 suppression attenuates atherosclerosis by modulating macrophagic GSK-3β/CEBP-β signaling pathway

ObjectiveThe study aims to investigate the effect of developmental endothelial locus-1(DEL-1) expression in atherosclerotic plaque formation and its mechanism. MethodsHuman left coronary arteries were collected to detect the DEL-1 expression. The ApoE−/− mice were used to establish the atherosclerosis mice model. The left coronary artery and mouse aorta were stained with HE, Oil Red O, and Movat staining. The DEL-1 levels, chemokines CXC chemokine receptor 4 (CXCR4) and its ligand stromal cell-derived factor-1alpha (SDF-1α), pathway protein glycogen synthase kinase-3β (GSK-3β), CCAAT enhanced binding protein β (C/EBPβ), and downstream inflammatory factors (C-X-C motif chemokine 2 (MIP-2or CXCL2), macrophage inflammatory protein-1alpha (MIP-1α or CCL3),Tumor Necrosis Factor alpha (TNF-α) were detected by immunoblotting and immunohistochemistry. Pearson correlation coefficient was used to analyze the correlation between DEL-1 gene expression and inflammatory factors in the lesion group and the correlation between DEL-1 gene expression and structure-related indexes. ResultsCompared with Control group(CON), the intravascular plaque area was widened, accompanied by narrowed lumens. The number of plaque foam cells was significantly increased in the high fat and high cholesterol (AS group) or AAV9-eGFP group (P < 0.05). Compared to CON, the enhanced fluorescence intensity of DEL-1 with CD68 in the AS or AAV9-eGFP groups. Diminished fluorescence of DEL-1 with CD68 expression in AAV9-CXCR4 group compared to AS group or AAV9-eGFP group. The DEL-1 and its downstream proteins in AS group or AAV9-eGFP group were mainly accumulated in the macrophage cytoplasm. The DEL-1 expression level was significantly and positively correlated with plaque area, lumen stenosis, plaque foam cell count, TNFα, CXCL2, and CCL3 levels. ConclusionDEL-1 inhibition decreases macrophagic inflammatory factors involved in atherosclerotic plaque formation.

Fabrication and characterization of bilayer scaffolds made of decellularized dermis/nanofibrous collagen for healing of full-thickness wounds.

Skin tissue engineering has progressed from simple wound dressings to biocompatible materials with desired physico-chemical properties that can deliver regenerative biomolecules. This study describes using a novel biomimetic hybrid scaffold of decellularized dermis/collagen fibers that can continuously deliver stromal cell-derived factor-1 alpha (SDF-1α) for skin regeneration. In diabetic rat models, the idea that sustained SDF-1α infusion could increase the recruitment of CXCR4-positive cells at the injury site and improve wound regeneration was investigated. The morphology of the scaffold, its biocompatibility, and the kinetics of SDF-1 release were all assessed. SDF-1α was successfully incorporated into collagen nanofibers, resulting in a 200-h continuous release profile. The microscopic observations exhibited that cells are attached and proliferated on proposed scaffolds. As evaluated by in vivo study and histological examination, fabricated scaffold with SDF-1α release capacity exhibited a remarkably more robust ability to accelerate wound regeneration than the control group. Besides, the SDF-1α-loaded scaffold demonstrated functional effects on the proliferation and recruitment of CD31 and CXCR4-positive cells in the wound bed. Additionally, no adverse effects such as hyperplasia or scarring were found during the treatment period. It may be concluded that the fabricated hybrid scaffold based on natural polymer opens up a new option for topical administration of bioactive molecules. We believe the SDF-1α-loaded hybrid scaffold has promise for skin tissue engineering.

Exploring causal correlations between inflammatory cytokines and systemic lupus erythematosus: A Mendelian randomization.

Previous studies have reported that a few inflammatory cytokines have associations with systemic lupus erythematosus (SLE)-for example, IL-6, IL-17, and macrophage inflammatory protein (MIP). This Mendelian randomization was conducted to further assess the causal correlations between 41 inflammatory cytokines and SLE. The two-sample Mendelian randomization utilized genetic variances of SLE from a large publicly available genome-wide association study (GWAS) (7,219 cases and 15,991 controls of European ancestry) and inflammatory cytokines from a GWAS summary containing 8,293 healthy participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted method. In addition, multiple sensitivity analyses including MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO were simultaneously applied to strengthen the final results. The results indicated that cutaneous T cell-attracting chemokine (CTACK) and IL-17 may be suggestively associated with the risk of SLE (odds ratio, OR: 1.21, 95%CI: 1.04-1.41, p = 0.015; OR: 1.37, 95%CI: 1.03-1.82, p = 0.029). In addition, cytokines including beta nerve growth factor, basic fibroblast growth factor, IL-4, IL-6, interferon gamma-induced protein 10, monokine induced by interferon-gamma, MIP1b, stromal cell-derived factor-1 alpha, and tumor necrosis factor-alpha are suggested to be the consequences of SLE disease (Beta: 0.035, p = 0.014; Beta: 0.021, p = 0.032; Beta: 0.024, p = 0.013; Beta: 0.019, p = 0.042; Beta: 0.040, p = 0.005; Beta: 0.046, p = 0.001; Beta: 0.021, p = 0.029; Beta: 0.019, p = 0.045; Beta: 0.029, p = 0.048). This study suggested that CTACK and IL-17 are probably the factors correlated with SLE etiology, while a couple of inflammatory cytokines are more likely to be involved in SLE development downstream.

Genistein, a Soybean Isoflavone, Promotes Wound Healing by Enhancing Endothelial Progenitor Cell Mobilization in Rats with Hemorrhagic Shock.

Severe trauma and hemorrhaging are often accompanied by delayed cutaneous wound healing. Soybean isoflavone is a natural phytoestrogen that has attracted great attention due to its protective effects against various injuries. Endothelial progenitor cells (EPCs) are precursor cells with directional differentiation characteristics. This study is to determine whether genistein (GEN), an isoflavone in soybean products, benefits wound healing in hemorrhagic shock (HS) rats by promoting EPC homing and to investigate the underlying mechanisms. In this study, it isfound that GEN promotes skin wound healing in HS rats, which is due at least partly to the mobilization of endogenous EPCs to the injury site via angiotensin II (Ang-II), stromal cell-derived factor-1alpha (SDF-1α), and transforming growth factor beta(TGF-β) signaling.

Peptides-tethered vascular grafts enable blood vessel regeneration via endogenous cell recruitment and neovascularization

Cardiovascular injuries cause huge morbidity and mortality worldwide. Arterial reconstructions are generally performed either by using native grafts or synthetic grafts, both of which are limited by several complications. Synthetic biodegradable polymers offer a promising platform, which may also be modified to foster in situ tissue regeneration through the recruitment of host cells. Vascular endothelial growth factor (VEGF) promotes endothelialization and neovascularization in vascular grafts, however, an overdose of VEGF may induce tumor-like vasculature, which requires alternative strategies. The objective of this study was to exploit prominin-1-derived VEGF-binding peptide (BP) to improve neovascularization and endothelialization, while stromal cell-derived factor 1-alpha (SDF-1α) peptide to encourage endogenous stem/progenitor cells mobilization and complement BP-mediated vascular remodeling. The BP and SDF-1α peptides were covalently conjugated with low molecular weight poly (ε-caprolactone) (LPCL) to afford LPCL-BP and LPCL-SDF-1α, respectively. Chemical analysis revealed successful modification of LPCL with peptides, which also displayed good cytocompatibility in vitro once blended along with high molecular weight PCL (HPCL). The bioactived vascular grafts were fabricated by blending LPCL-BP, LPCL-SDF-1α or dual peptide-polymer conjugates with HPCL. The in vivo tests of vascular grafts through rat abdominal aorta implantation model revealed that, compared with HPCL grafts, the dual peptides modified grafts exhibited superior patency and tissue regeneration at 4-week post-implantation, including stem cell recruitment, rapid endothelialization and functional SMC layer formation. Taken together, these results may have implications for the in situ regeneration of artificial blood vessels through the orchestration of host's responses and endogenous cell recruitment.

Fluorinated triphenylphosphonium analogs improve cell selectivity and invivo detection of mito-metformin.

Triphenylphosphonium (TPP+) conjugated compounds selectively target cancercells by exploiting their hyperpolarized mitochondrial membrane potential. Todate, studies have focused on modifying either the linker or the cargo of TPP+-conjugated compounds. Here, we investigated the biological effects ofdirect modification to TPP+ to improve the efficacy and detection of mito-metformin (MMe), a TPP+-conjugated probe we have shown to have promising preclinical efficacy against solid cancer cells. We designed, synthesized, and tested trifluoromethyl and methoxy MMe analogs (pCF3-MMe, mCF3-MMe, and pMeO-MMe) against multiple distinct human cancer cells. pCF3-MMe showed enhanced selectivity toward cancer cells compared to MMe, while retaining thesame signaling mechanism. Importantly, pCF3-MMe allowed quantitative monitoring of cellular accumulation via 19F-NMR invitro and invivo. Furthermore, adding trifluoromethyl groups to TPP+ reduced toxicity invivo while retaining anti-tumor efficacy, opening an avenue to de-risk these next-generation TPP+-conjugated compounds.