Glycogen Synthase Activity Research Articles

Growth, biochemical indices and transcriptomic profile of Chinese mitten crab (Eriocheir sinensis) respond to different ratios of dietary carbohydrates to lipids

IntroductionAlthough carbohydrates and lipids are important energy substances for Chinese mitten crab (Eriocheir sinensis), little is known about their synergistic effect on the growth, energy utilization characteristics and mechanisms involved in this process.MethodsA 58-d feeding experiment was conducted to investigate the effects of dietary carbohydrate to lipid ratio (C/L) on the growth performance, biochemical indices, and metabolism-related differential gene expression of juvenile E. sinensis in both intermolt (InM) and premolt (PrM) stages. Five experimental diets were formulated with increasing dietary C/L (1.34, 2.39, 3.59, 5.52 and 9.42).ResultsThe results showed that the weight growth rate of juvenile E. sinensis was highest in dietary C/L3.59 group, which was significantly higher than that in the other groups. As dietary C/L increased, the hepatic glycogen contents increased, but triglyceride contents decreased in the hepatopancreas of E. sinensis in the InM. In both two molting stages, the activities of glycogen synthase and fatty acid synthase paralleled with their contents, respectively. Crabs in the InM showed higher contents of triglyceride and the activities of glycolytic rate-limiting enzymes but lower contents of hepatic glycogen than those in the PrM, especially in the C/L 1.34 and C/L 3.59 groups. In all dietary groups, the activities and transcription of gluconeogenesis and fatty acid synthesis related enzymes were significantly higher in the InM than those in the PrM. KEGG analysis showed that differential genes were enriched in fatty acid biosynthesis, fatty acid metabolism, oxidative phosphorylation pathway, pentose phosphate pathway, pyruvate metabolism and steroid biosynthesis between different dietary groups and molting stages.DiscussionTo conclude, the optimal dietary C/L was estimated to be 3.59 for juvenile E. sinensis based on the survival and growth performance. Compared to PrM, E. sinensis in the InM was more active in the carbohydrate metabolism (glycolysis and gluconeogenesis) and fatty acid synthesis, with more triglyceride and less glycogen accumulated in the hepatopancreas.This study could contribute to better understanding the carbohydrate and lipid metabolism between different molting stages, and optimizing the precise feed formulation for juvenile E. sinensis.

Fibroblast growth factor 15, induced by elevated bile acids, mediates the improvement of hepatic glucose metabolism after sleeve gastrectomy.

Fibroblast growth factor (FGF) 15/19, which is expressed in and secreted from the distal ileum, can regulate hepatic glucose metabolism in an endocrine manner. The levels of both bile acids (BAs) and FGF15/19 are elevated after bariatric surgery. However, it is unclear whether the increase in FGF15/19 is induced by BAs. Moreover, it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery. To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy (SG). By calculating and comparing the changes of body weight after SG with SHAM group, we examined the weight-loss effect of SG. The oral glucose tolerance test (OGTT) test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG. By detecting the glycogen content, expression and activity of glycogen synthase as well as the glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (Pepck), we evaluated the hepatic glycogen content and gluconeogenesis activity. We examined the levels of total BA (TBA) together with the farnesoid X receptor (FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery. Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4 (FGFR4) with its corresponding signal pathways involved in glucose metabolism were detected. After surgery, food intake and body weight gain of SG group was decreased compare with the SHAM group. The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG, while the expression of the key enzyme for hepatic gluconeogenesis: G6Pase and Pepck, were depressed. TBA levels in serum and portal vein were both elevated after SG, the FXR-agonistic BA subspecies: Chenodeoxycholic acid (CDCA), lithocholic acid (LCA) in serum and CDCA, DCA, LCA in portal vein were all higher in SG group than that in SHAM group. Consequently, the ileal expression of FXR and FGF15 were also advanced in SG group. Moreover, the hepatic expression of FGFR4 was stimulated in SG-operated rats. As a result, the activity of its corresponding pathway for glycogen synthesis: FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated, while the corresponding pathway for hepatic gluconeogenesis: FGFR4- cAMP regulatory element-binding protein- peroxisome proliferator-activated receptor γ coactivator-1α pathway was suppressed. Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR. Furthermore, the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG.

Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer's disease as well as various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3β in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer's disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer's disease model.

The Hypoglycemic Activities and Underlying Mechanisms of Two Saponins-Rich Components from Fried Ziziphus jujuba Mill. Kernel.

Dried Ziziphus jujuba Mill. kernel is a potential natural source of nutraceutical and therapeutic agents in China. Recent researches have shown that the saponins of dried Z. jujuba Mill. kernel (SZJs: SZJ-1 and SZJ-2) have various biological effects. However, the hypoglycemic activities and underlying mechanisms of SZJs remain obscure. In the current study, two saponins SZJ-1 and SZJ-2 mainly composed of betulinic acid, spinosin, jujuboside A, and jujuboside B are extracted and is olated from dried Z. jujuba Mill. kernel. The SZJ-1 and SZJ-2 could significantly inhibit the activities of digestion enzymes α-glucosidase and α-amylases. The hypoglycemic ability of SZJ-1 and SZJ-2 is further investigated and the results show that SZJ-1 and SZJ-2 can improve the hyperglycemic by increasing the glucose consumption, improving the superoxide dismutase (SOD), hexokinase (HK), pyruvate kinase (PK) activities, and decrease the MDA content of insulin resistant HepG2 cells. Furthermore, SZJ-1 and SZJ-2 can activate the phosphorated adenosine 5'-monophosphate (AMP)-activated protein kinase α (p-AMPK), phosphoinositide 3-kinase p110α (PI3K-p110α), and phosphorated glycogen synthase kinase-3β (Ser9) (p-GSK3β). These resultsindicating that the SZJ-1 and SZJ-2 might improve the insulin resistant symptoms by improving the energy metabolic level and increasing the glycogen synthase activity of HepG2 cells.

Anti-fatigue properties of the ethanol extract of Moringa oleifera leaves in mice.

Moringa oleifera (M. oleifera) leaves are rich in nutrients and bioactive ingredients. This study was aimed at evaluating the anti-fatigue effect of the ethanol extract of M. oleifera leaves (MLEE) on mice and its primary mechanism of action using a weight-loaded forced swimming test. In the present study, MLEE was prepared by ultrasound-assisted extraction, and its anti-fatigue effect and antioxidant capacity were evaluated in mice. Mice were administrated MLEE (320 mg kg-1 body weight) for 15 days. MLEE supplementation significantly increased levels of glucose and non-esterified fatty acids (NEFA), while decreasing levels of lactate and blood urea nitrogen in serum (P < 0.05); the levels of glycogen in the liver and muscle were also increased, as was the activity of glycogen synthase and the level of NEFA in muscle (P < 0.05). According to a Western blot analysis, MLEE increased the expression of AMPKα1, JNK, AKT and STAT3 in the muscle of mice. Our findings indicate that MLEE has an anti-fatigue effect via the AMPK-linked route, which enables it to control energy metabolism and enhance antioxidant enzyme activity. © 2023 Society of Chemical Industry.

4-[(5-Methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone Inhibits MCPyV T Antigen Expression in Merkel Cell Carcinoma Independent of Aurora Kinase A.

Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV), and MCPyV-positive tumor cells depend on expression of the virus-encoded T antigens (TA). Here, we identify 4-[(5-methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone (PHT)-a reported inhibitor of Aurora kinase A-as a compound inhibiting growth of MCC cells by repressing noncoding control region (NCCR)-controlled TA transcription. Surprisingly, we find that TA repression is not caused by inhibition of Aurora kinase A. However, we demonstrate that β-catenin-a transcription factor repressed by active glycogen synthase kinase 3 (GSK3)-is activated by PHT, suggesting that PHT bears a hitherto unreported inhibitory activity against GSK3, a kinase known to function in promoting TA transcription. Indeed, applying an in vitro kinase assay, we demonstrate that PHT directly targets GSK3. Finally, we demonstrate that PHT exhibits in vivo antitumor activity in an MCC xenograft mouse model, suggesting a potential use in future therapeutic settings for MCC.

The Effect of Xenon on the Activity of Glycogen Synthase Kinase-Зβ in the Perifocal Zone of Ischemic Cerebral Infarction (Experimental Study)

Aim of the study. To determine the effects of xenon exposure at a dose of 0.5 MAC of different duration on the content and enzyme-inactivating phosphorylation of the glycogen synthase kinase-3β (GSK3β) in the perifocal zone of ischemic cerebral infarction in an experimental setting.Materials and methods. The Long method was used for modelling brain ischemia/reperfusion in 39 rats weighing 300-350 g. Study group animals was exposed to xenon at a dose of 0.5 MAC during 30, 60 and 120 minutes whereas control group animals received an oxygen-air mixture. Sham-operated animals served as a comparison group. The levels of GSK3β and phospho-GSK3β in brain homogenates were determined by blotting using specific antibodies.Results. In ischemic stroke model, the content of GSK3β did not significantly change in control animals compared to comparison group. However, control group animals exhibited significant (2.7-fold, P&lt;0.001) decrease in the content of its phospho-GSK3β in the perifocal zone of ischemic cerebral infarction. Inhalation of 0.5 MAC xenon during 30 minutes did not lead to an increase in phosphorylation of the GSK3β enzyme (P=0.9), however, 60 and 120 minutes of 0.5 MAC xenon exposures resulted in the increase in phosphorylated form of the enzyme by a factor of 2.1 (P=0.005) and 2.3 (P=0.001), respectively, compared to the control group.Conclusion. The results reveal a possible molecular mechanism (i. e., execution of neuroprotective and anti-inflammatory effects of xenon due to GSK-Зβ inactivation) and show the prospects for using 60 and 120 minutes of 0.5 MAC xenon exposures in ischemic brain damage after a stroke, traumatic brain injury and other brain lesions.

Douchi Peptides Vy and Sfllr Improve Glucose Homeostasis and Gut Dysbacteriosis In High-Fat Diet-Induced Insulin Resistant Mice.

Two peptides VY (Val-Tyr) and SFLLR (Ser-Phe-Leu-Leu-Arg) were recently identified from soy-fermented douchi with hypoglycemic activity in cells. The study aimed to understand their potential effects on glucose metabolism and insulin sensitivity as well as their mechanisms of action in a high-fat diet (HFD) induced insulin resistant model. C57BL/6 mice were fed HFD for 8 weeks, followed by peptide supplementation (doses: 10 and 50 mg/kg body weight) for 8 weeks. Peptides supplementation, especially SFLLR, reduced body weight gain, insulin resistance, hyperglycemia, inflammation, liver injury, and lipid accumulation. In both muscle and liver, both peptides activated glycogen synthase (GS), the key enzyme for glycogen synthesis, and also inhibited phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6PC), two rate-limiting enzymes for gluconeogenesis, via insulin and AMPK (5' adenosine monophosphate-activated protein kinase) signalling pathways. Furthermore, VY and SFLLR supplementation reversed HFD-induced gut dysbacteriosis by decreasing the abundance of Enterococcus, Oscillibacter, and Deferribacter, and also increased the abundances of Alistipes, Lactobacillus, Faecalibaculum, Akkermansia, and Bifidobacterium (usually beneficial in the intestine). Our study revealed the potential applications of peptides VY and SFLLR as a diet-based strategy for the prevention of type 2 diabetes. This article is protected by copyright. All rights reserved.

Starvation and Refeeding Regulate Glycogen Synthase Gene Expression in Rat Liver at the Posttranscriptional Level

Starvation and refeeding affect glycogen metabolism. The effects of starvation and refeeding on the level of glycogen synthase (GS) gene expression were examined in rat liver. Depletion of hepatic glycogen stores by 72 h of starvation (7% of control) was supercompensated by 24 h of refeeding a standard laboratory diet (247% of control). Upon further refeeding, glycogen concentration gradually returned to control levels after 120 h. After 72 h of starvation, GS activity and immunoreactive protein in the liver were 60–64% lower than in control rats with free access to food. After 72 h of refeeding, GS activity and immunoreactive protein returned to control values. No significant differences in GS mRNA levels were found between fed, starved and refed rats, as determined by Northern blot analysis and PCR quantification, indicating that the long-term regulation of GS gene expression in starvation and refeeding occurs via a posttranscriptional mechanism. The amount of GS mRNA associated with polyribosomes was 90% lower in starved than in fed rats. These data indicate that the efficiency of GS mRNA translation, rather than its abundance, decreases during starvation.

Dietary Methionine Restriction Alleviates Hyperglycemia in Pigs with Intrauterine Growth Restriction by Enhancing Hepatic Protein Kinase B Signaling and Glycogen Synthesis

BackgroundIndividuals with intrauterine growth restriction (IUGR) are prone to developing type 2 diabetes mellitus (T2DM). Dietary methionine restriction (MR) improves insulin sensitivity and glucose homeostasis in individuals with normal birth weight (NBW). ObjectiveThis study investigated the effects of MR on plasma glucose concentration and hepatic and muscle glucose metabolism in pigs with IUGR. MethodsThirty female NBW and 60 same-sex spontaneous IUGR piglets (Landrace × Yorkshire) were selected. After weaning (day 21), the piglets were fed diets with adequate methionine (NBW-CON and IUGR-CON) or 30% less methionine (IUGR-MR) (n = 6). At day 180, 1 pig with a body weight near the mean of each replication was selected for biochemical analysis. ResultsThe IUGR-CON group showed 41.6%, 68.6%, and 67.1% higher plasma glucose concentration, hepatic phosphoenolpyruvate carboxykinase activity, and glucose-6-phosphatase activity, respectively, than the NBW-CON group (P < 0.05). Muscle glycogen content and glycogen synthase activity were 36.9% and 38.8% lower, respectively, in the IUGR-CON than the NBW-CON group (P < 0.05), respectively, and there was decreased hepatic and muscle protein kinase B phosphorylation in the IUGR-CON group (P < 0.05). Compared with the IUGR-CON pigs, the IUGR-MR pigs had 28.7% lower plasma glucose concentrations (P < 0.05), which were similar to those of the NBW-CON pigs (P ≥ 0.05). The hepatic glycogen content and glycogen synthase activity of the IUGR-MR pigs were 62.9% and 50.8% higher than those of the IUGR-CON pigs (P < 0.05) and 53.5% and 84.3% higher than the NBW-CON pigs (P < 0.05), respectively. The IUGR-MR pigs’ hepatic and muscle protein kinase B phosphorylation was higher than that of the IUGR-CON pigs (P < 0.05) and similar to that of the NBW-CON pigs (P ≥ 0.05). ConclusionsMR attenuates hyperglycemia in IUGR pigs by enhancing hepatic protein kinase B signaling and glycogen synthesis, implying a potential nutritional strategy to prevent type 2 diabetes mellitus in IUGR offspring.

Active Glycogen Synthase in the Liver Prevents High-Fat Diet-Induced Glucose Intolerance, Decreases Food Intake, and Lowers Body Weight.

Many lines of evidence demonstrate a correlation between liver glycogen content and food intake. We previously demonstrated that mice overexpressing protein targeting to glycogen (PTG) specifically in the liver-which have increased glycogen content in this organ-are protected from high-fat diet (HFD)-induced obesity by reduced food intake. However, the use of PTG to increase liver glycogen implies certain limitations. PTG stimulates glycogen synthesis but also inhibits the enzyme responsible for glycogen degradation. Furthermore, as PTG is a regulatory subunit of protein phosphatase 1 (PP1), which regulates many cellular functions, its overexpression could have side effects beyond the regulation of glycogen metabolism. Therefore, it is necessary to determine whether the direct activation of glycogen synthesis, without affecting its degradation or other cellular functions, has the same effects. To this end, we generated mice overexpressing a non-inactivatable form of glycogen synthase (GS) specifically in the liver (9A-MGSAlb mice). Control and 9a-MGSAlb mice were fed a standard diet (SD) or HFD for 16 weeks. Glucose tolerance and feeding behavior were analyzed. 9A-MGSAlb mice showed an increase in hepatic glycogen in fed and fasting conditions. When fed an HFD, these animals preserved their hepatic energy state, had a reduced food intake, and presented a lower body weight and fat mass than control animals, without changes in energy expenditure. Furthermore, 9A-MGSAlb animals showed improved glucose tolerance when fed an SD or HFD. Moreover, liver triacylglycerol levels that were increased after HFD feeding were lower in these mice. These results confirm that increased liver glycogen stores contribute to decreased appetite and improve glucose tolerance in mice fed an HFD. On the basis of our findings, strategies to preserve hepatic glycogen stores emerge as potential treatments for obesity and hyperglycemia.

Xanthosine, a purine glycoside mediates hepatic glucose homeostasis through inhibition of gluconeogenesis and activation of glycogenesis via regulating the AMPK/ FoxO1/AKT/GSK3β signaling cascade

Type 2 Diabetes Mellitus (T2DM) is characterized by hepatic insulin resistance, which results in increased glucose production and reduced glycogen storage in the liver. There is no previous study in the literature that has explored the role of Xanthosine in hepatic insulin resistance. Moreover, mechanistic explanation for the beneficial effects of Xanthosine in lowering glucose production in diabetes is yet to be determined. This study for the first time investigated the beneficial effects of Tribulus terrestris (TT) and its active constituent, Xanthosine on gluconeogenesis and glycogenesis in Free Fatty Acid (FFA)-induced CC1 hepatocytes and streptozotocin (STZ)-induced Wistar rats. Xanthosine enhanced glucose uptake and decreased glucose production through phosphorylation of AMP-activated protein kinase (AMPK) and forkhead box transcription factor O1 (FoxO1), and downregulation of two rate limiting enzymes of gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression in FFA-induced CC1 cells. Xanthosine also prevented FFA-induced decreases in the phosphorylation of AKT/Protein kinase B, glycogen synthase kinase-3β (GSK3β), and increased glycogen synthase (GS) phosphorylation to increase the glycogen content in the hepatocytes. Moreover, in STZ-induced diabetic rats, oral administration of TT n-butanol fraction (TTBF) enriched with compound Xanthosine (10, 50 & 100 mg/kg body weight) improved insulin sensitivity, reduced fasting blood glucose levels, improved glucose homeostasis by reducing gluconeogenesis via AMPK/FoxO1-mediated PEPCK and G6Pase down-regulation and increasing glycogenesis via AKT/GSK3β-mediated GS activation. Overall, Xanthosine may be developed further for treating insulin resistance and hyperglycemia in T2DM.

The involvement of GSK3β for glycogen synthesis throughout the annual cycle of Pacific oyster, Crassostrea gigas (Magallana gigas)

Crassostrea gigas is a frequently studied species in understanding physiological processes in bivalves. Similar to other animals, oysters store glucose in the body as glycogen. Glycogen is known to supply energy for germ cell development and maintenance. Glycogen is synthesized by glycogen synthase. GSK3β regulates glycogen synthase activity and plays an important role in glycogen synthesis. Therefore, this study aims to examine the effect of GSK3β on the annual cycle of oysters and the glycogen synthesis pathway and to investigate the energy pathway in comparison with seasonal variation. Oysters were sampled monthly for one year and were subjected to glycogen content, RT-PCR, FISH, and western blot analysis. The year-round glycogen content significantly differs only in the mantle edge during spring and summer of both sexes but not in labial palp, digestive gland, gonad, and adductor muscle. The expression of GSK3β mRNA level was highest in October for females and April for males. Both sexes had the lowest expression in July. In the adductor muscle, females and males showed the highest expression in April and the lowest in July and October. The pattern of GSK3β expression in gonads and adductor muscle was similarly confirmed through FISH. As a result of examining the signaling system, p-GSK3β (serine 9) increased. At the same time, glycogen synthase decreased in May when the condition index was the highest, p-GSK3β decreased in October and July when spawning occurred, and glycogen synthase increased. Overall, it is thought that p-GSK3β expression is high in C. gigas at ripe, which inhibits glycogen synthesis and is used as energy for growth and maturation. Glycogen synthesis occurs for energy storage during degeneration.

Laforin targets malin to glycogen in Lafora progressive myoclonus epilepsy.

Glycogen is the largest cytosolic macromolecule and is kept in solution through a regular system of short branches allowing hydration. This structure was thought to solely require balanced glycogen synthase and branching enzyme activities. Deposition of overlong branched glycogen in the fatal epilepsy Lafora disease (LD) indicated involvement of the LD gene products laforin and the E3 ubiquitin ligase malin in regulating glycogen structure. Laforin binds glycogen, and LD-causing mutations disrupt this binding, laforin-malin interactions and malin's ligase activity, all indicating a critical role for malin. Neither malin's endogenous function nor location had previously been studied due to lack of suitable antibodies. Here, we generated a mouse in which the native malin gene is tagged with the FLAG sequence. We show that the tagged gene expresses physiologically, malin localizes to glycogen, laforin and malin indeed interact, at glycogen, and malin's presence at glycogen depends on laforin. These results, and mice, open the way to understanding unknown mechanisms of glycogen synthesis critical to LD and potentially other much more common diseases due to incompletely understood defects in glycogen metabolism.

ANTIGRAVIDADE SIMULADA LEVOU À TRANSFORMAÇÃO DO METABOLISMO DE GLICOLIPÍDIOS NO FÍGADO DE CAMUNDONGOS

ABSTRACT Objectives: The effects of weightlessness on the liver were studied using a tail suspension (TS) male mouse model. Methods: The effects of 0-, 2- and 4-week TS (CON, TS2 and TS4 groups) on glycogen and lipid content, as well as on the molecular processes of the synthesis and degradation pathways, were examined. Results: (1) The number of glycogenosomes under ultrastructure and the glycogen content were considerably larger in the TS4 group than in the other two groups. (2) In the TS4 group, glycogen synthase activity remained constant while glycogen phosphorylase activity dropped, indicating that glycogen breakdown was reduced. (3) The livers of the TS2 group had the highest lipid and triglyceride content, indicating lipid buildup in the liver at this time. (4) In the TS2 group, the activities of the fatty acid synthesis-related factors acetyl-CoA carboxylase and fatty acid synthase increased, while hepatic lipase decreased, indicating that lipid synthesis increased, while decomposition decreased. (5) In the TS2 group, the protein expression of glucose transporters 1 and 2 increased. Conclusions: From TS2 weeks to TS4 weeks, the main energy consumption mode in the livers of mice transitioned from glucose metabolism to lipid metabolism as glucose use decreased. Level of evidence II; Comparative prospective study.

Polygonatum sibiricum saponin Exerts Beneficial Hypoglycemic Effects in Type 2 Diabetes Mice by Improving Hepatic Insulin Resistance and Glycogen Synthesis-Related Proteins.

Type 2 diabetes mellitus (T2DM) is a systemic metabolic disorder characterized by insulin deficiency and insulin resistance. Recently, it has become a significant threat to public health. Polygonatum sibiricum saponin (PSS) has potential hypoglycemic effects, but its specific mechanism needs further study. In this study, PSS significantly decreased the level of blood glucose, water intake, and the organ index in diabetic mice. Meanwhile, PSS effectively reduced the content of total triglyceride (TG), total cholesterol (TCHO), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in the blood, and increased the content of high-density lipoprotein cholesterol (HDL-C). This suggests that PSS could reduce the content of blood lipids and initially improve the damage of hepatocytes. We found that PSS alleviated hepatic insulin resistance, repaired islet beta cells, and enabled insulin to play its biological role normally. It also improved oral glucose tolerance and abated serum lipopolysaccharide (LPS) and glycosylated hemoglobin (HbA1c) levels in T2DM mice. Furthermore, studies have found that PSS increased the content of phosphorylated protein kinase B (AKT), thereby promoting the effect of glucose transporter 4 (GLUT-4), and activating glycogen synthase kinase 3beta (GSK-3β) and glycogen synthase (GS) proteins to promote hepatic glycogen synthesis. Finally, we found that PSS could promote the growth of beneficial bacteria such as Bifidobacterium and Lactobacillus, reduce the growth of harmful bacteria such as Enterococcus and Enterobacter, and preliminarily improve the composition of important bacteria in the intestine. These studies indicate that PSS has an excellent hypoglycemic effect, which provides a potential new treatment for T2DM and guidance for more in-depth research.

Empagliflozin enhances neuroplasticity in rotenone-induced parkinsonism: Role of BDNF, CREB and Npas4

AimsParkinsonism is characterized by degeneration of dopaminergic neurons and impairment in neuroplasticity. Empagliflozin (EMPA) is an anti-diabetic drug that has been shown to improve cognitive dysfunctions and exerted antioxidant and anti-inflammatory effects in different models. This study aimed to determine the neuroprotective effects of EMPA against rotenone (ROT)-induced parkinsonism. Main methodsROT (1.5 mg/kg) was injected subcutaneously three times per week for two successive weeks. Mice were treated with EMPA (3 and 10 mg/kg, orally) for one week prior ROT administration and for another two weeks along with ROT. After that, motor functions and histopathological changes were assessed, and brains were isolated for biochemical analyses and immunohistochemical investigation. Key findingsResults indicated that, in a dose dependent manner, EMPA improved motor functions and histopathological changes induced by ROT, increased brain content of reduced glutathione (GSH), dopamine (DA), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), nuclear factor erythroid 2–related factor 2 (Nrf2), inositol trisphosphate (IP3), calcium (Ca2+), calcium/calmodulin-dependent protein kinase type IV (CaMKIV) and phospho-Protein kinase B (p-Akt) levels compared to ROT group. Additionally, EMPA decreased the levels of malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α), and inactivated glycogen synthase kinase-3 beta (GSK-3β). Improvement in neuroplasticity was also observed indicated by elevation in brain derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and neuronal PAS domain Protein 4 (Npas4). SignificanceEMPA improved motor functions possibly through improving neuroplasticity markers and antioxidant, anti-inflammatory, and neuroprotective effects in a dose dependent manner.

BENEFICIAL EFFECTS OF ROSMARINUS OFFICINALIS AND THYMUS NUMIDICUS ON KEY ENZYMES OF CARBOHYDRATE METABOLISM IN ALLOXAN-INDUCED DIABETIC RATS

The aim of this study is to evaluate the protective effects of the ethyl acetate fraction of Rosmarinus officinalis (RO-EA) and Thymus numidicus (TN-EA) plant extracts on carbohydrate metabolism enzymes during diabetes mellitus. To achieve this objective, two experiments were carried out. The first of which was evaluating the hypoglycemic and the anti-hyperglycemic effects on normal rats overloaded with glucose (4 mg/kg b.w), with the use of two doses (150 and 300 mg/kg b.w), for each plant in the presence of negative control (vehicle 0.5 ml/100 g b.w), and positive control (5 mg of glibenclamide /kg b.w). The second experiment aims at studying the dose-dependent effect of the two plants’ extracts on carbohydrate metabolism in Wistar rats rendered diabetic by intraperitoneal injection of Alloxan at (120 mg/kg b.w); 54 male rats of the Wistar strain were divided into 09 groups with 06 rats per group. 03 of the groups have normal rats receiving vehicle (0.5 ml/100 g bw), TN-EA (300 mg/kg b.w), RO-EA (300 mg/kg b.w), respectively. The 06 remaining groups were composed of diabetic rats receiving vehicle (0.5 ml/b.w), TN-EA (150 and 300 mg/kg b.w), RO-EA (150 and 300 mg/kg b.w) Glibenclamide (5 mg/kg b.w), respectively. The process lasted for 21 days. Then we proceeded to the assays. The analysis of the results showed a dose-dependent reduction in glycemia for the anti-hyperglycemic and hypoglycaemic tests of the RO-EA with the dose of 150 and 300 mg/kg b.w, the latter demonstrated a significant increase in insulin and hemoglobin hexokinase enzyme activity, glucose-6-phosphate dehydrogenase and a concomitant effect modulating plasma glucose levels. In addition to decreased plasma HbA1c levels, glucose-6-phosphatase and fructose-1,6-bisphosphatase enzymatic activity in diabetic rats. The administration of this fraction prevented the loss of body weight and led to an improvement in the activity of glycogen synthase and glycogen phosphorylase. In conclusion, the RO-EA fraction at a dose of 300 mg/kg b w has an anti-hyperglycemic power in diabetic rats, these results were confirmed by histological examination of the liver.

Polysaccharides from apple pomace exhibit anti-fatigue activity through increasing glycogen content.

The polysaccharides were isolated from apple pomace by hot-water extraction, and their anti-fatigue activity was evaluated in C2C12 muscle myoblasts and male Kunming mice. The purified polysaccharides from apple pomace (PAP) have a molecular weight of 1.74 × 105Da and were composed of mannose, rhamnose, glucose, galactose and arabinose. In C2C12 myoblasts, PAP showed no cytotoxicity in the concentrations of 0-300μg/ml. PAP treatment increased the glycogen content, while the ATP content was not affected in C2C12 myoblasts. Further investigation found that the activity and gene expression of glycogen synthase, rather than glycogen phosphorylase, were upregulated by PAP treatment. The studies in vivo showed that PAP treatment did not affect the food intake and weight again in mice. Importantly, PAP prolonged the exhaustive swimming time, increased hepatic and skeletal muscle glycogen levels, and effectively inhibited the accumulation of blood lactic and blood urea nitrogen in mice. Taken together, the results suggested that PAP exhibit anti-fatigue activity in vitro and in vivo through increasing glycogen content.

Phosphorylase phosphatase and flash activation of skeletal muscle glycogen phosphorylase-A tribute to Edmond H. Fischer.

Glycogen is a polymerized form of glucose that serves as an energy reserve in all types of organisms. In animals glycogen synthesis and degradation, especially in liver and skeletal muscle, are regulated by hormonal and physiological signals that reciprocally control the opposing activities of glycogen synthase and glycogen phosphorylase. These enzymes are under allosteric control by binding of metabolites (e.g., ATP, AMP, G6P) and covalent control by reversible phosphorylation by kinase and phosphatase all assembled together on glycogen. More than 50 years ago Edmond Fischer and colleagues showed "flash activation" of phosphorylase in glycogen particles. This involved transient and extensive inhibition of protein phosphatase but even today the phenomenon is not understood. Phosphatase regulation is known to rely on regulatory subunits including glycogen binding subunits that serve as scaffolds, binding catalytic subunit, glycogen, and substrates. This tribute article to Edmond Fischer highlights his thoughts and ideas about the transient inhibition of phosphorylase phosphatase during flash activation of phosphorylase and speculates that phosphatase regulation in glycogen particles might involve a/b hybrids of phosphorylase.