A central role for PI3K-AKT signaling pathway in linking SAMHD1-deficiency to the type I interferon signature

Abstract Background: Osteoarthritis (OA), the most common joint disorder, is characterized by a progressive degradation of articular cartilage. Increasing evidence suggests that OA is closely associated with cartilage pathologies including chondrocyte hypertrophy and fibrosis. Methods: In this study, we showed that asiatic acid (AA) treatment reduced chondrocyte hypertrophy and fibrosis. First, the cytotoxicity of AA (0, 5, 10, and 20 μM) to chondrocytes was evaluated, and 5 μM was selected for subsequent experiments. Then, we detected the gene and protein level of chondrocyte hypertrophic markers including type X collagen (COL-X), matrix metalloproteinase - 13 (MMP-13), alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and chondrocyte fibrosis markers including type I collagen (COL-Ι) and alpha-smooth muscle actin (α-SMA), and chondrogenic markers including SRY-related HMG box 9 (SOX9), type II collagen (COL-II) and aggrecan (ACAN). Further, we tested the mechanism of AA on inhibiting chondrocyte hypertrophy and fibrosis. Finally, we verified the results in an anterior cruciate ligament transection (ACLT) rat OA model.Results: We found that AA treatment inhibited the hypertrophic and fibrotic phenotype of chondrocytes, without affecting the chondrogenic phenotype. Moreover, we found that AA treatment activated AMP-activated protein kinase (AMPK) and inhibited phosphoinositide-3 kinase/protein kinase B (PI3K/AKT) signaling pathway in vitro. The results in an ACLT-rat OA model also indicated that AA significantly attenuated chondrocyte hypertrophy and fibrosis. Conclusion: AA treatment could reduce hypertrophic and fibrotic differentiation, and maintain the chondrogenic phenotype of articular chondrocytes by targeting the AMPK/PI3K/AKT signaling pathway. Our study suggested that AA might be a prospective drug component that targets hypertrophic and fibrotic chondrocytes for OA treatment.

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Connectivity map analysis identifies fisetin as a treatment compound for osteoporosis through activating the PI3K-AKT signaling pathway in mouse pre-osteoblastic MC3T3-E1 cells

Current Pharmaceutical Biotechnology ◽

10.2174/1389201022666210301141238 ◽

2021 ◽

Vol 22 ◽

Author(s):

Linxiao Xu ◽

Xinyunxi He ◽

Yuanyi Zhou ◽

Kailing Yu ◽

Mingyue Yuan ◽

...

Keyword(s):

Cell Viability ◽

Signaling Pathway ◽

Akt Signaling ◽

Gene Set Enrichment Analysis ◽

Type I ◽

Akt Signaling Pathway ◽

Rankl Expression ◽

Connectivity Map ◽

Expression Ratio ◽

Treatment Of Osteoporosis

Aims: This research aimed at exploring potential new compound in the treatment of osteoporosis by Connectivity Map (CMap) and determining the role of fisetin on osteoporosis according to its effects on PI3K-AKT signaling pathway in MC3T3-E1 pre-osteoblastic cells. Methods: Microarray analysis was used to obtain the differentially expressed genes in published gene expression data. Potent compounds for osteoporosis therapy were discovered by CMap analysis. DAVID and gene set enrichment analysis (GSEA) were used to discover signaling pathways that connected to osteoporosis disease. Cell viability was evaluated by a CCK-8 assay. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis were used to test the mRNA and protein expressions related to PI3K-AKT signaling pathway in MC3T3-E1 cells respectively. Results: CMap analysis identified fisetin as a promising compound for anti-osteoporosis treatment. DAVID and GSEA analysis showed that the PI3K-AKT signaling pathway was inactivated in osteoporosis. Cell experiments revealed that fisetin caused an elevation of cell viability, up-regulated the mRNA levels of the runt-related transcription factor-2 (Runx2), osterix (Osx), collagen type I 1 (Col1a1) and osteoprotegerin (OPG) while down-regulated the nuclear factor-κB ligand (RANKL) mRNA level. Discussion: The protein levels of Runx2, Col1a1 and osteocalcin(OCN) were also increased by fisetin. Furthermore, fisetin activated the phosphoinositide-3-kinase/protein kinase B (PI3K-AKT) signaling pathway, and blocking this pathway by the inhibitor LY-294002 could impair fisetin’s functions on proliferation, differentiation and OPG/RANKL expression ratio in the MC3T3-E1 cells. Conclusion: Our results demonstrated that fisetin could promote MC3T3-E1 cell proliferation, differentiation, and increase OPG/RANKL expression ratio through activating the PI3K-AKT pathway, which has potential in the treatment of osteoporosis.

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PDGF-BB induces conversion, proliferation, migration, and collagen synthesis of oral mucosal fibroblasts through PDGFR-β/PI3K/ AKT signaling pathway

Cancer Biomarkers ◽

10.3233/cbm-201681 ◽

2021 ◽

pp. 1-9

Author(s):

Jie Wang ◽

Jialing You ◽

Ding Gong ◽

Ying Xu ◽

Bo Yang ◽

...

Keyword(s):

Signaling Pathway ◽

Collagen Synthesis ◽

Akt Signaling ◽

Control Group ◽

Type I ◽

Akt Signaling Pathway ◽

Western Blots ◽

Tetrazolium Bromide ◽

Thiazolyl Blue Tetrazolium Bromide ◽

The Impact

OBJECTIVE: To explore the pathogenesis of oral submucosal fibrosis (OSF) by analyzing the impact of Platelet Derived Growth Factor (PDGF)-BB on oral mucosal fibroblasts (FB) and PDGFR-β/Phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase (AKT) signaling pathway. METHODS: The isolated and purified oral mucosal fibroblasts were divided into four groups: the control group (CON, 10% FBS DMEM), the PDGF-BB group (40 ng/ml PDGF-BB), the PDGF-BB+IMA group (40 ng/ml PDGF-BB and 60 μmol/L IMA), and the PDGF-BB+LY294002 group (40 ng/ml PDGF-BB and 48 μmol/L LY294002). Primary human FB cells were isolated and cultured for detecting the effects of PDGF-BB on α-smooth muscle actin (α-SMA) by indirect immunofluorescence. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H -tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide (MTT) method and scratch test were used to detect the proliferation and migration of FB. Western Blots were used to detect the synthesis of type I collagen (Col I) and the expression of PDGFR-β/PI3K/AKT signaling pathway-related proteins. The effects of PDGFR-β inhibitor and PI3K inhibitor were observed. RESULTS: Compared with group CON, group IMA, and group LY294002, α-SMA was upregulated in group PDGF-BB (p< 0.05), with higher OD490 nm value (p< 0.05), narrower average scratch width, and higher relative cell migration rate (p< 0.05). The expression levels of Col I, p-PDGFR-β, p-PI3K, and p-AKT were higher in group PDGF-BB (p< 0.05). CONCLUSIONS: PDGF-BB induces FB to transform into myofibroblasts (MFB) through the PDGFR-β/PI3K/AKT signaling pathway, and promotes the proliferation, migration, and collagen synthesis.

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Asiatic acid attenuates hypertrophic and fibrotic differentiation of articular chondrocytes via AMPK/PI3K/AKT signaling pathway

10.21203/rs.2.18562/v1 ◽

2019 ◽

Author(s):

Na Liu ◽

Dejie Fu ◽

Junjun Yang ◽

Pingju Liu ◽

Xiongbo Song ◽

...

Keyword(s):

Protein Kinase ◽

Signaling Pathway ◽

Type I Collagen ◽

Articular Chondrocytes ◽

Akt Signaling ◽

Type I ◽

Asiatic Acid ◽

Akt Signaling Pathway ◽

Chondrocyte Hypertrophy ◽

Chondrogenic Phenotype

Abstract Background Osteoarthritis (OA), the most common joint disorder, is characterized by a progressive degradation of articular cartilage. Increasing evidence suggests that OA is closely associated with cartilage pathologies including chondrocyte hypertrophy and fibrosis.Methods In this study, we showed that Asiatic acid (AA) treatment reduced chondrocyte hypertrophy and fibrosis. First, the cytotoxicity of AA (0, 5, 10, and 20 μM) to chondrocytes was evaluated, and 5 μM was selected for subsequent experiments. Then, we detected the gene and protein level of chondrocyte hypertrophic markers including type X collagen (COL-X), matrix metalloproteinase - 13 (MMP-13), alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and chondrocyte fibrosis markers including type I collagen (COL-Ι) and alpha-smooth muscle actin (α-SMA), and chondrogenic markers including SRY-related HMG box 9 (SOX9), type II collagen (COL-II) and aggrecan (ACAN). Further, we texted the mechanism of AA on inhibiting chondrocyte hypertrophy and fibrosis. Finally, we verified the results in an anterior cruciate ligament transection (ACLT) rat OA model.Results We found that AA treatment inhibited the hypertrophic and fibrotic phenotype of chondrocytes, without affecting the chondrogenic phenotype. Moreover, we found AA treatment activated AMP-activated protein kinase (AMPK) and inhibited phosphoinositide-3 kinase/protein kinase B (PI3K/AKT) signaling pathway in vitro. The results in an ACLT-rat OA model also indicated that AA significantly attenuated chondrocyte hypertrophy and fibrosis.Conclusion AA treatment could reduce hypertrophic and fibrotic differentiation, and maintain the chondrogenic phenotype of articular chondrocytes by targeting the AMPK/PI3K/AKT signaling pathway. Our study suggested that AA might be a prospective drug component that targets hypertrophic and fibrotic chondrocytes for OA treatment.

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Faculty Opinions recommendation of Rpn10 promotes tumor progression by regulating hypoxia-inducible factor 1 alpha through the PTEN/Akt signaling pathway in hepatocellular carcinoma.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734911165.793580826 ◽

2020 ◽

Author(s):

Leonardo Salmena

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Progression ◽

Signaling Pathway ◽

Hypoxia Inducible Factor ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Hypoxia Inducible Factor 1

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Effects of deguelin on proliferation and apoptosis of MCF-7 breast cancer cells by phosphatidylinositol 3-kinase/Akt signaling pathway

Journal of Chinese Integrative Medicine ◽

10.3736/jcim20110511 ◽

2011 ◽

Vol 9 (5) ◽

pp. 533-538 ◽

Cited By ~ 9

Author(s):

ZH Chu

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Breast Cancer Cells ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Phosphatidylinositol 3 Kinase ◽

Proliferation And Apoptosis ◽

Mcf 7 ◽

Phosphatidylinositol 3

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

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666201005143818 ◽

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.

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PI3K/Akt Signaling Pathway Ameliorates Oxidative Stress-Induced Apoptosis upon Manganese Exposure in PC12 Cells

Biological Trace Element Research ◽

10.1007/s12011-021-02687-1 ◽

2021 ◽

Author(s):

Yanli Tan ◽

Hong Cheng ◽

Cheng Su ◽

Pan Chen ◽

Xiaobo Yang

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Pc12 Cells ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Manganese Exposure ◽

Induced Apoptosis

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Retraction: Salvianolic acid B inhibits inflammatory response and cell apoptosis via the PI3K/Akt signaling pathway in IL-1β-induced osteoarthritis chondrocytes

RSC Advances ◽

10.1039/d1ra90026a ◽

2021 ◽

Vol 11 (8) ◽

pp. 4441-4441

Author(s):

Laura Fisher

Keyword(s):

Inflammatory Response ◽

Signaling Pathway ◽

Cell Apoptosis ◽

Akt Signaling ◽

Salvianolic Acid B ◽

Signalling Pathway ◽

Akt Signaling Pathway ◽

Salvianolic Acid ◽

Osteoarthritis Chondrocytes

Retraction of ‘Salvianolic acid B inhibits inflammatory response and cell apoptosis via the PI3K/Akt signalling pathway in IL-1β-induced osteoarthritis chondrocytes’ by Bin Zhu et al., RSC Adv., 2018, 8, 36422–36429, DOI: 10.1039/C8RA02418A.

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