No abstract

Immunosuppressive CD11b+Gr1+ myeloid-derived suppressor cells and TGF-β have been shown to negatively regulate host immunity against allografts. Our results demonstrated that Smad3-deficient mice or mice reconstituted with Smad3-deficient hematopoietic cells rejected allogeneic skin or heart grafts in a significantly slower manner compared with littermates or wild-type (WT) control mice. Transplanted Smad3−/− recipients produced markedly less anti-donor IgG Abs, especially IgG1 and IgG2b subclasses. T cells in alloskin-grafted Smad3-deficient mice were more likely to participate in a Th2-type immune response, as evidenced by more Th2-specific transcription factor, GATA3 expression, and increased IL-4 and IL-10 production, as well as less Th1-specific transcription factor, T-bet expression, and decreased IL-2 and IFN-γ production. More CD11b+Gr1+ neutrophil infiltration and less monocyte/macrophage and T cell infiltration in allografts were observed in Smad3−/− recipients compared with WT recipients. Increased CXCL1 and CXCL2 as well as decreased CCL3, MCP-1, and RANTES chemokines in allografts of Smad3−/− recipients were consistently detected by real-time PCR. Further studies indicated that the increased CD11b+Gr1+ myeloid cells in Smad3-deficient mice were immunosuppressive and responsible for the delayed allograft rejection mainly via an NO-dependent pathway. Thus, this study identifies Smad3 as an intrinsic negative regulator that critically inhibits the differentiation and function of immunosuppressive CD11b+Gr1+ myeloid-derived suppressor cells.

Immunomodulatory activity of mesenchymal stem cells (MSCs) is largely mediated by paracrine factors. Our previous studies showed that activation of nuclear factor-kappa B (NF-κB) regulates cytokine/growth factor secretion by MSCs. This study aimed to elucidate the role of Rap1 (repressor/activator protein), a novel modulator involved in the NF-κB pathway, in regulating the immunomodulatory potency of MSCs in acute allograft rejection of heart transplantation. The immunosuppressive potency of wild-type MSCs (WT-MSCs) or Rap1-deficient MSCs (Rap1−/−-MSCs) was examined in mice with acute allograft rejection following heart transplantation. With a combination of immunosuppressant rapamycin at a dose of 1 mg/kg/d, WT-MSCs notably prolonged the survival of the transplanted heart compared with Rap1−/−-MSCs. Rap1−/−-MSCs displayed a marked insensitivity to inhibit the mixed lymphocyte reaction (MLR) due to impaired cytokine production and a significantly reduced activity of NF-κB signaling in vitro. Finally, transplantation of encapsulated WT-MSCs greatly prolonged the survival of the heart allograft compared with encapsulated Rap1−/−-MSCs. Our results indicate that Rap1 is essential to maintain the immunomodulatory function of MSCs. Deletion of Rap1 results in impaired immunomodulatory function of MSCs.

Methylglyoxal, a reactive dicarbonyl compound, is mainly formed from glycolysis. Methylglyoxal can lead to the dysfunction of mitochondria, the depletion of cellular anti-oxidation enzymes and the formation of advanced glycation ends. Previous studies showed that the accumulation of methylglyoxal and advanced glycation ends can impair the oocyte maturation and reduce the oocyte quality in aged and diabetic females. In this study, we showed that resveratrol, a kind of phytoalexin found in the skin of grapes, red wine and other botanical extracts, can alleviate the adverse effects caused by methylglyoxal, such as inhibition of oocyte maturation and disruption of spindle assembly. Besides, methylglyoxal-treated oocytes displayed more DNA double strands breaks and this can also be decreased by treatment of resveratrol. Further investigation of these processes revealed that methylglyoxal may affect the oocyte quality by resulting in excessive reactive oxygen species production, aberrant mitochondrial distribution and high level lipid peroxidation, and resveratrol can block these cytotoxic changes. Collectively, our results showed that resveratrol can protect the oocytes from methylglyoxal-induced cytotoxicity and this was mainly through the correction of the abnormity of cellular reactive oxygen species metabolism.

The natural product berberine (BBR), present in various plants, arouses great interests because of its numerous pharmacological effects. However, the further development and application of BBR had been hampered by its poor oral bioavailability. In this work, we report on polymer-lipid hybrid nanoparticles (PEG-lipid-PLGA NPs) loaded with BBR phospholipid complex using a solvent evaporation method for enhancing the oral BBR efficiency. The advantage of this new drug delivery system is that the BBR-soybean phosphatidylcholine complex (BBR-SPC) could be used to enhance the liposolubility of BBR and improve the affinity with the biodegradable polymer to increase the drug-loading capacity and controlled/sustained release. The entrapment efficiency of the PEG-lipid-PLGA NPs/BBR-SPC was observed to approach approximately 89% which is more than 2.4 times compared with that of the PEG-lipid-PLGA NPs/BBR. To the best of our knowledge, this is the first report on using polymer material for effective encapsulation of BBR to improve its oral bioavailability. The prepared BBR delivery systems demonstrated a uniform spherical shape, a well-dispersed core-shell structure and a small particle size (149.6 ± 5.1 nm). The crystallographic and thermal analysis has indicated that the BBR dispersed in the PEG-lipid-PLGA NPs matrix is in an amorphous form. More importantly, the enhancement in the oral relative bioavailability of the PEG-lipid-PLGA NPs/BBR-SPC was ∼343% compared with that of BBR. These positive results demonstrated that PEG-lipid-PLGA NPs/BBR-SPC may have the potential for facilitating the oral drug delivery of BBR.