No abstract available.
Animals ; Glycogen Synthase ; Glycogen ; Insulin ; Rats

Neurofibrillary tangle (NFT) is a characteristic hallmark of Alzheimer's disease. GSK3beta has been reported to play a major role in the NFT formation of tau. Dysfunction of autophagy might facilitate the aggregate formation of tau. The present study examined the role of GSK3beta-mediated phosphorylation of tau species on their autophagic degradation. We transfected wild type tau (T4), caspase-3-cleaved tau at Asp421 (T4C3), or pseudophosphorylated tau at Ser396/Ser404 (T4-2EC) in the presence of active or enzyme-inactive GSK3beta. Trehalose and 3-methyladenine (3-MA) were used to enhance or inhibit autophagic activity, respectively. All tau species showed increased accumulation with 3-MA treatment whereas reduced with trehalose, indicating that tau undergoes autophagic degradation. However, T4C3 and T4-2EC showed abundant formation of oligomers than T4. Active GSK3beta in the presence of 3-MA resulted in significantly increased formation of insoluble tau aggregates. These results indicate that GSK3beta-mediated phosphorylation and compromised autophagic activity significantly contribute to tau aggregation.
Adenine ; Alzheimer Disease ; Autophagy ; Glycogen ; Glycogen Synthase ; Glycogen Synthase Kinase 3 ; Glycogen Synthase Kinases ; Neurofibrillary Tangles ; Phosphorylation ; Trehalose

Little is known about the effects of chronic alcohol intake on the outcome of acute kidney injury (AKI). Hence, we examined the effects of chronic alcohol intake on the development of renal fibrosis following AKI in an animal model of bilateral renal ischemia–reperfusion (IR) injury. We first found that chronic alcohol exposure exacerbated bilateral IR-induced renal fibrosis and renal function impairment. This phenomenon was associated with increased bilateral IR-induced extracellular matrix deposition and an increased myofibroblast population as well as increased bilateral IR-induced expression of fibrosis-related genes in the kidneys. To explore the mechanisms underlying this phenomenon, we showed that chronic alcohol exposure enhanced β-arrestin 2 (Arrb2) expression and Akt and glycogen synthase kinase-3 (GSK3)β activation in the kidneys. Importantly, pharmacological GSK3 inhibition alleviated bilateral IR-induced renal fibrosis and renal function impairment. Furthermore, we demonstrated that Arrb2(−/−) mice exhibited resistance to IR-induced renal fibrosis and renal function impairment following chronic alcohol exposure, and these effects were associated with attenuated GSK3β activation in the kidneys. Taken together, our results suggest that chronic alcohol exposure may potentiate AKI via β-arrestin 2/Akt/GSK3β-mediated signaling in the kidney.
Acute Kidney Injury* ; Animals ; Extracellular Matrix ; Fibrosis ; Glycogen Synthase Kinase 3* ; Glycogen Synthase Kinases* ; Glycogen Synthase* ; Glycogen* ; Kidney ; Mice* ; Models, Animal ; Myofibroblasts

The muscle glycogen is an important energy source for muscle contraction especially in prolonged exercise. One of the important factors for improvement of physical performance in athletes is the storage of extra-amount of glycogen (supercompensation) in liver and muscles. During 120 minutes treadmill exercise (intensity of exercise was approximatly 80% VO2max), the glycogen concentration was significantly decreased to 36% in liver and 46% in muscles after 60 minutes exercise. At 90 and 120 minutes of exercise, the level of glycogen concentration of liver and muscles statistically were not different from the levels of the 60 minutes exercise. The repletions of glycogen in the liver and muscles in overnight fasted control(C) and 120 minutes treadmill exercise(E) groups during l80minutes after glucose ingestion were investigatect. ln the liver, the concentration of glycogen in C and E groups were markdly increased till 120 minutes after zlucose ingestion, hut the levels of concentration at 180 minutes were decreased comparing to the levels of 120 minutes in both groups. In the muscles, the repletion of glycogen at 60, 120 and 180 minutes of C and E groups were significantly increased comparing to 0 minute of respective groups in the soleus and plantaris muscles. In soleus(SOL), the repletion of glycogen in all of the E groups was significantly higher than that of the respective C groups. However, the repletion of glycogen in all of the E groups of plantaris was revealed higher tendency comparing to respective C groups. Mean repletion rates of glycogen in liver and muscles after glucose ingestion were highest during the first 60 minutes in all groups and the rates of E groups were 2-3 times than those of respective C groups. These results suggest that the glycogen supercompensation in the muscle be provided with decrement of glycogen concentration by exercise, increment of glucose uptake by muscuiar contraction itself and increased insuJin level, and the activation of glycogen synthetase by insulin.
Animals ; Athletes ; Eating* ; Glucose* ; Glycogen Synthase ; Glycogen* ; Humans ; Insulin ; Liver* ; Muscle Contraction ; Muscles ; Rats*

OBJECTIVEThis study was purposed to detect the expressions of β-catenin and P-GSK-3 β in Wnt signaling pathway of patients with mantle cell lymphoma(MCL), and investigate its relationship with the pathogenesis of MCL.

METHODSThe expression levels of β -catenin protein and P-GSK-3 protein in mantle cell lymphoma and hyperplastic lymphadenitis were detected by using anti-β-catenin, P-GSK-3β polyclonal antibody and S-P staining technique.

RESULTSThe abnormal expression of β-catenin protein(73.33%) in mantle cell lymphoma group was significantly higher than that (6.7%) in reactive lymph node hyperplasia group (P<0.05); and the positive rate of P-GSK-3 β(66.67%) in mantle cell lymphoma group was significantly higher than that (16.67%) in reactive hyperplasia of lymph node group (P<0.05). Spearman correlation analysis showed that there was obvious positive correlation (R=0.852, P<0.01).

CONCLUSIONThe abnormal high expressions of β-catenin and P-GSK-3 β protein have been confirmed to appeare in mantle cell lymphoma.

Animals ; Drug Tolerance ; Glycogen Synthase Kinase 3 ; metabolism ; Glycogen Synthase Kinase 3 beta ; Morphine ; Phosphorylation ; Rats ; Signal Transduction

OBJECTIVE: Glycogen synthase kinase 3β (GSK3β) is a pluripotent protein kinase involved in the development of cancers through regulation of numerous oncogenic molecules. Cyclin D1, an important regulator of G1 to S phase transition in various cells, is one of target proteins that GSK3β regulate. Our objective was to assess the expression of GSK3β and cyclin D1 in cervical neoplasm of different histologic grades and to identify their correlation in cervical carcinogenesis. METHODS: Immunohistochemical analysis of GSK3β and cyclin D1 was performed in a total of 137 patients with 12 normal, 62 cervical intraepithelial neoplasia (CIN) (31 CIN1 and 31 CIN3) and 63 invasive cancers including 56 squamous cell carcinomas and 7 adenocarcinomas. RESULTS: The expression of GSK3β increased in parallel with the lesion grade, while that of cyclin D1 decreased with severity of the lesion (P<0.001). There was a significant inverse correlation between GSK3β and cyclin D1 expression in overall cervical neoplasia (Φ=-0.413, P<0.001). GSK3β expression was higher in squamous cell carcinoma than in adenocarcinoma (P=0.049). CONCLUSION: These results suggest that the expressional increase in GSK3β plays a role in cervical carcinogenesis and has inverse correlation with cyclin D1 expression in this process. In addition, GSK3β expression appears to be associated with the histologic type of cervical cancer, especially squamous cell carcinoma.
Adenocarcinoma ; Carcinogenesis* ; Carcinoma, Squamous Cell ; Cervical Intraepithelial Neoplasia ; Cyclin D1* ; Cyclins* ; Glycogen Synthase Kinases* ; Glycogen Synthase* ; Glycogen* ; Humans ; Immunohistochemistry ; Protein Kinases ; S Phase ; Uterine Cervical Neoplasms

In the present study, we investigated influences of glycogen synthase kinase (GSK) 3beta on the development and/or progression of amyotrophic lateral sclerosis (ALS). We used transgenic mice expressing a human Cu/Zn superoxide dismutase mutant (SOD1G93A) as an in vivo model of ALS and examined expressional changes of GSK3beta immunohistochemically in the spinal cord, brain stem and cerebellum. With these experiments we demonstrate that the neurons in these regions of symptomatic SOD1G93A transgenic mice showed increased GSK3beta immunoreactivities compared with wild-type SOD1 transgenic mice. In contrast to symptomatic SOD1G93A transgenic mice, few GSK3beta immunoreactivity changes were detected in 8w- and 13w-old presymptomatic SOD1G93A transgenic mice. These data suggest the possibility that GSK3 functions as a modulating factor of apoptosis-related alterations in ALS and that GSK3beta exert differential functions in the development and/or progression of ALS. But the exact functional significances of these changes require further elucidation.
Amyotrophic Lateral Sclerosis ; Animals ; Brain Stem ; Central Nervous System* ; Cerebellum ; Glycogen Synthase Kinases* ; Glycogen Synthase* ; Glycogen* ; Humans ; Mice ; Mice, Transgenic* ; Neurons ; Spinal Cord ; Superoxide Dismutase

Glycogen synthase kinase (GSK)-3β and related enzymes are associated with various forms of neuroinflammation, including spinal cord injury (SCI). Our aim was to evaluate whether lithium, a non-selective inhibitor of GSK-3β, ameliorated SCI progression, and also to analyze whether lithium affected the expression levels of two representative GSK-3β–associated molecules, nuclear factor erythroid 2-related factor-2 (Nrf-2) and heme oxygenase-1 (HO-1) (a target gene of Nrf-2). Intraperitoneal lithium chloride (80 mg/kg/day for 3 days) significantly improved locomotor function at 8 days post-injury (DPI); this was maintained until 14 DPI (P<0.05). Western blotting showed significantly increased phosphorylation of GSK-3β (Ser9), Nrf-2, and the Nrf-2 target HO-1 in the spinal cords of lithium-treated animals. Fewer neuropathological changes (e.g., hemorrhage, inflammatory cell infiltration, and tissue loss) were observed in the spinal cords of the lithium-treated group compared with the vehicle-treated group. Microglial activation (evaluated by measuring the immunoreactivity of ionized calcium-binding protein-1) was also significantly reduced in the lithium-treated group. These findings suggest that GSK-3β becomes activated after SCI, and that a non-specific enzyme inhibitor, lithium, ameliorates rat SCI by increasing phosphorylation of GSK-3β and the associated molecules Nrf-2 and HO-1.
Animals ; Blotting, Western ; Glycogen Synthase Kinases ; Glycogen Synthase* ; Glycogen* ; Heme Oxygenase-1* ; Heme* ; Hemorrhage ; Lithium Chloride ; Lithium* ; Phosphorylation ; Rats* ; Spinal Cord Injuries* ; Spinal Cord*

BACKGROUND: Neurodegenerative diseases (ND) are associated with oxidative stress, and antioxidants including epigallocatechin gallate (EGCG) have been tried as potential therapeutic regimens of an experimental model of ND. We performed this study to determine the neuroprotective role of EGCG on up stream and down stream signals in oxidative-stress-injured PC12 cells by exposing them to H2O2. METHODS: Following 100 microM H2O2 exposure, the viability of PC12 cells (not pretreated vs EGCG or z-VAD-fmk pretreated) was evaluated by using a MTT assay. Immunoreactivity (IR) of cytochrome c, caspase-3, poly (ADP-ribose) polymerase (PARP), PI3K/Akt and GSK-3 was examined by using a Western blot. RESULTS: EGCG or z-VAD-fmk pretreated PC12 cells showed increased viability. Dose-dependent inhibition of caspase-3 activation and PARP cleavage was demonstrated by the pretreatment of both agents. However, the inhibition of cytochrome c release was only detected in EGCG pretreated cells. On the pathway through PI3K/Akt and GSK-3, however, the result of a western blot in EGCG pretreated cells showed decreased IR of Akt and GSK-3 and increased IR of p85a PI3K, phosphorylated Akt and GSK-3, and contrasted with that in z-VAD-fmk pretreated cells showing no changes. CONCLUSIONS: These data show that EGCG affects apoptotic pathways through upstream signals including PI3K/Akt and GSK-3 pathways as well as downstream signals including cytochrome c and caspase-3 pathways. Therefore, these results suggest that EGCG mediated activation of PI3K/Akt and inhibition GSK-3 could be a new protective mechanism on the pathogenesis of ND.
Animals ; Antioxidants ; Apoptosis ; Blotting, Western ; Caspase 3 ; Cytochromes c ; Glycogen Synthase Kinase 3 ; Glycogen Synthase* ; Glycogen* ; Models, Theoretical ; Neurodegenerative Diseases ; Oxidative Stress ; PC12 Cells* ; Rivers