The overexpression of RBM3 alleviates TBI-induced behaviour impairment and AD-like tauopathy in mice.

The therapeutic hypothermia is an effective tool for TBI-associated brain impairment, but its side effects limit in clinical routine use. Hypothermia up-regulates RNA-binding motif protein 3 (RBM3), which is verified to protect synaptic plasticity. Here, we found that cognitive and LTP deficits, loss of spines, AD-like tau pathologies are displayed one month after TBI in mice. In contrast, the deficits of LTP and cognitive, loss of spines and tau abnormal phosphorylation at several sites are obviously reversed in TBI mice combined with hypothermia pre-treatment (HT). But, the neuroprotective role of HT disappears in TBI mouse models under condition of blocking RBM3 expression with RBM3 shRNA. In other hand, overexpressing RBM3 by AAV-RBM3 plasmid can mimic HT-like neuroprotection against TBI-induced chronic brain injuries, such as improving LTP and cognitive, loss of spines and tau hyperphosphorylation in TBI mouse models. Taken together, hypothermia pre-treatment reverses TBI-induced chronic AD-like pathology and behaviour deficits in RBM3 expression dependent manner, RBM3 may be a potential target for neurodegeneration diseases including Alzheimer disease.

Tespa1 deficiency reduces the antitumour immune response by decreasing CD8+T cell activity in a mouse Lewis lung cancer model.

Thymocyte-expressed, positive selection-associated 1 (Tespa1) is a key molecule in T-cell development and has been linked to immune diseases. However, its role in antitumour CD8+T cell immunity remains unclear. Here, we demonstrated that Tespa1 plays an important role in antitumour CD8+T cell immunity. First, compared with wild-type (WT) mice, Lewis lung cancer cells grew faster in Tespa1 knockout (Tespa1-/-) mice, with reduced apoptosis, and decreased CD8+T cells in peripheral blood and tumor tissues. Second, the proportion of CD8+T and Th1 cells in the splenocytes of Tespa1-/- mice was lower than that in WT mice. Third, Tespa1-/- CD8+ tumor-infiltrating lymphocytes (TILs) showed weakened proliferation, invasion, cytotoxicity, and protein expression of IL-2 signalling pathway components compared to WT CD8+TILs. Furthermore, PD-1 expression in CD8+TILs was higher in Tespa1-/- than in WT mice. Lastly, CD8+TILs in WT mice improved the antitumour ability of Tespa1-/- mice. In conclusion, these findings suggest that Tespa1 plays a critical role in the tumor immune system by regulating CD8+T cells.

Lumiflavin Reduces Cisplatin Resistance in Cancer Stem-Like Cells of OVCAR-3 Cell Line by Inducing Differentiation.

Ovarian cancer stem-like cells (CSCs) play a vital role in drug resistance and recurrence of ovarian cancer. Inducing phenotypic differentiation is an important strategy to enhance the effects of chemotherapy and reduce the drug resistance of CSCs. This study found that lumiflavin, a riboflavin decomposition product, reduced the development of CSC resistance and enhanced the chemotherapy effect of cisplatin (DDP) on CSCs in DDP-resistant ovarian cancer OVCAR-3 cell line (CSCs/DDP) and was related to the induction of CSC phenotypic differentiation. Results showed that the development of DDP-resistant OVCAR-3 cells was related to the increase in the proportion of CSCs/DDP, and the treatment with lumiflavin reduced the DDP-resistance levels of OVCAR-3 cells and proportion of CSCs/DDP. Further investigation found that lumiflavin synergistic with DDP increased apoptosis, decreased mitochondrial membrane potential, and inhibited the clonal formation of CSCs/DDP. Meanwhile, in vivo experiments showed that lumiflavin dose-dependently enhanced the chemotherapy effect of DDP on tumor-bearing nude mice inoculated by CSCs/DDP. Lumiflavin treatment also reduced the ratio of CD133+/CD177+ to CD44+/CD24 cells, which is the identification of CSCs, in CSCs/DDP. In addition, transcriptome sequencing results suggested that the role of lumiflavin was related to the notch and stem cell pathway, and Western blot analysis showed that lumiflavin inhibited the protein expression of notch signaling pathway in CSCs/DDP. In conclusion, lumiflavin reduces the development of the drug resistance of OVCAR-3 cell and increases the sensitivity of CSCs/DDP to DDP by inducing phenotypic differentiation, which may have a potential role in the chemotherapy treatment of ovarian cancer.

Inhibition of mTORC1 improves STZ-induced AD-like impairments in mice.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share some pathological features, including tau hyperphosphorylation and deficits in insulin signaling, but the underlying mechanism and effective drugs for treating AD are unknown. The AD-like brain impairments are almost same in both of mouse type 2 DM models induced by the multiple low-dose intraperitoneal (i.p.) streptozotocin (STZ) injection and twice intracerebroventricular (i.c.v.) STZ injection. We found that memory disorders, impairment of insulin signaling, and AD-like tauopathies were exhibited in two different STZ-induced mouse models and that the level of Advanced Glycation End Products (AGEs) was increased in two STZ mouse models. Inhibition of mTORC1 with rapamycin reversed the deficits of insulin signaling associated kinases activity, decreased levels of AGEs and AD-like tau phosphorylation, and also improved memory deficit in both STZ mice. Rapamycin attenuated HG-induced tau hyperphosphorylation via the AKT/AMPK/GSK-3ß pathways and p70S6K in SH-SY5Y cells. Taken together, these data demonstrated that rapamycin improved STZ-induced AD-like tauopathies and memory deficit in mice via improving p70S6K and AKT/AMPK/GSK-3ß signaling and decreasing AGEs. Therefore, regulating insulin signaling via mTORC1 is a new strategy for preventing T2DM-associated AD, and mTORC1 is a potential drug target.

Enriched gestation activates the IGF pathway to evoke embryo-adult benefits to prevent Alzheimer's disease.

BACKGROUND: Building brain reserves before dementia onset could represent a promising strategy to prevent Alzheimer's disease (AD), while how to initiate early cognitive stimulation is unclear. Given that the immature brain is more sensitive to environmental stimuli and that brain dynamics decrease with ageing, we reasoned that it would be effective to initiate cognitive stimulation against AD as early as the fetal period. METHODS: After conception, maternal AD transgenic mice (3 × Tg AD) were exposed to gestational environment enrichment (GEE) until the day of delivery. The cognitive capacity of the offspring was assessed by the Morris water maze and contextual fear-conditioning tests when the offspring were raised in a standard environment to 7 months of age. Western blotting, immunohistochemistry, real-time PCR, immunoprecipitation, chromatin immunoprecipitation (ChIP) assay, electrophysiology, Golgi staining, activity assays and sandwich ELISA were employed to gain insight into the mechanisms underlying the beneficial effects of GEE on embryos and 7-10-month-old adult offspring. RESULTS: We found that GEE markedly preserved synaptic plasticity and memory capacity with amelioration of hallmark pathologies in 7-10-m-old AD offspring. The beneficial effects of GEE were accompanied by global histone hyperacetylation, including those at bdnf promoter-binding regions, with robust BDNF mRNA and protein expression in both embryo and progeny hippocampus. GEE increased insulin-like growth factor 1 (IGF1) and activated its receptor (IGF1R), which phosphorylates Ca2+/calmodulin-dependent kinase IV (CaMKIV) at tyrosine sites and triggers its nuclear translocation, subsequently upregulating histone acetyltransferase (HAT) and BDNF transcription. The upregulation of IGF1 mimicked the effects of GEE, while IGF1R or HAT inhibition during pregnancy abolished the GEE-induced CaMKIV-dependent histone hyperacetylation and BDNF upregulation. CONCLUSIONS: These findings suggest that activation of IGF1R/CaMKIV/HAT/BDNF signaling by gestational environment enrichment may serve as a promising strategy to delay AD progression.

Deletion of Type-2 Cannabinoid Receptor Induces Alzheimer's Disease-Like Tau Pathology and Memory Impairment Through AMPK/GSK3ß Pathway.

Although several studies have shown that type-2 cannabinoid receptor (CB2R) is involved in Alzheimer's disease (AD) pathology, the effects of CB2R on AD-like tau abnormal phosphorylation and its underlying mechanism remain unclear. Herein, we employed the CB2R-/- mice as the animal model to explore roles of CB2R in regulating tau phosphorylation and brain function. We found that CB2R-/- mice display AD-like tau hyperphosphorylation, hippocampus-dependent memory impairment, increase of GSK3ß activity, decrease of AMPK and Sirt1 activity and mitochondria dysfunction. Interestingly, AICAR or resveratrol (AMPK agonist) could efficiently rescue most alternations caused by solo deletion of CB2R in CB2R-/- mice. Moreover, JWH133, a selective agonist of CB2R, reduces phosphorylation of tau and GSK3ß activity in HEK293 tau cells, but the effects of JWH133 on phosphorylation of tau and GSK3ß disappeared while blocking AMPK activity with compound C or Prkaa2-RNAi. Taken together, our study indicated that deletion of CB2R induces behavior damage and AD-like pathological alternation via AMPK/GSK3ß pathway. These findings proved that CB2R/AMPK/GSK3ß pathway can be a promising new drug target for AD.

Hypothermia pretreatment improves cognitive impairment via enhancing synaptic plasticity in a traumatic brain injury model.

Posttraumatic hypothermia attenuates cognitive deficits caused by TBI when it is administered at an early stage. However, little is known regarding the effect of hypothermia pretreatment on cognitive deficits one month after TBI. In the current study, the behavior test revealed that hypothermia pretreatment mitigates the learning and memory impairment induced by TBI in mice. Hypothermia treatment significantly increased the expression of PSD93, PSD95 and NR2B one month after TBI in the cortex and hippocampus compared with the normothermia group. Hypothermia pretreatment also restored the decreased spine number and the impairment in LTP and decreased the number of activated microglia one month after TBI. On the other hand, hypothermia pretreatment increased glucose metabolism in TBI mice. Taken together, these data suggested that hypothermia pretreatment is an effective method with which to prevent spine loss, maintain normal LTP and preserve learning and memory function after TBI. The neuroprotective role might be associated with the preservation of postsynaptic protein expression, the inhibition of activated microglia and the increase in glucose metabolism.

Transient Receptor Potential-canonical 1 is Essential for Environmental Enrichment-Induced Cognitive Enhancement and Neurogenesis.

Transient receptor potential-canonical 1 (TRPC1) plays a crucial role in neuronal survival, nerve regeneration, and protects neurons from neurotoxic injury, but it is not reported whether or how TRPC1 may affect learning and memory. Here, we found that TRPC1 knockout did not significantly affect the spatial learning and memory ability when the mice were housed in standard cages (SC). Interestingly, after the mice were exposed to environmental enrichment (EE) for 4 weeks, TRPC1 knockout abolished the EE-induced spatial memory enhancement, LTP induction, and neurogenesis in hippocampal DG subset. By stereotaxic infusion of the recombinant adeno-associated viruses (rAAV)-TRPC1 into the hippocampal DG subsets bilaterally, we observed that the EE-associated neurogenesis, LTP induction and the cognitive enhancement were efficiently rescued in TRPC1 knockout mice. EE increased the phosphorylation levels of ERK, p38, and cyclic AMP response element-binding protein (CREB) in wild-type mice, whereas the activation of ERK and CREB was not seen in TRPC1 knockout mice, and the phosphorylation of p38 was same in EE-TRPC1-/- and WT-EE. Finally, EE increased TRPC1 expression and overexpression of TRPC1 increased neurogenesis and activated ERK/CREB pathway in the wild-type mice. These findings suggest that TRPC1 is indispensable for the EE-induced hippocampal neurogenesis and cognitive enhancement.

[The effects of Shadu Cao Mixture on immune functions of immunosuppression mice].

OBJECTIVE: To investigate the effects of Shadu Cao Mixture (SDCM, traditional Chinese medicine) on immune functions of immunosuppression mice. METHODS: Fifty BALB/C mice were randomly divided into blank control group, model group, SDCM low-dose, middle-dose and high-dose group. Except the blank control group, other groups were intraperitoneal injected with cyclophosphamide (40 mg/kg) to establish immunosuppression mice model. The blank control group and model group received gavage administration with nonnal saline, while the other groups received gavage administration with different doses of SDCM (10, 20, 40 m/kg for 15 days) respectively. The number of leukocytes and serum levels of interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in peripheral blood, spleen index, and the function of NK cells were measured. RESULTS: Compared with the model group , SDCM increased the number of leukocytes and serum concentrations of IL-2, TNF-α and IFN-γ in peripheral blood and improved the spleen index and the function of NK cells significantly (P < 0.05-0.01). CONCLUSION: SDCM could remarkably enhance the immune functions of immunosuppression mice induced by cyclophosphamide.