VRK3-mediated nuclear localization of HSP70 prevents glutamate excitotoxicity-induced apoptosis and A beta accumulation via enhancement of ERK phosphatase VHR activity

Most of neurodegenerative disorders are associated with protein aggregation. Glutamate-induced excitotoxicity and persistent extracellular signal-regulated kinase (ERK) activation are also implicated in neurodegenerative diseases. Here, we found that vaccinia-related kinase 3 (VRK3) facilitates nuclear localization of glutamate-induced heat shock protein 70 (HSP70). Nuclear HSP70 leads to enhancement of vaccinia H1-related phosphatase (VHR) activity via protein-protein interaction rather than its molecular chaperone activity, thereby suppressing excessive ERK activation. Moreover, glutamate-induced ERK activation stimulates the expression of HSP70 and VRK3 at the transcriptional level. Downregulation of either VRK3 or HSP70 rendered cells vulnerable to glutamate-induced apoptosis. Overexpression of HSP70 fused to a nuclear localization signal attenuated apoptosis more than HSP70 alone. The importance of nuclear localization of HSP70 in the negative regulation of glutamate-induced ERK activation was further confirmed in VRK3-deficient neurons. Importantly, we showed a positive correlation between levels of VRK3 and HSP70 in the progression of Alzheimer's and Parkinson's diseases in humans, and neurons with HSP70 nuclear localization exhibited less A beta accumulation in brains from patients with Alzheimer's disease. Therefore, HSP70 and VRK3 could potentially serve as diagnostic and therapeutic targets in neurodegenerative diseases.1173Ysciescopu

Myricetin improves endurance capacity and mitochondrial density by activating SIRT1 and PGC-1alpha

Robust mitochondrial respiration provides energy to support physical performance and physiological well-being, whereas mitochondrial malfunction is associated with various pathologies and reduced longevity. In the current study, we tested whether myricetin, a natural flavonol with diverse biological activities, may impact mitochondrial function and longevity. The mice were orally administered myricetin (50 mg/kg/day) for 3 weeks. Myricetin significantly potentiated aerobic capacity in mice, as evidenced by their increased running time and distance. The elevated mitochondrial function was associated with induction of genes for oxidative phosphorylation and mitochondrial biogenesis in metabolically active tissues. Importantly, myricetin treatment led to decreased PGC-1alpha acetylation through SIRT1 activation. Furthermore, myricetin significantly improved the healthspan and lifespan of wild-type, but not Sir-2.1-deficient, C. elegans. These results demonstrate that myricetin enhances mitochondrial activity, possibly by activating PGC-1alpha and SIRT1, to improve physical endurance, strongly suggesting myricetin as a mitochondria-activating agent

HnRNP Q Has a Suppressive Role in the Translation of Mouse Cryptochrome1

Precise regulation of gene expression is especially important for circadian timekeeping which is maintained by the proper oscillation of the mRNA and protein of clock genes and clock-controlled genes. As a main component of the core negative arm feedback loops in the circadian clock, the Cry1 gene contributes to the maintenance of behavioral and molecular rhythmicity. Despite the central role of Cry1, the molecular mechanisms regulating expression levels of Cry1 mRNA and protein are not well defined. In particular, the post-transcriptional regulation of Cry1 mRNA fate decisions is unclear. Here, we demonstrate that hnRNP Q binds to mCry1 mRNA via the 5'UTR. Furthermore, hnRNP Q inhibits the translation of mCry1 mRNA, leading to altered rhythmicity in the mCRY1 protein profile.1145Ysciescopu

Deficiency of Capicua disrupts bile acid homeostasis

Capicua (CIC) has been implicated in pathogenesis of spinocerebellar ataxia type 1 and cancer in mammals; however, the in vivo physiological functions of CIC remain largely unknown. Here we show that Cic hypomorphic (Cic-L-/-) mice have impaired bile acid (BA) homeostasis associated with induction of proinflammatory cytokines. We discovered that several drug metabolism and BA transporter genes were down-regulated in Cic-L-/- liver, and that BA was increased in the liver and serum whereas bile was decreased within the gallbladder of Cic-L-/- mice. We also found that levels of proinflammatory cytokine genes were up-regulated in Cic-L-/- liver. Consistent with this finding, levels of hepatic transcriptional regulators, such as hepatic nuclear factor 1 alpha (HNF1 alpha), CCAAT/enhancer-binding protein beta (C/EBP beta), forkhead box protein A2 (FOXA2), and retinoid X receptor alpha (RXR alpha), were markedly decreased in Cic-L-/- mice. Moreover, induction of tumor necrosis factor alpha (Tnf alpha) expression and decrease in the levels of FOXA2, C/EBP beta, and RXRa were found in Cic-L-/- liver before BA was accumulated, suggesting that inflammation might be the cause for the cholestasis in Cic-L-/- mice. Our findings indicate that CIC is a critical regulator of BA homeostasis, and that its dysfunction might be associated with chronic liver disease and metabolic disorders.open11810Ysciescopu

Glycogen synthase kinase 3 beta suppresses polyglutamine aggregation by inhibiting Vaccinia-related kinase 2 activity

Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the N-terminal of huntingtin. The amount of aggregate-prone protein is controlled by various mechanisms, including molecular chaperones. Vaccinia-related kinase 2 (VRK2) is known to negatively regulate chaperonin TRiC, and VRK2-facilitated degradation of TRiC increases polyQ protein aggregation, which is involved in HD. We found that VRK2 activity was negatively controlled by glycogen synthase kinase 3 beta (GSK3 beta). GSK3 beta directly bound to VRK2 and inhibited the catalytic activity of VRK2 in a kinase activity-independent manner. Furthermore, GSK3 beta increased the stability of TRiC and decreased the formation of HttQ103-GFP aggregates by inhibiting VRK2. These results indicate that GSK3 beta signaling may be a regulatory mechanism of HD progression and suggest targets for further therapeutic trials for HD.1131Ysciescopu

A Fomitopsis pinicola Jeseng Formulation Has an Antiobesity Effect and Protects against Hepatic Steatosis in Mice with High-Fat Diet-Induced Obesity

This study investigated the antiobesity effect of an extract of the Fomitopsis pinicola Jeseng-containing formulation (FAVA), which is a combination of four natural components: Fomitopsis pinicola Jeseng; Acanthopanax senticosus; Viscum album coloratum; and Allium tuberosum. High-fat diet-(HFD-) fedmale C57BL/6J mice were treated with FAVA (200 mg/kg/day) for 12 weeks to monitor the antiobesity effect and amelioration of nonalcoholic fatty liver diseases (NAFLD). Body and white adipose tissue (WAT) weights were reduced in FAVA-treated mice, and a histological examination showed an amelioration of fatty liver in FAVA-treated mice without decreasing food consumption. Additionally, FAVA reduced serumlipid profiles, leptin, and insulin levels compared with the HFD control group. The FAVA extract suppressed lipogenic mRNA expression levels from WAT concomitantly with the cholesterol biosynthesis level in the liver. These results demonstrate the inhibitory effects of FAVA on obesity and NAFLD in the diet-induced obese (DIO) mouse model. Therefore, FAVA may be an effective therapeutic candidate for treating obesity and fatty liver caused by a high-fat diet.110Nsciescopu

Selective uptake of epidermal growth factor-conjugated gold nanoparticle (EGF-GNP) facilitates non-thermal plasma (NTP)-mediated cell death

Non-thermal atmospheric pressure plasma (NTP) has been shown to induce cell death in various mammalian cancer cells. Accumulated evidence also shows that NTP could be clinically used in cancer therapy. However, the current NTP-based applications lack target specificity. Here, a novel method in NTP-mediated cancer therapeutics was described with enhanced target specificity by treating EGF (epidermal growth factor)-conjugated GNP (gold nanoparticle). The treatment with EGF-conjugated GNP complex, followed by NTP irradiation showed selective apoptosis of cells having receptor-mediated endocytosis. NTP triggered gamma-H2AX elevation which is a typical response elicited by DNA damage. These results suggest that EGF-conjugated GNP functions as an important adjuvant which gives target specificity in applications of conventional plasma therapy.111Ysciescopu

Opposing effects of protein kinase A and C on capacitative calcium entry into HL-60 promyelocytes.

Treatment of HL-60 cells with thapsigargin, a microsomal Ca2+/ATPase inhibitor, led to depletion of intracellular calcium stores followed by capacitative calcium entry. Stimulation of adenylyl cyclase with forskolin enhanced thapsigargin-induced Ca2+ influx. The forskolin effect was confirmed by enhanced fluorescence quenching induced by Mn2+ entry into fura-2 loaded cells. 1,9-Dideoxy-forskolin, an inactive analog of forskolin, did not affect capacitative calcium entry. On the other hand, phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, inhibited thapsigargin-induced Ca2+ entry. Histamine and prostaglandin E2 (PGE2) elevated intracellular adenosine 3′:5′-cyclic monophosphate (cAMP) levels and enhanced the thapsigargin-induced capacitative calcium entry. Incubation with N-[2-(p-bromocynnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), an inhibitor of protein kinase A (PKA), blocked the forskolin effect, and GF109203X, an inhibitor of protein kinase C (PKC), blocked the phorbol 12-myristate 13-acetate effect. The results suggest that protein kinase A regulates capacitative calcium entry positively, but that protein kinase C regulates Ca2+ influx negatively. Furthermore, after differentiation of HL-60 promyelocytes with dimethylsulfoxide to granulocytes, the inhibitory effect of phorbol 12-myristate 13-acetate became more pronounced, whereas the stimulatory effect of prostaglandin E2 did not change. This result suggests that the regulation of capacitative calcium entry by protein kinase C and protein kinase A develops differently during differentiation

Heterogeneous nuclear ribonucleoprotein (hnRNP) L promotes DNA damage-induced cell apoptosis by enhancing the translation of p53

The tumor suppressor p53 is an essential gene in the induction of cell cycle arrest, DNA repair, and apoptosis. p53 protein is induced under cellular stress, blocking cell cycle progression and inducing DNA repair. Under DNA damage conditions, it has been reported that post-transcriptional regulation of p53 mRNA contributes to the increase in p53 protein level. Here we demonstrate that heterogeneous nuclear ribonucleoprotein (hnRNP) L enhances p53 mRNA translation. We found that hnRNP L is increased and binds to the 5' UTR of p53 mRNA in response to DNA damage. Increased hnRNP L caused enhancement of p53 mRNA translation. Conversely, p53 protein levels were decreased following hnRNP L knock-down, rendering them resistant to apoptosis and arrest in the G2/M phase after DNA damage. Thus, our findings suggest that hnRNP L functions as a positive regulator of p53 translation and promotes cell cycle arrest and apoptosis.11Ysciescopu