Antifibrotic action of Yifei Sanjie formula enhanced autophagy via PI3K-AKT-mTOR signaling pathway in mouse model of pulmonary fibrosis

Abstract BackgroundIdiopathic pulmonary fibrosis (IPF) is characterised by accumulation of myofibroblasts and deposition of extracellular matrix proteins. Fibroblast-to-myofibroblast transdifferentiation and myofibroblast hyperproliferation plays a major role in pulmonary fibrosis. Moreover, mTOR signaling pathway and SIRT6 play a critical role in pulmonary fibrosis. However, the mechanisms whether SIRT6 affect the myofibroblasts differentiation during IPF remain unclear.MethodWe investigated myofibroblast differentiation using a bleomycin-induced mouse pulmonary fibrosis model and TGF-b1 induced human fetal lung fibroblasts (MRC5) in vitro. We used both SIRT6 siRNA and rapamycin to study the role of SIRT6 and mTOR signaling pathway in the normal human lung fibroblasts and the myofibroblasts from human IPF lungs.ResultsOur data show that high level of SIRT6 was detected in IPF samples, and SIRT6 was signiﬁcantly upregulated by TGF-β1 in a time and concentration-dependent manner. SIRT6 expression and activation of mTORC1 signalling pathway were upregulated in fibrotic lung tissues and primary lung fibroblasts isolated from patients with IPF and bleomycin-challenged mice. Furthermore, rapamycin treatment inhibited mTORC1 pathway activity and SIRT6 protein expression. SIRT6 SiRNA failed to mediate the activity of mTORC1 pathway and autophagy induction. However, SIRT6 knockdown could promote TGF-b1 induced pro-fibrotic cytokines.ConclusionActivated mTORC1 signalling pathway regulated SIRT6 overexpression. Deficiency of SIRT6 mediated myofibroblasts differentiation through induced pro-fibrotic cytokines production in the present of TGF-β1. The study indicated that manipulations of SIRT6 expression may provide a new therapeutic strategy to prevent and reverse the progression of pulmonary fibrosis.

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Abstract 2986: Targeting multiple nodes in the RTK- PI3K/AKT/mTOR signaling pathway in a p53-/- mouse model of DIPG induces G2/M phase cell cycle arrest

10.1158/1538-7445.am2016-2986 ◽

2016 ◽

Cited By ~ 1

Author(s):

Yue Linda Wu ◽

Uday Bhanu Maachani ◽

Melanie Schweitzer ◽

Oren J. Becher ◽

Melinda Wang ◽

...

Keyword(s):

Cell Cycle ◽

Mouse Model ◽

Cell Cycle Arrest ◽

Signaling Pathway ◽

Mtor Signaling ◽

Phase Cell ◽

Mtor Signaling Pathway ◽

Cycle Arrest ◽

M Phase

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Dual Targeting of the Akt/mTOR Signaling Pathway Inhibits Castration-Resistant Prostate Cancer in a Genetically Engineered Mouse Model

Cancer Research ◽

10.1158/0008-5472.can-12-0283 ◽

2012 ◽

Vol 72 (17) ◽

pp. 4483-4493 ◽

Cited By ~ 49

Author(s):

Nicolas Floc'h ◽

Carolyn Waugh Kinkade ◽

Takashi Kobayashi ◽

Alvaro Aytes ◽

Celine Lefebvre ◽

...

Keyword(s):

Prostate Cancer ◽

Mouse Model ◽

Signaling Pathway ◽

Genetically Engineered ◽

Mtor Signaling ◽

Castration Resistant Prostate Cancer ◽

Mtor Signaling Pathway ◽

Castration Resistant ◽

Dual Targeting ◽

Genetically Engineered Mouse Model

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Fluorofenidone attenuates paraquat‑induced pulmonary fibrosis by regulating the PI3K/Akt/mTOR signaling pathway and autophagy

Molecular Medicine Reports ◽

10.3892/mmr.2021.12044 ◽

2021 ◽

Vol 23 (6) ◽

Author(s):

Feiya Jiang ◽

Sha Li ◽

Yu Jiang ◽

Zhuo Chen ◽

Tongtong Wang ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Signaling Pathway ◽

Mtor Signaling ◽

Mtor Signaling Pathway

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miR-20b and miR-451a Are Involved in Gastric Carcinogenesis through the PI3K/AKT/mTOR Signaling Pathway: Data from Gastric Cancer Patients, Cell Lines and Ins-Gas Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms21030877 ◽

2020 ◽

Vol 21 (3) ◽

pp. 877 ◽

Cited By ~ 5

Author(s):

Greta Streleckiene ◽

Ruta Inciuraite ◽

Simonas Juzenas ◽

Violeta Salteniene ◽

Ruta Steponaitiene ◽

...

Keyword(s):

Gastric Cancer ◽

Mouse Model ◽

Signaling Pathway ◽

Cell Lines ◽

Target Genes ◽

Mtor Signaling ◽

Luciferase Reporter ◽

Mtor Signaling Pathway ◽

Gastrointestinal Malignancies

Gastric cancer (GC) is one of the most common and lethal gastrointestinal malignancies worldwide. Many studies have shown that development of GC and other malignancies is mainly driven by alterations of cellular signaling pathways. MicroRNAs (miRNAs) are small noncoding molecules that function as tumor-suppressors or oncogenes, playing an essential role in a variety of fundamental biological processes. In order to understand the functional relevance of miRNA dysregulation, studies analyzing their target genes are of major importance. Here, we chose to analyze two miRNAs, miR-20b and miR-451a, shown to be deregulated in many different malignancies, including GC. Deregulated expression of miR-20b and miR-451a was determined in GC cell lines and the INS-GAS mouse model. Using Western Blot and luciferase reporter assay we determined that miR-20b directly regulates expression of PTEN and TXNIP, and miR-451a: CAV1 and TSC1. Loss-of-function experiments revealed that down-regulation of miR-20b and up-regulation of miR-451a expression exhibits an anti-tumor effect in vitro (miR-20b: reduced viability, colony formation, increased apoptosis rate, and miR-451a: reduced colony forming ability). To summarize, the present study identified that expression of miR-20b and miR-451a are deregulated in vitro and in vivo and have a tumor suppressive role in GC through regulation of the PI3K/AKT/mTOR signaling pathway.

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Successful reversal of ovarian hyperstimulation syndrome in a mouse model by rapamycin, an mTOR pathway inhibitor

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaz033 ◽

2019 ◽

Vol 25 (8) ◽

pp. 445-457 ◽

Cited By ~ 1

Author(s):

Wenwen Liu ◽

Chi Zhang ◽

Lu Wang ◽

Xuan Huang ◽

Jing Zhang ◽

...

Keyword(s):

Mouse Model ◽

Signaling Pathway ◽

Ovarian Hyperstimulation Syndrome ◽

Mtor Signaling ◽

Ovarian Hyperstimulation ◽

Matrix Remodeling ◽

Mtor Signaling Pathway ◽

Functional Roles ◽

Life Threatening ◽

Endothelial Growth Factor

Abstract Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening, iatrogenic complication of ovarian stimulation in assisted reproduction technology. This complex syndrome is characterised by enlarged ovaries with multiple corpora luteum, elevated sex steroid hormones in serum and increased capillary permeability. Until now, the pathogenesis of OHSS remains obscure, and no absolute strategy can fully prevent OHSS without any side effect on ovulation and clinical pregnancy. Using cultured human or mouse granulosa cells, our study revealed the time-dependent activation of the mTOR signaling pathway after human chorionic gonadotropin (hCG) treatment. The involvement of the mTOR signaling pathway was also observed in the development of OHSS in a mouse model. Selectively inhibiting mTOR signals by only two injections of rapamycin (2 mg/kg body weight), before or just after hCG treatment, significantly reduced vascular leakage and the severity of OHSS symptoms. Although ovarian angiogenesis was significantly inhibited, rapamycin could not decrease the elevated levels of vascular endothelial growth factor, IL-6 and IL-11 in OHSS ovaries. Further study showed the functional roles of the mTOR signaling pathway in the hyperstimulation-induced ovarian extracellular matrix remodeling as the expression of α2M, a broad proteolytic inhibitor in both ovary and serum, was dramatically decreased after rapamycin treatment. Since a single injection of rapamycin during superovulation had no side effects on ovulation and early embryonic development, we propose rapamycin may be a good candidate to lower and prevent the risk of OHSS in the future.

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mTORC1 Signaling Pathway Mediated SIRT6 Overexpression in TGF-β1-Induced Pulmonary Fibrosis

10.21203/rs.3.rs-1149371/v1 ◽

2021 ◽

Author(s):

Ji Zhang ◽

Yi Hu ◽

Huiping Huang ◽

Qun Liu ◽

Yang Du ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Signaling Pathway ◽

Critical Role ◽

Mtor Signaling ◽

Lung Fibroblasts ◽

Dependent Manner ◽

Mtor Signaling Pathway ◽

Mtorc1 Signaling ◽

Mtorc1 Pathway ◽

Tgf Β1

Abstract Fibroblast-to-myofibroblast transdifferentiation and myofibroblast hyperproliferation play a major role in Idiopathic pulmonary fibrosis (IPF). It was also reported that mTOR signaling pathway and SIRT6 have a critical role in pulmonary fibrosis. However, the mechanisms whether mTOR signaling pathway and SIRT6 affect the myofibroblasts differentiation in IPF remain unclear. The results show that SIRT6 is significantly upregulated by TGF-β1 with a time and concentration-dependent manner in MRC5 line and primary lung fibroblasts isolated from IPF patients. SIRT6 protein is also increased in IPF fibrotic lung tissues and bleomycin-challenged mice lung tissues. Also, the activity of mTOR signaling is activated in MRC5 and primary lung fibroblasts. Furthermore, the inhibitor of mTOR, rapamycin treatment significantly suppress mTORC1 pathway activity and SIRT6 protein expression. SIRT6 siRNA failed to mediate the activity of mTORC1 pathway and autophagy induction. Finally, deficiency of SIRT6 could promote TGF-β1 induced pro-fibrotic cytokines. In summary, the study have suggested that SIRT6 is a downstream of mTORC1 signaling pathway in the pulmonary fibrosis caused by TGF-β1-induced. Deficiency of SIRT6 mediated myofibroblasts differentiation through induced pro-fibrotic cytokines production but not induced-autophagy. It was indicated that manipulations of SIRT6 expression may provide a new therapeutic strategy to reverse the progression of pulmonary fibrosis.

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