ABSTRACT
BACKGROUND: Neuroinflammation is a multifactorial condition related to glial cells and neurons activation, and it is implicated in CNS disorders including depression. BDNF is a crucial molecule that related to the pathology of depression, and it is the target of DNA methylation. DNA hydroxymethylation, an active demethylation process can convert 5-mC to 5-hmC by Tets catalyzation to regulate gene transcription. The regulatory function for BDNF gene in response to neuroinflammation remains poorly understood. METHODS: Neuroinflammation and depressive-like behaviors were induced by lipopolysaccharide (LPS) administration in mice. The microglial activation and cellular 5-hmC localization in the hippocampus were confirmed by immunostaining. The transcripts of Tets and BDNF were examined by qPCR method. The global 5-hmC levels and enrichment of 5-hmC in BDNF gene in the hippocampus were analyzed using dot bolt and hMeDIP-sequencing analysis. RESULTS: LPS administration induced a spectrum of depression-like behaviors (including behavioral despair and anhedonia) and increased expression of Iba-1, a marker for microglia activation, in hippocampus, demonstrating that LPS treatment cloud provide stable model of neuroinflammation with depressive-like behaviors as expected. Our results showed that Tet1, Tet2 and Tet3 mRNA expressions and consequent global 5-hmC levels were significantly decreased in the hippocampus of LPS group compared to saline group. We also demonstrated that 5-hmC fluorescence in the hippocampus located in excitatory neurons identified by CaMK II immunostaining. Furthermore, we demonstrated that the enrichment of 5-hmC in BDNF gene was decreased and corresponding BDNF mRNA was down-regulated in the hippocampus in LPS group compared to saline group. CONCLUSION: Neuroinflammation-triggered aberrant BDNF gene hydroxymethylation in the hippocampus is an important epigenetic element that relates with depression-like behaviors.
Subject(s)
Brain-Derived Neurotrophic Factor , Depression , Mice , Animals , Depression/genetics , Depression/metabolism , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Neuroinflammatory Diseases , Lipopolysaccharides , Hippocampus/metabolismABSTRACT
Mesoporous silica nanoparticles (MSNs) have been functionalized with supramolecular switches, composed of cleavable disulfide bond-containing alkylammonium stalks encircled by water-soluble sulfonatocalix[4,6]arenes, to result in smart mechanized MSNs. Cargo can be encased tightly in the nanopores of these mechanized MSNs in their closed state, but are released efficiently either in response to L-glutathione (GSH), by cleaving the disulfide bonds in the stalks, or in response to pH variation, by turning on the calixarene-based supramolecular switches. The higher concentration of GSH in cancer cell cytosol and the relatively lower pH value of cancer cell lysosome can simultaneously activate the mechanized MSNs, enabling them to release the pre-loaded cargo in place. This sufficient use of the different environment of cancer cells and normal healthy cells can enhance the targeting effect of delivery vehicles and effectively lower the side effects of delivered anti-cancer drugs. In vitro cytotoxicity tests suggest good biocompatibility and low toxicity of these newly developed drug-delivery systems.
Subject(s)
Calixarenes/pharmacology , Nanoparticles/chemistry , Silicon Dioxide/pharmacology , Calixarenes/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Molecular Structure , Particle Size , Porosity , Silicon Dioxide/chemistry , Structure-Activity Relationship , Surface PropertiesABSTRACT
A dynamic cross-linked supramolecular network of poly(glycidyl methacrylate)s derivative chains was constructed on mesoporous silica nanoparticles via disulfide bond and ion-dipole interactions between cucurbit[7]urils and protonated diamines in the polymer chains. This kind of multifunctional organic-inorganic hybrid material with pH- and glutathione- (GSH-) stimuli responsiveness can be applied to anticancer drug delivery and controlled release. Good release performance toward doxorubicin hydrochloride (DOX) was achieved under the simulative tumor intracellular environment (pH = 5.0, CGSH = 2-10 mM). Significantly, the release amount of DOX increased upon lowering the solution pH value and increasing the concentration of GSH, as demonstrated by a series of controlled release experiments. Furthermore, the DOX-loaded hybrid nanomaterials displayed apparent cell-growth inhibition effects to cancer cell lines, as evidenced by MTT assay and confocal laser scanning microscopy.
