Epidemiological studies show that maternal diabetes is associated with an increased risk of autism spectrum disorders (ASDs), although the detailed mechanisms remain unclear. The present study aims to investigate the potential effect of maternal diabetes on autism-like behavior in offspring. The results of in vitro study showed that transient hyperglycemia induces persistent reactive oxygen species (ROS) generation with suppressed superoxide dismutase 2 (SOD2) expression. Additionally, we found that SOD2 suppression is due to oxidative stress-mediated histone methylation and the subsequent dissociation of early growth response 1 (Egr1) on the SOD2 promoter. Furthermore, in vivo rat experiments showed that maternal diabetes induces SOD2 suppression in the amygdala, resulting in autism-like behavior in offspring. SOD2 overexpression restores, while SOD2 knockdown mimics, this effect, indicating that oxidative stress and SOD2 expression play important roles in maternal diabetes-induced autism-like behavior in offspring, while prenatal and postnatal treatment using antioxidants permeable to the blood–brain barrier partly ameliorated this effect. We conclude that maternal diabetes induces autism-like behavior through hyperglycemia-mediated persistent oxidative stress and SOD2 suppression. Here we report a potential mechanism for maternal diabetes-induced ASD.

Dietary phytochemicals, including nobiletin and auraptene, have been shown to exert inhibiting effects in several chemically induced carcinogenesis models. We here investigated the influence of nobiletin and auraptene on prostate carcinogenesis using transgenic rats developing adenocarcinoma of the prostate (TRAP) bearing the SV40 T antigen transgene under control of the probasin promoter and human prostate cancer cells. Starting at 5 weeks of age, male TRAP rats received powder diet containing 500 p.p.m. nobiletin or auraptene, or the basal diet for 15 weeks and then were sacrificed for analysis of serum testosterone levels and histological changes. The body and relative prostate weights and serum testosterone levels did not differ among the groups. Since all animals developed prostate carcinomas, these were semiquantitatively measured and expressed as relative areas of prostate epithelial cells. Nobiletin caused significant reduction in the ventral (P < 0.01), lateral (P < 0.001) and dorsal (P < 0.05) prostate lobes, while decreasing high grade lesions (P < 0.05) in the ventral and lateral lobes. Feeding of auraptene also effectively reduced the epithelial component (P < 0.05) and high grade lesions (P < 0.05), in the lateral prostate. A further experiment demonstrated that growth of androgen sensitive LNCaP and androgen insensitive DU145 and PC3 human prostate cancer cells, was suppressed by both nobiletin and to a lesser extent auraptene in a dose-dependent manner, with significant increase in apoptosis. In conclusion, these compounds, particularly nobiletin, may be valuable for prostate cancer prevention. (Cancer Sci 2007; 98: [471][472][473][474][475][476][477]

The present study clearly demonstrated that gamma-tocopherol suppresses prostate tumor progression in an in vivo TRAP model, and could be a candidate chemopreventive agent for human prostate cancer.

The results indicate that PFJ and EA are potential chemopreventive agents for prostate cancer, and EA may be the active component of PFJ that exerts these anti-cancer effects.

Edited by Mike Shipston The cardiac mechanosensitive BK (Slo1) channels are gated by Ca 2؉ , voltage, and membrane stretch. The neuropeptide GsMTx4 is a selective inhibitor of mechanosensitive (MS) channels. It has been reported to suppress stretch-induced cardiac fibrillation in the heart, but the mechanism underlying the specificity and even the targeting channel(s) in the heart remain elusive. Here, we report that GsMTx4 inhibits a stretch-activated BK channel (SAKcaC) in the heart through a modulation specific to mechano-gating. We show that membrane stretching increases while GsMTx4 decreases the open probability (P o) of SAKcaC. These effects were mostly abolished by the deletion of the STREX axis-regulated (STREX) exon located between RCK1 and RCK2 domains in BK channels. Single-channel kinetics analysis revealed that membrane stretch activates SAKcaC by prolonging the open-time duration (O) and shortening the closed-time constant (C). In contrast, GsMTx4 reversed the effects of membrane stretch, suggesting that GsMTx4 inhibits SAKcaC activity by interfering with mechano-gating of the channel. Moreover, GsMTx4 exerted stronger efficacy on SAKcaC under membrane-hyperpolarized/resting conditions. Molecular dynamics simulation study revealed that GsMTx4 appeared to have the ability to penetrate deeply within the bilayer, thus generating strong membrane deformation under the hyperpolarizing/resting conditions. Immunostaining results indicate that BK variants containing STREX are also expressed in mouse ventricular cardiomyocytes. Our results provide common mechanisms of peptide actions on MS channels and may give clues to therapeutic suppression of cardiac arrhythmias caused by excitatory currents through MS channels under hyper-mechanical stress in the heart.

To reduce cancer mortality, understanding of mechanisms of cancer metastasis is crucial. We have established six rat hepatocellular carcinoma (HCC) cell lines, which exhibit differing metastatic potential to the lung after inoculation into the tail veins of nude mice. In the present experiment, we investigated the process of cell attachment to metastatic sites and possible regulating factors. One hour after inoculation, two of two HCC cell lines with high metastatic potential and one of two HCC cell lines with low metastatic potential exhibited many attached cells in the lung. One day after inoculation, lung metastatic foci were observed only with highly-metastatic cells with elevated connexin 43 (Cx43) expression as assessed by cDNA array analysis. Furthermore, 24 or 48 h after transfection of an siRNA targeting Cx43, in vitro invasion and migration were suppressed by 68% (P < 0.001) and 36% (P < 0.05) compared with control-siRNA transfected cells, despite no differences in cellular morphology, cell proliferation or apoptotic activity. Moreover, the number of metastatic nodules per lung area in nude mice was significantly (P < 0.01) reduced. In conclusion, suppression of Cx43 expression in tumor cells reduced in vitro migration and invasion capacity and in vivo metastatic ability so that Cx43 has potential as a molecular target for prevention of cancer metastasis with Cx43 overexpressing tumors. (Cancer Sci 2012; 103: 860-867) D espite significant improvements in diagnosis, surgical techniques, general patient care and local and systemic adjuvant therapies, most deaths from cancer are due to metastases that are resistant to conventional therapies. To reduce cancer mortality, an understanding of the mechanisms of cancer metastasis and the development of treatments focusing on prevention and/or care of metastases are a high priority.We have established six rat hepatocellular carcinoma (HCC) cell lines(1) from an in vivo rat HCC model, (2)(3)(4) in which combination treatment of N-nitrosomorpholine and diethylnitrosamine induces liver tumors metastasizing to the lung. These cell lines (HSU-C1, -C2, -C5F, -C6, -N1 and -L2) show similar in vitro doubling times but widely differing metastatic ability after inoculation into the tail vein or transplantation into the subcutis of nude mice.(1) In particular, the N1 and L2 lines are particularly metastatic to the lung when inoculated into the tail vein, as compared with the other lines. All these lines express the glutathione S-transferase placental form (GST-P), known to be upregulated during rat hepato-carcinogenesis, from preneoplastic liver cell foci to hepatocellular carcinoma.(5-7) Thus, immunohistochemistry for rat GST-P can readily visualize the cells in mouse tissue.Metastasis is a multi-step process, involving angiogenesis, invasion, detachment, circulation, adhesion and extravasation.(8) The genes and factors responsible for promotion or suppression of metastasis are multiple for each step and reasons for differences in metastatic potential remain to be eluc...

These data provide a new concept that ARBs are promising potential chemopreventive and chemotherapeutic agents for prostate cancer.

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