Stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, are crucial for homing and migration of multiple stem cell types. Their potential role in mediating bone marrow-derived mesenchymal stem cell (BMSC) migration in areas of myocardial infarction (MI) has not been demonstrated. In this study, rat heart MI was created by left coronary artery ligation, and green fluorescent protein-labeled BMSCs were directly infused into the left ventricular cavity. Reverse transcriptase-polymerase chain reaction and Western blot analysis showed that SDF-1 was predominantly localized in the MI lesion, and its levels peaked by 3 to 7 days and were maintained at least 14 days. Additionally, this was matched with increased accumulation of BMSCs and an improvement in cardiac function. Furthermore, this effect was blocked by the phosphoinositide 3-kinase inhibitor, LY294002. In vitro experiments showed that CXCR4 expression by BMSCs was elevated during hypoxia and SDF-1 induced a concentration-dependent migration of BMSCs. This migration was CXCR4-dependent as confirmed by its total inhibition by AMD3100, a CXCR4-specific antagonist. Migration was also almost completely blocked by LY294002. Analysis showed that phosphorylated Akt was highly increased in SDF-1-treated BMSCs. Together these results demonstrated that SDF-1/CXCR4 may mediate the migration of BMSCs toward heart MI through activation of PI3K/Akt.

Background:The immunosuppressive activity of mesenchymal stem cells (MSCs) has been exploited to induce tolerance after organ transplantation. The indoleamine 2,3-dioxygenase (IDO) may have beneficial effects in the immunoregulatory properties of MSCs. It was recently revealed that exosomes derived from MSCs play important roles in mediating the biological functions of MSCs. This study aimed to explore the roles of exosomes derived from MSCs in the induction of immune tolerance.Methods:Dendritic cells (DCs) and T-cells were cultured with exosomes derived from rat bone marrow MSCs (BMSCs) overexpressing IDO1 or controls. For the in-vivo study, rats received heart transplants and were treated with exosomes from IDO-BMSCs and heart function was evaluated. Flow cytometry was used to detect expression of cell surface markers. Cytokine levels were detected in culture supernatants or serum samples. Protein and microRNA expressions in exosomes were investigated by chips.Results:Exosomes from IDO-BMSCs cultured with DCs and T-cells (1) downregulated CD40, CD86, CD80, MHC-II, CD45RA, CD45RA+CD45RB, OX62, and upregulated CD274 expression, (2) increased the number of regulatory T-cells (Tregs) and decreased the number of CD8+ T-cells, and (3) decreased the levels of pro-inflammatory cytokines, but increased the levels of anti-inflammatory cytokines compared with the other groups. Transplanted rats, which were injected with exosomes from IDO-BMSCs, had reduced allograft-targeting immune responses and improved cardiac allograft function. Exosomes secreted by IDO-BMSCs exhibited significant upregulations of the immunoregulatory protein FHL-1, miR-540-3p, and a downregulation of miR-338-5p.Conclusion:Exosomes derived from IDO-BMSCs can be used to promote immunotolerance and prolong the survival of cardiac allografts.

This study aimed to investigate whether exosomes secreted by mouse GATA-4-expressing bone marrow mesenchymal stem cells (BMSCs) could induce BMSC differentiation into myocyte precursors, decrease cardiomyocyte apoptosis, and improve cardiac function following myocardial infarction (MI). BMSCs were transduced with a lentivirus carrying a doxycycline (DOX)-inducible GATA-4 or control lentivirus, and secreted exosomes from these BMSCs were collected and co-cultured with BMSCs or cardiomyocytes under hypoxic and serum free conditions. Furthermore, exosomes were injected into mice 48 h after MI. Cardiac function was evaluated by echocardiography at 48, 72, and 96 h after exosome treatment. Quantitative PCR showed that co-culture of BMSCs with GATA-4-BMSC exosomes increased cardiomyocyte-related marker expression. Co-culture of GATA-4-BMSC exosomes with cardiomyocytes in anoxic conditions decreased apoptosis as detected by flow cytometry. Injection of GATA-4-BMSC exosomes in mice 48 h after MI increased cardiac function over the next 96 h; increased cardiac blood vessel density and number of c-kit-positive cells and decreased apoptotic cardiomyocyte cells were also observed. Differential expression of candidate differentiation- and apoptosis-related miRNAs and proteins that may mediate these effects was also identified. Exosomes isolated from GATA-4-expressing BMSCs induce differentiation of BMSCs into cardiomyocyte-like cells, decrease anoxia-induced cardiomyocyte apoptosis, and improve myocardial function after infarction.

Considering the potential hazardous effects of disinfectant residues on environment, organisms and biodiversity, the sharp rise in use of disinfectants during COVID-19 pandemic has been considered highly likely to cause worldwide secondary disasters in ecosystems and human health. This questionnaire-based survey investigated the impact of COVID-19 outbreak on household disinfectant product consumption levels and behaviour of 3667 Chinese residents. In particular, in the context that no strategy is currently available to minimize the disinfectant pollution, based on the similarities between disinfectants and pharmaceuticals, we proposed a perspective of ecopharmacovigilance (EPV), which is an effective measure to minimize the environmental risks posed by pharmaceuticals using drug administration protocols, for disinfectant environmental risk management. The public’s environmental perceptions, attitudes and the related practices regarding household disinfectant consumption from an EPV perspective were also included in the study. The results showed that the COVID-19 outbreak caused a tremendous rise in the public’s household disinfectant consumption and usage levels in China. After the COVID-19 outbreak, the chlorine-based and alcohol-based disinfectants were considered as the most preferred products for household disinfection and hand sanitization, respectively. Importantly, the Chinese public’s environmental perceptions and practice on disinfectants were poor. Less than half respondents had positive attitudes toward the source control of disinfectant pollution. The population groups including females, the middle aged adults, those having healthcare professional background, as well as the higher-educated could be focused on to develop targeted efforts for the future control of disinfectant pollution in environment.

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and Technology, China. Design of the study, manuscript writing, critical revision, supervised all phases of the study.

Macrophages are largely involved in the whole process of atherosclerosis from an initiation lesion to an advanced lesion. Endothelial disruption is the initial step and macrophage-derived foam cells are the hallmark of atherosclerosis. Promotion of vascular integrity and inhibition of foam cell formation are two important strategies for preventing atherosclerosis. How can we inhibit even the reverse negative role of macrophages in atherosclerosis? The present study was performed to investigate if overexpressing endogenous human vascular endothelial growth factor (VEGF) could facilitate transdifferentiation of macrophages into endothelial-like cells (ELCs) and inhibit foam cell formation. We demonstrated that VEGF-modified macrophages which stably overexpressed human VEGF (hVEGF165) displayed a high capability to alter their phenotype and function into ELCs in vitro. Exogenous VEGF could not replace endogenous VEGF to induce the transdifferentiation of macrophages into ELCs in vitro. We further showed that VEGF-modified macrophages significantly decreased cytoplasmic lipid accumulation after treatment with oxidized LDL (ox-LDL). Moreover, down-regulation of CD36 expression in these cells was probably one of the mechanisms of reduction in foam cell formation. Our results provided the in vitro proof of VEGF-modified macrophages as atheroprotective therapeutic cells by both promotion of vascular repair and inhibition of foam cell formation.

Infantile hemangioma is the most common benign tumor in infants. Many studies have confirmed that basic fibroblast growth factor (bFGF) and its key receptor FGFR1 are highly expressed in hemangioma. Moreover, several miRNAs can regulate angiogenesis. In this regard, miR-424 often plays a role as tumor suppressor gene. This study was designed to investigate the mechanism of miR-424 in infantile skin hemangioma. Our results showed low expression of miR-424 in infantile skin hemangioma tissues, and that miR-424 overexpression downregulated FGFR1 expression in hemangioma-derived endothelial cells, while miR-424 inhibition upregulated FGFR1 expression. Luciferase reporter analysis confirmed that FGFR1 was a target gene of miR-424. CCK-8, flow cytometry, transwell migration and tube formation assays demonstrated that miR-424 overexpression inhibited cell proliferation, migration and tube formation, at least in part by blocking the bFGF/FGFR1 pathway. In contrast, miR-424 inhibition significantly enhanced these functions. Furthermore, miR-424 overexpression significantly inhibited ERK1/2 phosphorylation, whereas miR-424 inhibition enhanced ERK1/2 phosphorylation. In conclusion, miR-424 could suppress the bFGF/FGFR1 pathway, thereby inhibit ERK1/2 phosphorylation, and thus inhibit cell proliferation, migration and tube formation capabilities and the development of infantile skin hemangioma.