Deficiency of parkin suppresses melanoma tumor development and metastasis through inhibition of MFN2 ubiquitination.

Parkin, a critical gene of Parkinson's disease, is involved in the development of numerous cancers. However, the effect of parkin deficiency on melanoma growth and metastasis has not been reported. We showed that the tumor size and number of surface lung metastases, and expression of tumor growth and metastasis marker proteins were significantly lower in parkin-KO mice than those observed in non-transgenic controls. In an in vitro study, we also showed that parkin siRNA inhibited cell growth and migration of B16F10 and SK-Mel-28 cells. Parkin-specific ubiquitination of mitofusin-2 (MFN2) was decreased in tumors and metastasized lung tissues of parkin-KO mice. Moreover, we showed that parkin directly binds and ubiquitinates MFN2. Knockdown of MFN2 decreased the expression of Bax and apoptotic cell death, but increased that of Bcl2 and apoptotic cancer cell death. However, these effects were reversed by knockdown of parkin. Conversely, inhibitory effects on melanoma growth and migration of parkin siRNA were reversed by MFN2 siRNA. These data indicate that melanoma development was inhibited in parkin-KO mice through maintaining of MFN2 level by inhibition of ubiquitinating ability of parkin.

Estrogen deficiency exacerbates Aß-induced memory impairment through enhancement of neuroinflammation, amyloidogenesis and NF-ĸB activation in ovariectomized mice.

Estrogen is well known to have a preventative effect in Alzheimer's disease (AD) pathology. Several studies have demonstrated that nuclear factor kappa-B (NF-ĸB) can contribute to the effects of estrogen on the development of AD. We investigated whether NF-ĸB affects amyloid-beta (Aß)-induced memory impairment in an estrogen-lacking condition. In the present study, nine-week-old Institute cancer research (ICR) mice were ovariectomized to block estrogen stimulation. Ten weeks after the ovariectomization, mice were administered with Aß (300 pmol) via intracerebroventricular (ICV) infusion for 2 weeks. Memory impairment, neuroinflammatory protein expression, and amyloidogenic pathways were then measured. Ovariectomized mice demonstrated severe memory impairment, Aß accumulation, neprilysin downregulation, and activation of NF-ĸB signaling compared to sham-control mice. In vitro experiments demonstrated that ß-estradiol (10 µM) inhibited Aß (1 µM)-induced neuroinflammation in microglial BV-2 cells and prevented Aß-induced cell death in primary cultured neuronal cells. As in in vivo experiments, NF-ĸB activation was significantly upregulated in in vitro experiments. Furthermore ß-estradiol treatment inhibited NF-ĸB activation in both of microglial BV-2 cells and cultured neuronal cells. These findings suggest that estrogen may protect against memory impairment through the regulation of Aß accumulation and neurogenic inflammation by inhibiting NF-κB activity.

Antarctic Krill Oil Diet Protects against Lipopolysaccharide-Induced Oxidative Stress, Neuroinflammation and Cognitive Impairment.

Oxidative stress and neuroinflammation are implicated in the development and pathogenesis of Alzheimer's disease (AD). Here, we investigated the anti-inflammatory and antioxidative effects of krill oil. Oil from Euphausia superba (Antarctic krill), an Antarctic marine species, is rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We examined whether krill oil diet (80 mg/kg/day for one month) prevents amyloidogenesis and cognitive impairment induced by intraperitoneal lipopolysaccharide (LPS) (250 µg/kg, seven times daily) injections in AD mice model and found that krill oil treatment inhibited the LPS-induced memory loss. We also found that krill oil treatment inhibited the LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and decreased reactive oxygen species (ROS) and malondialdehyde levels. Krill oil also suppresses IκB degradation as well as p50 and p65 translocation into the nuclei of LPS-injected mice brain cells. In association with the inhibitory effect on neuroinflammation and oxidative stress, krill oil suppressed amyloid beta (1-42) peptide generation by the down-regulating APP and BACE1 expression in vivo. We found that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (50 and 100 µM) dose-dependently decreased LPS-induced nitric oxide and ROS generation, and COX-2 and iNOS expression as well as nuclear factor-κB activity in cultured microglial BV-2 cells. These results suggest that krill oil ameliorated impairment via anti-inflammatory, antioxidative, and anti-amyloidogenic mechanisms.