Small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells improve postoperative cognitive dysfunction in mice with diabetes.

Postoperative cognitive dysfunction (POCD) is a common surgical complication. Diabetes mellitus (DM) increases risk of developing POCD after surgery. DM patients with POCD seriously threaten the quality of patients' life, however, the intrinsic mechanism is unclear, and the effective treatment is deficiency. Previous studies have demonstrated neuronal loss and reduced neurogenesis in the hippocampus in mouse models of POCD. In this study, we constructed a mouse model of DM by intraperitoneal injection of streptozotocin, and then induced postoperative cognitive dysfunction by transient bilateral common carotid artery occlusion. We found that mouse models of DM-POCD exhibited the most serious cognitive impairment, as well as the most hippocampal neural stem cells (H-NSCs) loss and neurogenesis decline. Subsequently, we hypothesized that small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-sEVs) might promote neurogenesis and restore cognitive function in patients with DM-POCD. iMSC-sEVs were administered via the tail vein beginning on day 2 after surgery, and then once every 3 days for 1 month thereafter. Our results showed that iMSC-sEVs treatment significantly recovered compromised proliferation and neuronal-differentiation capacity in H-NSCs, and reversed cognitive impairment in mouse models of DM-POCD. Furthermore, miRNA sequencing and qPCR showed miR-21-5p and miR-486-5p were the highest expression in iMSC-sEVs. We found iMSC-sEVs mainly transferred miR-21-5p and miR-486-5p to promote H-NSCs proliferation and neurogenesis. As miR-21-5p was demonstrated to directly targete Epha4 and CDKN2C, while miR-486-5p can inhibit FoxO1 in NSCs. We then demonstrated iMSC-sEVs can transfer miR-21-5p and miR-486-5p to inhibit EphA4, CDKN2C, and FoxO1 expression in H-NSCs. Collectively, these results indicate significant H-NSC loss and neurogenesis reduction lead to DM-POCD, the application of iMSC-sEVs may represent a novel cell-free therapeutic tool for diabetic patients with postoperative cognitive dysfunction.

Metabolism of Peptide Drugs and Strategies to Improve their Metabolic Stability.

BACKGROUND: Despite the therapeutic use of peptides is limited because of their metabolism in vivo, there are no systematic reviews explaining degradation of peptides by peptidases. This review summarizes peptidases present in the tissues and metabolic characteristics of peptides, and provides recent strategies for improving the metabolic stability of peptides. METHOD: We reviewed a number of peptidases including their functional groups, tissue localization and cleavage specificity. Given the broad distribution of peptidases in the body, several tissues, such as the liver, kidney, lung, blood, nasal epithelial cells, placenta and skin, have the capacity to metabolize peptides. We compared the metabolic characteristics of peptides in these tissues and then summarized strategies for improving peptide stability. RESULTS: In addition to the primary organs including liver, kidney, gastrointestinal tract and blood involved in peptide metabolism, other organs such as the lung, skin, placenta and nasal mucosa may also play a role in peptide degradation. At present, the main measures to improve the stability of the peptide include N- and/or C-terminal modification or substitution, D-amino acid or unnatural amino acid substitution, cyclization, backbone modification, nanoparticle formulations and increased molecular mass. CONCLUSION: This review summarized the key in vivo peptidases and their tissue distribution characteristics, and presented strategies to improve the metabolic stability and bioavailability of peptide drugs. These viewpoints will benefit the further development and utilization of peptide drugs.

Effects of endosulfan on the immune function of erythrocytes, and potential protection by testosterone propionate.

While the immunotoxicity of endosulfan has been studied, little is known about its influence on immune function associated with erythrocytes (RBC). The aim of this study was to investigate the possible effects of endosulfan, and any possible mitigation by testosterone propionate (TP), on erythrocyte immune function in a mouse model. To this end, rosette formation [as erythrocyte C3b receptor(E-C3bR) and erythrocyte immune complexes (E-IC)], as well as measures of the erythrocyte C3b receptor rosette-forming enhancing rate (RFER; reflecting immunoenhancing factor activity) and C3b receptor rosette-forming inhibitory rate (RFIR; reflecting immunosuppressive factor activity) were performed. The effects of RBC on regulating NK cell function or T-cell adherence were also analyzed. Lastly, to begin to assess potential mechanisms by which endosulfan could impact on the measured endpoints, CD35, CD58, and CD59 expression on RBC was evaluated; expression/mRNA levels of complement receptor I-related gene/protein y (Crry) on cells/splenic tissues was also assessed. The data show that E-C3bR rosette ratios decreased, and those of E-IC increased, due to endosulfan treatment. In these hosts, RFER (i.e., immunoenhancing factor in plasma) was decreased, but RFIR (i.e., immunosuppressive factor) was unchanged.There were no clear effects from endosulfan on RBC regulatory function against NK or T-cells. Lastly, Crry mRNA levels in tissues/cells from these mice were significantly decreased; however, CD59 and CD58 expression levels were unaffected. The data also show that TP co-treatment reversed or mitigated effects of endosulfan on each endpoint, in part, by two possible mechanisms; the TP may be increasing the activity of the innate immune enhancing factor, or, an anti-oxidant effect of TP might help to protect membrane structures and increase Crry stability on the RBC.

Assessing the ecological security of the Tibetan plateau: methodology and a case study for Lhaze County.

A system for assessing the ecological security of Lhaze County in China's Tibetan Autonomous Region was developed using a pressure-state-response model and the analytic hierarchy process. We then used this model to comprehensively evaluate the status of ecological security in Lhaze County. Our results showed that the ecological environment in Lhaze County has deteriorated from an 'early stages of damage status' in the 1980s to 'moderately damaged status' today. This deterioration has become a major barrier to local economic development and social advancement. Natural and social aspects related to the population explosion, resource exploitation, and climate change that led to this ecological deterioration are discussed. Furthermore, we have suggested proposals for improving the ecological environment that include controlling population growth and enhancing the system of laws that protect the environment, upgrading 3 882.6 ha of low-yield farmland, planting 2 425.8, 548.8, and 1 207.4 ha of shelter belts for farmland protection, soil and water conservation, and fuelwood, respectively, and seeding 2 358.1 ha of artificial grassland. In the meantime, we propose strengthening the controls that limit soil and water loss, and optimizing industrial sectors that aspire to achieve high-efficiency, ecologically responsible agriculture.