κ­opioid receptor agonist, U50488H, inhibits pyroptosis through NLRP3 via the Ca2+/CaMKII/CREB signaling pathway and improves synaptic plasticity in APP/PS1 mice.

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder with slow onset in most cases. Clinically, dementia associated with AD is characterized by memory disorders, aphasia, executive dysfunction and personality and behavior changes. Currently, treatment strategies attempt to reduce certain symptoms, however there is no cure for AD. The aim of the present study was to identify a novel treatment strategy for AD. Thus, the protective effects of a κ­opioid receptor (KOR) agonist, U50488H on neural damage in AD mice were investigated. The underlying mechanism of the Ca2+/calcium/calmodulin­dependent protein kinase II/cyclic adenosine monophosphate­response element binding protein (Ca2+/CaMKII/CREB) signaling pathway was evaluated. Amyloid precursor protein (APP)/presenilin­1 (PS1) mice were treated subcutaneously with a KOR agonist for 28 days. The learning and memory abilities of the APP/PS1 mice were evaluated using the Morris water maze test. Damage to hippocampal neurons was assessed using hematoxylin and eosin staining. Inflammatory factors and brain injury markers were detected using ELISA. Neurons were examined using immunofluorescence and dendritic spines were observed using Golgi­Cox staining. Western blotting was used to detect NOD­, LRR­ and pyrin domain­containing protein 3, microglial ptosis and the Ca2+/CaMKII/CREB­related protein pathway. The KOR agonist significantly improved the brain injury observed in APP/PS1 mice, inhibited microglia pyroptosis and improved the synaptic plasticity of APP/PS1 mice, which was reversed by a KOR antagonist. Thus, the KOR agonist improved the symptoms of APP/PS1 mice by inhibiting the Ca2+/CaMKII/CREB signaling pathway.

Berberine reduces temozolomide resistance by inducing autophagy via the ERK1/2 signaling pathway in glioblastoma.

BACKGROUND: The ability to treat glioblastoma (GBM) using the chemotherapeutic agent temozolomide (TMZ) has been hampered by the development of therapeutic resistance. In this study, we assessed the ability of the isoquinoline alkaloid berberine to alter GBM TMZ resistance using two different TMZ-resistant cell lines to mimic a physiologically relevant GBM experimental system. METHODS: By treating these resistant cell lines with berberine followed by TMZ, we were able to assess the chemosensitivity of these cells and their parental strains, based on their performance in the MTT and colony formation assays, as well as on the degree of detectable apoptosis that was detected in the strains. Furthermore, we used Western blotting to assess autophagic responses in these cell lines, and we extended this work into a xenograft mouse model to assess the in vivo efficacy of berberine. RESULTS: Through these experiments, our findings indicated that berberine enhanced autophagy and apoptosis in TMZ-resistant cells upon TMZ treatment in a manner that was linked with ERK1/2 signaling. Similarly, when used in vivo, berberine increased GBM sensitivity to TMZ through ERK1/2 signaling pathways. CONCLUSIONS: These findings demonstrate that berberine is an effective method of increasing the sensitization of GBM cells to TMZ treatment in a manner that is dependent upon the ERK1/2-mediated induction of autophagy, thus making berberine a potentially viable therapeutic agent for GBM treatment.

All-trans retinoic acid enhances bystander effect of suicide-gene therapy against medulloblastomas.

In our previous study we evaluated the antitumor effect of herpes simplex virus-thymidine kinase gene (HSV-tk) on human medulloblastomas (MBs) in a therapeutic delivery system using the immortalized neural stem cell (NSC) line C17.2. However, our findings indicated that the bystander effect between C17.2tk and Daoy MB cells was weak compared to the bystander effect between NSCtk and C6 glioma cells. Gap junction intercellular communication (GJIC) is the main mechanism mediating the bystander effect in HSV-tk gene therapy. All-trans retinoic acid (ATRA) has been shown to up-regulate the expression of Connexin43 and GJIC. In this study we investigated the synergistic effect of ATRA and HSV-tk gene therapy in the treatment of MBs. We found that the expression of Connexin43 in Daoy cells was significantly increased when cells were exposed to 3µmol/l of ATRA (P<0.05). After co-culturing C17.2tk cells with Daoy cells at different ratios ranging from 1:1 to 1:16, ATRA significantly increased the bystander anti-tumor effect compared to ATRA-untreated cells (P<0.05). In intracranial co-implantation experiments, mice co-implanted with C17.2tk/Daoy cells and treated with a combination of ATRA and GCV had significantly smaller tumors compared to the animals treated with GCV alone (P<0.05). Together, our results show that ATRA enhanced the tumoricidal effect in HSVtk/GCV suicide gene therapy against Daoy MB cells by strengthening the bystander effect in vitro and in vivo.