Journal articles: 'GSK-3β MODULATION'

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Vyas, Dharmesh R., Espen E. Spangenburg, Tsghe W. Abraha, Thomas E. Childs, and Frank W. Booth. "GSK-3β negatively regulates skeletal myotube hypertrophy." American Journal of Physiology-Cell Physiology 283, no. 2 (August 1, 2002): C545—C551. http://dx.doi.org/10.1152/ajpcell.00049.2002.

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To determine whether changes in glycogen synthase kinase-3β (GSK-3β) phosphorylation contribute to muscle hypertrophy, we delineated the effects of GSK-3β activity on C2C12 myotube size. We also examined possible insulin-like growth factor I (IGF-I) signaling of NFAT (nuclear factors of activated T cells)-inducible gene activity and possible modulation of NFAT activation by GSK-3β. Application of IGF-I (250 ng/ml) or LiCl (10 mM) alone (i.e., both inhibit GSK-3β activity) increased the area of C2C12 myotubes by 80 and 85%, respectively. The application of IGF-I (250 ng/ml) elevated GSK-3β phosphorylation and reduced GSK-3β kinase activity by ∼800% and ∼25%, respectively. LY-294002 (100 μM) and wortmannin (150 μM), specific inhibitors of phosphatidylinositol 3′-kinase, attenuated IGF-I-induced GSK-3β phosphorylation by 67 and 92%, respectively. IGF-I suppressed the kinase activity of GSK-3β. IGF-I (250 ng/ml), but not LiCl (10 mM), induced an increase in NFAT-activated luciferase reporter activity. Cotransfection of a constitutively active GSK-3β (cGSK-3β) inhibited the induction by IGF-I of NFAT-inducible reporter activity. LiCl, which inhibits GSK-3β, removed the block by cGSK-3β on IGF-I-inducible NFAT-responsive reporter gene activity. These data suggest that the IGF-I-induced increase in skeletal myotube size is signaled, in part, through the inhibition of GSK-3β.

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Li, C., H. Xin, Y. Shi, and J. Mu. "Knockdown of TRIM24 suppresses growth and induces apoptosis in acute myeloid leukemia through downregulation of Wnt/GSK-3β/β-catenin signaling." Human & Experimental Toxicology 39, no. 12 (July 16, 2020): 1725–36. http://dx.doi.org/10.1177/0960327120938845.

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Tripartite motif-containing protein 24 (TRIM24) has currently emerged as a crucial cancer-related gene present in a wide range of human cancer types. However, the involvement of TRIM24 in acute myeloid leukemia (AML) has not been well investigated. The present study aims to investigate the significance, cellular function, and potential regulatory mechanism of TRIM24 in AML. We found that TRIM24 expression was significantly upregulated in AML compared with normal tissues. AML patients with low expression of TRIM24 had higher survival rates than those expressing TRIM24 at higher levels. High expression of TRIM24 was also detected in AML cells and its knockdown markedly restricted proliferation and promoted apoptosis in AML cells. Further investigation revealed that TRIM24 contributed to the regulation of Wnt/β-catenin signaling, which was associated with modulating the phosphorylation status of glycogen synthase kinase-3β (GSK-3β). Inactivation of GSK-3β partially reversed the TRIM24 knockdown-mediated antitumor effects observed in AML cells. Furthermore, knockdown of TRIM24 retarded the growth of AML-derived xenograft tumors in nude mice in vivo. Overall, these findings demonstrate that knockdown of TRIM24 impedes the AML tumor growth through the modulation of Wnt/GSK-3β/β-catenin signaling. These findings highlight the potential TRIM24 as an attractive anticancer target to treat AML.

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Bai, J., P. Jia, Y. Zhang, K. Wang, and G. Wu. "Paraoxonase 2 protects against oxygen-glucose deprivation/reoxygenation-induced neuronal injury by enhancing Nrf2 activation via GSK-3β modulation." Human & Experimental Toxicology 40, no. 8 (February 24, 2021): 1342–54. http://dx.doi.org/10.1177/0960327121996032.

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Paraoxonase 2 (PON2) is a powerful antioxidant that mediates cell survival under oxidative stress; however, its protection neurons against cerebral ischemia-reperfusion injury-induced oxidative stress remains unclear. This study aimed to determine the precise regulating role of PON2 in neuronal survival under oxidative stress. An in vitro model of cerebral ischemia-reperfusion injury was used to assess the effect of PON2 on oxidative stress induced by oxygen–glucose deprivation/reoxygenation (OGD/R). Results showed that PON2 expression in neurons was decreased due to OGD/R exposure. A series of functional experiments revealed that upregulated PON2 improved OGD/R-impaired viability and attenuated OGD/R-induced increases in apoptosis and reactive oxygen species in neurons. Decreased PON2 expression enhanced neuronal sensitivity to OGD/R-induced injury. Overexpressed PON2 markedly enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in the nucleus and increased the levels of Nrf2-mediated transcriptional activity. Furthermore, PON2 enhanced the Nrf2 activation by modulating glycogen synthase kinase-3β (GSK-3β). Inhibition of GSK-3β substantially abrogated the PON2 knockdown-mediated suppression of Nrf2 activity. Notably, Nrf2 inhibition partially reversed the neuroprotective effects of PON2 overexpression in OGD/R-exposed neurons. These findings indicate that PON2 alleviates OGD/R-induced apoptosis and oxidative stress in neurons by potentiating Nrf2 activation via GSK-3β modulation. This study highlights the potential neuroprotective function of PON2 against cerebral ischemia-reperfusion injury.

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Zhu, Jiang, Mario J. Rebecchi, Peter S. A. Glass, Peter R. Brink, and Lixin Liu. "Cardioprotection of the aged rat heart by GSK-3β inhibitor is attenuated: age-related changes in mitochondrial permeability transition pore modulation." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 3 (March 2011): H922—H930. http://dx.doi.org/10.1152/ajpheart.00860.2010.

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It is well established that inhibition of glycogen synthase kinase (GSK)-3β in the young adult myocardium protects against ischemia-reperfusion (I/R) injury through inhibition of mitochondrial permeability transition pore (mPTP) opening. Here, we investigated age-associated differences in the ability of GSK-3β inhibitor [SB-216763 (SB)] to protect the heart and to modulate mPTP opening during I/R injury. Fischer 344 male rats were assigned from their respective young or old age groups. Animals were subjected to 30 min ischemia following 120 min reperfusion to determine myocardial infarction (MI) size in vivo. Ischemic tissues were collected 10 min after reperfusion for nicotinamide adenine dinucleotide (NAD+) measurements and immunoblotting. In parallel experiments, ventricular myocytes isolated from young or old rats were exposed to oxidative stress through generation of reactive oxygen species (ROS), and mPTP opening times were measured by using confocal microscopy. Our results showed that SB decreased MI in young SB-treated rats compared with young untreated I/R animals, whereas SB failed to significantly affect MI in the old animals. SB also significantly increased GSK-3β phosphorylation in young rats, but phosphorylation levels were already highly elevated in old control groups. There were no significant differences observed between SB-treated and untreated old animals. NAD+levels were better maintained in young SB-treated animals compared with the young untreated group during I/R, but this relative improvement was not observed in old animals. SB also significantly prolonged the time to mPTP opening induced by ROS in young cardiomyocytes, but not in aged cardiomyocytes. These results demonstrate that this GSK-3β inhibitor fails to protect the aged myocardium in response to I/R injury or prevent mPTP opening following a rise in ROS and suggest that healthy aging alters mPTP regulation by GSK-3β.

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Qiu, Qi, Xia Lei, Yueying Wang, Hui Xiong, Yanming Xu, Huifeng Sun, Hongdan Xu, and Ning Zhang. "Naringin Protects against Tau Hyperphosphorylation in Aβ25–35-Injured PC12 Cells through Modulation of ER, PI3K/AKT, and GSK-3β Signaling Pathways." Behavioural Neurology 2023 (February 15, 2023): 1–16. http://dx.doi.org/10.1155/2023/1857330.

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Alzheimer’s disease (AD) is the most common form of dementia and a significant social and economic burden. Estrogens can exert neuroprotective effects and may contribute to the prevention, attenuation, or even delay in the onset of AD; however, long-term estrogen therapy is associated with harmful side effects. Thus, estrogen alternatives are of interest for countering AD. Naringin, a phytoestrogen, is a key active ingredient in the traditional Chinese medicine Drynaria. Naringin is known to protect against nerve injury induced by amyloid beta-protein (Aβ) 25–35, but the underlying mechanisms of this protection are unclear. To investigate the mechanisms of naringin neuroprotection, we observed the protective effect on Aβ25–35-injured C57BL/6J mice’s learning and memory ability and hippocampal neurons. Then, an Aβ25–35 injury model was established with adrenal phaeochromocytoma (PC12) cells. We examined the effect of naringin treatment on Aβ25–35-injured PC12 cells and its relationship with estrogen receptor (ER), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and glycogen synthase kinase (GSK)-3β signaling pathways. Estradiol (E2) was used as a positive control for neuroprotection. Naringin treatment resulted in improved learning and memory ability, the morphology of hippocampal neurons, increased cell viability, and reduced apoptosis. We next examined the expression of ERβ, p-AKT (Ser473, Thr308), AKT, p-GSK-3β (Ser9), GSK-3β, p-Tau (Thr231, Ser396), and Tau in PC12 cells treated with Aβ25–35 and either naringin or E2, with and without inhibitors of the ER, PI3K/AKT, and GSK-3β pathways. Our results demonstrated that naringin inhibits Aβ25–35-induced Tau hyperphosphorylation by modulating the ER, PI3K/AKT, and GSK-3β signaling pathways. Furthermore, the neuroprotective effects of naringin were comparable to those of E2 in all treatment groups. Thus, our results have furthered our understanding of naringin’s neuroprotective mechanisms and indicate that naringin may comprise a viable alternative to estrogen therapy.

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Chen, Rong-Fu, Yun-Nan Lin, Keng-Fan Liu, Chun-Ting Wang, Savitha Ramachandran, Ching-Jen Wang, and Yur-Ren Kuo. "The Acceleration of Diabetic Wound Healing by Low-Intensity Extracorporeal Shockwave Involves in the GSK-3β Pathway." Biomedicines 9, no. 1 (December 30, 2020): 21. http://dx.doi.org/10.3390/biomedicines9010021.

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Previous studies have demonstrated that extracorporeal shock wave therapy (ESWT) could accelerate diabetic wound healing and that the inhibition of glycogen synthase kinase-3β (GSK-3β) is involved in epithelial differentiation during wound healing. This study investigated whether the enhancement of diabetic wound healing by ESWT is associated with the GSK-3β-mediated Wnt/β-catenin signaling pathway. A dorsal skin wounding defect model using streptozotocin-induced diabetic rodents was established. Rats were divided into 4 groups: group 1, normal controls without diabetes; group 2, diabetic controls without treatment; group 3, diabetic rats receiving ESWT; and group 4, rats receiving 6-bromoindirubin-3′oxime (BIO), a GSK-3β inhibitor, to trigger Wnt/β-catenin signaling. Tissue samples were collected and analyzed by immunohistochemical (IHC) staining and quantitative RT-PCR. The ESWT and BIO-treated groups both exhibited significant promotion of wound healing compared to the healing in controls without treatment. RT-PCR analysis of Wnt-1, -3a, -4, -5a, and -10 and β-catenin expression showed significantly increased expression in the ESWT group. The IHC staining showed that Wnt-3a and -5a and β-catenin levels were significantly increased in the ESWT and BIO treatment groups compared to the control groups. ESWT enhancement of diabetic wound healing is associated with modulation of the GSK-3β-mediated Wnt/β-catenin signaling pathway.

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Silva, Guilherme M., Rosivaldo S. Borges, Kelton L. B. Santos, Leonardo B. Federico, Isaque A. G. Francischini, Suzane Q. Gomes, Mariana P. Barcelos, Rai C. Silva, Cleydson B. R. Santos, and Carlos H. T. P. Silva. "Revisiting the Proposition of Binding Pockets and Bioactive Poses for GSK-3β Allosteric Modulators Addressed to Neurodegenerative Diseases." International Journal of Molecular Sciences 22, no. 15 (July 31, 2021): 8252. http://dx.doi.org/10.3390/ijms22158252.

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Glycogen synthase kinase-3 beta (GSK-3β) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out due to their selective and subtle modulation, lowering the chance of producing side effects. The mechanism of GSK-3β allosteric modulators may be considered still vague in terms of elucidating a well-defined binding pocket and a bioactive pose for them. In this context, we propose to reinvestigate and reinforce such knowledge by the application of an extensive set of in silico methodologies, such as cavity detection, ligand 3D shape analysis and docking (with robust validation of corresponding protocols), and molecular dynamics. The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3β allosteric modulators. We further applied this to the prospect for new compounds by ligand-based virtual screening and analyzed the potential of the two obtained virtual hits by quantum chemical calculations. All potential hits achieved will be subsequently tested by in vitro assays in order to validate our approaches as well as to unveil novel chemical entities as GSK-3β allosteric modulators.

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Kim, Nayoung, Mi Yeon Kim, Woo Seon Choi, Eunbi Yi, Hyo Jung Lee, and Hun Sik Kim. "GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner." Cancers 13, no. 8 (April 9, 2021): 1802. http://dx.doi.org/10.3390/cancers13081802.

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Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.

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Kehn-Hall, Kylene, Aarthi Narayanan, Lindsay Lundberg, Gavin Sampey, Chelsea Pinkham, Irene Guendel, Rachel Van Duyne, et al. "Modulation of GSK-3β Activity in Venezuelan Equine Encephalitis Virus Infection." PLoS ONE 7, no. 4 (April 4, 2012): e34761. http://dx.doi.org/10.1371/journal.pone.0034761.

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Tong, Yixin, Sohyun Park, Di Wu, Thurl E. Harris, Christopher A. Moskaluk, David L. Brautigan, and Zheng Fu. "Modulation of GSK 3β autoinhibition by Thr‐7 and Thr‐8." FEBS Letters 592, no. 4 (February 2018): 537–46. http://dx.doi.org/10.1002/1873-3468.12990.

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Breit, Andreas, Laura Miek, Johann Schredelseker, Mirjam Geibel, Martha Merrow, and Thomas Gudermann. "Insulin-like growth factor-1 acts as a zeitgeber on hypothalamic circadian clock gene expression via glycogen synthase kinase-3β signaling." Journal of Biological Chemistry 293, no. 44 (September 14, 2018): 17278–90. http://dx.doi.org/10.1074/jbc.ra118.004429.

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Brain and muscle ARNT-like protein-1 (BMAL-1) is an important component of the cellular circadian clock. Proteins such as epidermal (EGF) or nerve growth factor (NGF) affect the cellular clock via extracellular signal–regulated kinases-1/2 (ERK-1/2) in NIH3T3 or neuronal stem cells, but no such data are available for the insulin-like growth factor-1 (IGF-1). The hypothalamus expresses receptors for all three growth factors, acts as a central circadian pacemaker, and releases hormones in a circadian fashion. However, little is known about growth factor–induced modulation of clock gene activity in hypothalamic cells. Here, we investigated effects of IGF-1, EGF, or NGF on the Bmal-1 promoter in two hypothalamic cell lines. We found that only IGF-1 but not EGF or NGF enhanced activity of the Bmal-1 promoter. Inhibition of ERK-1/2 activity did not affect IGF-1–induced Bmal-1 promoter activation and all three growth factors similarly phosphorylated ERK-1/2, questioning a role for ERK-1/2 in controlling BMAL-1 promoter activity. Of note, only IGF-1 induced sustained phosphorylation of glycogen synthase kinase-3β (GSK-3β). Moreover, the GSK-3β inhibitor lithium or siRNA-mediated GSK-3β knockdown diminished the effects of IGF-1 on the Bmal-1 promoter. When IGF-1 was used in the context of temperature cycles entraining hypothalamic clock gene expression to a 24-h rhythm, it shifted the phase of Bmal-1 promoter activity, indicating that IGF-1 functions as a zeitgeber for cellular hypothalamic circadian clocks. Our results reveal that IGF-1 regulates clock gene expression and that GSK-3β but not ERK-1/2 is required for the IGF-1–mediated regulation of the Bmal-1 promoter in hypothalamic cells.

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Shin, Jong Ho, Kyeong Min Kim, Jin Uk Jeong, Jae Min Shin, Ju Hyung Kang, Kitae Bang, and Joo-Heon Kim. "Nrf2-Heme Oxygenase-1 Attenuates High-Glucose-Induced Epithelial-to-Mesenchymal Transition of Renal Tubule Cells by Inhibiting ROS-Mediated PI3K/Akt/GSK-3β Signaling." Journal of Diabetes Research 2019 (August 6, 2019): 1–8. http://dx.doi.org/10.1155/2019/2510105.

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Background. Epithelial-to-mesenchymal transition (EMT) is thought to play a significant role in the advancement to chronic kidney disease and contributes to the deposition of extracellular matrix proteins and renal fibrosis relating to diabetic nephropathy. Method. We studied the effect of Nrf2-HO-1 signaling on high-glucose- (HG-) induced EMT in normal human tubular epithelial cells, that is, HK2 cells. In short, we treated HK2 cells with HG and sulforaphane (SFN) as an Nrf2 activator. EMT was evaluated by the expression activity of the epithelial marker E-cadherin and mesenchymal markers such as vimentin and fibronectin. Results. Exposure of HK2 cells to HG (60 mM) activated the expression of vimentin and fibronectin but decreased E-cadherin. Treatment of HK2 cells with SFN caused HG-induced attenuation in EMT markers with activated Nrf2-HO-1. We found that SFN decreased HG-induced production of reactive oxygen species (ROS), phosphorylation of PI3K/Akt at serine 473, and inhibitory phosphorylation of serine/threonine kinase glycogen synthase kinase-3β (GSK-3β) at serine 9. Subsequently, these signaling led to the downregulation of the Snail-1 transcriptional factor and the recovery of E-cadherin. Conclusion. The present study suggests that Nrf2-HO-1 signaling has an inhibitory role in the regulation of EMT through the modulation of ROS-mediated PI3K/Akt/GSK-3β activity, highlighting Nrf2-HO-1 and GSK-3β as potential therapeutic targets in diabetic nephropathy.

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Yang, Wen, Yue Liu, Qing-Qing Xu, Yan-Fang Xian, and Zhi-Xiu Lin. "Sulforaphene Ameliorates Neuroinflammation and Hyperphosphorylated Tau Protein via Regulating the PI3K/Akt/GSK-3β Pathway in Experimental Models of Alzheimer’s Disease." Oxidative Medicine and Cellular Longevity 2020 (September 11, 2020): 1–17. http://dx.doi.org/10.1155/2020/4754195.

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Alzheimer’s disease (AD) is the most common form of dementia characterized by progressive loss of cognitive functions due to neuronal death mainly in the hippocampal and cortical brain. Sulforaphene (SF) is one of the main isothiocyanates isolated from a Chinese herb Raphani Semen. In this study, we aimed to investigate the neuroprotective effects of SF using in vitro and in vivo models of AD. Streptozotocin (STZ) was intracranially injected into the rats; then, SF (25 and 50 mg/kg) was given orally once a day for 6 consecutive weeks. After drug treatment, the cognitive functions were assessed using the Morris Water Maze Test (MWMT). After the MWMT, the rats were euthanized and brain tissues were collected. In the in vitro test, BV-2 microglia were pretreated with SF (1 and 2 μM) for 1 h and then stimulated with lipopolysaccharide (LPS) for another 23 h. Both molecular and histological methods were used to unravel the action mechanisms and elucidate the signaling pathway. The MWMT results showed that SF treatment significantly improved the STZ-induced cognitive deficits in rats. SF treatment markedly suppressed the production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) but increased the release of IL-10 in the STZ-treated rats. In addition, SF significantly inhibited the phosphorylation of tau protein at Thr205, Ser396, and Ser404 sites, while enhancing the ratios of p-Akt (Ser473)/Akt and p-GSK-3β (Ser9)/GSK-3β in the hippocampus of the STZ-treated rats. On the other hand, SF (1 and 2 μM) treatment also markedly attenuated the cytotoxicity induced by LPS in BV-2 cells. In addition, SF treatment obviously suppressed the releases of nitric oxide (NO), TNF-α, and IL-6 in the LPS-stimulated BV-2 cells. Moreover, SF treatment significantly mitigated the nuclear translocation of p-NF-κB p65 and the ratio of p-GSK-3β (Ser9)/GSK-3β in LPS-stimulated BV-2 cells. Taken together, SF possessed neuroprotective effects against the STZ-induced cognitive deficits in rats and LPS-induced neuroinflammation in BV-2 cells via modulation of the PI3K/Akt/GSK-3β pathway and inhibition of the NF-κB activation, suggesting that SF is a promising neuroprotective agent worthy of further development into AD treatment.

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Wesslau, Karl-Philipp, Anabel Stein, Michael Kasper, and Kathrin Barth. "P2X7 Receptor Indirectly Regulates the JAM-A Protein Content via Modulation of GSK-3β." International Journal of Molecular Sciences 20, no. 9 (May 9, 2019): 2298. http://dx.doi.org/10.3390/ijms20092298.

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The alveolar epithelial cells represent an important part of the alveolar barrier, which is maintained by tight junction proteins, particularly JAM-A, occludin, and claudin-18, which regulate paracellular permeability. In this study, we report on a strong increase in epithelial JAM-A expression in P2X7 receptor knockout mice when compared to the wildtype. Precision-cut lung slices of wildtype and knockout lungs and immortal epithelial lung E10 cells were treated with bleomycin, the P2X7 receptor inhibitor oxATP, and the agonist BzATP, respectively, to evaluate early changes in JAM-A expression. Biochemical and immunohistochemical data showed evidence for P2X7 receptor-dependent JAM-A expression in vitro. Inhibition of the P2X7 receptor using oxATP increased JAM-A, whereas activation of the receptor decreased the JAM-A protein level. In order to examine the role of GSK-3β in the expression of JAM-A in alveolar epithelial cells, we used lithium chloride for GSK-3β inhibiting experiments, which showed a modulating effect on bleomycin-induced alterations in JAM-A levels. Our data suggest that an increased constitutive JAM-A protein level in P2X7 receptor knockout mice may have a protective effect against bleomycin-induced lung injury. Bleomycin-treated precision-cut lung slices from P2X7 receptor knockout mice responded with a lower increase in mRNA expression of JAM-A than bleomycin-treated precision-cut lung slices from wildtype mice.

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Rico, Anabel, Garazi Guembelzu, Valle Palomo, Ana Martínez, Ana Aiastui, Leire Casas-Fraile, Andrea Valls, Adolfo López de Munain, and Amets Sáenz. "Allosteric Modulation of GSK-3β as a New Therapeutic Approach in Limb Girdle Muscular Dystrophy R1 Calpain 3-Related." International Journal of Molecular Sciences 22, no. 14 (July 8, 2021): 7367. http://dx.doi.org/10.3390/ijms22147367.

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Limb-girdle muscular dystrophy R1 calpain 3-related (LGMDR1) is an autosomal recessive muscular dystrophy produced by mutations in the CAPN3 gene. It is a rare disease and there is no cure or treatment for the disease while the pathophysiological mechanism by which the absence of calpain 3 provokes the dystrophy in muscles is not clear. However, key proteins implicated in Wnt and mTOR signaling pathways, which regulate muscle homeostasis, showed a considerable reduction in their expression and in their phosphorylation in LGMDR1 patients’ muscles. Finally, the administration of tideglusib and VP0.7, ATP non-competitive inhibitors of glycogen synthase kinase 3β (GSK-3β), restore the expression and phosphorylation of these proteins in LGMDR1 cells, opening the possibility of their use as therapeutic options.

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Mohd Alaraj, Irena Kosinska, Bahaa Deen Al-Trad, Ammar Almaaytah, Tarek D. Hussein, Ashfaque Hossain, and Mohamed Jamal Saadh. "Differential expression of glycogen synthase kinase 3α and 3β isomers in brain cortex of mice following high doses of glucose." International Journal of Research in Pharmaceutical Sciences 11, no. 1 (February 3, 2020): 993–99. http://dx.doi.org/10.26452/ijrps.v11i1.1926.

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Glycogen synthase kinase 3 (GSK3) encodes a serine/threonine protein kinase. We investigated the effects of Subcutaneous (SC) glucose administration on the expression of glycogen synthase kinase 3 (GKS-3) isomers (α and β) genes in the cerebral cortex of mice with the aim of determining the possible mechanism(s) involved in mitochondrial dysfunction induced by hyperglycemia. Adult male BALB/c mice were treated with 12 gm/kg glucose solution SC once daily for 3 days. Ultrastructure study, histopathological analysis, and Real-time PCR investigations were carried out on the cerebral cortex from glucose treated mice and from vehicle-treated control animals. We observed significant ultrastructural damage of mitochondria in the cerebral cortex of mice received high doses of glucose. Histopathological alterations in the cortex of these animals were also detected. A significant increased of GSK-3α gene expression and decreased expressions of GKS-3β gene in high glucose treated animals were noticed. The hyperglycemia-induced ultrastructural changes may occur via modulation of gene expression of GSK-3 isomers, and we hypothesize this as an early etiopathological factor in hyperglycemia-related neurodegenerative diseases (NDD). It considered the first study describing "modulation of expression of GSK-3 isomer genes" as a possible mechanism of hyperglycemia-induced mitochondrial dysfunction.

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Nishihara, Masahiro, Tetsuji Miura, Takayuki Miki, Masaya Tanno, Toshiyuki Yano, Kazuyuki Naitoh, Katsuhiko Ohori, Hiroyuki Hotta, Yoshiaki Terashima, and Kazuaki Shimamoto. "Modulation of the mitochondrial permeability transition pore complex in GSK-3β-mediated myocardial protection." Journal of Molecular and Cellular Cardiology 43, no. 5 (November 2007): 564–70. http://dx.doi.org/10.1016/j.yjmcc.2007.08.010.

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Abu-Elfotuh, Karema, Amina M. A. Tolba, Furqan H. Hussein, Ahmed M. E. Hamdan, Mohamed A. Rabeh, Saad A. Alshahri, Azza A. Ali, et al. "Anti-Alzheimer Activity of Combinations of Cocoa with Vinpocetine or Other Nutraceuticals in Rat Model: Modulation of Wnt3/β-Catenin/GSK-3β/Nrf2/HO-1 and PERK/CHOP/Bcl-2 Pathways." Pharmaceutics 15, no. 8 (July 31, 2023): 2063. http://dx.doi.org/10.3390/pharmaceutics15082063.

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Alzheimer’s disease (AD) is a devastating illness with limited therapeutic interventions. The aim of this study is to investigate the pathophysiological mechanisms underlying AD and explore the potential neuroprotective effects of cocoa, either alone or in combination with other nutraceuticals, in an animal model of aluminum-induced AD. Rats were divided into nine groups: control, aluminum chloride (AlCl3) alone, AlCl3 with cocoa alone, AlCl3 with vinpocetine (VIN), AlCl3 with epigallocatechin-3-gallate (EGCG), AlCl3 with coenzyme Q10 (CoQ10), AlCl3 with wheatgrass (WG), AlCl3 with vitamin (Vit) B complex, and AlCl3 with a combination of Vit C, Vit E, and selenium (Se). The animals were treated for five weeks, and we assessed behavioral, histopathological, and biochemical changes, focusing on oxidative stress, inflammation, Wnt/GSK-3β/β-catenin signaling, ER stress, autophagy, and apoptosis. AlCl3 administration induced oxidative stress, as evidenced by elevated levels of malondialdehyde (MDA) and downregulation of cellular antioxidants (Nrf2, HO-1, SOD, and TAC). AlCl3 also upregulated inflammatory biomarkers (TNF-α and IL-1β) and GSK-3β, leading to increased tau phosphorylation, decreased brain-derived neurotrophic factor (BDNF) expression, and downregulation of the Wnt/β-catenin pathway. Furthermore, AlCl3 intensified C/EBP, p-PERK, GRP-78, and CHOP, indicating sustained ER stress, and decreased Beclin-1 and anti-apoptotic B-cell lymphoma 2 (Bcl-2) expressions. These alterations contributed to the observed behavioral and histological changes in the AlCl3-induced AD model. Administration of cocoa, either alone or in combination with other nutraceuticals, particularly VIN or EGCG, demonstrated remarkable amelioration of all assessed parameters. The combination of cocoa with nutraceuticals attenuated the AD-mediated deterioration by modulating interrelated pathophysiological pathways, including inflammation, antioxidant responses, GSK-3β-Wnt/β-catenin signaling, ER stress, and apoptosis. These findings provide insights into the intricate pathogenesis of AD and highlight the neuroprotective effects of nutraceuticals through multiple signaling pathways.

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Hao, Qingqing, Feifei Zhang, Yudan Wang, Yingxiao Li, and Xiaoyong Qi. "Cardiac Contractility Modulation Attenuates Chronic Heart Failure in a Rabbit Model via the PI3K/AKT Pathway." BioMed Research International 2020 (January 9, 2020): 1–8. http://dx.doi.org/10.1155/2020/1625362.

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The Akt plays an important role in regulating cardiac growth, myocardial angiogenesis, and cell death in cardiac myocytes. However, there are few studies to focus on the responses of the Akt pathway to cardiac contractility modulation (CCM) in a chronic heart failure (HF) model. In this study, the effects of CCM on the treatment of HF in a rabbit model were investigated. Thirty six-month-old rabbits were randomly separated into control, HF, and CCM groups. The rabbits in HF and CCM groups were pressure uploaded, which can cause an aortic constriction. Then, CCM was gradually injected to the myocardium of rabbits in the CCM group, and this process lasted for four weeks with six hours per day. Rabbit body weight, heart weight, and heart beating rates were recorded during the experiment. To assess the CCM impacts, rabbit myocardial histology was examined as well. Additionally, western blot analysis was employed to measure the protein levels of Akt, FOXO3, Beclin, Pi3k, mTOR, GSK-3β, and TORC2 in the myocardial histology of rabbits. Results showed that the body and heart weight of rabbits decreased significantly after suffering HF when compared with those in the control group. However, they gradually recovered after CCM application. The CCM significantly decreased collagen volume fraction in myocardial histology of HF rabbits, indicating that CCM therapy attenuated myocardial fibrosis and collagen deposition. The levels of Akt, FOXO3, Beclin, mTOR, GSK-3β, and TORC2 were significantly downregulated, but Pi3k concentration was greatly upregulated after CCM utilization. Based on these findings, it was concluded that CCM could elicit positive effects on HF therapy, which was potentially due to the variation in the Pi3k/Akt signaling pathway.

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Larabee, Jason L., Francisco J. Maldonado-Arocho, Sergio Pacheco, Bryan France, Kevin DeGiusti, Salika M. Shakir, Kenneth A. Bradley, and Jimmy D. Ballard. "Glycogen Synthase Kinase 3 Activation Is Important for Anthrax Edema Toxin-Induced Dendritic Cell Maturation and Anthrax Toxin Receptor 2 Expression in Macrophages." Infection and Immunity 79, no. 8 (May 16, 2011): 3302–8. http://dx.doi.org/10.1128/iai.05070-11.

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ABSTRACTAnthrax edema toxin (ET) is one of two binary toxins produced byBacillus anthracisthat contributes to the virulence of this pathogen. ET is an adenylate cyclase that generates high levels of cyclic AMP (cAMP), causing alterations in multiple host cell signaling pathways. We previously demonstrated that ET increases cell surface expression of the anthrax toxin receptors (ANTXR) in monocyte-derived cells and promotes dendritic cell (DC) migration toward the lymph node-homing chemokine MIP-3β. In this work, we sought to determine if glycogen synthase kinase 3 (GSK-3) is important for ET-induced modulation of macrophage and DC function. We demonstrate that inhibition of GSK-3 dampens ET-induced maturation and migration processes of monocyte-derived dendritic cells (MDDCs). Additional studies reveal that the ET-induced expression of ANTXR in macrophages was decreased when GSK-3 activity was disrupted with chemical inhibitors or with small interfering RNA (siRNA) targeting GSK-3. Further examination of the ET induction of ANTXR revealed that a dominant negative form of CREB could block the ET induction of ANTXR, suggesting that CREB or a related family member was involved in the upregulation of ANTXR. Because CREB and GSK-3 activity appeared to be important for ET-induced ANTXR expression, the impact of GSK-3 on ET-induced CREB activity was examined in RAW 264.7 cells possessing a CRE-luciferase reporter. As with ANTXR expression, the ET induction of the CRE reporter was decreased by reducing GSK-3 activity. These studies not only provide insight into host pathways targeted by ET but also shed light on interactions between GSK-3 and CREB pathways in host immune cells.

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Mateus, Vanessa, João Rocha, Paula Alves, Hélder Mota-Filipe, Bruno Sepodes, and Rui Pinto. "Thiadiazolidinone-8 Ameliorates Inflammation Associated with Experimental Colitis in Mice." Pharmacology 101, no. 1-2 (September 30, 2017): 35–42. http://dx.doi.org/10.1159/000471808.

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Thiadiazolidinone-8 (TDZD-8) is an effective thiadiazolidinone derivate that is able to suppress the expression of inflammatory cytokines; it also presents tissue protective actions by glycogen synthase kinase (GSK)-3β inhibition, promoting thus an anti-inflammatory effect. Since inflammatory bowel disease is a chronic disease with reduced quality of life, where currently available therapies are only able to induce or maintain the patient in remission, it is crucial to investigate new pharmacological approaches. The main objective of this study was to evaluate the effect of TDZD-8 in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Male CD-1 mice with TNBS-induced colitis were treated with a daily dose of TDZD-8 5 mg/kg/day IP during 4 days. The anti-inflammatory properties of TDZD-8 in the TNBS-induced colitis were confirmed by suppression of pro-inflammatory mediators, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and myeloperoxidase, as well as by the significant increase of the anti-inflammatory cytokine, IL-10. These treated mice also presented a reduction in fecal hemoglobin and alkaline phosphatase, suggesting a beneficial effect of TDZD-8. Furthermore, renal and hepatic biomarkers remained stabilized after treatment. In conclusion, TDZD-8 reduces the inflammatory response associated with TNBS-induced colitis in mice, and modulation of GSK-3β seems to be an interesting pharmacological target in colitis.

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Li, Yan-Chun, Min-Juan Wang, and Wen-Jun Gao. "Hyperdopaminergic modulation of inhibitory transmission is dependent on GSK-3β signaling-mediated trafficking of GABAA receptors." Journal of Neurochemistry 122, no. 2 (June 7, 2012): 308–20. http://dx.doi.org/10.1111/j.1471-4159.2012.07790.x.

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Vallée, Alexandre, Jean-Noël Vallée, and Yves Lecarpentier. "Lithium and Atypical Antipsychotics: The Possible WNT/β Pathway Target in Glaucoma." Biomedicines 9, no. 5 (April 26, 2021): 473. http://dx.doi.org/10.3390/biomedicines9050473.

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Glaucoma is a progressive neurodegenerative disease that represents the major cause of irreversible blindness. Recent findings have shown which oxidative stress, inflammation, and glutamatergic pathway have main roles in the causes of glaucoma. Lithium is the major commonly used drug for the therapy of chronic mental illness. Lithium therapeutic mechanisms remain complex, including several pathways and gene expression, such as neurotransmitter and receptors, circadian modulation, ion transport, and signal transduction processes. Recent studies have shown that the benefits of lithium extend beyond just the therapy of mood. Neuroprotection against excitotoxicity or brain damages are other actions of lithium. Moreover, recent findings have investigated the role of lithium in glaucoma. The combination of lithium and atypical antipsychotics (AAPs) has been the main common choice for the treatment of bipolar disorder. Due to the possible side effects gradually introduced in therapy. Currently, no studies have focused on the possible actions of AAPs in glaucoma. Recent studies have shown a down regulation of the WNT/β-catenin pathway in glaucoma, associated with the overactivation of the GSK-3β signaling. The WNT/β-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Lithium is correlated with upregulation the WNT/β-catenin pathway and downregulation of the GSK-3β activity. Thus, this review focuses on the possible actions of lithium and AAPs, as possible therapeutic strategies, on glaucoma and some of the presumed mechanisms by which these drugs provide their possible benefit properties through the WNT/β-catenin pathway.

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Chung, Hun Taeg, Yeonsoo Joe, Sena Kim, Hyo Jeong Kim, Se-ung Park, Yingqing Chen, Jeongmin Park, and Hyeok-Jun Park. "ER stress-induced IRE1α activation obliterates endotoxin tolerance through modulation of cytokine production via GSK-3βand XBP-1." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 200.9. http://dx.doi.org/10.4049/jimmunol.196.supp.200.9.

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Abstract Endotoxin tolerance occurs in the late phase of sepsis in order to protect cells from the early hyper-inflammatory response. However, as it induces immunosuppressive environment, septic patients in their late phase are suffering from secondary infections, particularly the bacterial pneumonia. Here we show that induction of ER stress leads to activation of GSK-3β and XBP-1 in an IRE1α-mediated manner, which in turn obliterates endotoxin tolerance. Consequently, from the lung of septic host infected with P. aeruginosa, symptoms of pneumonia have been improved and the bacteria cleared. Thus, for septic patients, determination of immune status would be helpful in guiding the selective usage of appropriate immune modulation, in that ER stress can be a novel therapeutic maneuver, restoring the immune response in patients with endotoxin tolerance.

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Zhu, Yuankai, Xiangyu Tang, Zhaoting Cheng, Qingjian Dong, and Ge Ruan. "The Anti-Inflammatory Effect of Preventive Intervention with Ketogenic Diet Mediated by the Histone Acetylation of mGluR5 Promotor Region in Rat Parkinson’s Disease Model: A Dual-Tracer PET Study." Parkinson's Disease 2022 (September 5, 2022): 1–12. http://dx.doi.org/10.1155/2022/3506213.

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Background and Objectives. The exact pathological mechanism of Parkinson’s disease (PD) remains elusive, and the existing therapies fail to reverse the disease progression. This study intended to explore the epigenetic anti-inflammatory mechanism of ketogenic diet (KD). Materials and Methods. The neuroprotective effect of ketosis state prior to the onset of PD (preventive KD, KDp) was compared with that receiving KD after the onset (therapeutic KD, KDt) in the lipopolysaccharide- (LPS-) induced rat PD model. A total of 100 rats were randomly assigned to the following 4 groups: sham, LPS, LPS + KDp, and LPS + KDt groups. Results. Significant dopamine deficient behaviors (rotational behavior and contralateral forelimb akinesia), upregulation of proinflammatory mediators (TNF-α, IL-1β, and IL-6), loss of dopaminergic neurons, reduction of mGluR5+ microglia cells, increase of TSPO+ microglia cells, reduction of H3K9 acetylation in the mGluR5 promoter region and mGluR5 mRNA expression, and decline in the phosphorylation levels of Akt/GSK-3β/CREB pathway were observed after the intervention of LPS ( P < 0.01 ). TSPO and DAT PET imaging revealed the increased uptake of 18F-DPA-714 in substantia nigra and decreased uptake of 18F-FP-CIT in substantia nigra and striatum in LPS-treated rats ( P < 0.001 ). These impairments were alleviated by the dietary intervention of KD, especially with the strategy of KDp ( P < 0.05 ). Conclusions. The anti-inflammatory effect of KD on PD was supposed to be related to the modulation of Akt/GSK-3β/CREB signaling pathway mediated by the histone acetylation of mGluR5 promotor region. The KD intervention should be initiated prior to the PD onset in high-risk population to achieve a more favorable outcome.

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Bai, Chunhua, Jiaqi Zhao, Jielin Su, Jiaxin Chen, Xinmu Cui, Manqing Sun, and Xuewu Zhang. "Curcumin induces mitochondrial apoptosis in human hepatoma cells through BCLAF1-mediated modulation of PI3K/AKT/GSK-3β signaling." Life Sciences 306 (October 2022): 120804. http://dx.doi.org/10.1016/j.lfs.2022.120804.

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Terashima, Yoshiaki, Tetsuji Miura, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Toshiyuki Yano, Hiroyuki Hotta, Satoko Ishikawa, and Kazuaki Shimamoto. "Role of GSK-3β modulation in cytoprotective regulation of mitochondrial permeability transition pores by mitochondrial KATP channel activation." Journal of Molecular and Cellular Cardiology 45, no. 4 (October 2008): S22. http://dx.doi.org/10.1016/j.yjmcc.2008.09.662.

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Datusalia, Ashok Kumar, and Shyam Sunder Sharma. "Amelioration of Diabetes-induced Cognitive Deficits by GSK-3β Inhibition is Attributed to Modulation of Neurotransmitters and Neuroinflammation." Molecular Neurobiology 50, no. 2 (January 14, 2014): 390–405. http://dx.doi.org/10.1007/s12035-014-8632-x.

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XING, C., S. duan, B. zhang, Y. yuan, and C. zhang. "MON-338 Modulation of GSK-3β Expression by AMPK Ameliorates Diabetic Kidney Injury by Promoting IR Phosphorylation Cascade." Kidney International Reports 4, no. 7 (July 2019): S136. http://dx.doi.org/10.1016/j.ekir.2019.05.346.

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Dalal, Suman, Christopher R. Daniels, Ying Li, Gary L. Wright, Mahipal Singh, and Krishna Singh. "Exogenous ubiquitin attenuates hypoxia/reoxygenation-induced cardiac myocyte apoptosis via the involvement of CXCR4 and modulation of mitochondrial homeostasis." Biochemistry and Cell Biology 98, no. 4 (August 2020): 492–501. http://dx.doi.org/10.1139/bcb-2019-0339.

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Exogenous ubiquitin (UB) plays a protective role in β-adrenergic receptor-stimulated and ischemia/reperfusion (I/R)-induced myocardial remodeling. Here, we report that UB treatment inhibits hypoxia/reoxygenation (H/R)-induced apoptosis in adult rat ventricular myocytes (ARVMs). The activation of Akt was elevated, whereas the activation of glycogen synthase kinase-3β was reduced in UB-treated cells post-H/R. The level of oxidative stress was lower, whereas the number of ARVMs with polarized mitochondria was significantly greater in the UB-treated samples. ARVMs express CXCR4 with majority of CXCR4 localized in the membrane fraction. CXCR4 antagonism using AMD3100, and siRNA-mediated knockdown of CXCR4 negated the protective effects of UB. Two mutated UB proteins (unable to bind CXCR4) had no effect on H/R-induced apoptosis, activation of Akt and GSK-3β, or oxidative stress. UB treatment enhanced mitochondrial biogenesis, and inhibition of mitochondrial fission using mdivi1 inhibited H/R-induced apoptosis. Ex vivo, UB treatment significantly decreased infarct size and improved functional recovery of the heart following global I/R. Activation of caspase-9, a key player of the mitochondrial death pathway, was significantly lower in UB-treated hearts post-I/R. UB, most likely acting via CXCR4, plays a protective role in H/R-induced myocyte apoptosis and myocardial I/R injury via modulation of mitochondrial homeostasis and the mitochondrial death pathway of apoptosis.

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Fang, Yifei. "Unleashing Anti-Tumor Activity of Natural Killer Cells Via Modulation of Immune Checkpoints Receptors and Molecules." Highlights in Science, Engineering and Technology 8 (August 17, 2022): 463–71. http://dx.doi.org/10.54097/hset.v8i.1196.

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As vital innate lymphocytes, natural killer (NK) cells suppress cancer progression chiefly by inducing cell lysis and secreting pro-inflammatory cytokines. NK cell activation relies on the balance between inhibitory and stimulating signals mediated by a wide range of surface receptors. Specific receptors initiate intracellular signaling pathways, which are negatively regulated by specific checkpoint molecules. Synergistic activation is controlled by Cbl proteins and GSK-3β, while the downstream signaling pathways induced by ITIM-bearing receptors are regulated by SHP-1. These intracellular NK checkpoints are attractive targets for immune checkpoint blockade therapies, but not enough attention has been given. Hence, this paper discusses the major signaling pathways regulated by the intracellular checkpoints and their potential clinical application. The current progress in the investigation of NK checkpoint receptors is also summarized. This paper aims to promote the development of novel immunotherapies that optimize the tumor-suppressive activity of NK cells while suppressing tumor immunological evasion.

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Rao, A. S., N. Kremenevskaja, J. Resch, and G. Brabant. "Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/β-catenin signalling." European Journal of Endocrinology 153, no. 6 (December 2005): 929–38. http://dx.doi.org/10.1530/eje.1.02038.

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Background: Lithium, clinically used in the treatment of bipolar disorders, is well known to induce thyroid growth. However, the mechanism involved is only incompletely characterized. Although it is conventionally believed that thyroid proliferation depends on the thyroid-stimulating hormone (TSH)/cAMP/cAMP response element binding protein (CREB) pathway, recent data indicate that Wnt/β-catenin signalling may be of critical importance. In other cell types lithium activates canonical Wnt signalling by GSK-3β inhibition, which in turn stabilizes cytosolic free β-catenin. Here we investigated the potential modulation of Wnt/β-catenin signalling under lithium treatment in primary and neoplastic human thyrocytes. Methods: Primary (S18) and neoplastic (NPA, FTC133) thyrocytes treated with and without LiCl were analysed using Western blotting, immunoprecipitation, reporter-gene assay, MTT proliferation assay and transfection studies. Results: LiCl dose-dependently inhibited GSK-3β, stabilized free β-catenin and inhibited β-catenin degradation. Furthermore, LiCl altered the assembly of adherens junction by upregulating the E-cad-herin repressor, Snail, and downregulated E-cadherin expression. At a dose of 5 mM, LiCl significantly increased the proliferative potency of thyrocytes, which appeared to be mediated by β-catenin, since nuclear β-catenin stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription and upregulated downstream targets like cyclin D1. To characterize the specificity of Wnt/β-catenin-driven thyrocyte proliferation, we transfected primary thyrocytes and FTC133 cells with dominant negative TCF4 to block Wnt-dependent pathways or with dominant negative CREB to inhibit the TSH/cAMP cascade. In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/β-catenin by dominant negative TCF4 reduced proliferation by approx. 50%. Conclusion: Our data indicate that Wnt/β-catenin signalling is of major importance in the control of lithium-dependent thyrocyte proliferation.

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Yu, Wei, Wenliang Zha, Zhiqiang Ke, Qing Min, Cairong Li, Huirong Sun, and Chao Liu. "Curcumin Protects Neonatal Rat Cardiomyocytes against High Glucose-Induced Apoptosis via PI3K/Akt Signalling Pathway." Journal of Diabetes Research 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/4158591.

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The function of curcumin on NADPH oxidase-related ROS production and cardiac apoptosis, together with the modulation of protein signalling pathways, was investigated in cardiomyocytes. Primary cultures of neonatal rat cardiomyocytes were exposed to 30 mmol/L high glucose with or without curcumin. Cell viability, apoptosis, superoxide formation, the expression of NADPH oxidase subunits, and potential regulatory molecules, Akt and GSK-3β, were assessed in cardiomyocytes. Cardiomyocytes exposure to high glucose led to an increase in both cell apoptosis and intracellular ROS levels, which were strongly prevented by curcumin treatment (10 μM). In addition, treatment with curcumin remarkably suppressed the increased activity of Rac1, as well as the enhanced expression ofgp91phoxandp47phoxinduced by high glucose. Lipid peroxidation and SOD were reversed in the presence of curcumin. Furthermore, curcumin treatment markedly inhibited the reduced Bcl-2/Bax ratio elicited by high glucose exposure. Moreover, curcumin significantly increased Akt and GSK-3βphosphorylation in cardiomyocytes treated with high glucose. In addition, LY294002 blocked the effects of curcumin on cardiomyocytes exposure to high glucose. In conclusion, these results demonstrated that curcumin attenuated high glucose-induced cardiomyocyte apoptosis by inhibiting NADPH-mediated oxidative stress and this protective effect is most likely mediated by PI3K/Akt-related signalling pathway.

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Kinsella, Gemma K., Stefania Cannito, Valentina Bordano, John C. Stephens, Arianna C. Rosa, Gianluca Miglio, Valeria Guaschino, Valeria Iannaccone, John B. C. Findlay, and Elisa Benetti. "GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells." International Journal of Molecular Sciences 22, no. 19 (October 5, 2021): 10784. http://dx.doi.org/10.3390/ijms221910784.

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GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT(Ser473)/tot-AKT and phGSK-3β(Ser9)/tot-GSK-3β, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance.

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Yu, Manshu, Jun Shi, Meixiao Sheng, Kun Gao, Lu Zhang, Li Liu, and Yilin Zhu. "Astragalus Inhibits Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelial Cells by Down-Regulating β-Catenin." Cellular Physiology and Biochemistry 51, no. 6 (2018): 2794–813. http://dx.doi.org/10.1159/000495972.

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Background/Aims: The epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) is a crucial event in the induction of peritoneal fibrosis (PF), in which canonical Wnt/β-catenin signaling participates. Smads signaling is reported to interact with β-catenin and synergistically regulates EMT. This study was aimed to reveal the effect of Astragalus on β-catenin in EMT of PMCs. Methods: To obtain the role of β-catenin in EMT, gene transfer into HMrSV5 cell line and rats has been achieved. After Astragalus treatment, EMT markers and signaling pathway-related indicators were detected by western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation and real time-PCR. Results: β-catenin knockdown suppressed EMT of HMrSV5 cells. Astragalus alleviated EMT of PMCs characterized by increased E-cadherin and decreased α-SMA and Vimentin. In rat model of peritoneal dialysis (PD), Astragalus attenuated peritoneal thickening and fibrosis. Astragalus down-regulated β-catenin by stabilizing the Glycogen synthase kinase-3β (GSK-3β)/β-catenin complex and further inhibited the nuclear translocation of β-catenin. Meanwhile, Astragalus down-regulated β-catenin by enhancing Smad7 expression. Silencing Smad7 antagonized the EMT-inhibitory effect of Astragalus. Conclusion: Astragalus inhibits EMT of PMCs by down-regulating β-catenin. The modulation of β-catenin in peritoneum can be a novel tool to prevent PF.

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Long, Qingzhi, Xiang Li, Hui He, and Dalin He. "Autophagy activation protects shock wave induced renal tubular epithelial cell apoptosis may through modulation of Akt/ GSK-3β pathway." International Journal of Biological Sciences 12, no. 12 (2016): 1461–71. http://dx.doi.org/10.7150/ijbs.16864.

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Hui, Jiaojie, Jianping Zhang, Mengjia Pu, Xingliang Zhou, Liang Dong, Xuqiang Mao, Guofeng Shi, et al. "Modulation of GSK-3β/β-Catenin Signaling Contributes to Learning and Memory Impairment in a Rat Model of Depression." International Journal of Neuropsychopharmacology 21, no. 9 (April 23, 2018): 858–70. http://dx.doi.org/10.1093/ijnp/pyy040.

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Mao, Yelin, Liangliang Wang, Ye Zhu, Yu Liu, Hongwei Dai, Jianping Zhou, Dechun Geng, Lin Wang, and Yong Ji. "Tension force-induced bone formation in orthodontic tooth movement via modulation of the GSK-3β/β-catenin signaling pathway." Journal of Molecular Histology 49, no. 1 (December 9, 2017): 75–84. http://dx.doi.org/10.1007/s10735-017-9748-x.

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Md, Shadab, Nabil A. Alhakamy, Mohamed A. Alfaleh, Obaid Afzal, Abdulmalik S. A. Altamimi, Ashif Iqubal, and Rasheed A. Shaik. "Mechanisms Involved in Microglial-Interceded Alzheimer’s Disease and Nanocarrier-Based Treatment Approaches." Journal of Personalized Medicine 11, no. 11 (October 29, 2021): 1116. http://dx.doi.org/10.3390/jpm11111116.

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Alzheimer’s disease (AD) is a common neurodegenerative disorder accountable for dementia and cognitive dysfunction. The etiology of AD is complex and multifactorial in origin. The formation and deposition of amyloid-beta (Aβ), hyperphosphorylated tau protein, neuroinflammation, persistent oxidative stress, and alteration in signaling pathways have been extensively explored among the various etiological hallmarks. However, more recently, the immunogenic regulation of AD has been identified, and macroglial activation is considered a limiting factor in its etiological cascade. Macroglial activation causes neuroinflammation via modulation of the NLRP3/NF-kB/p38 MAPKs pathway and is also involved in tau pathology via modulation of the GSK-3β/p38 MAPK pathways. Additionally, microglial activation contributes to the discrete release of neurotransmitters and an altered neuronal synaptic plasticity. Therefore, activated microglial cells appear to be an emerging target for managing and treating AD. This review article discussed the pathology of microglial activation in AD and the role of various nanocarrier-based anti-Alzeihmenr’s therapeutic approaches that can either reverse or inhibit this activation. Thus, as a targeted drug delivery system, nanocarrier approaches could emerge as a novel means to overcome existing AD therapy limitations.

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Pekary, Albert Eugene, Schetema A. Stevens, James D. Blood, and Albert Sattin. "Rapid modulation of TRH and TRH-like peptide release in rat brain, pancreas, and testis by a GSK-3β inhibitor." Peptides 31, no. 6 (June 2010): 1083–93. http://dx.doi.org/10.1016/j.peptides.2010.03.020.

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Oh, Sunhwa, Hyungjoo Kim, KeeSoo Nam, and Incheol Shin. "Silencing of Glut1 induces chemoresistance via modulation of Akt/GSK-3β/β-catenin/survivin signaling pathway in breast cancer cells." Archives of Biochemistry and Biophysics 636 (December 2017): 110–22. http://dx.doi.org/10.1016/j.abb.2017.08.009.

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Abdallah, Hossam M., Nesrine S. El Sayed, Alaa Sirwi, Sabrin R. M. Ibrahim, Gamal A. Mohamed, and Nora O. Abdel Rasheed. "Mangostanaxanthone IV Ameliorates Streptozotocin-Induced Neuro-Inflammation, Amyloid Deposition, and Tau Hyperphosphorylation via Modulating PI3K/Akt/GSK-3β Pathway." Biology 10, no. 12 (December 8, 2021): 1298. http://dx.doi.org/10.3390/biology10121298.

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Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized by amyloid deposition and neurofibrillary tangles formation owing to tau protein hyperphosphorylation. Intra-cerebroventricular (ICV) administration of streptozotocin (STZ) has been widely used as a model of sporadic AD as it mimics many neuro-pathological changes witnessed in this form of AD. In the present study, mangostanaxanthone IV (MX-IV)-induced neuro-protective effects in the ICV-STZ mouse model were investigated. STZ (3 mg/kg, ICV) was injected once, followed by either MX-IV (30 mg/kg/day, oral) or donepezil (2.5 mg/kg/day, oral) for 21 days. Treatment with MX-IV diminished ICV-STZ-induced oxidative stress, neuro-inflammation, and apoptosis which was reflected by a significant reduction in malondialdehyde (MDA), hydrogen peroxide (H2O2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) brain contents contrary to increased glutathione (GSH) content. Moreover, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase content and cleaved caspase-3 activity were reduced together with a marked decrement in amyloid plaques number and phosphorylated tau expression via PI3K/Akt/GSK-3β pathway modulation, leading to obvious enhancement in neuronal survival and cognition. Therefore, MX-IV is deemed as a prosperous nominee for AD management with obvious neuro-protective effects that were comparable to the standard drug donepezil.

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Feng, Xiaolei, Jue Jiang, Lei Sun, and Qi Zhou. "CDK5RAP3 acts as a putative tumor inhibitor in papillary thyroid carcinoma via modulation of Akt/GSK-3β/Wnt/β-catenin signaling." Toxicology and Applied Pharmacology 440 (April 2022): 115940. http://dx.doi.org/10.1016/j.taap.2022.115940.

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Aourz, Najat, Fred Van Leuven, Wissal Allaoui, Ann Van Eeckhaut, Dimitri De Bundel, and Ilse Smolders. "Unraveling the Effects of GSK-3β Isoform Modulation against Limbic Seizures and in the 6 Hz Electrical Kindling Model for Epileptogenesis." ACS Chemical Neuroscience 13, no. 6 (March 7, 2022): 796–805. http://dx.doi.org/10.1021/acschemneuro.1c00782.

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Simão, Fabrício, Aline Matté, Aline S. Pagnussat, Carlos A. Netto, and Christianne G. Salbego. "Resveratrol prevents CA1 neurons against ischemic injury by parallel modulation of both GSK-3β and CREB through PI3-K/Akt pathways." European Journal of Neuroscience 36, no. 7 (July 22, 2012): 2899–905. http://dx.doi.org/10.1111/j.1460-9568.2012.08229.x.

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Fishman, Pnina, Sara Bar-Yehuda, Gil Ohana, Faina Barer, Avivit Ochaion, Abigail Erlanger, and Lea Madi. "An agonist to the A3 adenosine receptor inhibits colon carcinoma growth in mice via modulation of GSK-3β and NF-κB." Oncogene 23, no. 14 (March 15, 2004): 2465–71. http://dx.doi.org/10.1038/sj.onc.1207355.

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Chowdhury, Debabrata, Dinesh Kumar, Utpal Bhadra, Tangutur Anjana Devi, and Manika Pal Bhadra. "Prohibitin confers cytoprotection against ISO-induced hypertrophy in H9c2 cells via attenuation of oxidative stress and modulation of Akt/Gsk-3β signaling." Molecular and Cellular Biochemistry 425, no. 1-2 (November 16, 2016): 155–68. http://dx.doi.org/10.1007/s11010-016-2870-3.

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Cheng, Dai, Guangliang Wang, Xuerui Wang, Jinlei Tang, Qianqian Yu, Xinyu Zhang, and Shuo Wang. "Neuro-protection of Chlorogenic acid against Al-induced apoptosis in PC12 cells via modulation of Al metabolism and Akt/GSK-3β pathway." Journal of Functional Foods 70 (July 2020): 103984. http://dx.doi.org/10.1016/j.jff.2020.103984.

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Lee, Ki Won, Seyeon Lim, and Kwang Dong Kim. "The Function of N-Myc Downstream-Regulated Gene 2 (NDRG2) as a Negative Regulator in Tumor Cell Metastasis." International Journal of Molecular Sciences 23, no. 16 (August 19, 2022): 9365. http://dx.doi.org/10.3390/ijms23169365.

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Abstract:

N-myc downstream-regulated gene 2 (NDRG2) is a tumor-suppressor gene that suppresses tumorigenesis and metastasis of tumors and increases sensitivity to anti-cancer drugs. In this review, we summarize information on the clinicopathological characteristics of tumor patients according to NDRG2 expression in various tumor tissues and provide information on the metastasis inhibition-related cell signaling modulation by NDRG2. Loss of NDRG2 expression is a prognostic factor that correlates with TNM grade and tumor metastasis and has an inverse relationship with patient survival in various tumor patients. NDRG2 inhibits cell signaling, such as AKT-, NF-κB-, STAT3-, and TGF-β-mediated signaling, to induce tumor metastasis, and induces activation of GSK-3β which has anti-tumor effects. Although NDRG2 operates as an adaptor protein to mediate the interaction between kinases and phosphatases, which is essential in regulating cell signaling related to tumor metastasis, the molecular mechanism of NDRG2 as an adapter protein does not seem to be fully elucidated. This review aims to assist the research design regarding NDRG2 function as an adaptor protein and suggests NDRG2 as a molecular target to inhibit tumor metastasis and improve the prognosis in tumor patients.

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Li, Chuankun, Jingya Yang, Sen Lei, and Wei Wang. "SKA3 promotes glioblastoma proliferation and invasion by enhancing the activation of Wnt/β-catenin signaling via modulation of the Akt/GSK-3β axis." Brain Research 1765 (August 2021): 147500. http://dx.doi.org/10.1016/j.brainres.2021.147500.

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Journal articles on the topic 'GSK-3β MODULATION'

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