scholarly journals Sophora Tomentosa Extract Prevents MPTP-Induced Parkinsonism in C57BL/6 Mice Via the Inhibition of GSK-3β Phosphorylation and Oxidative Stress

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 252 ◽  
Author(s):  
Hung-Chi Chang ◽  
Keng-Fan Liu ◽  
Chia-Jen Teng ◽  
Shu-Chen Lai ◽  
Shu-Er Yang ◽  
...  
Keyword(s):  
Tyrosine Hydroxylase ◽  
Glycogen Synthase ◽  
Radical Scavenging ◽  
Antioxidant Defenses ◽  
Motor Deficit ◽  
Motor Deficits ◽  
Phenolic Contents ◽  
Mouse Striatum ◽  
Gsk 3Β

Sophora species are used as dietary medicines in aging-associated symptoms. Sophora tomentosa L. (ST) is a native medicinal plant in Southeast Asia; however, there is no pharmacological literature about ST extract. The present study evaluates the antioxidant phytoconstituent contents and radical scavenging capacities of ST extract. The further investigation was to clarify the neuroprotective mechanism of ST extract against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism by assaying the activities of the dopaminergic system and antioxidant defenses, glycogen synthase kinase 3β (GSK3-β) phosphorylation, and α-synuclein levels in C57BL/6 mice. The results show that ST extract alleviated the motor deficits in MPTP-induced Parkinsonism with four behavioral tests, including a rearing locomotor, catalepsy test, balance beam walking test, and pole test. ST extract reversed the number of tyrosine hydroxylase (TH)-positive neurons in substantia nigra (SN) that had decreased by MPTP. ST extract also restored the decreased levels of dopamine and the expression of tyrosine hydroxylase (TH) in the striatum. Furthermore, ST extract restored the levels of glutathione (GSH) and the activities of antioxidant enzymes, and decreased the elevated levels of malondialdehyde (MDA) in mouse striatum. ST extract also decreased α-synuclein overexpression and GSK-3β phosphorylation in mouse striatum. In vitro, ST extract exerted higher 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging capacities through its higher phenolic contents, especially protocatechuic acid and epicatechin. These results suggest that ST extract has the potential to counteract MPTP-induced motor deficit. The neuroprotective mechanism of ST extract against MPTP-induced Parkinsonism might be related to decreasing GSK-3β phosphorylation and restoring the activities of striatal antioxidant defenses to restore the nigrostriatal dopaminergic function and decrease α-synuclein accumulation.

scholarly journals GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 610
Author(s):  
Robin Park ◽  
Andrew L. Coveler ◽  
Ludimila Cavalcante ◽  
Anwaar Saeed
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
In Vivo Models ◽  
Gsk 3Β ◽  
Early Phase Clinical Trials

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

scholarly journals Aqueous Extract of Davallia mariesii Attenuates 6-Hydroxydopamine-Induced Oxidative Damage and Apoptosis in B35 Cells Through Inhibition of Caspase Cascade and Activation of PI3K/AKT/GSK-3β Pathway

Nutrients ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 1449 ◽  
Author(s):  
Chi-Rei Wu ◽  
Hung-Chi Chang ◽  
Yih-Dih Cheng ◽  
Wan-Cheng Lan ◽  
Shu-Er Yang ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Radical Scavenging ◽  
Neuroblastoma Cells ◽  
Antioxidant Defenses ◽  
Protective Mechanism ◽  
Scavenging Capacity ◽  
Intracellular Ros ◽  
Caspase Cascade ◽  
Gsk 3Β ◽  
6 Hydroxydopamine

The medicinal ferns of Polydiaceae and Davalliaceae species are called “Gusuibu” by Chinese physicians and used as antiaging dietary medicines. Our previous report revealed that Drynaria fortunei (Polydiaceae) protected against 6-hydroxydopamine (6-OHDA)-induced oxidative damage via the PI3K/AKT pathway in B35 neuroblastoma cells. The present study compares the antioxidant phytoconstituent contents and radical scavenging capacities of five Davalliaceae species. The further aim was to clarify the protective mechanism of Davallia mariesii (DM) against 6-OHDA-induced oxidative damage and apoptosis in B35 cells. The results show that Araiostegia perdurans (AP) and DM extracts have better radical scavenging capacities against 1,1-diphenyl-2-picryhydrazyl (DPPH) and reactive oxygen species (ROS) than other Davalliaceae species. However, only DM extract inhibited 6-OHDA autoxidation under cell-free systems and increased cell viability, compared to B35 cells solely exposed to 6-OHDA. DM extract decreased apoptosis and restored mitochondrial expression in 6-OHDA-treated B35 cells. Additional data indicated that DM extract decreased intracellular ROS and nitric oxide levels generated by 6-OHDA exposure. DM extract also restored glutathione (GSH) levels and the activities of glutathione peroxidase and reductase, and then decreased the elevated malondialdehyde (MDA) levels. Finally, DM extract regulated the protein expression of the caspase cascade and PI3K/AKT/GSK-3β pathways. These results suggest that the protective mechanism of DM extract against 6-OHDA-induced oxidative damage and apoptosis might be related to its radical scavenging capacity, maintaining the mitochondrial function to inhibit the Bcl-2/caspase cascade pathway and activating intracellular antioxidant defenses (GSH recycling, HO-1 and NQO-1) by modulating the activation of the PI3K/AKT/GSK-3β pathway.

scholarly journals hPMSCs protects against D-galactose-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling 

2020 ◽  
Author(s):  
Yanlian Xiong ◽  
Yueming Wang ◽  
Jiashen Zhang ◽  
Nannan Zhao ◽  
Hengchao Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nuclear Translocation ◽  
Cell Senescence ◽  
Antioxidant Defenses ◽  
Control Group ◽  
Akt Inhibitor ◽  
Gsk 3Β ◽  
T Cell Senescence

Abstract Background: Mesenchymal stem cells (MSCs) was considered as regenerative therapeutic approach in both acute and chronic diseases. However, whether MSCs regulate the antioxidant metabolism of CD4+ T cells and weaken immunosenescence remains unclear. Here, we reported the protective effects of hPMSCs in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a D-gal induced mouse aging model.Methods: In vivo study, 40 male C57BL/6 mice (8 weeks) were randomly divided into four groups: control group, D-gal group, hPMSC group and PBS group. In in vitro experiment, human naive CD4+ T (CD4CD45RA) cells were prepared using a naive CD4+ T cell isolation kit II and pretreated with the Akt inhibitor LY294002 and Nrf2 inhibitor ML385. Then, isolated naive CD4+ T cell were cocultured with hPMSCs for 72 h in the absence or presence of anti-CD3/CD28 Dynabeads and IL-2 as a mitogenic stimulus. Intracellular ROS changes were detected by flow cytometry. The activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase and catalase were measured by colorimetric analysis. The senescent T cells were detected SA-β-gal stain. The expression of aging related proteins were detected by Western blotting, RT-PCR and confocal microscopy.Results: We found that hPMSC treatment markedly decreased the ROS level, SA-β-gal positive cells number, senescence-associated secretory phenotype (IL-6 and OPN) expression and aging-related protein (P16 and P21) expression in senescent CD4+ T cells. Furthermore, hPMSC treatment effectively upregulated Nrf2 nuclear translocation and the expression of downstream target genes (HO-1, CAT, GCLC and NQO1) in senescent CD4+ T cells. Moreover, in vitro studies revealed that hPMSCs attenuated CD4+ T cell senescence by upregulating the Akt/GSK-3β/Fyn pathway to activate Nrf2 functions. Conversely, the antioxidant effects of hPMSCs were blocked by the Akt inhibitor LY294002 and Nrf2 inhibitor ML385 in senescent CD4+ T cells.Conclusions: Our results indicate that hPMSCs attenuate D-gal induced CD4+ T cell senescence by activating Nrf2-mediated antioxidant defenses and that upregulation of Nrf2 by hPMSCs is regulated via the Akt/GSK-3β/Fyn pathway.

scholarly journals Design and Synthesis of New Benzo[d]oxazole-Based Derivatives and Their Neuroprotective Effects on β-Amyloid-Induced PC12 Cells

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5391
Author(s):  
Zheng Liu ◽  
Ming Bian ◽  
Qian-Qian Ma ◽  
Zhuo Zhang ◽  
Huan-Huan Du ◽  
...  
Keyword(s):  
Pc12 Cells ◽  
Glycogen Synthase ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
In Vivo Studies ◽  
Neuroprotective Effects ◽  
Β Amyloid ◽  
Gsk 3Β

A series of novel synthetic substituted benzo[d]oxazole-based derivatives (5a–5v) exerted neuroprotective effects on β-amyloid (Aβ)-induced PC12 cells as a potential approach for the treatment of Alzheimer’s disease (AD). In vitro studies show that most of the synthesized compounds were potent in reducing the neurotoxicity of Aβ25-35-induced PC12 cells at 5 μg/mL. We found that compound 5c was non-neurotoxic at 30 μg/mL and significantly increased the viability of Aβ25-35-induced PC12 cells at 1.25, 2.5 and 5 μg/mL. Western blot analysis showed that compound 5c promoted the phosphorylation of Akt and glycogen synthase kinase (GSK-3β) and decreased the expression of nuclear factor-κB (NF-κB) in Aβ25-35-induced PC12 cells. In addition, our findings demonstrated that compound 5c protected PC12 cells from Aβ25-35-induced apoptosis and reduced the hyperphosphorylation of tau protein, and decreased the expression of receptor for AGE (RAGE), β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), inducible nitric oxide synthase (iNOS) and Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) via Akt/GSK-3β/NF-κB signaling pathway. In vivo studies suggest that compound 5c shows less toxicity than donepezil in the heart and nervous system of zebrafish.

scholarly journals Derivatives of the β-Crinane Amaryllidaceae Alkaloid Haemanthamine as Multi-Target Directed Ligands for Alzheimer’s Disease

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1307 ◽  
Author(s):  
Eliška Kohelová ◽  
Rozálie Peřinová ◽  
Negar Maafi ◽  
Jan Korábečný ◽  
Daniela Hulcová ◽  
...  
Keyword(s):  
Active Sites ◽  
Glycogen Synthase ◽  
Binding Modes ◽  
Structural Determinants ◽  
Inhibitory Potential ◽  
Gsk 3Β ◽  
Inhibition Potency ◽  
Derivatives Of ◽  
In Vitro Data

Twelve derivatives 1a–1m of the β-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3β (GSK-3β) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11-O-(2-methylbenzoyl)-haemanthamine (1j) and 11-O-(4-nitrobenzoyl)-haemanthamine (1m), revealed the most intriguing profile, both being acetylcholinesterase (hAChE) inhibitors on a micromolar scale, with GSK-3β inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds’ plausible binding modes in the active sites of hAChE and hBuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.

scholarly journals RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/β-catenin signaling pathway

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Jikui Sun ◽  
Quanfeng Ma ◽  
Banban Li ◽  
Chen Wang ◽  
Lidong Mo ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Inhibitory Effect ◽  
Who Grade ◽  
Pathway Network ◽  
Mechanistic Investigation ◽  
Signaling Axis ◽  
Gsk 3Β

Abstract Accumulating evidence indicates that the dysregulation of the miRNAs/mRNA-mediated carcinogenic signaling pathway network is intimately involved in glioma initiation and progression. In the present study, by performing experiments and bioinformatics analysis, we found that RPN2 was markedly elevated in glioma specimens compared with normal controls, and its upregulation was significantly linked to WHO grade and poor prognosis. Knockdown of RPN2 inhibited tumor proliferation and invasion, promoted apoptosis, and enhanced temozolomide (TMZ) sensitivity in vitro and in vivo. Mechanistic investigation revealed that RPN2 deletion repressed β-catenin/Tcf-4 transcription activity partly through functional activation of glycogen synthase kinase-3β (GSK-3β). Furthermore, we showed that RPN2 is a direct functional target of miR-181c. Ectopic miR-181c expression suppressed β-catenin/Tcf-4 activity, while restoration of RPN2 partly reversed this inhibitory effect mediated by miR-181c, implying a molecular mechanism in which TMZ sensitivity is mediated by miR-181c. Taken together, our data revealed a new miR-181c/RPN2/wnt/β-catenin signaling axis that plays significant roles in glioma tumorigenesis and TMZ resistance, and it represents a potential therapeutic target, especially in GBM.

scholarly journals hPMSCs protects against aging-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling

2020 ◽  
Author(s):  
Yanlian Xiong ◽  
Yueming Wang ◽  
Jiashen Zhang ◽  
Nannan Zhao ◽  
Aiping Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nuclear Translocation ◽  
Cell Senescence ◽  
Antioxidant Defenses ◽  
Control Group ◽  
Akt Inhibitor ◽  
Gsk 3Β ◽  
T Cell Senescence

Abstract Background: Mesenchymal stem cells (MSCs) was considered as regenerative therapeutic approach in both acute and chronic diseases. However, whether MSCs regulate the antioxidant metabolism of CD4+ T cells and weaken immunosenescence remains unclear. Here, we reported the protective effects of hPMSCs in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a D-gal induced mouse aging model.Methods: In vivo study, 40 male C57BL/6 mice (8 weeks) were randomly divided into four groups: control group, D-gal group, hPMSC group and PBS group. In in vitro experiment, human naive CD4+ T (CD4CD45RA) cells were prepared using a naive CD4+ T cell isolation kit II and pretreated with the Akt inhibitor LY294002 and Nrf2 inhibitor ML385. Then, isolated naive CD4+ T cell were cocultured with hPMSCs for 72 h in the absence or presence of anti-CD3/CD28 Dynabeads and IL-2 as a mitogenic stimulus. Intracellular ROS changes were detected by flow cytometry. The activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase and catalase were measured by colorimetric analysis. The senescent T cells were detected SA-β-gal stain. The expression of aging related proteins were detected by Western blotting, RT-PCR and confocal microscopy.Results: We found that hPMSC treatment markedly decreased the ROS level, SA-β-gal positive cells number, senescence-associated secretory phenotype (IL-6 and OPN) expression and aging-related protein (P16 and P21) expression in senescent CD4+ T cells. Furthermore, hPMSC treatment effectively upregulated Nrf2 nuclear translocation and the expression of downstream target genes (HO-1, CAT, GCLC and NQO1) in senescent CD4+ T cells. Moreover, in vitro studies revealed that hPMSCs attenuated CD4+ T cell senescence by upregulating the Akt/GSK-3β/Fyn pathway to activate Nrf2 functions. Conversely, the antioxidant effects of hPMSCs were blocked by the Akt inhibitor LY294002 and Nrf2 inhibitor ML385 in senescent CD4+ T cells.Conclusions: Our results indicate that hPMSCs attenuate D-gal induced CD4+ T cell senescence by activating Nrf2-mediated antioxidant defenses and that upregulation of Nrf2 by hPMSCs is regulated via the Akt/GSK-3β/Fyn pathway.

scholarly journals In Vitro Assessment of Antioxidant Enzymes, Phenolic Contents and Antioxidant Capacity of the Verdolaga (Portulacaceae)

2020 ◽  
Vol 4 (4) ◽  
pp. 36-47
Author(s):  
Yaaser Q. Almulaiky ◽  
Yaaser Q. Almulaiky ◽  
Musab Aldhahri ◽  
Musab Aldhahri ◽  
Fahad A. Al-abbasi ◽  
...  
Keyword(s):  
Polyphenol Oxidase ◽  
Radical Scavenging ◽  
Reducing Power ◽  
Deionized Water ◽  
Phenolic Contents ◽  
High Antioxidant Activity ◽  
Phenolic Substances ◽  
In Vitro Assessment ◽  
Stems And Leaves

In this study, the antioxidants and photosynthetic compounds of Verdolaga were examined. Compounds were extracted from distinctive segments of the verdolaga using various solvents such as methanol (40, 60, 80%), ethanol (40, 60, 80%), acetone (40, 60, 80%), and deionized water. The use of 80% methanol led to the highest extracted concentration of phenolic substances and flavonoids. The extracted products (Leaves, Stem strips, and Root strips) were evaluated for their radical scavenging capabilities with DPPH (IC50= 22.26, 20.56, and 32.10), and ABTS (IC50= 2.86, 3.70, and 5.24), reducing power (EC50= 15.70, 16.39, and 21.69), and peroxide scavenging activity (1C50= 1.717, 2.937, and 3.255), respectively. The extracted products were analyzed by a gas chromatography-mass spectrometer. Peroxidase, catalase, and polyphenol oxidase assays were completed for the crude extract of verdolaga’s leave, stem strips, and root strips. As indicated by these tests, extracts of the verdolaga’s roots, stems and leaves using 80% methanol yielded high antioxidant activity. The most elevated concentrations of extracted chlorophyll, lycopene, and carotenoids were from the leaves and the highest concentration of extracted tannin was noted from strips of stems. The highest measures of peroxidase and polyphenol oxidase were identified in root strips and the highest units of catalase was identified in leaves.

scholarly journals Inhibition of GSK-3β restores delayed gastric emptying in obesity-induced diabetic female mice

2020 ◽  
Vol 319 (4) ◽  
pp. G481-G493 ◽  
Author(s):  
Chethan Sampath ◽  
Shanthi Srinivasan ◽  
Michael L. Freeman ◽  
Pandu R. Gangula
Keyword(s):  
Gastric Emptying ◽  
Delayed Gastric Emptying ◽  
Glycogen Synthase ◽  
Related Factor ◽  
Female Mice ◽  
Downstream Signaling ◽  
Gsk 3Β ◽  
Sb 216763 ◽  
Oxide Synthase

Inhibition of glycogen synthase kinase 3β (GSK-3β) with SB 216763 attenuates delayed gastric emptying through gastric nuclear factor erythroid 2-related factor 2 (Nrf2) -phase II enzymes in high-fat diet-fed female mice. SB 216763 restored impaired gastric PI3K/AKT/ β-catenin/caspase 3 expression. Inhibition of GSK-3β normalized gastric dihydrofolate reductase, neuronal nitric oxide synthase-α expression, dimerization and nitrergic relaxation. SB 216763 normalized both serum estrogen and nitrate levels in female obese/Type 2 diabetes mice. SB 216763 reduced downstream signaling of GSK-3β in enteric neuronal cells in vitro.

scholarly journals In-vitro Antioxidant and Cytotoxicity Studies of Annona squamosa Linn.

1970 ◽  
Vol 2 (1) ◽  
pp. 32-36
Author(s):  
Israt Jahan Biva ◽  
Md Mynol Islam Vhuiyan ◽  
Moni Rani Saha ◽  
Muhammad Shahidul Islam ◽  
Shammy Sarwar
Keyword(s):  
Radical Scavenging ◽  
Pharmaceutical Sciences ◽  
Annona Squamosa ◽  
Soluble Extract ◽  
Phenolic Contents ◽  
Cytotoxicity Studies ◽  
Ic50 Value ◽  
Vincristine Sulphate ◽  
Ic50 Values

n-Hexane, chloroform and methanol soluble extracts of the leaves of Annona squamosa were screened fortheir possible antioxidant activitiy by DPPH free radical scavenging and cytotoxicity by brine shrimp lethalitybioassay. In DPPH radical scavenging assay, methanol soluble extract was found to be the most potent withan IC50 value of 103.5 μg/ml. The amount of total phenolics was also found to the highest in the methanolsoluble extract (283.16 ± 8.90 mg/g), followed by chloroform soluble extract (216.90 ± 4.48 mg/g). Here BHTand ascorbic acid were used as standards with IC50 values 8.2 μg/ml and 25 μg/ml respectively. In the brineshrimp lethality bioassay, the most significant cytotoxicity was observed with chloroform soluble extract withan LC50 of 4.16 μg/ml where vincristine sulphate was used as standard (LC50 0.29 μg/ml).Key Words: Annona squamosa; DPPH; Folin-Ciocalteu Reagent; Phenolic Contents; Brine ShrimpDOI: 10.3329/sjps.v2i1.5813Stamford Journal of Pharmaceutical Sciences Vol.2(1) 2009: 32-36

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