GSK 3a

Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2 H )-one ( 1 ), aryl(or heteroaryl)glyoxal monohydrates ( 2a - h ), and hydrazine monohydrate (NH2 NH2 •H2 O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[ h ]cinnoline derivatives ( 3a - h )...

Jaceosidin (JAC) is a natural flavonoid with anti-oxidant and other pharmacological activities; however, its anti-cancer mechanism remains unclear. We investigated the mechanism of action of JAC in gastric cancer cells. Cytotoxicity and apoptosis assays showed that JAC effectively killed multiple gastric cancer cells and induced apoptosis in human gastric adenocarcinoma AGS cells via the mitochondrial pathway. Network pharmacological analysis suggested that its activity was linked to reactive oxygen species (ROS), AKT, and MAPK signaling pathways...

Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. ACC is composed of myoepithelial and epithelial neoplastic cells which grow slowly and have a tendency for neural invasion. The long term prognosis is still relatively poor. Although several gene abnormalities, such as fusions involving MYB or MYBL1 oncogenes and the transcription factor gene NFIB, and overexpression of KIT have been reported in ACC, their precise functions in the pathogenesis of ACC remain unclear. We recently demonstrated that the elevated expression of Semaphorin 3A (SEMA3A), specifically expressed in myoepithelial neoplastic cells, might function as a novel oncogene-related molecule to enhance cell proliferation through activated AKT signaling in 9/10 (90%) ACC cases...

Clinically, the immune checkpoint inhibitor anti-PD-1 antibody has shown a certain effect in the treatment of hepatocellular carcinoma (HCC), which is limited to a small number of patients with HCC. This study aims to reveal whether carnosic acid nanocluster-based framework (CA-NBF) has a sensitization effect on anti-PD-1 antibody in the treatment of HCC at the cellular and animal levels. MHCC97H cells were treated with CA-NBF, anti-PD-1 and their combination. The effects of CA-NBF and anti-PD-1 on cell proliferation, cell cycle, apoptosis, invasion, and migration were evaluated by MTT assay, flow cytometry, and scratch test...

We previously reported that kenpaullone, which inhibits GSK-3a/b and CDKs inhibited CCCP mediated mitochondrial depolarisation and augments the mitochondrial network. To investigate the actions of this class of drug further, we compared the ability of kenpaullone, alsterpaullone, 1-azakenapaullone, AZD5438, AT7519 (CDK and GSK-3a/b inhibitors) and dexpramipexole and olesoxime (mitochondrial permeability transition pore inhibitors) to prevent CCCP mediated mitochondrial depolarisation and found that AZD5438 and AT7519, were the most effective...

We have previously reported that juglone, a natural compound found in Juglandaceae with a wide range of biological activities, can reduces the developmental competence of bovine oocytes. In the current study, we investigated the possible mechanisms behind the toxicity of juglone and the relationship with PI3K/AKT/mTOR signaling during the in vitro maturation (IVM) of oocytes. Results show that oocyte exposure to juglone was associated with a significant decrease in filamentous actin (F-actin) accumulation. The RT-qPCR showed downregulation of the meiosis progression indicator GSK-3A, oocyte development marker BMP15, mitochondria fusion controlling MFN1, oxidative stress-related OGG1, and histone methylation-related EZH1, EZH2, SUZ12, G9a, and SUV39H2 genes in juglone-treated oocytes...

Ovarian cancer (OC) is the most lethal gynecological cancer. OC cells have high proliferative capacity, are invasive, resist apoptosis, and tumors often display rearrangement of extracellular matrix (ECM) components, contributing to accelerated tumor progression. The multifunctional protein tissue transglutaminase (TG2) is known to be secreted in the tumor microenvironment, where it interacts with fibronectin (FN) and the cell surface receptor integrin β1. However, the mechanistic role of TG2 in cancer cell proliferation is unknown...

The present study aimed to investigate the effects of long non‑coding (lncRNA) dihydrofolate reductase‑like 1 (DHFRL1‑4) on cerebral ischemia/reperfusion (I/R)‑induced injury. For this purpose, mice injected with lentivirus with small interfering RNA targeting DHFRL1‑4 or negative control siRNA were used to construct models of cerebral I/R injury. Following the establishment of the model, the infarct size, neurological deficit score, apoptosis and the expression levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), Wnt family member 3a (Wnt3a), glycogen synthase kinase‑3β (GSK‑3β) and phosphorylated GSK‑3β were assessed...

Flurochloridone (FLC), a wildly used herbicide, could induce hepatotoxicity after long-term exposure to male rat, in addition to its reactive oxygen species (ROS)-dependent reproductive toxicity. The hepatotoxicity effect and mechanism was investigeted using 1, 10 and 100 μmol L-1 FLC treated BRL-3A liver cell in this study. The function of mitochondrial respiration, glycolysis rate and real time ATP production rate are determined by seahorse XF analyzer, and the bio-transformers of FLC, intermediates of TCA cycle and glycolysis, and related amino acids are determined and identified by [U-13 C] Glucose metabolic flux technology based on UPLC-HRMS...

BACKGROUND: Bmal1 and Per2 are the core components of the circadian clock genes (CCGs). Bmal1-/- mice exhibit premature aging, as indicated by hypotrichosis and osteoporosis, with a loss of proliferation ability. The same occurs in Per2-/- mice, albeit to a less severe degree. However, whether the effects of Bmal1 and Per2 on proliferation and osteogenic differentiation are synergistic or antagonistic remains unclear. Thus, our study aimed to explore the effects and specific mechanism...

BACKGROUND: DNA methylation plays an important role in regulating gene expression in mammals. The covalent DNMT1 inhibitors 5-azacytidine and decitabine are widely used in research to reduce DNA methylation levels, but they impart severe cytotoxicity which limits their demethylation capability and confounds interpretation of experiments. Recently, a non-covalent inhibitor of DNMT1 called GSK-3484862 was developed by GlaxoSmithKline. We sought to determine whether GSK-3484862 can induce demethylation more effectively than 5-azanucleosides...

Co-treatment with actinomycin D and nutlin-3a (A + N) strongly activates p53. Previously we reported that CHIR-98014 (GSK-3 kinase inhibitor), acting in cells exposed to A + N, prevents activation of TREM2 -an innate immunity and p53-regulated gene associated with Alzheimer's disease. In order to find novel candidate p53-target genes and genes regulated by CHIR-98014, we performed RNA-Seq of control A549 cells and the cells exposed to A + N, A + N with CHIR-98014 or to CHIR-98014. We validated the data for selected genes using RT-PCR and/or Western blotting...

The glycogen synthase kinase 3β (GSK-3β) is a protein kinase involved in regulating numerous physiological processes such as embryonic development, transcription, insulin action, cell division cycle and multiple neuronal functions. The overexpression of this enzyme is related to many diseases such as schizophrenia, Alzheimer's disease, diabetes and cancer. One of the basic methods of treatment in these cases is the usage of ATP-competitive inhibitors. A significant group of such compounds are indirubin and its analogs, e...

BACKGROUND: Histone deacetylase 4 (HDAC4) regulates chondrocyte hypertrophy and bone formation. The aim of the present study was to explore the effects of HDAC4 on Interleukin 1 beta (IL-1β)-induced chondrocyte extracellular matrix degradation and whether it is regulated through the WNT family member 3A (WNT3A)/β-catenin signaling pathway. METHODS: Primary chondrocytes (CC) and human chondrosarcoma cells (SW1353 cells) were treated with IL-1β and the level of HDAC4 was assayed using Western blotting...

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...

Following injury to the peripheral and central nervous systems, tissue levels of transforming growth factor (TGF)-β1 often increase, which is key for wound healing and scarring. However, active wound regions and scars appear to inhibit process outgrowth by regenerating neurons. We recently showed that corneal wound myofibroblasts block corneal nerve regeneration in vivo, and sensory neurite outgrowth in vitro in a manner that relies critically on TGF-β1. In turn, delayed, abnormal re-innervation contributes to long-term sensory dysfunctions of the ocular surface...

OBJECTIVE: Aberrant apoptosis of nucleus pulposus cells (NPCs) is one of the most remarkable pathological changes in intervertebral disc degeneration (IDD) development. Albeit the advances in the application of stem cell-based therapy in IDD treatment, the molecular mechanisms underlying the anti-apoptotic actions of mesenchymal stem cell (MSC) remain poorly elucidated. PATIENTS AND METHODS: The expression patterns of apoptosis-related proteins and Wnt/β-catenin-related genes in NP samples isolated from patients with mild or severe IDD were compared by performing immunoblot assay and quantitative real-time polymerase chain reaction (qRT-PCR), respectively...

Diabetes mellitus poses a major threat towards global heath due to a lack of effective treatment. Fluoxetine hydrochloride, a selective 5‑hydroxytryptamine reuptake inhibitor, is the most commonly used antidepressant in clinical therapy; however, the potential molecular mechanisms of fluoxetine in diabetes remain unknown. In the present study, reduced glucose, total cholesterol and triglyceride levels and lipid metabolism, as well as upregulated proliferator‑activated receptor γ, fatty acid synthase and lipoprotein lipase, and downregulated sterol regulatory element‑binding protein 1‑c were detected in rats with streptozotocin (STZ)‑induced diabetes following treatment with fluoxetine...

BACKGROUND: Despite inhaled corticosteroid plus long-acting β2 -agonist (ICS/LABA) therapy, 30-50% of patients with moderate or severe asthma remain inadequately controlled. We investigated the safety and efficacy of single-inhaler fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/VI) compared with FF/VI. METHODS: In this double-blind, randomised, parallel-group, phase 3A study (Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler [CAPTAIN]), participants were recruited from 416 hospitals and primary care centres across 15 countries...

Pulmonary arterial hypertension (PAH) is a malignant disease characterized by pulmonary arterial remodeling due to the abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Dihydroartemisinin (DHA), an artemisinin derivative used to treat malaria, is able to inhibit fibrosis, neovascularization, and tumor proliferation. In this study, we hypothesized that DHA can be beneficial in treating PAH. To test this hypothesis, a rat model of pulmonary hypertension (PH) induced with monocrotaline (MCT) was employed...