Signaling Axis
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2022 ◽  
Kaifei Chu ◽  
Niannian Zhao ◽  
Rong Feng ◽  
Li Zhang ◽  
Xudong Hu ◽  

Abstract Background: Various metabolism diseases are closely related to lipid metabolism disorder, but long noncoding-RNAs (lncRNA) involve in regulating function of lipid was limited elucidated. Previous our work have found that lnc027912 involve in cholesterol metabolism. Here, we further explore the role of lipid metabolism-associated lncRNA-lnc027912 in oleic acid- (OA) and palmitic acid (PA)-induced hepatic cells. Methods: The overexpression of lnc027912 cell model was constructed by using virus particles transfection, and the level of lnc027912 in AML12 cells were detected by RT-qPCR. High fat cell model was established by treating AML12 cells with OA and PA, and the level of lipid drops was detected by Oil red O staining and triglyceride analyze Kit. The lipid metabolism related-genes, such as SREBP1C, FAS, PPARγ, MTTP, ApoE and ApoC3 level, was detected using RT-qPCR and Western blot. The role of SREBP1C in lipid metabolism was further analyzed using double luciferase reporter gene assay and Immunofluorescence. The Akt/mTOR signal pathway related genes was detected by Western blot. Results: We found that TG level was inhibited in overexpression of lnc027912 cell. Upregulated lnc027912 of AML12 cells treated with OA and PA showed a significant decrease in lipid accumulation and TG levels. Furthermore, overexpression of lnc027912, the lipid biosynthesis genes of SREBP1C, FAS and PPARγ was significantly decreased and a significant increase in expression of MTTP and ApoE. Interestingly, lnc027912 inhibited Akt/mTOR signaling axis and decreased SREBP1C transit into nucleus and the promoter activity of SREBP1C and regulated expression of its targets. Conclusions: Our study revealed a new insights into the molecular function of lnc027912 in lipid metabolism by Akt/mTOR/SREBP1C signaling axis and highlights the potential of lnc027912 as a new therapeutic target for lipid disorder diseases (such as, NAFLD).

2021 ◽  
Shanyi Lin ◽  
Yu Miao ◽  
Xu Zheng ◽  
Yang Dong ◽  
Qingcheng Yang ◽  

Abstract BackgroundAngiopoietin-like-4 (ANGPTL4), a secreted glycoprotein that is mainly recognized as a regulator in lipid metabolism, now, is implied in the regulation of the growth and metastasis of various carcinomas. However, less is known about its functions in the progression of sarcomas, let alone osteosarcoma (OS), which is the most common malignant diagnosed in musculoskeletal system.MethodsThe expression of ANGPTL4 in clinical OS samples and cell lines paired with their controls were analyzed in both mRNA and protein levels. Cell functional analysis including proliferation and colony formation were carried out to detect the roles ANGPTL4 takes in the progress of OS using stable ANGPTL4 overexpression and knockdown HOS/MNNG cell lines. The RNA-Seq and bioinformatics analysis were then employed to discover the BCAA metabolism related signaling which is involved in ANGPTL4 functioning on HOS/MNNG cell growth. Furthermore, BCAAs content measurement, and BCATs rescue experiments were performed to confirm the BCAA/mTOR signaling axis that ANGPTL4 triggered in HOS/MNNG cells. Finally, a xenograft mouse model was carried out to further verify the ANGPTL4 /BCAA/mTOR signaling axis discovered. ResultsWe found that the expression of ANGPTL4 is reduced in clinical OS tissues and cell lines compared to cancellous bone tissues and BMSCs, respectively. The knockdown of ANGPTL4 in HOS/MNNG cells results in enhanced cell growth and clone formation. Moreover, BCAA/mTOR signaling axis were discovered to be triggered by ANGPTL4 down regulation in HOS/MNNG cell using RNA-seq. It was also verified that the accumulation of BCAAs activates the mTOR signaling pathway, and in turn promotes HOS/MNNG cell growth using BCAAs content measurement, and BCAT inhibition. Finally, the IHC results of xenograft mouse model also confirmed this ANGPTL4/BCAA/mTOR signaling axis in vivo.ConclusionsTaken together, our results demonstrate that the expression of ANGPTL4 were negatively related to OS progress. Moreover, it was found the down-regulation of ANGPTL4 promoted OS cell growth via BCAAs/mTOR axis.

2021 ◽  
Vol 13 (1) ◽  
Shuo Zhang ◽  
Wei-Wei Ji ◽  
Wei Wei ◽  
Li-Xing Zhan ◽  
Xuan Huang

Abstract Background Colorectal cancer (CRC) remains the most common gastrointestinal cancer and a leading cause of cancer deaths worldwide, with most showing pathologies indicating the malignant transformation of early stage intestinal stem cells. The long non-coding RNA Meg3, which functions as a tumor suppressor, has been reported to be abnormal in multiple tumorigenesis events; however, the underlying mechanism by which Meg3 contributes to the malignant proliferation of colonic stem cells remains unclear. Methods We analyzed the expression levels of Meg3, miR-708, and SOCS3 in samples from Apc loss-of-function (Apcmin) mice and patients with CRC, particularly in colonic crypt cells. Apcmin mice and AMO/DSS-induced mice model (in vivo) and organoid culture system (in vitro) were used to explore the effect of the Meg3/miR-708/SOCS3 axis on tumorigenesis in the colon. In vitro, we performed RNApull-down, RNA immunoprecipitation, and luciferase reporter assays using DLD1 and RKO cell lines. Findings The Meg3/miR-708/SOCS3 signaling axis plays a critical role in the early stage of CRC development. Our data showed Meg3 levels negatively correlate with miR-708 levels both in clinical samples and in the Apcmin mouse model, which indicated that Meg3 acts as a competitive endogenous RNA (ceRNA) of miR-708. Then, miR-708 served as an oncogene, inducing neoplasia in both Apcmin mice and cultured colonic organoids. Put together, miR-708 appears to promote malignant proliferation of colonic stem cells by targeting SOCS3/STAT3 signaling. Interpretation These data revealed that Meg3 sponges miR-708 to inhibit CRC development via SOCS3-mediated repression of the malignant proliferation of colonic stem cells. The Meg3/miR-708/SOCS3 signaling axis provides potential targets for the diagnosis and treatment of CRC, particularly early stage CRC.

PLoS Genetics ◽  
2021 ◽  
Vol 17 (12) ◽  
pp. e1009982
Deepika Sharma ◽  
Anthony J. Mirando ◽  
Abigail Leinroth ◽  
Jason T. Long ◽  
Courtney M. Karner ◽  

Sonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in polydactyly and Shh-deficiency leads to digit number reductions. SHH/GLI3 signaling regulates cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating Grem1 to coordinate BMP-induced chondrogenesis. SHH/GLI3 signaling also coordinates the expression of additional genes, however their importance in digit formation remain unknown. Utilizing genetic and molecular approaches, we identified HES1 as a downstream modifier of the SHH/GLI signaling axis capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. Our data indicate that HES1, a direct SHH/GLI signaling target, induces mesenchymal cell proliferation via suppression of Cdkn1b, while inhibiting chondrogenic genes and the anterior autopod boundary regulator, Pax9. These findings establish HES1 as a critical downstream effector of SHH/GLI3 signaling in the development of PPD.

Plants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 2795
Yun Jung Lee ◽  
Yong Pyo Lee ◽  
Chang Seob Seo ◽  
Eun Sik Choi ◽  
Byung Hyuk Han ◽  

Carthamus tinctorius L., known as safflower, has been used in traditional treatment for cardiovascular, cerebrovascular, and diabetic vascular complications. We proposed to investigate how the ethanol extract of Carthamus tinctorius L. (ECT) can be used ethnopharmacologically and alleviate vascular inflammatory processes under cytokine stimulation in human vascular endothelial cells. Using the optimized HPLC method, six markers were simultaneously analyzed for quality control of ECT. Pretreatment with ECT (10–100 μg/mL) significantly reduced the increase of leukocyte adhesion to HUVEC by TNF-α in a dose-dependent manner. Cell adhesion molecules (CAMs) such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial cell selectin (E-selectin) are decreased by ECT. In addition, ECT significantly suppressed TNF-α-induced oxidative stress referring to reactive oxygen species (ROS) production. p65 NF-κB nuclear translocation and its activation were inhibited by ECT. Furthermore, pretreatment of ECT increased the HO-1 expression, and nuclear translocation of Nrf-2. These data suggest the potential role of ECT as a beneficial therapeutic herb in vascular inflammation via ROS/NF-kB pathway and the regulation of Nrf-2/HO-1 signaling axis is involved in its vascular protection. Thus, further study will be needed to clarify which compound is dominant for protection of vascular diseases.

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