Type 2 Diabetes-Induced Hematopoietic Stem Cell Oxidant Stress Attenuates the Differentiation, Skews M1/M2 Specification of Monocytes/Macrophages and Delays Wound Healing in db/db Mice

Rationale: After recruitment to wounds, monocytes differentiate into macrophages which play a central role in all stages of wound healing. Wound healing is significantly delayed in type 2 diabetics. Although accumulating evidence suggests that delayed wound healing in type 2 diabetics is related to macrophages specification into M1/M2 phenotypes, the mechanism remains unknown. Objective: This study tested the hypothesis that type 2 diabetes induces hematopoietic stem cells (HSCs) oxidant stress that reduces their differentiation towards monocytes and skews the specification of M1/M2 phenotype, thereby causing delayed wound healing. Methods and Results: HSCs were sorted from bone marrow of WT and db/db type 2 diabetic mice. DCF staining showed significant oxidant accumulation in HSCs from db/db mice which was reversed by the antioxidant, N-acetylcysteine (NAC). Bone marrow monocyte concentration (FACS analysis of cell surface markers f4/80, cd14 and cd115) was significantly lower in db/db mice than in WT mice. NAC also reversed the reduced differentiation towards monocytes. Wound closure rate was significantly delayed in db/db mice. Macrophages were isolated from wounds and their concentration and M1/M2 phenotype were quantified by flow cytometry. During the inflammatory phase of wound healing, macrophage concentration was decreased and the proportion of M1 macrophages was lower in db/db mice than in WT mice. During new tissue formation phase, macrophage concentration was decreased and the proportion of M2 macrophage was lower, but M1 macrophage was higher in db/db mice than in WT mice. During tissue remodeling phase, macrophage concentration was increased and M1 macrophage remained higher in db/db mice, but no difference was observed in the proportion of M2 macrophages. The reduced differentiation of HSCs towards monocytes and the delayed wound closure phenotype of db/db mice could be transferred to WT mice by transplanting db/db HSCs into lethally irradiated WT mice. Conclusion: Type 2 diabetes-induced HSC oxidant stress impairs HSC differentiation towards monocytes, skews the M1/M2 specification of macrophages and thereby accounts for the delayed wound healing. Type 2 diabetes-induced HSC oxidant stress may be a heretofore unrecognized critical regulator of dysinflammation in type 2 diabetic

Parameter-free prediction of phase transition in PbTiO3 through combination of quantum mechanics and statistical mechanics

Thermodynamics of ferroelectric materials and their ferroelectric to paraelectric (FE-PE) transitions including those in PbTiO3 is commonly described by the phenomenological Landau theory and more recently by effective Hamiltonian and various potentials, all with model parameters fitted to experimental or theoretical data. Here we show that the zentropy theory, which considers the total entropy of a system as a weighted sum of entropies of configurations that the system may experience and the statistical entropy among the configurations, can predict the FE-PE transition without fitting parameters. For PbTiO3, the configurations are identified as the FE configurations with 90- or 180-degree domain walls in addition to the ground state of the FE configuration without domain wall. With the domain wall energies predicted from first-principles calculations based on the density functional theory in the literature as the only inputs, the FE-PE transition for PbTiO3 is predicted showing remarkable agreement with experiments, unveiling the microscopic fundamentals of the transition

Optimization of pre-concentration, entrainer recycle and pressure selection for the extractive distillation of acetonitrile-water with ethylene glycol

We optimize the extractive distillation process for separating the acetonitrile – water azeotropic mixture with ethylene glycol by using a multi-objective genetic algorithm for minimizing under purity constraints the total cost, the energy consumption and the separation efficiency. For the first time we have shown the interest of five aspects by considering them simultaneously 1) the pre-concentration column has been included and 2) there is no need to set a distillate composition constraint (like being at the azeotropic composition) in the pre-concentration column. 3) The operating pressure should be lower than 1 atm because it enhances the relative volatility for 1.0-1a class system. 4) A closed loop optimization must be run, to handle the effect of impurity in the entrainer recycle since too much impurity limits the main product recovery and purity from the extractive column. 5) All three columns process must be optimized together rather than sequentially and with multiple objectives. The studied system belongs to class 1.0-1a and the impurity of the recycled entrainer has strong effect on the purity of acetonitrile product. Overall, 17 variables are optimized; column trays, all feed locations, refluxes, entrainer flow rate and all distillate products; under purity constraints for the acetonitrile and water product and for the entrainer recycle impurity. Among nearly 400 designs satisfying the purity specifications, the design case 3 shows an energy consumption and TAC reduced by more than 20% than a literature reference case, thanks to smaller entrainer flow rate, a reduction of 32 trays and lower operating pressures. The best design is a trade-off between first a feasibility governed by thermodynamics through composition profiles and relative volatility maps and second process cost and energy demands

Hypercholesterolemia Accelerates the Aging Phenotypes of Hematopoietic Stem Cells by a Tet1-Dependent Pathway

Hypercholesterolemia accelerates the phenotypes of aging in hematopoietic stem cells (HSCs). As yet, little is known about the underlying mechanism. We found that hypercholesterolemia downregulates Ten eleven translocation 1 (Tet1) in HSCs. The total HSC population was increased, while the long-term (LT) population, side population and reconstitution capacity of HSCs were significantly decreased in Tet1(-/-) mice. Expression of the Tet1 catalytic domain in HSCs effectively restored the LT population and reconstitution capacity of HSCs isolated from Tet1(-/-) mice. While Tet1 deficiency upregulated the expression of p19 and p21 in HSCs by decreasing the H3K27me3 modification, the restoration of Tet1 activity reduced the expression of p19, p21 and p27 by restoring the H3K27me3 and H3K36me3 modifications on these genes. These results indicate that Tet1 plays a critical role in maintaining the quiescence and reconstitution capacity of HSCs and that hypercholesterolemia accelerates HSC aging phenotypes by decreasing Tet1 expression in HSCs

Recovery from hind limb ischemia is less effective in type 2 than in type 1 diabetic mice: Roles of endothelial nitric oxide synthase and endothelial progenitor cells

ObjectiveWe sought to directly compare the effects of type 1 and type 2 diabetes on postischemic neovascularization and evaluate the mechanisms underlying differences between these groups. We tested the hypothesis that type 2 diabetic mice have a greater reduction in endothelial nitric oxide synthase (eNOS) expression, a greater increase in oxidative stress, and reduced arteriogenesis and angiogenesis, resulting in less complete blood flow recovery than type 1 diabetic mice after induction of hind limb ischemia.MethodsHind limb ischemia was generated by femoral artery excision in streptozotocin-treated mice (model of type 1 diabetes), in Leprdb/db mice (model of type 2 diabetes), and in control (C57BL/6) mice. Dependent variables included eNOS expression and markers of arteriogenesis, angiogenesis, and oxidative stress.ResultsPostischemia recovery of hind limb perfusion was significantly less in type 2 than in type 1 diabetic mice; however, neither group demonstrated a significant increase in collateral artery diameter or collateral artery angioscore in the ischemic hind limb. The capillary/myofiber ratio in the gastrocnemius muscle decreased in response to ischemia in control or type 1 diabetic mice but remained the same in type 2 diabetic mice. Gastrocnemius muscle eNOS expression was lower in type 1 and 2 diabetic mice than in control mice. This expression decreased after induction of ischemia in type 2 but not in type 1 diabetic mice. The percentage of endothelial progenitor cells (EPC) in the peripheral blood failed to increase in either diabetic group after induction of ischemia, whereas this variable significantly increased in the control group in response to ischemia. EPC eNOS expression decreased after induction of ischemia in type 1 but not in type 2 diabetic mice. EPC nitrotyrosine accumulation increased after induction of ischemia in type 2 but not in type 1 diabetic mice. EPC migration in response to vascular endothelial growth factor was reduced in type 1 and type 2 diabetic mice vs control mice. EPC incorporation into tubular structures was less effective in type 2 diabetic mice. Extensive fatty infiltration was present in ischemic muscle of type 2 but not in type 1 diabetic mice.ConclusionType 2 diabetic mice displayed a significantly less effective response to hind limb ischemia than type 1 diabetic mice.Clinical RelevanceDiabetes is important in the pathogenesis of peripheral artery disease. The present study demonstrates that the vascular response to acute hind limb ischemia is dependent on the type of diabetes present. Type 2 diabetic mice (Leprdb/db) demonstrated significantly less effective blood flow recovery than type 1 diabetic mice (streptozotocin-induced). Moreover, the differences between diabetic groups appeared contingent, at least in part, on differences in endothelial nitric oxide, oxidant stress, and endothelial progenitor cell function between the two diabetic groups. Although direct extrapolation of animal data to the human experience must be made with caution, these findings indicate that the type of diabetes present, and not just the presence of diabetes per se, may be important in the initiation of progression of peripheral artery disease

Type 2 Diabetes Impairs the Ability of Skeletal Muscle Pericytes to Augment Postischemic Neovascularization in db/db Mice

Peripheral artery disease is an atherosclerotic occlusive disease that causes limb ischemia and has few effective noninterventional treatments. Stem cell therapy is promising, but concomitant diabetes may limit its effectiveness. We evaluated the therapeutic potential of skeletal muscle pericytes to augment postischemic neovascularization in wild-type and type 2 diabetic (T2DM) mice. Wild-type C57BL/6J and leptin receptor spontaneous mutation db/db T2DM mice underwent unilateral femoral artery excision to induce limb ischemia. Twenty-four hours after ischemia induction, CD45-CD34-CD146+ skeletal muscle pericytes or vehicle controls were transplanted into ischemic hindlimb muscles. At postoperative day 28, pericyte transplantation augmented blood flow recovery in wild-type mice (79.3 ± 5% vs. 61.9 ± 5%; P = 0.04), but not in T2DM mice (48.6% vs. 46.3 ± 5%; P = 0.51). Pericyte transplantation augmented collateral artery enlargement in wild-type (26.7 ± 2 µm vs. 22.3 ± 1 µm, P = 0.03), but not T2DM mice (20.4 ± 1.4 µm vs. 18.5 ± 1.2 µm, P = 0.14). Pericyte incorporation into collateral arteries was higher in wild-type than in T2DM mice (P = 0.002). Unexpectedly, pericytes differentiated into Schwann cells in vivo. In vitro, Insulin increased Nox2 expression and decreased tubular formation capacity in human pericytes. These insulin-induced effects were reversed by N-acetylcysteine antioxidant treatment. In conclusion, T2DM impairs the ability of pericytes to augment neovascularization via decreased collateral artery enlargement and impaired engraftment into collateral arteries, potentially via hyperinsulinemia-induced oxidant stress. While pericytes show promise as a unique form of stem cell therapy to increase postischemic neovascularization, characterizing the molecular mechanisms by which T2DM impairs their function is essential to achieve their therapeutic potential

Saw Palmetto Extract Inhibits Metastasis and Antiangiogenesis through STAT3 Signal Pathway in Glioma Cell

Signal transducer and activator of transcription factor 3 (STAT3) plays an important role in the proliferation and angiogenesis in human glioma. Previous research indicated that saw palmetto extract markedly inhibited the proliferation of human glioma cells through STAT3 signal pathway. But its effect on tumor metastasis and antiangiogenesis is not clear. This study is to further clear the impact of saw palmetto extract on glioma cell metastasis, antiangiogenesis, and its mechanism. TUNEL assay indicated that the apoptotic cells in the saw palmetto treated group are higher than that in the control group (p<0.05). The apoptosis related protein is detected and the results revealed that saw palmetto extract inhibits the proliferation of human glioma. Meanwhile pSTAT3 is lower in the experimental group and CD34 is also inhibited in the saw palmetto treated group. This means that saw palmetto extract could inhibit the angiogenesis in glioma. We found that saw palmetto extract was an important phytotherapeutic drug against the human glioma through STAT3 signal pathway. Saw palmetto extract may be useful as an adjunctive therapeutic agent for treatment of individuals with glioma and other types of cancer in which STAT3 signaling is activated