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Aims Sevoflurane preconditioning (SPC) results in cerebral ischemic tolerance; however, the mechanism remains unclear. Promoting microglia/macrophages polarization from pro‐inflammatory state to anti‐inflammatory phenotype has been indicated as a potential treatment target against ischemic stroke. In this study, we aimed to assess the effect of SPC on microglia polarization after stroke and which signaling pathway was involved in this transition. Methods Mouse primary microglia with SPC were challenged by oxygen‐glucose deprivation (OGD) or lipopolysaccharide (LPS), and mice with SPC were subjected to middle cerebral artery occlusion (MCAO). Then, the mRNA and protein levels of pro‐inflammatory/anti‐inflammatory factors were analyzed. GSK‐3β phosphorylation and Nrf2 nuclear translocation were measured. The mRNA and protein expression of pro‐inflammatory/anti‐inflammatory factors, neurological scores, infarct volume, cellular apoptosis, the proportion of pro‐inflammatory/anti‐inflammatory microglia/macrophages, and the generation of super‐oxidants were examined after SPC or GSK‐3β inhibitor TDZD treatment with or without Nrf2 deficiency. Results Sevoflurane preconditioning promoted anti‐inflammatory and inhibited pro‐inflammatory microglia/macrophages phenotype both in vitro and in vivo. GSK‐3β phosphorylation at Ser9 was increased after SPC. Both SPC and TDZD administration enhanced Nrf2 nuclear translocation, reduced pro‐inflammatory microglia/macrophages markers expression, promoted anti‐inflammatory markers level, and elicited a neuroprotective effect. Nrf2 deficiency abolished the promoted anti‐inflammatory microglia/macrophages polarization and ischemic tolerance induced by TDZD treatment. The reduced percentage of pro‐inflammatory positive cells and super‐oxidants generation induced by SFC or TDZD was also reversed by Nrf2 knockdown. Conclusions Our results indicated that SPC exerts brain ischemic tolerance and promotes anti‐inflammatory microglia/macrophages polarization by GSK‐3β‐dependent Nrf2 activation, which provides a novel mechanism for SPC‐induced neuroprotection. SPC promoted microglia/macrophages polarization toward to anti‐inflammatory phenotype in vitro and in vivo. Both SPC and TDZD administration enhanced Nrf2 nuclear translocation.SPC promoted microglia/macrophages toward to anti‐inflammatory phenotype shifting via GSK‐3β‐dependent Nrf2 activation.

The aimf of this study was to explore effects of miR-132 and glycogen synthase kinase-3[beta] (GSK-3[beta]) on learning and memory in mice. miR-132 inhibitor GSK-3[beta] overexpression agent (sh-GSK-3[beta]) and normal saline (negative control group) were injected into the hippocampus of adult mice, and healthy adult mice were taken as the unrelated control group. The expression of miR-132 and GSK-3[beta] in the hippocampus of adult and elderly mice was detected using reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis. Morris water maze test was employed to detect learning and memory function in mice. The dual luciferase reporter was adopted to determine the relationship between miR-132 and GSK-3[beta]. Compared with the adult group, the expression of miR-132 was significantly downregulated in the hippocampus in the elderly group, while the expression of GSK-3[beta] was upregulated. Injecting miR-132 inhibitor into the hippocampus of adult mice led to a significant increase in escape latency and a significant decrease in the number of times of crossing platforms. The injection of GSK-3[beta] overexpression agent into the hippocampus of adult mice resulted in a marked increase in escape latency and a significant decrease in the number of times of crossing platforms in the water maze test. It was also found that downregulation of GSK-3[beta] reversed the decline in learning and memory in mice caused by downregulation of miR-132 expression. The dual luciferase report identified a targeted regulatory relationship between miR-132 and GSK-3[beta]. Overexpression of miR-132 can inhibit the expression of GSK-3[beta] in mouse learning and memory ability, which provides some inspiration for understanding the occurrence of learning and memory disorders and future treatment methods. Key words: miR-132, glycogen synthase kinase-3[beta], mice, learning and memory function

Mature B cells remain in a quiescent state until activated. Rickert and colleagues identify a prominent role for the kinase Gsk3 in resting naive B cells and in activated germinal center B cells that restrains the production of Myc and reactive oxygen species and prevents metabolic collapse. B cells predominate in a quiescent state until an antigen is encountered, which results in rapid growth, proliferation and differentiation of the B cells. These distinct cell states are probably accompanied by differing metabolic needs, yet little is known about the metabolic control of B cell fate. Here we show that glycogen synthase kinase 3 (Gsk3) is a metabolic sensor that promotes the survival of naive recirculating B cells by restricting cell mass accumulation. In antigen-driven responses, Gsk3 was selectively required for regulation of B cell size, mitochondrial biogenesis, glycolysis and production of reactive oxygen species (ROS), in a manner mediated by the co-stimulatory receptor CD40. Gsk3 was required to prevent metabolic collapse and ROS-induced apoptosis after glucose became limiting, functioning in part by repressing growth dependent on the myelocytomatosis oncoprotein c-Myc. Notably, we found that Gsk3 was required for the generation and maintenance of germinal center B cells, which require high glycolytic activity to support growth and proliferation in a hypoxic microenvironment.

Multiple insulin-regulated enzymes participate in hepatic glycogen synthesis, and the rate-controlling step responsible for insulin stimulation of glycogen synthesis is unknown. We demonstrate that glucokinase (GCK)-mediated glucose phosphorylation is the rate-controlling step in insulin-stimulated hepatic glycogen synthesis in vivo, by use of the somatostatin pancreatic clamp technique using [13C₆]glucose with metabolic control analysis (MCA) in three rat models: 1) regular chow (RC)-fed male rats (control), 2) high fat diet (HFD)-fed rats, and 3) RC-fed rats with portal vein glucose delivery at a glucose infusion rate matched to the control. During hyperinsulinemia, hyperglycemia dosedependently increased hepatic glycogen synthesis. At similar levels of hyperinsulinemia and hyperglycemia, HFD-fed rats exhibited a decrease and portal delivery rats exhibited an increase in hepatic glycogen synthesis via the direct pathway compared with controls. However, the strong correlation between liver glucose-6-phosphate concentration and net hepatic glycogen synthetic rate was nearly identical in these three groups, suggesting that the main difference between models is the activation of GCK. MCA yielded a high control coefficient for GCK in all three groups. We confirmed these findings in studies of hepatic GCK knockdown using an antisense oligonucleotide. Reduced liver glycogen synthesis in lipid-induced hepatic insulin resistance and increased glycogen synthesis during portal glucose infusion were explained by concordant changes in translocation of GCK. Taken together, these data indicate that the rate of insulin-stimulated hepatic glycogen synthesis is controlled chiefly through GCK translocation.

Stomatal cell lineage is an archetypal example of asymmetric cell division (ACD), which is necessary for plant survival 1 – 4 . In Arabidopsis thaliana , the GLYCOGEN SYNTHASE KINASE3 (GSK3)/SHAGGY-like kinase BRASSINOSTEROID INSENSITIVE 2 (BIN2) phosphorylates both the mitogen-activated protein kinase (MAPK) signalling module 5 , 6 and its downstream target, the transcription factor SPEECHLESS (SPCH) 7 , to promote and restrict ACDs, respectively, in the same stomatal lineage cell. However, the mechanisms that balance these mutually exclusive activities remain unclear. Here we identify the plant-specific protein POLAR as a stomatal lineage scaffold for a subset of GSK3-like kinases that confines them to the cytosol and subsequently transiently polarizes them within the cell, together with BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL), before ACD. As a result, MAPK signalling is attenuated, enabling SPCH to drive ACD in the nucleus. Moreover, POLAR turnover requires phosphorylation on specific residues, mediated by GSK3. Our study reveals a mechanism by which the scaffolding protein POLAR ensures GSK3 substrate specificity, and could serve as a paradigm for understanding regulation of GSK3 in plants. POLAR, identified in a survey of the protein interactome of BRASSINOSTEROID INSENSITIVE 2 in Arabidopsis thaliana , has a key role in coordinating cell polarity and enabling asymmetric cell division.

Background The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer’s disease (AD), the most common neurodegenerative disorder in the elderly. Main body Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating β- or γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogen-activated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients. Conclusion The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.

Facial jaw muscle is involved in the occurrence, development, treatment and maintenance of maxillofacial deformities. The structure and function of this tissue can be altered by changes in external stimuli, and orthodontists can regulate its reconstruction using orthopedic forces. The PI3K/Akt signaling pathway is most well-known for its biological functions in cell proliferation, survival and apoptosis. In the present study, the effects of the PI3K/Akt signaling pathway in cyclic stretch-induced myoblast apoptosis were investigated. For this purpose, L6 rat myoblasts were cultured under mechanical stimulation and treated with the PI3K kinase inhibitor, LY294002, to elucidate the role of the PI3K/Akt signaling pathway. cells were stained with Hoechst 33258 to visualize morphological changes and apoptosis of myoblasts, and western blotting was performed to detect expression of Akt, phosphorylated (p)-Akt (Ser473), glycogen synthase kinase 3[beta] (GSK-3[beta]) and p-GSK-3[beta] (Ser9). After addition of PI3K inhibitor, the expression of total Akt and GSK-3[beta] did not significantly differ among groups; however, the levels of p-Akt and p-GSK-3[beta] were lower in inhibitor-treated groups than in those treated with loading stress alone. In addition, the rate of apoptosis in myoblasts subjected to cyclic stretch increased in a time-dependent manner, peaking at 24 h. collectively, it was also demonstrated that the PI3K/Akt/GSK-3[beta] pathway plays an important role in stretch-induced myoblast apoptosis.

The purpose of this review is to summarize the research progress of PI3K/Akt signaling pathway in erythropoiesis and glycolysis. Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is activated by numerous genes and leads to protein kinase B (Akt) binding to the cell membrane, with the help of phosphoinositide-dependent kinase, in the PI3K/Akt signal transduction pathway. Threonine and serine phosphorylation contribute to Akt translocation from the cytoplasm to the nucleus and further mediates enzymatic biological effects, including those involved in cell proliferation, apoptosis inhibition, cell migration, vesicle transport and cell cancerous transformation. As a key downstream protein of the PI3K/Akt signaling pathway, hypoxia-inducible factor (HIF)-1 is closely associated with the concentration of oxygen in the environment. Maintaining stable levels of HIF-1 protein is critical under normoxic conditions; however, HIF-1 levels quickly increase under hypoxic conditions. HIF-1α is involved in the acute hypoxic response associated with erythropoietin, whereas HIF-2α is associated with the response to chronic hypoxia. Furthermore, PI3K/Akt can reduce the synthesis of glycogen and increase glycolysis. Inhibition of glycogen synthase kinase 3β activity by phosphorylation of its N-terminal serine increases accumulation of cyclin D1, which promotes the cell cycle and improves cell proliferation through the PI3K/Akt signaling pathway. The PI3K/Akt signaling pathway is closely associated with a variety of enzymatic biological effects and glucose metabolism.

Epithelial-mesenchymal transition (EMT) occurs in the tumor microenvironment and presents an important mechanism of tumor cell intravasation, stemness acquisition, and metastasis. During metastasis, tumor cells enter the circulation to gain access to distant tissues, but how this fluid microenvironment influences cancer cell biology is poorly understood. Here, we present both in vivo and in vitro evidence that EMT-like transition also occurs in circulating tumor cells (CTCs) as a result of hydrodynamic shear stress (+SS), which promotes conversion of CD24.sup.middle/CD44.sup.high/CD133.sup.middle/CXCR4.sup.low/ALDH1.sup.low primary patient epithelial tumor cells into specific high sphere-forming CD24.sup.low/CD44.sup.low/CD133.sup.high/CXCR4.sup.high/ALDH1.sup.high cancer stem-like cells (CSLCs) or tumor-initiating cells (TICs) with elevated tumor progression and metastasis capacity in vitro and in vivo. We demonstrate that conversion of CSLCs/TICs from epithelial tumor cells via +SS is dependent on reactive oxygen species (ROS)/nitric oxide (NO) generation, and suppression of extracellular signal-related kinase (ERK)/glycogen synthase kinase (GSK)3[beta], a mechanism similar to that operating in embryonic stem cells to prevent their differentiation while promoting self-renewal. Fluid shear stress experienced during systemic circulation of human breast tumor cells can lead to specific acquisition of mesenchymal stem cell (MSC)-like potential that promotes EMT, mesenchymal-epithelial transition, and metastasis to distant organs. Our data revealed that biomechanical forces appeared to be important microenvironmental factors that not only drive hematopoietic development but also lead to acquisition of CSLCs/TIC potential in cancer metastasis. Our data highlight that +SS is a critical factor that promotes the conversion of CTCs into distinct TICs in blood circulation by endowing plasticity to these cells and by maintaining their self-renewal signaling pathways.

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.