scholarly journals Mechanisms by Which Membrane and Nuclear ER Alpha Inhibit Adipogenesis in Cells Isolated From Female Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (11) ◽  
Author(s):  
Amrita Ahluwalia ◽  
Neil Hoa ◽  
Lisheng Ge ◽  
Bruce Blumberg ◽  
Ellis R Levin
Keyword(s):  
Stem Cells ◽  
Gene Promoter ◽  
Peroxisome Proliferator ◽  
Repressor Complex ◽  
Inhibit Gene Expression ◽  
Endogenous Estrogen ◽  
Er Alpha ◽  
Nuclear Estrogen Receptors ◽  
Pparγ Gene

Abstract Mesenchymal stem cells can differentiate into mature chondrocytes, osteoblasts, and adipocytes. Excessive and dysfunctional visceral adipocytes increase upon menopause and importantly contribute to altered metabolism in postmenopausal women. We previously showed both plasma membrane and nuclear estrogen receptors alpha (ERα) with endogenous estrogen are required to suppress adipogenesis in vivo. Here we determined mechanisms by which these liganded ER pools collaborate to inhibit the peroxisome proliferator-activated gamma (PPARγ) gene and subsequent progenitor differentiation. In 3T3-L1 pre-adipocytes and adipose-derived stem cells (ADSC), membrane ERα signaled through phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) to enhance ERα nuclear localization, importantly at the PPARγ gene promoter. AKT also increased overall abundance and recruitment of co-repressors GATA3, β-catenin, and TCF4 to the PPARγ promoter. Membrane ERα signaling additionally enhanced wingless-integrated (Wnt)1 and 10b expression. The components of the repressor complex were required for estrogen to inhibit rosiglitazone-induced differentiation of ADSC and 3T3-L1 cells to mature adipocytes. These mechanisms whereby ER cellular pools collaborate to inhibit gene expression limit progenitor differentiation to mature adipocytes.

scholarly journals Enhanced Therapeutic Potential of the Secretome Released from Adipose-Derived Stem Cells by PGC-1α-Driven Upregulation of Mitochondrial Proliferation

2019 ◽  
Vol 20 (22) ◽  
pp. 5589
Author(s):  
Jaeim Lee ◽  
Ok-Hee Kim ◽  
Sang Chul Lee ◽  
Kee-Hwan Kim ◽  
Jin Sun Shin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Liver Injury ◽  
Therapeutic Potential ◽  
Tissue Expression ◽  
In Vitro Models ◽  
Peroxisome Proliferator ◽  
Adipose Derived Stem Cells ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator activated receptor λ coactivator 1α (PGC-1α) is a potent regulator of mitochondrial biogenesis and energy metabolism. In this study, we investigated the therapeutic potential of the secretome released from the adipose-derived stem cells (ASCs) transfected with PGC-1α (PGC-secretome). We first generated PGC-1α-overexpressing ASCs by transfecting ASCs with the plasmids harboring the gene encoding PGC-1α. Secretory materials released from PGC-1α-overexpressing ASCs were collected and their therapeutic potential was determined using in vitro (thioacetamide (TAA)-treated AML12 cells) and in vivo (70% partial hepatectomized mice) models of liver injury. In the TAA-treated AML12 cells, the PGC-secretome significantly increased cell viability, promoted expression of proliferation-related markers, such as PCNA and p-STAT, and significantly reduced the levels of reactive oxygen species (ROS). In the mice, PGC-secretome injections significantly increased liver tissue expression of proliferation-related markers more than normal secretome injections did (p < 0.05). We demonstrated that the PGC-secretome does not only have higher antioxidant and anti-inflammatory properties, but also has the potential of significantly enhancing liver regeneration in both in vivo and in vitro models of liver injury. Thus, reinforcing the mitochondrial antioxidant potential by transfecting ASCs with PGC-1α could be one of the effective strategies to enhance the therapeutic potential of ASCs.

RNA interference by small hairpin RNAs synthesised under control of the human 7S K RNA promoter

2004 ◽  
Vol 385 (9) ◽  
pp. 791-794 ◽  
Author(s):  
Dorota Koper-Emde ◽  
Lutz Herrmann ◽  
Björn Sandrock ◽  
Bernd-Joachim Benecke
Keyword(s):  
Rna Interference ◽  
Gene Promoter ◽  
Target Sequence ◽  
Small Nuclear Rna ◽  
Small Interfering Rnas ◽  
Rna Duplexes ◽  
Inhibit Gene Expression ◽  
Short Hairpin Rnas ◽  
Rna Promoter

AbstractSmall interfering RNAs (siRNAs) represent RNA duplexes of 21 nucleotides in length that inhibit gene expression. We have used the human gene-external 7S K RNA promoter for synthesis of short hairpin RNAs (shRNAs) which efficiently target human lamin mRNA via RNA interference (RNAi). Here we demonstrate that orientation of the target sequence within the shRNA construct is important for interference. Furthermore, effective interference also depends on the length and/or structure of the shRNA. Evidence is presented that the human 7S K promoter is more activein vivothan other gene-external promoters, such as the human U6 small nuclear RNA (snRNA) gene promoter.

scholarly journals VDR–SOX2 signaling promotes colorectal cancer stemness and malignancy in an acidic microenvironment

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Pei-Shan Hu ◽  
Ting Li ◽  
Jin-Fei Lin ◽  
Miao-Zhen Qiu ◽  
De-Shen Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Vitamin D ◽  
Nuclear Export ◽  
High Throughput Sequencing ◽  
Nuclear Export Signal ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Acidic Microenvironment ◽  
Vitamin D Signaling

Abstract The acidic tumor microenvironment provides an energy source driving malignant tumor progression. Adaptation of cells to an acidic environment leads to the emergence of cancer stem cells. The expression of the vitamin D receptor (VDR) is closely related to the initiation and development of colorectal carcinoma (CRC), but its regulatory mechanism in CRC stem cells is still unclear. Our study revealed that acidosis reduced VDR expression by downregulating peroxisome proliferator-activated receptor delta (PPARD) expression. Overexpression of VDR effectively suppressed the stemness and oxaliplatin resistance of cells in acidosis. The nuclear export signal in VDR was sensitive to acidosis, and VDR was exported from the nucleus. Chromatin immunoprecipitation (ChIP) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses showed that VDR transcriptionally repressed SRY-box 2 (SOX2) by binding to the vitamin D response elements in the promoter of SOX2, impairing tumor growth and drug resistance. We demonstrated that a change in the acidic microenvironment combined with overexpression of VDR substantially restricted the occurrence and development of CRC in vivo. These findings reveal a new mechanism by which acidosis could affect the stemness of CRC cells by regulating the expression of SOX2 and show that abnormal VDR expression leads to ineffective activation of vitamin D signaling, resulting in a lack of efficacy of vitamin D in antineoplastic process.

scholarly journals Upregulated PPARG2 facilitates interaction with demethylated AKAP12 gene promoter and suppresses proliferation in prostate cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Feng Li ◽  
Tingting Lu ◽  
Dongmei Liu ◽  
Chong Zhang ◽  
Yonghui Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanism ◽  
Molecular Mechanisms ◽  
Epigenetic Modification ◽  
Gene Promoter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cycle Arrest

AbstractProstate cancer (PCA) is one of the most common male genitourinary tumors. However, the molecular mechanisms involved in the occurrence and progression of PCA have not been fully clarified. The present study aimed to investigate the biological function and molecular mechanism of the nuclear receptor peroxisome proliferator-activated receptor gamma 2 (PPARG2) in PCA. Our results revealed that PPARG2 was downregulated in PCA, and overexpression of PPARG2 inhibited cell migration, colony formation, invasion and induced cell cycle arrest of PCA cells in vitro. In addition, PPARG2 overexpression modulated the activation of the Akt signaling pathway, as well as inhibited tumor growth in vivo. Moreover, mechanistic analysis revealed that PPARG2 overexpression induced increased expression level of miR-200b-3p, which targeted 3′ UTR of the downstream targets DNMT3A/3B, and facilitated interaction with demethylated AKAP12 gene promoter and suppressed cell proliferation in PCA. Our findings provided the first evidence for a novel PPARG2-AKAP12 axis mediated epigenetic regulatory network. The study identified a molecular mechanism involving an epigenetic modification that could be possibly targeted as an antitumoral strategy against prostate cancer.

scholarly journals Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells

2020 ◽  
Vol 13 (633) ◽  
pp. eaay8203 ◽  
Author(s):  
Zhiqiang Liu ◽  
Huan Liu ◽  
Jin He ◽  
Pei Lin ◽  
Qiang Tong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Formation ◽  
Direct Consequence ◽  
Peroxisome Proliferator ◽  
Integrin Subunit ◽  
Peroxisome Proliferator Activated Receptor ◽  
Myeloma Cells

The suppression of bone formation is a hallmark of multiple myeloma. Myeloma cells inhibit osteoblastogenesis from mesenchymal stem cells (MSCs), which can also differentiate into adipocytes. We investigated myeloma-MSC interactions and the effects of such interactions on the differentiation of MSCs into adipocytes or osteoblasts using single-cell RNA sequencing, in vitro coculture, and subcutaneous injection of MSCs and myeloma cells into mice. Our results revealed that the α4 integrin subunit on myeloma cells stimulated vascular cell adhesion molecule–1 (VCAM1) on MSCs, leading to the activation of protein kinase C β1 (PKCβ1) signaling and repression of the muscle ring-finger protein-1 (MURF1)–mediated ubiquitylation of peroxisome proliferator–activated receptor γ2 (PPARγ2). Stabilized PPARγ2 proteins enhanced adipogenesis and consequently reduced osteoblastogenesis from MSCs, thus suppressing bone formation in vitro and in vivo. These findings reveal that suppressed bone formation is a direct consequence of myeloma-MSC contact that promotes the differentiation of MSCs into adipocytes at the expense of osteoblasts. Thus, this study provides a potential strategy for treating bone resorption in patients with myeloma by counteracting tumor-MSC interactions.

scholarly journals Upregulation of IL-1 Receptor Antagonist by Aspirin in Glial Cells via Peroxisome Proliferator-Activated Receptor-Alpha

2021 ◽  
pp. 1-15
Author(s):  
Sudipta Chakrabarti ◽  
Tim Prorok ◽  
Avik Roy ◽  
Dhruv Patel ◽  
Sridevi Dasarathi ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Glial Cells ◽  
Interleukin 1 ◽  
Gene Promoter ◽  
Brain Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Primary Mouse ◽  
The Brain

Background: Neuroinflammation is a recognized aspect of Alzheimer’s disease (AD) and other neurological illnesses. Interleukin 1 receptor antagonist (IL-1Ra) is an anti-inflammatory molecule, which inhibits inflammatory molecules in different cells including brain cells. However, mechanisms for upregulating IL-1Ra in brain cells are poorly understood. Objective: Since aspirin is a widely available pain reliever that shows promise beyond its known pain-relieving capacity, we examined whether aspirin could upregulate the IL-1Ra in the brain. Methods: We employed PCR, real-time PCR, western blot, immunostaining, chromatin immunoprecipitation (ChIP), and lentiviral transduction in glial cells. 5xFAD mice, an animal model of AD, were treated with aspirin orally via gavage. Results: Aspirin increased the expression of IL-1Ra mRNA and protein in primary mouse astrocytes and mouse BV-2 microglial cells. While investigating the mechanism, we found that the IL-1Ra gene promoter harbors peroxisome proliferator response element (PPRE) and that aspirin upregulated IL-1Ra in astrocytes isolated from peroxisome proliferator-activated receptor-beta knockout (PPARβ –/–), but not PPARα –/–, mice. Moreover, we observed that aspirin bound to tyrosine 314 residue of PPARα to stimulate IL-1Ra and that aspirin treatment also increased the recruitment of PPARα to the IL-1Ra promoter. Accordingly, aspirin increased IL-1Ra in vivo in the brain of wild type and PPARβ –/–, but not in PPARα –/– mice. Similarly, aspirin treatment also increased astroglial and microglial IL-1Ra in the cortex of 5xFAD, but not 5xFAD/PPARα –/– mice. Conclusion: Aspirin may reduce the severity of different neurological conditions by upregulating IL-1Ra and reducing the inflammation.

Peroxisome proliferator-activated receptor (PPAR)-γ ligand inhibits the progression of pancreatic fibrosis in vivo and profibrogenic action in pancreatic myofibroblast

2001 ◽  
Vol 120 (5) ◽  
pp. A111-A111
Author(s):  
K SHIMIZU ◽  
S HISADA ◽  
K SHIRATORI ◽  
M KOBAYASHI ◽  
N HAYASHI
Keyword(s):  
Pancreatic Fibrosis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Autologous transplantation of mesenchymal stem cells into the portal vein of the miniature pig; a preliminary experiment for NOTES approach

2019 ◽  
Vol 98 (9) ◽  
pp. 350-355
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Therapy ◽  
Portal Vein ◽  
Liver Parenchyma ◽  
Miniature Pig ◽  
Hepatic Diseases ◽  
Study Results

Introduction: There is evidence that mesenchymal stem cells (MSCs) could trans-differentiate into the liver cells in vitro and in vivo and thus may be used as an unfailing source for stem cell therapy of liver disease. Combination of MSCs (with or without their differentiation in vitro) and minimally invasive procedures as laparoscopy or Natural Orifice Transluminal Endoscopic Surgery (NOTES) represents a chance for many patients waiting for liver transplantation in vain. Methods: Over 30 millions of autologous MSCs at passage 3 were transplanted via the portal vein in an eight months old miniature pig. The deposition of transplanted cells in liver parenchyma was evaluated histologically and the trans-differential potential of CM-DiI labeled cells was assessed by expression of pig albumin using immunofluorescence. Results: Three weeks after transplantation we detected the labeled cells (solitary, small clusters) in all 10 samples (2 samples from each lobe) but no diffuse distribution in the samples. The localization of CM-DiI+ cells was predominantly observed around the portal triads. We also detected the localization of albumin signal in CM-DiI labeled cells. Conclusion: The study results showed that the autologous MSCs (without additional hepatic differentiation in vitro) transplantation through the portal vein led to successful infiltration of intact miniature pig liver parenchyma with detectable in vivo trans-differentiation. NOTES as well as other newly developed surgical approaches in combination with cell therapy seem to be very promising for the treatment of hepatic diseases in near future.

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