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Neurotrophic factors are essential for neuronal survival, plasticity, and development and have been implicated in the action mechanism of antidepressants. In this study, we assessed the neurotrophic factor-inducing and neuroprotective properties of antidepressants. In the first part of the study, we found that fluoxetine, imipramine, and milnacipran (i.p., 20 mg/kg/day for 1 week or 3 weeks) upregulated brain-derived neurotrophic factor in the striatum and substantia nigra both at 1 week and 3 weeks. In contrast, an increase in the glial-derived neurotrophic factor was more obvious at 3 weeks after the antidepressants treatment. Specifically, it was found that fluoxetine and imipramine are more potent in raising the levels of neurotrophic factors than milnacipran. Furthermore, antidepressants elevated the phosphorylation of extracellular signal-regulated-protein kinase (ERK1/2) and the serine/threonine kinase Akt. In the second part of the study, we compared the neuroprotective effects of fluoxetine, imipramine, and milnacipran in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Pretreament with fluoxetine, imipramine or milnacipran for 3 weeks reduced MPTP-induced dopaminergic neurodegeneration and microglial activation in the nigrostriatal pathway. Neurochemical analysis by HPLC exhibited that antidepressants attenuated the depletion of striatal dopamine. In consistent, beam test showed that behavioral impairment was ameliorated by antidepressants. Neuroprotective effects were more prominent in the fluoxetine or imipramine treatment group than in milnacipran treatment group. Finally, we found that neuroprotection of the antidepressants against 1-methyl-4-phenylpyridinium neurotoxicity in SH-SY5Y cells was attenuated by ERK or Akt inhibitor. These results indicate that neuroprotection by antidepressants might be associated with the induction of neurotrophic factors, and antidepressant could be a potential therapeutic intervention for treatment of Parkinson's disease.

Tumor microenvironment (TME)-responsive nanocarrier systems that keep the photosensitizer (PS) inactive during systemic circulation and then efficiently release or activate the PS in response to unique TME conditions have attracted much attention. Herein, we report novel TME-responsive, self-quenched polysaccharide nanoparticles (NPs) with a reactive oxygen species (ROS)-sensitive cascade. The PS, pheophorbide A (PhA), was conjugated to a water-soluble glycol chitosan (GC) through an ROS-sensitive thioketal (TK) linker. The amphiphilic GC–TK–PhA conjugates could arrange themselves into NPs and remain photoinactive due to their self-quenching effects. Upon reaching the ROS-rich hypoxic core of the tumor tissue, the NPs release the PS in a photoactive form by efficient, ROS-sensitive TK bond cleavage, thus generating potent phototoxic effects. Following near-infrared irradiation, the increase in locoregional ROS levels further accelerates the release and activation of PS. These cascade reactions caused a significant reduction in the tumor volume, demonstrating good antitumor potential.

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Non-neuronal cells are depleted using immunomagnetic separation and density-gradient centrifugation, resulting in purified primary neurons, obtained 800× faster, while maintaining superior viability and purity, compared to the conventional method.

Subunit vaccines consist of non-genetic material, such as peptides or proteins. They are considered safe because they have fewer side effects; however, they have low immunogenicity when used alone. We aimed to enhance the immune response of peptide-based vaccines by using self-assembled multimeric peptide amphiphiles (PAs). We designed two epitope PAs by conjugating epitope peptides from Enterovirus 71 (EV71) virus particle (VP) 1 and VP3 capsid proteins with different fatty acid chain lengths (VP1PA and VP3PA). These PAs self-assembled into supramolecular structures at a physiological pH, and the resulting structures were characterized using atomic force microscopy. Multi-epitope PAs (m-PAs) consisted of a 1:1 mixture of VP1PA and VP3PA solutions. To evaluate immunogenicity, m-PA constructs were injected with adjuvant subcutaneously into female Balb/c mice. Levels of antigen-specific immunoglobulin G (IgG) and IgG1 in m-PA-injected mice serum samples were analyzed using ELISA and Western blotting. Additionally, cytokine production stimulated by each antigen was measured in splenocytes cultured from immunized mice groups. We found that m-PA showed improved humoral and cellular immune responses compared to the control and peptide groups. The sera from m-PA immunized mice group could neutralize EV71 infection and protect host cells. Thus, self-assembled m-PAs can promote a protective immune response and can be developed as a potential platform technology to produce peptide vaccines against infectious viral diseases.

In this study, a reduction-responsive poly (ethylene glycol)-dexamethasone biarm conjugate was synthesized as intracellular targeted drug delivery carriers. The hydroxyl end group of methoxy poly (ethylene glycol) (mPEG) was modified to introduce a biarm structure with bioreducible disulfide bond and amine end groups. Dexamethasone (Dex) as a nuclear targeting moiety was conjugated to the amine end groups of mPEG biarm derivatives, mPEG-(NH 2 ) 2 or mPEG-(ss-NH 2 ) 2 , with or without bioreducible disulfide bonds. The bioreducible and nonreducible mPEG-Dex biarm conjugates, R-mPEG-Dex and N-mPEG-Dex, were synthesized and characterized by various analytical methods, proton nuclear magnetic resonance ( 1 H-NMR), Fourier transform infraredspectroscopy (FT-IR), dynamic light scattering (DLS), and fluorescence measurements. Amphiphilic mPEG-Dex conjugates self-assembled in aqueous solutions to form nanoparticles (NPs) with a size range of 130 to 150 nm, and their critical micelle concentrations (CMCs) were determined to be 12.4 and 15.3 mg/L, respectively, for bioreducible and nonreducible ones. The R-mPEG-Dex NPs maintained good colloidal stability in the presence of bovine serum albumin (BSA) for more than 1 week but demonstrated a significant change in colloidal stability in the presence of dithiothreitol (DTT). In DTT-containing phosphate-buffered saline (PBS), the bioreducible NPs showed not only reduction-responsive destabilization with PEG shedding but also thiol-dependent drug release profile. Our observations indicated that the R-mPEG-Dex NPs have a promising prospective as an efficient nanocarrier for intracellular targeted delivery of various anticancer drugs.