scholarly journals MST4 Kinase Inhibitor Hesperadin Attenuates Autophagy and Behavioral Disorder via the MST4/AKT Pathway in Intracerebral Hemorrhage Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Xiaodong Wu ◽  
Jinting Wu ◽  
Wenjie Hu ◽  
Qinghua Wang ◽  
Hairong Liu ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Signaling Pathway ◽  
Brain Edema ◽  
Kinase Inhibitor ◽  
Protein Localization ◽  
Akt Signaling ◽  
Behavioral Disorder ◽  
Akt Signaling Pathway ◽  
Akt Phosphorylation ◽  
Neurobehavioral Function

Background. The aim of this study was to explore the role of hesperadin in intracerebral hemorrhage (ICH) mice, with the involvement of the mammalian ste20-like kinase 4 (MST4)/AKT signaling pathway. Methods. All mice were divided into four groups: sham group, sham+hesperidin group, ICH group, and ICH+hesperadin group. The effects of hesperadin were assessed on the basis of brain edema and neurobehavioral function. Furthermore, we observed MST4, AKT, phosphorylation of AKT (pAKT), and microtubule-associated protein light chain 3 (LC3) by western blotting. Protein localization of MST4 and LC3 was determined by immunofluorescence. Results. The expression of MST4 was upregulated at 12 h and 24 h after ICH. Brain edema was significantly decreased and neurological function was improved in the hesperadin treatment group compared to the ICH group (P<0.05). Hesperadin decreases the expressions of MST and increases pAKT after ICH. Autophagy significantly increased in the ICH group, while hesperadin reduced this increase. Conclusion. Hesperadin provides neuroprotection against ICH by inhibiting the MST4/AKT signaling pathway.

scholarly journals 17β-Estradiol Attenuates Intracerebral Hemorrhage-Induced Blood–Brain Barrier Injury and Oxidative Stress Through SRC3-Mediated PI3K/Akt Signaling Pathway in a Mouse Model

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110384
Author(s):  
Han Xiao ◽  
Jianyang Liu ◽  
Jialin He ◽  
Ziwei Lan ◽  
Mingyang Deng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Mouse Model ◽  
Intracerebral Hemorrhage ◽  
Signaling Pathway ◽  
Brain Edema ◽  
Akt Signaling ◽  
Neurological Deficits ◽  
Akt Signaling Pathway ◽  
And Oxidative Stress

Estrogen is neuroprotective in brain injury models, and steroid receptor cofactor 3 (SRC3) mediates estrogen signaling. We aimed to investigate whether and how SRC3 is involved in the neuroprotective effects of 17ß-estradiol (E2) in a mouse model of intracerebral hemorrhage (ICH). Ovariectomized female mice were treated with E2 after autologous blood injection-induced ICH. Brain damage was assessed by neurological deficit score, brain water content, and oxidative stress levels. Blood–brain barrier (BBB) integrity was evaluated by Evan's blue extravasation and claudin-5, ZO-1, and occludin levels. SRC3 expression and PI3K/Akt signaling pathway were examined in ICH mice treated with E2. The effect of SRC3 on E2-mediated neuroprotection was determined by examining neurological outcomes in SRC3-deficient mice undergone ICH and E2 treatment. We found that E2 alleviated ICH-induced brain edema and neurological deficits, protected BBB integrity, and suppressed oxidative stress. E2 enhanced SRC3 expression and PI3K-/Akt signaling pathway. SRC3 deficiency abolished the protective effects of E2 on ICH-induced neurological deficits, brain edema, and BBB integrity. Our results suggest that E2 suppresses ICH-induced brain injury and SRC3 plays a critical role in E2-mediated neuroprotection.

scholarly journals Downregulation of cAMP-Dependent Protein Kinase Inhibitor-b Promotes Preeclampsia by Decreasing Phosphorylated Akt

2020 ◽  
Vol 28 (1) ◽  
pp. 178-185
Author(s):  
Chunfeng Liu ◽  
Hao Wang ◽  
Mo Yang ◽  
Yiheng Liang ◽  
Li Jiang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Matrix Metalloproteinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Dependent Protein Kinase ◽  
Phosphorylated Akt ◽  
Dependent Protein

AbstractPreeclampsia is a multi-system disease that is unique to human pregnancy. Impaired extravillous trophoblast migration and invasion accompanied by poor spiral vascular remodeling is thought to be the initial reason. This study investigated cAMP-dependent protein kinase inhibitor-b(PKIB) expression in placentas and its involvement in the pathogenesis of PE. We used immunohistochemistry and western blotting to calculate PKIB levels in the placentas. Then we knocked down PKIB by siRNA and used real-time cell analysis to assess the invasion and migration ability of trophoblasts. Tube formation assay and spheroid sprouting assay were utilized to identify the ability to form vessels of trophoblasts. At last, western blotting was used to demonstrate the level of phosphorylated Akt, as well as downstream-related genes of Akt signaling pathway in trophoblasts. We first found that PKIB expression level was lower in the PE placentas than in the normal placentas. In addition, we found that downregulation of PKIB can inhibit the migration, invasion, and the ability to form vessels of HTR8/SVneo cells. Downregulation of PKIB leaded to a decrease in phosphorylated Akt, as well as downstream proteins such as matrix metalloproteinase 2, matrix metalloproteinase 9, and glycogen synthase kinase 3β, which are related to migration and invasion. Our study revealed that the downregulation of PKIB expression resulted in decreased migration, invasion, and vessel formation ability by regulating Akt signaling pathway in placental trophoblasts in PE.

scholarly journals LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Amin Huang ◽  
Peiting Zeng ◽  
Yinguang Li ◽  
Wenhua Lu ◽  
Yaoming Lai
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Response Duration ◽  
Akt Signaling ◽  
Clinical Activity ◽  
Akt Signaling Pathway ◽  
Atp Production ◽  
Pi3k Inhibitor Ly294002

Internal tandem duplications (ITD) mutation within FMS-like tyrosine kinase 3 (FLT3), the most frequent mutation happens in almost 20% acute myeloid leukemia (AML) patients, always predicts a poor prognosis. As a small molecule tyrosine kinase inhibitor, sorafenib is clinically used for the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and differentiated thyroid cancer (DTC), with its preclinical and clinical activity demonstrated in the treatment of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutant AML. Even though it shows a rosy future in the AML treatment, the short response duration remains a vital problem that leads to treatment failure. Rapid onset of drug resistance is still a thorny problem that we cannot overlook. Although the mechanisms of drug resistance have been studied extensively in the past years, there is still no consensus on the exact reason for resistance and without effective therapeutic regimens established clinically. My previous work reported that sorafenib-resistant FLT3-ITD mutant AML cells displayed mitochondria dysfunction, which rendered cells depending on glycolysis for energy supply. In my present one, we further illustrated that losing the target protein FLT3 and the continuously activated PI3K/Akt signaling pathway may be the reason for drug resistance, with sustained activation of PI3K/AKT signaling responsible for the highly glycolytic activity and adenosine triphosphate (ATP) generation. PI3K inhibitor, LY294002, can block PI3K/AKT signaling, further inhibit glycolysis to disturb ATP production, and finally induce cell apoptosis. This finding would pave the way to remedy the FLT3-ITD mutant AML patients who failed with FLT3 targeted therapy.

scholarly journals Molecular mechanisms of hydrogen sulfide against uremic accelerated atherosclerosis through cPKCβII/Akt signal pathway

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Ruifang Xiong ◽  
Xiangxue Lu ◽  
Jinghong Song ◽  
Han Li ◽  
Shixiang Wang
Keyword(s):  
Hydrogen Sulfide ◽  
Signaling Pathway ◽  
Sham Group ◽  
Akt Signaling ◽  
Signal Pathway ◽  
Control Group ◽  
Akt Signaling Pathway ◽  
Membrane Translocation ◽  
Enos Expression ◽  
Akt Phosphorylation

Abstract Background Cardiovascular disease is the most common complication and leading cause of death in maintenance hemodialysis patients. The protection mechanism of hydrogen sulfide (H2S) and the specific role of conventional protein kinase C βII (cPKCβII)/Akt signaling pathway in the formation of atherosclerosis is still controversial. Methods 8-week-old male ApoE−/− mice were treated with 5/6 nephrectomy and high-fat diet to make uremia accelerated atherosclerosis (UAAS) model. Mice were divided into normal control group (control group), sham operation group (sham group), UAAS group, L-cysteine group (UAAS+L-cys group), sodium hydrosulfide group (UAAS+NaHS group), and propargylglycine group (UAAS+PPG group). Western blot was used to detect cPKCβII activation, Akt phosphorylation and endothelial nitric oxide synthase (eNOS) expression in mice aorta. Results The membrane translocation of cPKCβII in UAAS group was higher than sham group, and L-cys or NaHS injection could suppress the membrane translocation, but PPG treatment resulted in more membrane translocation of cPKCβII (P < 0.05, n = 6 per group). Akt phosphorylation and the eNOS expression in UAAS group was lower than sham group, and L-cys or NaHS injection could suppress the degradation of Akt phosphorylation and the eNOS expression, but PPG treatment resulted in more decrease in the Akt phosphorylation and the eNOS expression (P < 0.05, n = 6 per group). Conclusion Endogenous cystathionine-γ-lyase (CSE)/H2S system protected against the formation of UAAS via cPKCβII/Akt signal pathway. The imbalance of CSE/H2S system may participate in the formation of UAAS by affecting the expression of downstream molecule eNOS, which may be mediated by cPKCβII/Akt signaling pathway.

Effects and Mechanisms of Tripartite Motif Containing 14 Downregulation on Proliferation, Migration, and Invasion of Cancerous Pancreatic PANC-1 Cells

2021 ◽  
Vol 11 (3) ◽  
pp. 402-406
Author(s):  
Huaping Gong ◽  
Long Chen ◽  
Ruipeng Dong
Keyword(s):  
Protein Expression ◽  
Signaling Pathway ◽  
Cellular Proliferation ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Control Group ◽  
Akt Signaling Pathway ◽  
Sirna Transfection ◽  
Akt Phosphorylation

This study aimed to investigate the effect and mechanism of TRIM14 downregulation on the apoptosis, migration, and invasion of cancerous pancreatic PANC-1 cells. PANC-1 cells cultured in vitrowere classified to a control (normal culture), negative (neutral siRNA transfection), and siTRIM14 group (TRIM14 siRNA transfection). RT-PCR was adopted to test TRIM14 mRNA expression. Cellular proliferation was determined by CCK-8, and transwell chamber invasion and apoptosis by flow cytometry. AKT signaling pathway related proteins CyclinD1, MMP-2, Bcl-2, and AKT phosphorylation, and TRIMI14 protein expression, were determined by western blotting. Compared with the control group, TRIMI14 expression, cellular proliferation ability, infiltration, transfer AKT phosphorylation, and TRIMI14, CyclinD1, MMP-2, and Bcl-2 protein expression were greatly reduced in siTRIM14 cells, and the apoptotic ability was significantly enhanced (P < 0.05). However, no striking differences were detected between the negative and control groups (P > 0.05). Downregulating TRIM14 expression can inhibit the proliferation, invasion, and migration of PANC-1 cells, and promote apoptosis. The mechanism may be associated with the inhibition of AKT signaling pathway activation.

Latent Membrane Protein 1 Antibody Inhibited Cell Stemness Growth of Nasopharyngeal Carcinoma by Regulating PI3K/AKT Signaling Pathway

2020 ◽  
Vol 10 (6) ◽  
pp. 768-775
Author(s):  
Dawei Zhang ◽  
Lin Xiong ◽  
Liang Li ◽  
Yuan Chen ◽  
Xiaojun Tang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Latent Membrane Protein 1 ◽  
The Novel ◽  
Akt Signaling Pathway ◽  
Akt Phosphorylation ◽  
Sphere Formation

Objective: The aim of the study was to investigate the effects of LMP1-Fab antibody on Nasopharyngeal carcinoma (NPC) cancer stem cells (CSCs). Methods/Results: LMP1 was identified to play an important role in maintaining the stemness characteristics of NPC by sphere formation, as is evidenced by CCK-8 and colony formation assays. Furthermore, CCK8 and TUNEL assays indicated that LMP1-Fab antibody could accelerate cell apoptosis while inhibiting cell proliferation in nasopharyngeal carcinoma stem cell. Notably, LMP1-Fab antibody inhibited NPC xenograft cancer growth in the nude mice. At the molecular level, LMP1-Fab antibody inhibited the phosphorylation of PI3K/AKT signaling pathway both in vitro and in vivo. More importantly, these effects were blocked by PI3K/AKT phosphorylation inhibitor LY294002. Conclusion: These results suggested that the novel antibody-targeting LMP1 is likely to be a promising strategy for the treatment of NPC.

scholarly journals Sphingosine-1-phosphate induces the migration and angiogenesis of EPCs through the Akt signaling pathway via sphingosine-1-phosphate receptor 3/platelet-derived growth factor receptor-β

2015 ◽  
Vol 20 (4) ◽  
Author(s):  
Hang Wang ◽  
Ke-Yin Cai ◽  
Wei Li ◽  
Hao Huang
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Akt Signaling ◽  
Platelet Derived Growth Factor ◽  
Akt Signaling Pathway ◽  
Akt Inhibitor ◽  
Sphingosine 1 Phosphate

AbstractEndothelial progenitor cells (EPCs) play a fundamental role in neoangiogenesis and tumor angiogenesis. Through the sphingosine-1-phosphate receptor 3 (S1PR3), sphingosine-1-phosphate (S1P) can stimulate the functional capacity of EPCs. Platelet-derived growth factor receptor-beta (PDGFR-β) contributes to the migration and angiogenesis of EPCs. This study aimed to investigate whether S1P induces the migration and angiogenesis of EPCs through the S1PR3/PDGFR-β/Akt signaling pathway. We used the Transwell system and the Chemicon In Vitro Angiogenesis Assay Kit with CAY10444 (an S1PR3 antagonist), AG1295 (a PDGFR kinase inhibitor) and sc-221226 (an Akt inhibitor) to examine the role of the S1PR3/PDGFR-β/Akt pathway in the S1Pinduced migration and angiogenesis of EPCs.

Bioinformatics Analysis of a Regulatory lncRNA–miRNA–mRNA Network and Signaling Pathways in Patients With Cardiomyopathy

2021 ◽  
Author(s):  
Tao Chen ◽  
Yu-Yao Liu ◽  
Shu-Jun Li ◽  
Hong Che ◽  
Sheng-Lin Ge
Keyword(s):  
Signaling Pathway ◽  
Target Genes ◽  
Kinase Inhibitor ◽  
Biological Effects ◽  
Akt Signaling ◽  
Differentially Expressed ◽  
Control Group ◽  
Messenger Rnas ◽  
Akt Signaling Pathway ◽  
Original Dataset

Abstract Background:Cardiomyopathy is a disease with a very low cure rate and a very complex pathogenesis.Although genes are known to play an important role in various types of cardiomyopathy, the specific mechanism has not been well studied.Methods:We screened the GSE29819 dataset from the Gene Expression Omnibus database (GEO) for long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) with significant differences using R software. microRNAs (miRNAs) regulated by the lncRNAs were retrieved from the miRcode database. The downstream target genes of the miRNAs were predicted by miRDB, miRTarBase, and TargetScan, and genes consistent with the original dataset were selected to construct a lncRNA–miRNA–mRNA network. Finally, the biological effects of these genes were studied by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis.Results: 223 differentially expressed genes and 13 differentially expressed lncRNAs has been screened in the cardiomyopathy tissues.After database screening and matching, the final lncRNA–miRNA–mRNA network included three lncRNAs, eight miRNAs, and nine mRNAs. These nine genes are mainly involved in the prolactin signaling pathway, EGFR tyrosine kinase inhibitor resistance, toxoplasmosis, the chemokine signaling pathway, and the PI3K–Akt signaling pathway. In the PI3K–Akt signaling pathway, the expression levels of these genes are significantly upregulated compared with the control group, and the main genes involved in regulation are JAK2/DDIT4/FOXO3. JAK2 and FOXO3 play an important regulatory role in the PI3K–Akt signaling pathway.Conclusion:The AC017002–miRNA-590-5p–FOXO3 network may be involved in the pathogenesis of cardiomyopathy, which will enable the determination of new markers to predict cardiomyopathy, and thus reduce the risk of developing the disease.

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