Although platelet-derived growth factors (PDGFs) and receptors (PDGFRs) are abundantly expressed in the central nervous system, their functions largely remain elusive. We investigated the role of PDGFR-β in tissue responses and functional recovery after photothrombolic middle cerebral artery occlusion (MCAO). In the normal adult mouse brain, PDGFR-β was mainly localized in neurons and in pericyte/vascular smooth muscle cells (PC/vSMCs). From 3 to 28 days after MCAO, postnatally induced systemic PDGFR-β knockout mice (Esr-KO) exhibited the delayed recovery of body weight and behavior, and larger infarction volume than controls. In Esr-KO, PC/vSMC coverage was decreased and vascular leakage of infused fluorescent-labeled albumin was extensive within the ischemic lesion, but not in the uninjured cerebral cortex. Angiogenesis levels were comparable between Esr-KO and controls. In another PDGFR-β conditional KO mouse (Nestin-KO), PDGFR-β was deleted in neurons and astrocytes from embryonic day 10.5, but was preserved in PC/vSMCs. After MCAO, vascular leakage and infarction volume in Nestin-KO were worse than controls, but partly improved compared with Esr-KO. Astroglial scar formation in both Esr-KO and Nestin-KO was similarly reduced compared with controls after MCAO. These data suggested that PDGFR-β signaling is crucial for neuroprotection, endogenous tissue repair, and functional recovery after stroke by targeting neurons, PC/vSMCs, and astrocytes.
Highlights d Oligodendrocyte progenitor cells (OPCs) disappeared and then repopulated in CAGG-iKO mice d Repopulated OPCs are partly derived from pericyte and/or mesenchymal cell population (PC/MC) d PC/MC-derived OPCs differentiate into MBP-expressing mature oligodendrocytes
Neural progenitor cells undergo identity transitions during development to ensure the generation different types of neurons and glia in the correct sequence and proportions. A number of temporal identity factors that control these transitions in progenitor competence have been identified, but the molecular mechanisms underlying their function remain unclear. Here, we asked how Casz1, the mammalian orthologue of Drosophila castor, regulates competence during retinal development. We show that Casz1 is required to control the transition between neurogenesis and gliogenesis. Using BioID proteomics, we reveal that Casz1 interacts with the nucleosome remodeling and deacetylase (NuRD) complex in retinal cells. Finally, we show that both the NuRD and the polycomb repressor complexes are required for Casz1 to promote the rod fate and suppress gliogenesis. As additional temporal identity factors have been found to interact with the NuRD complex in other contexts, we propose that these factors might act through this common biochemical process to regulate neurogenesis.
BackgroundAdipokines are involved in the pathogenesis of metabolic disorders including obesity and type 2 diabetes mellitus (T2DM). This study investigates the levels of leptin, resistin, visfatin, secreted frizzled-related protein 5 (SFRP5), monocyte chemoattractant protein-1 (MCP-1) and retinol-binding protein 4 (RBP4) and their correlations with clinical parameters of overweight and T2DM.MethodsWe recruited overweight 50 patients with T2DM, 88 non-overweight patients with T2DM, 29 overweight and 100 non-overweight individuals devoid of T2DM for this study. The levels of studied adipokines were measured by enzyme-linked immunosorbent assay and correlated with clinical parameters.ResultsThe levels of MCP-1 and SFRP5 were decreased while visfatin and RBP4 levels were increased in patients with T2DM compared to those in the control individuals (P < 0.01). Among patients with T2DM, leptin and resistin levels were higher while RBP4 levels were lower in patients with overweight T2DM compared to those in patients with non-overweight T2DM (P < 0.0001, 0.019 and 0.05, respectively). Leptin and MCP-1 levels were correlated with HOMA-IR, QUICKI and HOMA-β. Leptin/MCP-1 ratio was correlated with insulin levels, HOMA-IR and HOMA-β indexes. Resistin/RBP4, visfatin/MCP-1 and MCP-1/RBP4 ratios were strongly correlated with the levels of fasting glucose, HbA1c and HOMA-β. In addition, ROC curve analyses indicated a diagnostic potential of resistin/RBP4 and MCP-1/RBP4 indexes for T2DM (AUC = 0.81 and 0.83, respectively) and β-cell function (AUC = 0.76 and 0.74, respectively).ConclusionsAdipokines (leptin, resistin, visfatin, SFRP5, MCP-1, and RBP4) are associated with overweight and T2DM and may serve as a potential prognostic marker and therapeutic intervention for overweight-related T2DM.
The human amniotic membrane is a highly abundant and readily available tissue that may be useful for regenerative medicine and cell therapy. The amniotic membrane stem cells can differentiate into multiple cell lineages; they have low immunogenicity and anti-inflammatory functions. This research aims to examine the protocols for the isolation of human amniotic membrane stem cells, including their phenotypic characterization and in vitro potential for differentiation toward keratinocytes. Human placentas were obtained from selected cesarean-sectioned births. We isolated amniotic stem cells by trypsin and collagenase B digestion and centrifuged with Percoll. After monolayer expansion of adherent cells, the cells were characterized by immunocytology with octamer-binding transcription factor 4 and differentiated into keratinocytes by treating the cells with insulin, hydrocortisone, BMP-4, and vitamin C. Protocol for isolation of stem cells from amniotic membrane has high efficiency. Differentiation markers of stem cells into keratinocytes, such as vimentin, cytokeratin (CK) 14, and CK19, were determined by reverse transcription-polymerase chain reaction increase over time in culture. Stem cells isolated from the amniotic membrane can differentiate into keratinocytes. It has opened the prospect of using stem cells to regenerate skin and clinical applications.
Vitamin E (VitE) is a potent antioxidant and contributes as an apoptosis inhibitor by preventing apoptotic death by suppressing cell membrane scrambling with phosphatidylserine translocation and caspase activites. Fas ligand (FasL) is well known to induce cell apoptosis. Activation of phosphoinositide 3 kinase (PI3K) signalling is stimulated by VitE. The present study addressed the effects of VitE on survival of mouse dendritic cells (DCs) and signalling molecules underlying. To this end, mouse bone marrow cells were isolated and cultured to attain bone marrow-derived DCs (BMDCs). The cells were treated with FasL in the presence or absence of VitE. Western blotting and FACS analysis were performed to determine expression of signalling molecules and their involvement in DC apoptosis. As a result, FasL treatment resulted in activation of caspase 8 and an increased number of Annexin V+ cells, the effects were significantly suppressed when VitE was present in the cell culture. Importantly, the anti-apoptotic effects of VitE were abolished by using pharmacological inhibition of PI3K signaling with LY294002. Our results showed that VitE inhibited FasL-mediated DC apoptosis through PI3K signalling, the effect is expected to facilitate the survival of DCs and promote the immune response against pathogens. Keywords Caspase, Dendritic cell; Fas ligand; PI3K and vitamin E. References [1] J. Banchereau, R.M. Steinman, Dendritic cells and the control of immunity, Nature 392 (1998) 245-52.[2] E. Ingulli, A. Mondino, A. Khoruts, M.K. Jenkins, In vivo detection of dendritic cell antigen presentation to CD4(+) T cells, J Exp Med 185 (1997) 2133-41.[3] C. Yang, H.Z. Liu, Z.X. Fu, PEG-liposomal oxaliplatin induces apoptosis in human colorectal cancer cells via Fas/FasL and caspase-8, Cell Biol Int 36 (2012) 289-96.[4] Q.G. Yan, J.G. Shi, F. Zhang, Q.T. Zhao, X.W. Pang, R. Chen, P.Z. Hu, Q.L. Li, Z. Wang, G.S. 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Provinciali, Gamma- and delta-tocotrienols exert a more potent anticancer effect than alpha-tocopheryl succinate on breast cancer cell lines irrespective of HER-2/neu expression, Life Sci 86 (2010) 668-75.[12] A.A. Albahrani, R.F. Greaves, Fat-Soluble Vitamins: Clinical Indications and Current Challenges for Chromatographic Measurement, Clin Biochem Rev 37 (2016) 27-47.[13] E. Shumilina, N. Zahir, N.T. Xuan, F. Lang, Phosphoinositide 3-kinase dependent regulation of Kv channels in dendritic cells, Cell Physiol Biochem 20 (2007) 801-8.[14] X. Jin, L. Song, X. Liu, M. Chen, Z. Li, L. Cheng, H. Ren, Protective efficacy of vitamins C and E on p,p'-DDT-induced cytotoxicity via the ROS-mediated mitochondrial pathway and NF-kappaB/FasL pathway, PLoS One 9 (2014) e113257.[15] B.C. Richardson, N.D. Lalwani, K.J. Johnson, R.M. Marks, Fas ligation triggers apoptosis in macrophages but not endothelial cells, Eur J Immunol 24 (1994) 2640-5.[16] J. Tschopp, M. Irmler, M. 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Purpose Angiopoietin-Like3 is a protein that plays an important role in regulating plasma triglyceride concentrations by inhibiting the enzyme lipoprotein lipase. Lipid metabolism and glucose metabolism are closely related and interact with each other. ANGPTL3 may also be a factor involved in blood glucose regulation through an increase in free fatty acids generated from enhanced lipolysis in adipose tissue leading to insulin resistance. This study aimed to investigate plasma ANGPTL3 concentrations and their correlation with lipid and glucose metabolic markers in newly diagnosed type 2 Diabetes Mellitus patients. Subject and Methods A cross-sectional descriptive study was conducted on 98 healthy subjects (control group) and 103 patients with type 2 diabetes at the first diagnosis, without any treatment (patient group). Plasma ANGPTL3 concentration was quantified by the ELISA method. The study determines the correlation of ANGPTL3 concentration with some indicators reflecting lipid and glucose metabolism. Results The concentration of ANGPTL3 in the newly diagnosed type 2 Diabetes Mellitus patient group was lower than in the control group, the difference was statistically significant with p < 0.05. In the patient group: there was an inverse correlation between ANGPTL3 concentration and HDL-C concentration (r = −0.37; p<0.001), and a positive correlation with triglyceride concentration (r = 0.275; p < 0.05). There was no correlation between plasma ANGPTL3 levels and anthropometric indices, total cholesterol, HDL-C, glucose, HbA1C, insulin, and HOMA-IR. In the control group: there was no correlation between ANGPTL3 and any of the indicators mentioned above. Conclusion ANGPTL3 levels in newly diagnosed type 2 diabetes mellitus patients were statistically significantly lower than in healthy subjects. Plasma ANGPTL3 was positively correlated with triglyceride levels and inversely correlated with HDL-C levels in newly diagnosed type 2 Diabetes mellitus patients.
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