scholarly journals Role of Sphingosine ‐1‐Phosphate on Expression of MAPK and Akt Signaling Pathways in Hypoxic Human Extravillous Trophoblasts

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Kenneth F. Swan ◽  
Gabriella Pridjian ◽  
Thomas Swayze ◽  
Brennan R. Gagen ◽  
Suttira Intapad
Keyword(s):  
Signaling Pathways ◽  
Akt Signaling ◽  
Sphingosine 1 Phosphate ◽  
Extravillous Trophoblasts

Biological role of AKT, and regulation of AKT signaling pathway by thymoquinone: perspectives in cancer therapeutics

2020 ◽  
Vol 20 ◽  
Author(s):  
Md. Junaid ◽  
Yeasmin Akter ◽  
Syeda Samira Afrose ◽  
Mousumi Tania ◽  
Md. Asaduzzaman Khan
Keyword(s):  
Clinical Trials ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Akt Signaling ◽  
Review Article ◽  
Therapeutic Drug ◽  
Akt Signaling Pathway ◽  
Anti Cancer

Background: AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to the carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs. Objective: In this review article, we have interpreted the role of AKT signaling pathways in cancer and natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanism. Method: We have collected the updated information and data on AKT, their role in cancer and inhibitory effect of TQ in AKT signaling pathway from google scholar, PubMed, Web of Science, Elsevier, Scopus and many more. Results: There are many drugs already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer. Conclusion: This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ’s future as a cancer therapeutic drug.

scholarly journals Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sophia K. Theodossiou ◽  
Jett B. Murray ◽  
LeeAnn A. Hold ◽  
Jeff M. Courtright ◽  
Anne M. Carper ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Akt Signaling ◽  
Cell Alignment ◽  
Limited Information ◽  
Akt Inhibitor ◽  
Tenogenic Differentiation

Abstract Background Tissue engineered and regenerative approaches for treating tendon injuries are challenged by the limited information on the cellular signaling pathways driving tenogenic differentiation of stem cells. Members of the transforming growth factor (TGF) β family, particularly TGFβ2, play a role in tenogenesis, which may proceed via Smad-mediated signaling. However, recent evidence suggests some aspects of tenogenesis may be independent of Smad signaling, and other pathways potentially involved in tenogenesis are understudied. Here, we examined the role of Akt/mTORC1/P70S6K signaling in early TGFβ2-induced tenogenesis of mesenchymal stem cells (MSCs) and evaluated TGFβ2-induced tenogenic differentiation when Smad3 is inhibited. Methods Mouse MSCs were treated with TGFβ2 to induce tenogenesis, and Akt or Smad3 signaling was chemically inhibited using the Akt inhibitor, MK-2206, or the Smad3 inhibitor, SIS3. Effects of TGFβ2 alone and in combination with these inhibitors on the activation of Akt signaling and its downstream targets mTOR and P70S6K were quantified using western blot analysis, and cell morphology was assessed using confocal microscopy. Levels of the tendon marker protein, tenomodulin, were also assessed. Results TGFβ2 alone activated Akt signaling during early tenogenic induction. Chemically inhibiting Akt prevented increases in tenomodulin and attenuated tenogenic morphology of the MSCs in response to TGFβ2. Chemically inhibiting Smad3 did not prevent tenogenesis, but appeared to accelerate it. MSCs treated with both TGFβ2 and SIS3 produced significantly higher levels of tenomodulin at 7 days and morphology appeared tenogenic, with localized cell alignment and elongation. Finally, inhibiting Smad3 did not appear to impact Akt signaling, suggesting that Akt may allow TGFβ2-induced tenogenesis to proceed during disruption of Smad3 signaling. Conclusions These findings show that Akt signaling plays a role in TGFβ2-induced tenogenesis and that tenogenesis of MSCs can be initiated by TGFβ2 during disruption of Smad3 signaling. These findings provide new insights into the signaling pathways that regulate tenogenic induction in stem cells.

Abstract T P87: Hydrogen Sulfide Enhances Neurogenesis through the IRAK-1/GSK3β/AKT Signaling Pathways after Ischemic Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Pradip K Kamat ◽  
Anuradha Kalani ◽  
Neetu Tyagi
Keyword(s):  
Hydrogen Sulfide ◽  
Signaling Pathways ◽  
Ventricular Zone ◽  
Ischemia Reperfusion ◽  
Analysis Data ◽  
Akt Signaling ◽  
Artery Occlusion ◽  
Cortical Region ◽  
Neuronal Function

Background and purpose: Increasing evidence signifying that inflammation has an ample role in the ischemia and; neurogenesis is somehow affected by inflammation. Current approved therapy for stroke is limited and new strategies need to be investigated. Hydrogen sulfide (H2S) showed neuro-protective however, role of H2S in stroke-induced neurogenesis is not known. Therefore, the present study was to determine the role of H2S in ischemia induced neurogenesis. Methods: To perform this study; we employed 8-10 weak old C57BL/6 mice with following groups: WT-Sham; WT+ ischemia reperfusion (IR) for 7 days; IR+GYY4137 (H2S donor, 30μM for 7 days; Intra peritoneal injection); and Sham+ GYY4137 (30μM for 7 day). Ischemia was created by the middle cerebral artery occlusion, (MCAO) for 50 min followed by reperfusion for 7 days. The brain tissue from different groups was used for biochemical, infarct area molecular and immunohistochemistry analysis. Data were analyzed by one way ANOVA followed by Tukey test. Results: We found increased protein expression of IRAK-1 (F=3, 27.01; P<.005), GSK3β 9 (F=3, 89.47; P<.005), p-AKT (F=3, 89.47; P<.005) and reduced expression of AKT p-AKT(F=3, 112.2; P<.005) in I/R group as compared to sham that indicates alteration of inflammatory signaling pathways. Further, we also found decreased level of Nestin (F=3, 35.32; P<.005), GFAP (F=3, 95.14; P<.001), NeuN (F=3, 123.4; P<.001), TUJ-1 (F=3, 112; P<.005), MAP-2 (F=3, 31.54; P<.0001), IL-6 (F=3, 55.7; p<.05) and BDNF (F=3, 166.5; P<.005) in cortical region of I/R group which indicates loss of neuronal function. Additionally, immunohistochemistry assay also revealed the loss of Nestin (P<.05), BDNF (P<.05), MAP-2 (P<.05) along with increased GSK-3β (P<.005) expression in sub ventricular zone (SVZ) and hippocampal region. Further, GYY4137 treatment for 7 days in ischemic group significantly restored the Nestin, GFAP, IL-6, NeuN, TUJ-1, MAP-2 and BDNF levels via regulating IRAK-1/GSK3β/AKT signaling pathways. Conclusion: Present study clearly demonstrate that H2S plays an important role in ischemia induced neurogenesis as well as protecting neuronal function through inhibition of IRAK1/GSK3β/AKT signaling pathways. Acknowledgement: This work was supported by NTHL107640-NT.

scholarly journals Thrombin Preconditioning Boosts Biogenesis of Extracellular Vesicles from Mesenchymal Stem Cells and Enriches Their Cargo Contents via Protease-Activated Receptor-Mediated Signaling Pathways

2019 ◽  
Vol 20 (12) ◽  
pp. 2899 ◽  
Author(s):  
Dong Kyung Sung ◽  
Se In Sung ◽  
So Yoon Ahn ◽  
Yun Sil Chang ◽  
Won Soon Park
Keyword(s):  
Stem Cells ◽  
Signaling Pathways ◽  
Extracellular Vesicles ◽  
Akt Signaling ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Specific Antagonist

We investigated the role of protease-activated receptor (PAR)-mediated signaling pathways in the biogenesis of human umbilical cord blood-derived mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) and the enrichment of their cargo content after thrombin preconditioning. Immunoblot analyses showed that MSCs expressed two PAR subtypes: PAR-1 and PAR-3. Thrombin preconditioning significantly accelerated MSC-derived EV biogenesis more than five-fold and enriched their cargo contents by more than two-fold via activation of Rab5, early endosomal antigen (EEA)-1, and the extracellular signal regulated kinase (ERK)1/2 and AKT signaling pathways. Blockage of PAR-1 with the PAR-1-specific antagonist, SCH79797, significantly suppressed the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways and subsequently increased EV production and enriched EV cargo contents. Combined blockage of PAR-1 and PAR-3 further and significantly inhibited the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways, accelerated EV production, and enriched EV cargo contents. In summary, thrombin preconditioning boosted the biogenesis of MSC-derived EVs and enriched their cargo contents largely via PAR-1-mediated pathways and partly via PAR-1-independent, PAR-3-mediated activation of Rab5, EEA-1, and the ERK1/2 and AKT signaling pathways.

scholarly journals IL-13 promotes in vivo neonatal cardiomyocyte cell cycle activity and heart regeneration

2019 ◽  
Vol 316 (1) ◽  
pp. H24-H34 ◽  
Author(s):  
Dylan J. Wodsedalek ◽  
Samantha J. Paddock ◽  
Tina C. Wan ◽  
John A. Auchampach ◽  
Aria Kenarsary ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signaling Pathways ◽  
Rna Sequencing ◽  
Akt Signaling ◽  
Heart Regeneration ◽  
Newborn Mice ◽  
Neonatal Cardiomyocyte

There is great interest in identifying signaling mechanisms by which cardiomyocytes (CMs) can enter the cell cycle and promote endogenous cardiac repair. We have previously demonstrated that IL-13 stimulated cell cycle activity of neonatal CMs in vitro. However, the signaling events that occur downstream of IL-13 in CMs and the role of IL-13 in CM proliferation and regeneration in vivo have not been explored. Here, we tested the role of IL-13 in promoting neonatal CM cell cycle activity and heart regeneration in vivo and investigated the signaling pathway(s) downstream of IL-13 specifically in CMs. Compared with control, CMs from neonatal IL-13 knockout (IL-13−/−) mice showed decreased proliferative markers and coincident upregulation of the hypertrophic marker brain natriuretic peptide ( Nppb) and increased CM nuclear size. After apical resection in anesthetized newborn mice, heart regeneration was significantly impaired in IL-13−/− mice compared with wild-type mice. Administration of recombinant IL-13 reversed these phenotypes by increasing CM proliferation markers and decreasing Nppb expression. RNA sequencing on primary neonatal CMs treated with IL-13 revealed activation of gene networks regulated by ERK1/2 and Akt. Western blot confirmed strong phosphorylation of ERK1/2 and Akt in both neonatal and adult cultured CMs in response to IL-13. Our data demonstrated a role for endogenous IL-13 in neonatal CM cell cycle and heart regeneration. ERK1/2 and Akt signaling are important pathways known to promote CM proliferation and protect against apoptosis, respectively; thus, targeting IL-13 transmembrane receptor signaling or administering recombinant IL-13 may be therapeutic approaches for activating proregenerative and survival pathways in the heart. NEW & NOTEWORTHY Here, we demonstrate, for the first time, that IL-13 is involved in neonatal cardiomyocyte cell cycle activity and heart regeneration in vivo. Prior work has shown that IL-13 promotes cardiomyocyte cell cycle activity in vitro; however, the signaling pathways were unknown. We used RNA sequencing to identify the signaling pathways activated downstream of IL-13 in cardiomyocytes and found that ERK1/2 and Akt signaling was activated in response to IL-13.

STAT3 and AKT signaling pathways mediate oncogenic role of NRSF in hepatocellular carcinoma

2020 ◽  
Vol 52 (10) ◽  
pp. 1063-1070
Author(s):  
Ming Ma ◽  
Yunhe Zhou ◽  
Ruilin Sun ◽  
Jiahao Shi ◽  
Yutong Tan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathways ◽  
Zinc Finger Protein ◽  
Akt Signaling ◽  
Nervous System Development ◽  
Migration And Invasion ◽  
Tumor Type ◽  
Dependent Manner ◽  
Rnai Technology

Abstract Neuron-restrictive silencer factor (NRSF) is a zinc finger protein that acts as a negative transcriptional regulator by recruiting histone deacetylases and other co-factors. It plays a crucial role in nervous system development and is recently reported to be involved in tumorigenesis in a tumor type-dependent manner; however, the role of NRSF in hepatocellular carcinoma (HCC) tumorigenesis remains unclear. Here, we found that NRSF expression was up-regulated in 27 of 49 human HCC tissue samples examined. Additionally, mice with conditional NRSF-knockout in the liver exhibited a higher tolerance against diethylnitrosamine (DEN)-induced acute liver injury and were less sensitive to DEN-induced HCC initiation. Our results showed that silencing NRSF in HepG2 cells using RNAi technology significantly inhibited HepG2 cell proliferation and severely hindered their migration and invasion potentials. Our results demonstrated that NRSF plays a pivotal role in promoting DEN-induced HCC initiation via a mechanism related to the STAT3 and AKT signaling pathways. Thus, NRSF could be a potential therapeutic target for treating human HCC.

scholarly journals aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2–mediated SphK1-S1PR1-Akt signaling axis

2021 ◽  
Vol 118 (49) ◽  
pp. e2106623118
Author(s):  
Olivia Molinar-Inglis ◽  
Cierra A. Birch ◽  
Dequina Nicholas ◽  
Lennis Orduña-Castillo ◽  
Metztli Cisneros-Aguirre ◽  
...  
Keyword(s):  
Cell Death ◽  
Endothelial Dysfunction ◽  
Signaling Pathways ◽  
Activated Protein C ◽  
Akt Signaling ◽  
Endothelial Barrier ◽  
Structural Protein ◽  
Signaling Axis ◽  
Sphingosine 1 Phosphate ◽  
Apoptotic Activity

Endothelial dysfunction is associated with vascular disease and results in disruption of endothelial barrier function and increased sensitivity to apoptosis. Currently, there are limited treatments for improving endothelial dysfunction. Activated protein C (aPC), a promising therapeutic, signals via protease-activated receptor-1 (PAR1) and mediates several cytoprotective responses, including endothelial barrier stabilization and anti-apoptotic responses. We showed that aPC-activated PAR1 signals preferentially via β-arrestin-2 (β-arr2) and dishevelled-2 (Dvl2) scaffolds rather than G proteins to promote Rac1 activation and barrier protection. However, the signaling pathways utilized by aPC/PAR1 to mediate anti-apoptotic activities are not known. aPC/PAR1 cytoprotective responses also require coreceptors; however, it is not clear how coreceptors impact different aPC/PAR1 signaling pathways to drive distinct cytoprotective responses. Here, we define a β-arr2–mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. Using human cultured endothelial cells, we found that endogenous PAR1 and S1PR1 coexist in caveolin-1 (Cav1)–rich microdomains and that S1PR1 coassociation with Cav1 is increased by aPC activation of PAR1. Our study further shows that aPC stimulates β-arr2–dependent SphK1 activation independent of Dvl2 and is required for transactivation of S1PR1-Akt signaling and protection against cell death. While aPC/PAR1-induced, extracellular signal–regulated kinase 1/2 (ERK1/2) activation is also dependent on β-arr2, neither SphK1 nor S1PR1 are integrated into the ERK1/2 pathway. Finally, aPC activation of PAR1-β-arr2–mediated protection against apoptosis is dependent on Cav1, the principal structural protein of endothelial caveolae. These studies reveal that different aPC/PAR1 cytoprotective responses are mediated by discrete, β-arr2–driven signaling pathways in caveolae.

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