Disrupted-in-schizophrenia-1 protects synaptic plasticity in a transgenic mouse model of Alzheimer's disease as a mitophagy receptor.

Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Accumulated damaged mitochondria, which are associated with impaired mitophagy, contribute to neurodegeneration in AD. We show levels of Disrupted-in-schizophrenia-1 (DISC1), which is genetically associated with psychiatric disorders and AD, decrease in the brains of AD patients and transgenic model mice and in Aß-treated cultured cells. Disrupted-in-schizophrenia-1 contains a canonical LC3-interacting region (LIR) motif (210 FSFI213 ), through which DISC1 directly binds to LC3-I/II. Overexpression of DISC1 enhances mitophagy through its binding to LC3, whereas knocking-down of DISC1 blocks Aß-induced mitophagy. We further observe overexpression of DISC1, but not its mutant (muFSFI) which abolishes the interaction of DISC1 with LC3, rescues Aß-induced mitochondrial dysfunction, loss of spines, suppressed long-term potentiation (LTP). Overexpression of DISC1 via adeno-associated virus (serotype 8, AAV8) in the hippocampus of 8-month-old APP/PS1 transgenic mice for 4 months rescues cognitive deficits, synaptic loss, and Aß plaque accumulation, in a way dependent on the interaction of DISC1 with LC3. These results indicate that DISC1 is a novel mitophagy receptor, which protects synaptic plasticity from Aß accumulation-induced toxicity through promoting mitophagy.

Stereotactic body radiation therapy for centrally-located lung tumors.

The application of high-dose irradiation to centrally-located lung tumors is generally considered to be of high risk in causing bronchial injury. The aim of the present retrospective study was to investigate the safety and efficacy of stereotactic body radiation therapy (SBRT) for patients with centrally-located lung tumors. In total, 28 patients who underwent SBRT for lung tumors within 2 cm of a major bronchus were retrospectively analyzed. The median total dose prescribed was 45 Gy (range, 36.3-52.5 Gy), the median fraction was 12 (range, 10-15) and the median dose per fraction was 3.6 Gy (range, 3-5 Gy). The median follow-up period for the surviving patients was 14 months (range, 10-41 months). The local control rate of SBRT was 100%, with a complete response (CR) rate of 32.1% (9/28); a partial response (PR) rate of 50% (14/28) and a stable disease (SD) rate of 17.9% (5/28). In total, 15 patients survived and 13 patients succumbed; 11 patients succumbed to tumor progression, one to congestive heart failure and one to a brain hemorrhage. The main side-effects included grade 2 esophagitis (17.9%; 5/28) atelectasis (10.7%; 3/28) and grade 2 late radiation pneumonitis (7.1%; 2/28). Severe late toxicity (≥ grade 3) was not observed in any patient. SBRT is an effective and safe therapy for centrally-located lung tumors.

CCK-8S increases the firing frequency of CCK-positive neurons and facilitates excitatory synaptic transmission in primary rat hippocampal neurons.

The neuropeptide cholecystokinin octapeptide (CCK) is involved in a variety of brain functions. In the hippocampus, most CCK is released from CCK-positive (CCK+) neurons, but the effects of CCK on CCK+ neurons are poorly understood. We employed primary hippocampal cultures to explore the modulatory effect of CCK on CCK+ neurons. CCK-8S (0.2 µM) was added to the culture medium from day in vitro 2 (DIV-2) to DIV-11. An adenovirus integrated with the CCK promoter was used to label CCK+ neurons. Whole-cell patch clamp recording was carried on to record the electrophysiology properties. The results show that: (1) CCK-8S significantly decreased membrane capacity but increased the membrane resistance (Rm) of CCK+ neurons, (2) CCK-8S increased action potential (AP) firing frequency of CCK+ neurons but did not affect the firing pattern, (3) CCK-8S facilitated CCK+ neuron excitatory synaptic transmission but attenuated inhibitory synaptic transmission, and (4) the expression of postsynaptic density-95 (PSD-95) in cultured hippocampal neurons was elevated by CCK-8S treatment. Our results demonstrate that CCK-8S significantly alters the membrane electrophysiological characteristics and synaptic activity of cultured hippocampal CCK+ neurons. These findings may enhance our understanding of the modulatory effect of CCK in the brain.

CCK-8S increased the filopodia and spines density in cultured hippocampal neurons of APP/PS1 and wild-type mice.

Cholecystokinin (CCK), a neuropeptide, is widely distributed in the brain. The function of CCK is involved in many brain functions including learning and memory, but the cellular mechanism is poorly understood. In the present study, we investigated the effect of CCK on dendritic filopodia and spines of cultured hippocampal neurons from wild-type and APP/PS1 mice. The cultured hippocampal neurons were infected with CMV-GFP (CMV promoter with green fluorescent protein) adenovirus 24h before image acquisition to display the subtle structure of dendrites. Cholecystokinin octapeptide sulfated (CCK-8S, 0.2µM) was added into the cultured solution from divided in vitro day 2 (DIV 2). A decrease of filopodia and spines density was observed in APP/PS1 mice compared with that of wild type mice. CCK-8S increased the density of filopodia and spines at DIV 7, DIV 14 and DIV 21 in hippocampal neurons of both wild-type and APP/PS1 mice. In addition, this effect was inhibited by CI988, an antagonist of CCK-2 receptor. Those results indicate that CCK-8S can influence the dendritic development and spine genesis of cultured hippocampal neurons derived from both wild-type and APP/PS1 mice. These data suggest that CCK may play an important role in learning and memory.

Aged black garlic extract induces inhibition of gastric cancer cell growth in vitro and in vivo.

There is mounting evidence that garlic extracts possess significant anticancer actions. However, no studies have been reported on the effects of aged black garlic extracts (ABGE) on gastric cancer in vitro or in vivo. To examine the potential action of ABGE against gastric cancer, the present study evaluated its effect on the inhibition of cell proliferation and induction of apoptosis in SGC-7901 human gastric cancer cells. Additionally, we performed an in vivo study by inoculating the murine foregastric carcinoma cell line in Kunming mice and treating them with various doses of ABGE (0, 200, 400 and 800 mg/kg, intraperitoneally) for 2 weeks. Dose-dependent apoptosis was detected in ABGE-treated cells in in vitro studies. In tumor-bearing mice, significant antitumor effects of ABGE were observed, such as growth inhibition of inoculated tumors. Further investigation of serum superoxide dismutases, glutathione peroxidase, interleukin-2 and the increased indices of spleen and thymus indicated that the anticancer action of ABGE may be partly due to its antioxidant and immunomodulative effects.

Inhibition of LTP by beta-amyloid is prevented by activation of beta2 adrenoceptors and stimulation of the cAMP/PKA signalling pathway.

Beta-amyloid (Abeta) is the main component of the extracellular plaques present in patients with Alzheimer's disease (AD) and studies have shown that exogenous application of Abeta results in neurodegeneration. As a model of the neurodegenerative action of Abeta, we have previously shown that acutely applied Abeta inhibits the induction of LTP in the hippocampus in vitro. In the present studies, we have studied the effect of beta-adrenoceptor activation on the Abeta inhibition of LTP. Pharmacological activation of beta2 adrenoceptors, but not of beta1 adrenoceptors, was found to prevent the Abeta evoked inhibition of LTP in the dentate gyrus of adult animals. The prevention of the effect of Abeta was shown to occur via the cAMP/PKA signaling pathway as the adenylate cyclase-stimulating agent forskolin prevented the Abeta inhibition of LTP, an action prevented by the PKA inhibitor, Rp-8-Br-cAMPs. We suggest microglia as a likely site of action of the neuroprotective effect of beta2 adrenoceptor activation. Therapeutic treatment for AD may include agents that activate beta2 receptors and elevate cAMP.