Dihydroartemisinin (DHA), a widely used antimalarial agent, has clinical potential for the treatment of hepatic carcinoma. Although chemotherapy is indispensable for tumor therapy, it is generally limited by poor solubility, low efficiency, rapid clearance, and side effects. As an emerging treatment method, photothermal therapy (PTT) has many outstanding properties, but suffers from poor photostability of photosensitizer and incomplete ablation. Multimodal therapies could combine the advantages of different therapy methods to improve antitumor efficiency. Hence, we designed a nano-delivery system (ICG&DHA@ZIF-8) using zeolitic imidazolate framework-8 (ZIF-8) with a high porous rate and pH sensitivity property, to co-load DHA and indocyanine green (ICG). Dynamic light scattering and transmission electron microscopy were used to characterize the prepared nanoparticles. The photothermal conversion and drug release performances of ICG&DHA@ZIF-8 were investigated. In vitro antitumor efficacy and cellular uptake were studied. The mechanism of the combination treatment was studied by reactive oxygen species level detection and western blot assays. In vivo antitumor assays were then studied with the guidance of ex vivo imaging. The results showed that the ICG&DHA@ZIF-8 based combination therapy could efficiently kill hepatic carcinoma cells and suppress tumor growth. This research provides a potential nanodrug for the treatment of hepatic carcinoma.

Protein posttranslational modification regulates synaptic protein stability, sorting and trafficking, and is involved in emotional disorders. Yet the molecular mechanisms regulating emotional disorders remain unelucidated. Here we report unknown roles of protein palmitoylation/nitrosylation crosstalk in regulating anxiety-like behaviors in rats. According to the percentages of open arm duration in the elevated plus maze test, the rats were divided into high-, intermediate- and low-anxiety groups. The palmitoylation and nitrosylation levels were detected by acyl-biotin exchange assay, and we found low palmitoylation and high nitrosylation levels in the basolateral amygdala (BLA) of high-anxiety rats. Furthermore, we observed that 2-bromopalmitate (2-BP), a palmitoylation inhibitor, induced anxiety-like behaviors, accompanied with decreased amplitude and frequency of mEPSCs and mIPSCs in the BLA. Additionally, we also found that inhibiting nNOS activity with 7-nitroindazole (7-NI) in the BLA caused anxiolytic effects and reduced the synaptic transmission. Interestingly, diazepam (DZP) rapidly elevated the protein palmitoylation level and attenuated the protein nitrosylation level in the BLA. Specifically, similar to DZP, the voluntary wheel running exerted DZP-like anxiolytic action, and induced high palmitoylation and low nitrosylation levels in the BLA. Lastly, blocking the protein palmitoylation with 2-BP induced an increase in protein nitrosylation level, and attenuating the nNOS activity by 7-NI elevated the protein palmitoylation level. Collectively, these results show a critical role of protein palmitoylation/nitrosylation crosstalk in orchestrating anxiety behavior in rats, and it may serve as a potential target for anxiolytic intervention.

Several lines of evidence implicate that chronic periodontitis (CP) increases the risk of mental illnesses, such as anxiety and depression, yet, the associated molecular mechanism for this remains poorly defined. Here, it is reported that mice subjected to CP exhibited depression‐like behaviors and hippocampal memory deficits, accompanied by synapse loss and neurogenesis impairment in the hippocampus. RNA microarray analysis disclosed that albumin D‐site‐binding protein (DBP) is identified as the most prominently upregulated target gene following CP, and in vivo and in vitro immunofluorescence methods showed that DBP is preferentially expressed in microglia but not neurons or astrocytes in the hippocampus. Interestingly, it is found that the expression of DBP is significantly increased in microglia after CP, and knockdown of microglial DBP ameliorated the behavioral abnormality, as well as reversed the synapse loss and hippocampal neurogenesis damage induced by CP. Furthermore, DBP knockdown improved the CP‐induced hippocampal inflammation and microglial polarization. Collectively, these results indicate a critical role of DBP in orchestrating chronic periodontitis‐related behavioral abnormality, hippocampal synapse loss and neurogenesis deficits, in which the microglial activation may be indispensably involved.

Background A-kinase anchoring protein 79/150 (AKAP150) has been suggested to be involved in learning and memory, and synaptic plasticity in the hippocampus is closely associated with memory. However, its effect and underlying mechanisms have not yet been fully elucidated. Result Here, we show that there is a significant increase in global and AKAP150 palmitoylation level after high frequency stimulation (HFS). 2-bromopalmitic acid (2-BP), a palmitoylation inhibitor, attenuated the increased palmitoylation level of AKAP150, and abolished the increased interaction between AKAP150 and postsynaptic density protein 95 (PSD-95) induced by HFS. We also found that HFS increased the synaptic expression of protein kinase A (PKA), but not calcineurin (CaN), and the HFS-mediated high affinity binding of PKA to AKAP150 was reversed by 2-BP. Furthermore, the activity of DHHC2, an enzyme responsible for palmitoylation of AKAP150, was upregulated after HFS, and DHHC2 knockdown decreased the level of glutamate receptor 1 phosphorylation at Ser845, as well as induced an impairment of long term potentiation (LTP) in the hippocampus. Importantly, DHHC2 knockdown in the hippocampus impaired the LTP induced by fear conditioning, as well as fear memory. Conclusion Our results suggest that DHHC2-mediated AKAP150 palmitoylation plays a critical role in the regulation of hippocampal synaptic plasticity and fear memory.