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1. Ribosome rescue factor PELOTA modulates translation start site choice for C/EBPα protein isoforms.

Author

Fernandez, Samantha, Ferguson, Lucas, and Ingolia, Nicholas

Subjects
Protein Isoforms, Humans, Ribosomes, CCAAT-Enhancer-Binding Protein-alpha, Protein Biosynthesis, RNA, Messenger, Animals, Peptide Chain Initiation, Translational, Mice, TOR Serine-Threonine Kinases, HEK293 Cells
Abstract

Translation initiation at alternative start sites can dynamically control the synthesis of two or more functionally distinct protein isoforms from a single mRNA. Alternate isoforms of the developmental transcription factor CCAAT/enhancer-binding protein α (C/EBPα) produced from different start sites exert opposing effects during myeloid cell development. This choice between alternative start sites depends on sequence features of the CEBPA transcript, including a regulatory uORF, but the molecular basis is not fully understood. Here, we identify the factors that affect C/EBPα isoform choice using a sensitive and quantitative two-color fluorescent reporter coupled with CRISPRi screening. Our screen uncovered a role of the ribosome rescue factor PELOTA (PELO) in promoting the expression of the longer C/EBPα isoform by directly removing inhibitory unrecycled ribosomes and through indirect effects mediated by the mechanistic target of rapamycin kinase. Our work uncovers further links between ribosome recycling and translation reinitiation that regulate a key transcription factor, with implications for normal hematopoiesis and leukemogenesis.

Published
2024

2. Inhaled Vitamin D: A Novel Strategy to Enhance Neonatal Lung Maturation

Author

Taylor, Sneha K, Sakurai, Reiko, Sakurai, Tokusho, and Rehan, Virender K

Subjects
Paediatrics, Biomedical and Clinical Sciences, Nutrition, Preterm, Low Birth Weight and Health of the Newborn, Pediatric, Lung, Perinatal Period - Conditions Originating in Perinatal Period, Neonatal Respiratory Distress, 5.1 Pharmaceuticals, Respiratory, Administration, Inhalation, Alveolar Epithelial Cells, Animals, CCAAT-Enhancer-Binding Protein-alpha, Calcitriol, Calcium, Cell Differentiation, Choline, Endothelium, Mesoderm, PPAR gamma, Pulmonary Surfactant-Associated Protein B, Rats, Rats, Sprague-Dawley, Receptors, Calcitriol, Receptors, Leptin, Triolein, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Vitamin D, Vitamins, Prematurity, Childhood asthma, Lung development, Bronchopulmonary dysplasia, Active vitamin D, Cardiorespiratory Medicine and Haematology, Respiratory System, Cardiovascular medicine and haematology
Abstract

IntroductionThe physiologic vitamin D (VD), 1α,25(OH)2D3 (1,25D) is a local paracrine/autocrine effecter of fetal lung maturation. By stimulating alveolar type II cell and lipofibroblast proliferation and differentiation, parenterally administered 1,25D has been shown to enhance neonatal lung maturation; but due to the potential systemic side effects of the parenteral route, the translational value of these findings might be limited. To minimize the possibility of systemic toxicity, we examined the effects of VD on neonatal lung maturation, when delivered directly to lungs via nebulization.MethodsOne-day-old rat pups were administered three different doses of 1,25D and its physiologic precursor 25(OH)D (25D), or the diluent, via nebulization daily for 14 days. Pups were sacrificed for lung, kidneys, and blood collection to determine markers of lung maturation, and serum 25D and calcium levels.ResultsCompared to controls, nebulized 25D and 1,25D enhanced lung maturation as evidenced by the increased expression of markers of alveolar epithelial (SP-B, leptin receptor), mesenchymal (PPARγ, C/EBPα), and endothelial (VEGF, FLK-1) differentiation, surfactant phospholipid synthesis, and lung morphology without any significant increases in serum 25D and calcium levels.ConclusionsInhaled VD is a potentially safe and effective novel strategy to enhance neonatal lung maturation.

Published
2016

3. Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family

Author

Pathak, Anand, Seipel, Katja, Pemov, Alexander, Dewan, Ramita, Brown, Christina, Ravichandran, Sarangan, Luke, Brian T, Malasky, Michael, Suman, Shalabh, Yeager, Meredith, Laboratory, NCI DCEG Cancer Genomics Research, Group, NCI DCEG Cancer Sequencing Working, Gatti, Richard A, Caporaso, Neil E, Mulvihill, John J, Goldin, Lynn R, Pabst, Thomas, McMaster, Mary L, and Stewart, Douglas R

Subjects
Pediatric, Rare Diseases, Clinical Research, Human Genome, Hematology, Genetics, Cancer, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Alleles, CCAAT-Enhancer-Binding Protein-alpha, Child, Child, Preschool, Exome, Family, Female, Follow-Up Studies, Gene Expression Regulation, Leukemic, Genotype, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute, Male, Middle Aged, Models, Molecular, Pedigree, Protein Conformation, Protein Interaction Domains and Motifs, Protein Multimerization, Young Adult, NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Immunology
Abstract

Familial acute myeloid leukemia is rare and linked to germline mutations in RUNX1, GATA2 or CCAAT/enhancer binding protein-α (CEBPA). We re-evaluated a large family with acute myeloid leukemia originally seen at NIH in 1969. We used whole exome sequencing to study this family, and conducted in silico bioinformatics analysis, protein structural modeling and laboratory experiments to assess the impact of the identified CEBPA Q311P mutation. Unlike most previously identified germline mutations in CEBPA, which were N-terminal frameshift mutations, we identified a novel Q311P variant that was located in the C-terminal bZip domain of C/EBPα. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mu-tant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation, consistent with a loss-of-function mutation. From 45 years of follow up, we observed incomplete penetrance (46%) of CEBPA Q311P. This study of a large multi-generational pedigree reveals that a germline mutation in the C-terminal bZip domain can alter the ability of C/EBP-α to bind DNA and reduces transactivation, leading to acute myeloid leukemia.

Published
2016

4. Maternal High-Fat Feeding Increases Placental Lipoprotein Lipase Activity by Reducing SIRT1 Expression in Mice.

Author

Qiao, Liping, Guo, Zhuyu, Bosco, Chris, Guidotti, Stefano, Wang, Yunfeng, Wang, Mingyong, Parast, Mana, Schaack, Jerome, Hay, William W, Moore, Thomas R, and Shao, Jianhua

Subjects
Cell Line, Trophoblasts, Placenta, Animals, Mice, Inbred C57BL, Humans, Mice, Pregnancy Complications, Overnutrition, Obesity, Disease Models, Animal, Lipoprotein Lipase, Glycerol-3-Phosphate O-Acyltransferase, Fatty Acids, Nonesterified, Triglycerides, CCAAT-Enhancer-Binding Protein-alpha, Receptors, LDL, PPAR gamma, RNA, Messenger, Maternal Exposure, Pregnancy, Female, Fatty Acid-Binding Proteins, 1-Acylglycerol-3-Phosphate O-Acyltransferase, Sirtuin 1, Diet, High-Fat, Fatty Acid Binding Protein 3, CD36 Antigens, Nutrition, 5.1 Pharmaceuticals, Cardiovascular, Medical and Health Sciences, Endocrinology & Metabolism
Abstract

This study investigated how maternal overnutrition and obesity regulate expression and activation of proteins that facilitate lipid transport in the placenta. To create a maternal overnutrition and obesity model, primiparous C57BL/6 mice were fed a high-fat (HF) diet throughout gestation. Fetuses from HF-fed dams had significantly increased serum levels of free fatty acid and body fat. Despite no significant difference in placental weight, lipoprotein lipase (LPL) protein levels and activity were remarkably elevated in placentas from HF-fed dams. Increased triglyceride content and mRNA levels of CD36, VLDLr, FABP3, FABPpm, and GPAT2 and -3 were also found in placentas from HF-fed dams. Although both peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer binding protein-α protein levels were significantly increased in placentas of the HF group, only PPARγ exhibited a stimulative effect on LPL expression in cultured JEG-3 human trophoblasts. Maternal HF feeding remarkably decreased SIRT1 expression in placentas. Through use of an SIRT1 activator and inhibitor and cultured trophoblasts, an inhibitory effect of SIRT1 on LPL expression was demonstrated. We also found that SIRT1 suppresses PPARγ expression in trophoblasts. Most importantly, inhibition of PPARγ abolished the SIRT1-mediated regulatory effect on LPL expression. Together, these results indicate that maternal overnutrition induces LPL expression in trophoblasts by reducing the inhibitory effect of SIRT1 on PPARγ.

Published
2015

5. The dietary ingredient, genistein, stimulates cathelicidin antimicrobial peptide expression through a novel S1P-dependent mechanism.

Author

Park, Kyungho, Kim, Young-Il, Shin, Kyong-Oh, Seo, Ho, Kim, Jong, Mann, Taj, Oda, Yuko, Lee, Yong-Moon, Holleran, Walter, Uchida, Yoshikazu, and Elias, Peter

Subjects
Cathelicidin antimicrobial peptide, Estrogen receptor β, Genistein, Innate immunity, Keratinocytes, Antimicrobial Cationic Peptides, CCAAT-Enhancer-Binding Protein-alpha, Cathelicidins, Cells, Cultured, Ceramidases, Estradiol, Estrogen Receptor beta, Fulvestrant, Genistein, Humans, Keratinocytes, Lysophospholipids, Oxazoles, Phenols, Receptors, Calcitriol, Sphingosine
Abstract

We recently discovered that a signaling lipid, sphingosine-1-phosphate (S1P), generated by sphingosine kinase 1, regulates a major epidermal antimicrobial peptides [cathelicidin antimicrobial peptide (CAMP)] expression via an NF-κB→C/EBPα-dependent pathway, independent of vitamin D receptor (VDR) in epithelial cells. Activation of estrogen receptors (ERs) by either estrogens or phytoestrogens also is known to stimulate S1P production, but it is unknown whether ER activation increases CAMP production. We investigated whether a phytoestrogen, genistein, simulates CAMP expression in keratinocytes, a model of epithelial cells, by either a S1P-dependent mechanism(s) or the alternate VDR-regulated pathway. Exogenous genistein, as well as an ER-β ligand, WAY-200070, increased CAMP mRNA and protein expression in cultured human keratinocytes, while ER-β antagonist, ICI182780, attenuated the expected genistein- and WAY-200070-induced increase in CAMP mRNA/protein expression. Genistein treatment increased acidic and alkaline ceramidase expression and cellular S1P levels in parallel with increased S1P lyase inhibition, accounting for increased CAMP production. In contrast, siRNA against VDR did not alter genistein-mediated up-regulation of CAMP. Taken together, genistein induces CAMP production via an ER-β→S1P→NF-κB→C/EBPα- rather than a VDR-dependent mechanism, illuminating a new role for estrogens in the regulation of epithelial innate immunity and pointing to potential additional benefits of dietary genistein in enhancing cutaneous antimicrobial defense.

Published
2014

6. Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo

Author

Reebye, Vikash, Sætrom, Pål, Mintz, Paul J, Huang, Kai‐Wen, Swiderski, Piotr, Peng, Ling, Liu, Cheng, Liu, Xiaoxuan, Lindkær‐Jensen, Steen, Zacharoulis, Dimitris, Kostomitsopoulos, Nikolaos, Kasahara, Noriyuki, Nicholls, Joanna P, Jiao, Long R, Pai, Madhava, Spalding, Duncan R, Mizandari, Malkhaz, Chikovani, Tinatin, Emara, Mohamed M, Haoudi, Abdelali, Tomalia, Donald A, Rossi, John J, and Habib, Nagy A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Digestive Diseases, Rare Diseases, Biotechnology, Cancer, Liver Cancer, Liver Disease, Chronic Liver Disease and Cirrhosis, Albumins, Animals, CCAAT-Enhancer-Binding Protein-alpha, Carcinoma, Hepatocellular, Drug Evaluation, Preclinical, Gene Expression Regulation, Genetic Therapy, Hep G2 Cells, Humans, Injections, Intravenous, Liver, Liver Cirrhosis, Liver Function Tests, Liver Neoplasms, Experimental, Male, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins c-myc, RNA, Rats, Rats, Wistar, Receptors, Interleukin-6, STAT3 Transcription Factor, Medical Biochemistry and Metabolomics, Clinical Sciences, Immunology, Gastroenterology & Hepatology, Clinical sciences
Abstract

UnlabelledHepatocellular carcinoma (HCC) occurs predominantly in patients with liver cirrhosis. Here we show an innovative RNA-based targeted approach to enhance endogenous albumin production while reducing liver tumor burden. We designed short-activating RNAs (saRNA) to enhance expression of C/EBPα (CCAAT/enhancer-binding protein-α), a transcriptional regulator and activator of albumin gene expression. Increased levels of both C/EBPα and albumin mRNA in addition to a 3-fold increase in albumin secretion and 50% decrease in cell proliferation was observed in C/EBPα-saRNA transfected HepG2 cells. Intravenous injection of C/EBPα-saRNA in a cirrhotic rat model with multifocal liver tumors increased circulating serum albumin by over 30%, showing evidence of improved liver function. Tumor burden decreased by 80% (P = 0.003) with a 40% reduction in a marker of preneoplastic transformation. Since C/EBPα has known antiproliferative activities by way of retinoblastoma, p21, and cyclins, we used messenger RNA (mRNA) expression liver cancer-specific microarray in C/EBPα-saRNA-transfected HepG2 cells to confirm down-regulation of genes strongly enriched for negative regulation of apoptosis, angiogenesis, and metastasis. Up-regulated genes were enriched for tumor suppressors and positive regulators of cell differentiation. A quantitative polymerase chain reaction (PCR) and western blot analysis of C/EBPα-saRNA-transfected cells suggested that in addition to the known antiproliferative targets of C/EBPα, we also observed suppression of interleukin (IL)6R, c-Myc, and reduced STAT3 phosphorylation.ConclusionA novel injectable saRNA-oligonucleotide that enhances C/EBPα expression successfully reduces tumor burden and simultaneously improves liver function in a clinically relevant liver cirrhosis/HCC model.

Published
2014

7. Resveratrol stimulates sphingosine-1-phosphate signaling of cathelicidin production.

Author

Park, Kyungho, Shin, Kyong-Oh, Lee, Yong-Moon, Holleran, Walter, Uchida, Yoshikazu, Hupe, Melanie, Borkowski, Andrew, Elias, Peter, and Gallo, Richard

Subjects
Animals, Antimicrobial Cationic Peptides, Antioxidants, CCAAT-Enhancer-Binding Protein-alpha, Cathelicidins, Cell Line, Transformed, Cyclic AMP, Endoplasmic Reticulum Stress, Epidermal Cells, Epidermis, Female, Humans, Immunity, Innate, Keratinocytes, Lysophospholipids, Mice, Mice, Hairless, NF-kappa B, Resveratrol, Signal Transduction, Sphingosine, Staphylococcal Skin Infections, Stilbenes
Abstract

We recently discovered a regulatory mechanism that stimulates the production of the multifunctional antimicrobial peptide cathelicidin antimicrobial peptide (CAMP). In response to subtoxic levels of ER stress, increased sphingosine-1-phosphate (S1P) production activates an NFκBC/EBPα-dependent pathway that enhances CAMP production in cultured human keratinocytes. As the multifunctional stilbenoid compound resveratrol (RESV) increases ceramide (Cer) levels, a precursor of S1P, we hypothesized and assessed whether RESV could exploit the same pathway to regulate CAMP production. Accordingly, RESV significantly increased Cer and S1P levels in cultured keratinocytes, paralleled by increased CAMP mRNA/protein expression. Furthermore, topical RESV also increased murine CAMP mRNA/protein expression in mouse skin. Conversely, blockade of Cer-->sphingosine-->S1P metabolic conversion, with specific inhibitors of ceramidase or sphingosine kinase, attenuated the expected RESV-mediated increase in CAMP expression. The RESV-induced increase in CAMP expression required both NF-κB and C/EBPα transactivation. Moreover, conditioned media from keratinocytes treated with RESV significantly suppressed Staphylococcus aureus growth. Finally, topical RESV, if not coapplied with a specific inhibitor of sphingosine kinase, blocked S. aureus invasion into murine skin. These results demonstrate that the dietary stilbenoid RESV stimulates S1P signaling of CAMP production through an NF-κB-->C/EBPα-dependent mechanism, leading to enhanced antimicrobial defense against exogenous microbial pathogens.

Published
2013

8. Antagonistic Regulation by the Transcription Factors C/EBPα and MITF Specifies Basophil and Mast Cell Fates

Author

Qi, Xiaopeng, Hong, Jessie, Chaves, Lee, Zhuang, Yonghua, Chen, Yuhong, Wang, Demin, Chabon, Jacob, Graham, Brian, Ohmori, Keitaro, Li, Yapeng, and Huang, Hua

Subjects
Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Aetiology, 2.1 Biological and endogenous factors, Animals, Basophils, Blotting, Western, CCAAT-Enhancer-Binding Protein-alpha, Cell Differentiation, Cell Lineage, Cells, Cultured, Flow Cytometry, Gene Expression Profiling, Granulocyte-Macrophage Progenitor Cells, HEK293 Cells, Humans, Mast Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microphthalmia-Associated Transcription Factor, Myeloid Cells, Oligonucleotide Array Sequence Analysis, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, STAT5 Transcription Factor, Stem Cells, Immunology
Abstract

It remains unclear whether basophils and mast cells are derived from a common progenitor. Furthermore, how basophil versus mast cell fate is specified has not been investigated. Here, we have identified a population of granulocyte-macrophage progenitors (GMPs) that were highly enriched in the capacity to differentiate into basophils and mast cells while retaining a limited capacity to differentiate into myeloid cells. We have designated these progenitor cells "pre-basophil and mast cell progenitors" (pre-BMPs). STAT5 signaling was required for the differentiation of pre-BMPs into both basophils and mast cells and was critical for inducing two downstream molecules: C/EBPα and MITF. We have identified C/EBPα as the critical basophil transcription factor for specifying basophil cell fate and MITF as the crucial transcription factor for specifying mast cell fate. C/EBPα and MITF silenced each other's transcription in a directly antagonistic fashion. Our study reveals how basophil and mast cell fate is specified.

Published
2013

9. A novel role of a lipid species, sphingosine-1-phosphate, in epithelial innate immunity.

Author

Shin, Kyoung-Oh, Lee, Yong-Moon, Hupe, Melanie, Borkowski, Andrew, Park, Kyungho, Holleran, Walter, Uchida, Yoshikazu, Elias, Peter, Gallo, Richard, and Saba, Julie

Subjects
Animals, Antimicrobial Cationic Peptides, CCAAT-Enhancer-Binding Protein-alpha, Cathelicidins, Cells, Cultured, Ceramides, Endoplasmic Reticulum Stress, Gene Expression Regulation, Humans, Immunity, Innate, Keratinocytes, Lysophospholipids, Mice, Mice, Inbred C57BL, NF-kappa B, Skin, Sphingosine, Staphylococcal Infections, Staphylococcus aureus
Abstract

A variety of external perturbations can induce endoplasmic reticulum (ER) stress, followed by stimulation of epithelial cells to produce an innate immune element, the cathelicidin antimicrobial peptide (CAMP). ER stress also increases production of the proapoptotic lipid ceramide and its antiapoptotic metabolite, sphingosine-1-phosphate (S1P). We demonstrate here that S1P mediates ER stress-induced CAMP generation. Cellular ceramide and S1P levels rose in parallel with CAMP levels following addition of either exogenous cell-permeating ceramide (C2Cer), which increases S1P production, or thapsigargin (an ER stressor), applied to cultured human skin keratinocytes or topically to mouse skin. Knockdown of S1P lyase, which catabolizes S1P, enhanced ER stress-induced CAMP production in cultured cells and mouse skin. These and additional inhibitor studies show that S1P is responsible for ER stress-induced upregulation of CAMP expression. Increased CAMP expression is likely mediated via S1P-dependent NF-κB-C/EBPα activation. Finally, lysates of both ER-stressed and S1P-stimulated cells blocked growth of virulent Staphylococcus aureus in vitro, and topical C2Cer and LL-37 inhibited invasion of Staphylococcus aureus into murine skin. These studies suggest that S1P generation resulting in increased CAMP production comprises a novel regulatory mechanism of epithelial innate immune responses to external perturbations, pointing to a new therapeutic approach to enhance antimicrobial defense.

Published
2013

10. Hepatocyte-specific CCAAT/enhancer binding protein α restricts liver fibrosis progression.

Author

Yan T, Yan N, Xia Y, Sawaswong V, Zhu X, Dias HB, Aibara D, Takahashi S, Hamada K, Saito Y, Li G, Liu H, Yan H, Velenosi TJ, Krausz KW, Huang J, Kimura S, Rotman Y, Qu A, Hao H, and Gonzalez FJ

Subjects
Humans, Mice, Animals, Hepatocytes metabolism, Liver Cirrhosis genetics, Liver Cirrhosis metabolism, Liver metabolism, Disease Models, Animal, CCAAT-Enhancer-Binding Protein-alpha, Non-alcoholic Fatty Liver Disease etiology
Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) - previously described as nonalcoholic steatohepatitis (NASH) - is a major driver of liver fibrosis in humans, while liver fibrosis is a key determinant of all-cause mortality in liver disease independent of MASH occurrence. CCAAT/enhancer binding protein α (CEBPA), as a versatile ligand-independent transcriptional factor, has an important function in myeloid cells, and is under clinical evaluation for cancer therapy. CEBPA is also expressed in hepatocytes and regulates glucolipid homeostasis; however, the role of hepatocyte-specific CEBPA in modulating liver fibrosis progression is largely unknown. Here, hepatic CEBPA expression was found to be decreased during MASH progression both in humans and mice, and hepatic CEBPA mRNA was negatively correlated with MASH fibrosis in the human liver. CebpaΔHep mice had markedly enhanced liver fibrosis induced by a high-fat, high-cholesterol, high-fructose diet or carbon tetrachloride. Temporal and spatial hepatocyte-specific CEBPA loss at the progressive stage of MASH in CebpaΔHep,ERT2 mice functionally promoted liver fibrosis. Mechanistically, hepatocyte CEBPA directly repressed Spp1 transactivation to reduce the secretion of osteopontin, a fibrogenesis inducer of hepatic stellate cells. Forced hepatocyte-specific CEBPA expression reduced MASH-associated liver fibrosis. These results demonstrate an important role for hepatocyte-specific CEBPA in liver fibrosis progression, and may help guide the therapeutic discoveries targeting hepatocyte CEBPA for the treatment of liver fibrosis.

Published
2024
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11. Investigators from National Cancer Institute (NCI) Release New Data on Liver Fibrosis (Hepatocyte-specific Ccaat/enhancer Binding Protein A Restricts Liver Fibrosis Progression).

Subjects
HEPATIC fibrosis, CARRIER proteins, DATA release, DIGESTIVE system diseases, DNA-binding proteins
Abstract

A recent study conducted by investigators from the National Cancer Institute (NCI) has shed light on the role of hepatocyte-specific CCAAT/enhancer binding protein alpha (CEBPA) in liver fibrosis progression. The researchers found that decreased expression of CEBPA in hepatocytes was associated with the progression of metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis in both humans and mice. They also discovered that hepatocyte-specific CEBPA loss promoted liver fibrosis by repressing the secretion of osteopontin, a fibrogenesis inducer. These findings suggest that targeting hepatocyte CEBPA could be a potential therapeutic strategy for treating liver fibrosis. [Extracted from the article]

Published
2024

12. Recent Findings from Southern Medical University Provides New Insights into Tissue Engineering (Combined Use of Autologous Sustained-release Scaffold of Adipokines and Acellular Adipose Matrix To Construct Vascularized Adipose Tissue).

Abstract

A recent study conducted by researchers at Southern Medical University in Guangzhou, China, explores the use of a combination of biomaterials to construct vascularized adipose tissue for soft-tissue reconstruction. The researchers found that the use of an adipose-derived extracellular matrix collagen scaffold, called adipose collagen fragment (ACF), in combination with an acellular adipose matrix (AAM), resulted in the formation of highly vascularized, mature adipose tissue. The study utilized label-free proteomics methods to analyze the protein components of ACF and AAM and evaluated their effects on adipogenesis and tube formation in vitro. The findings suggest that the combined use of ACF and AAM could be a promising strategy for soft-tissue reconstruction. [Extracted from the article]

Published
2024

13. Sinomenine alleviates glomerular endothelial permeability by activating the C/EBP-α/claudin-5 signaling pathway

Author

Li Zhang and Junxia Wang

Subjects
Cancer Research, Morphinans, CCAAT-Enhancer-Binding Protein-alpha, Interleukin-18, Animals, Endothelial Cells, Diabetic Nephropathies, Claudin-5, Cell Biology, Permeability, Rats, Signal Transduction
Abstract

Diabetic nephropathy (DN) is one of the main complications of diabetes. It is closely associated with the dysfunction of glomerular endothelial cells (GECs) under hyperglycemia. Severe inflammation is an important inducer for the development of GECs dysfunction, and it contributes to the disruption of tight junctions in GECs and the increased endothelial permeability. Sinomenine, an alkaloid monomer extracted from the rhizome of Sinomenium acutum, is recognized for its multiple pharmacological functions, including an anti-DN property. The present study aimed to explore the potential functional mechanism of Sinomenine against DN. Animals were randomly divided into Sham, DN, DN + Sinomenine (20 mg/kg), and DN + Sinomenine (40 mg/kg) groups. The Sinomenine or vehicle was administered every day for 6 weeks, followed by collecting renal tissues for further detection. Increased body weights, elevated blood glucose levels and UAE values, aggravated renal tissue pathology, higher concentrations of IL-18 and IL-1β in renal tissues, and reduced claudin-5 expression were observed in DN rats. However, the administration of Sinomenine significantly alleviated all these DN-related changes. Furthermore, human renal glomerular endothelial cells (HrGECs) were treated with high glucose (HG, 30 mM) with or without Sinomenine (50, 100 μM) for 24 h. We found that Sinomenine treatment ameliorated the elevated production of IL-18 and IL-1β, increased fluorescence intensity of FITC-dextran, declined trans-endothelial electrical resistance (TEER) value, and reduction of claudin-5 and C/EBP-α in HG-treated HrGECs. Moreover, the regulatory effect of Sinomenine on endothelial monolayer permeability in HG-treated HrGECs was abolished by the knockdown of C/EBP-α, indicating C/EBP-α is required for the effect of Sinomenine. We concluded that Sinomenine alleviated diabetic nephropathy-induced renal glomerular endothelial dysfunction via activating the C/EBP-α/claudin-5 axis.

Published
2022

14. Somatostatin receptor ligands suppressed proliferation and lipogenesis in 3T3‐L1 preadipocytes

Author

Zhe Zhao, Fengying Gong, Lian Duan, Xiaorui Lv, Haijie Wu, Yan Tang, Huijuan Zhu, and Xiaoguang Chen

Subjects
Pharmacology, Lipogenesis, Cell Differentiation, General Medicine, Ligands, Toxicology, PPAR gamma, Mice, Phosphatidylinositol 3-Kinases, 3T3-L1 Cells, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, Receptors, Somatostatin, Somatostatin, Proto-Oncogene Proteins c-akt, Cell Proliferation
Abstract

Somatostatin and its analogues, known as somatostatin receptor ligands (SRLs), have been reported to attenuate weight gain in some clinical settings. However, their direct effects on preadipocytes are barely investigated. Therefore, this study aimed to evaluate the influence of SRLs on preadipocytes and to further explore the potential mechanisms. Cell Counting Kit-8 assay, Oil Red O staining, triglyceride contents measurements, quantitative polymerase chain reaction (qPCR) and western blot were used to investigate the effects of SRLs on preadipocytes. We found that three SRLs (octreotide, TT232 and pasireotide) inhibited cell viability after 8-48 h but not 4 h. Further western blot results showed that they significantly suppressed activation of PI3K/Akt pathway. Besides, lipid accumulation was also significantly inhibited by these SRLs. Moreover, mRNA levels of some critical adipogenic markers, including Pparg, Cebpa, Fasn, Fabp4, Acaca and Lpl, were downregulated by the treatments of all these SRLs. Consistently, the protein expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα) and fatty acid synthase (FAS) was also suppressed by SRLs. SRLs inhibit the proliferation and lipogenesis in preadipocytes. Their inhibitory effects on cell proliferation may be mediated by the downregulated PI3K/Akt pathway, and the suppressive actions on lipogenesis may be related to the decreased PPARγ and C/EBPα expression.

Published
2022

15. Anti-Obesity Effect of Porcine Collagen Peptide in 3T3-L1 Adipocytes and High-Fat Diet-Fed Mice by Regulating Adipogenesis

Author

Eunji Lee, Jiyoung Bang, Jeong Yoon Lee, Woojin Jun, and Yoo-Hyun Lee

Subjects
Adipogenesis, Nutrition and Dietetics, Swine, Body Weight, Medicine (miscellaneous), Diet, High-Fat, Weight Gain, Mice, Inbred C57BL, PPAR gamma, Mice, 3T3-L1 Cells, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, Anti-Obesity Agents, Collagen, Obesity, Fatty Acid Synthases, Peptides
Abstract

Obesity is one of the most common diseases caused by an imbalance in the intake and expenditure of energy, and it is associated with various metabolic complications. This study aimed at investigating the anti-obesity effects and mechanisms of porcine collagen peptide (PCP) using 3T3-L1 preadipocytes and high-fat diet (HFD)-fed mice. The PCP treatment significantly inhibited the adipocyte differentiation and attenuated the mRNA expression of transcription factors (CCAAT/enhancer-binding protein alpha [C/EBP

Published
2022

16. Brown Algae Dictyopteris divaricata Attenuates Adipogenesis by Modulating Adipocyte Differentiation and Promoting Lipolysis through Heme Oxygenase-1 Activation in 3T3-L1 Cells.

Author

Dayarathne LA, Ko SC, Yim MJ, Lee JM, Kim JY, Oh GW, Kim CH, Kim KW, Lee DS, and Je JY

Subjects
Animals, Mice, Lipolysis, 3T3-L1 Cells, Heme Oxygenase-1 metabolism, PPAR gamma metabolism, Glycerol pharmacology, Glycerol metabolism, Cell Differentiation, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Transcription Factors metabolism, Lipids pharmacology, Adipogenesis, Phaeophyceae
Abstract

The present study aims to explore the probable anti-adipogenesis effect of Dictyopteris divaricata ( D. divaricata ) in 3T3-L1 preadipocytes by regulating heme oxygenase-1 (HO-1). The extract of D. divaricata retarded lipid accretion and decreased triglyceride (TG) content in 3T3-L1 adipocytes but increased free glycerol levels. Treatment with the extract inhibited lipogenesis by inhibiting protein expressions of fatty acid synthase (FAS) and lipoprotein lipase (LPL), whereas lipolysis increased by activating phosphorylation of hormone-sensitive lipase (p-HSL) and AMP-activated protein kinase (p-AMPK). The extract inhibited adipocyte differentiation of 3T3-L1 preadipocytes through down-regulating adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP1). This is attributed to the triggering of Wnt/β-catenin signaling. In addition, this study found that treatment with the extract activated HO-1 expression. Pharmacological approaches revealed that treatment with Zinc Protoporphyrin (ZnPP), an HO-1 inhibitor, resulted in an increase in lipid accumulation and a decrease in free glycerol levels. Finally, three adipogenic transcription factors, such as PPARγ, C/EBPα, and SREBP1, restored their expression in the presence of ZnPP. Analysis of chemical constituents revealed that the extract of D. divaricata is rich in 1,4-benzenediol, 7-tetradecenal, fucosterol, and n-hexadecanoic acid, which are known to have multiple pharmacological properties.

Published
2024
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18. The prognostic factors in acute myeloid leukaemia with double‐mutated CCAAT/enhancer‐binding protein alpha <scp> ( CEBPA dm </scp> )

Author

Hui Wei, Chunlin Zhou, Bingcheng Liu, Dong Lin, Yan Li, Shuning Wei, Benfa Gong, Guangji Zhang, Kaiqi Liu, Xiaoyuan Gong, Qiuyun Fang, Yuntao Liu, Shaowei Qiu, Runxia Gu, Zhen Song, Jiayuan Chen, Miao Yang, Junping Zhang, Jingjing Jin, Ying Wang, Yingchang Mi, and Jianxiang Wang

Subjects
Leukemia, Myeloid, Acute, Mutation, Receptors, Colony-Stimulating Factor, CCAAT-Enhancer-Binding Protein-alpha, CCAAT-Enhancer-Binding Proteins, Cytarabine, Humans, Hematology, Neoplasm Recurrence, Local, Homoharringtonine, Prognosis, Retrospective Studies
Abstract

The prognostic factors to stratify acute myeloid leukaemia (AML) with double-mutated CCAAT/enhancer-binding protein alpha (CEBPAdm) into different risk groups remains to be determined. In this retrospective study, we evaluated 171 consecutive patients with newly diagnosed AML with CEBPAdm by a Cox proportional hazards regression model. In univariate analyses, colony stimulating factor 3 receptor (CSF3R) and Wilms tumour 1 (WT1) mutations were associated with poor relapse-free survival (RFS). The induction regimens including homoharringtonine (omacetaxine mepesuccinate) or intermediate-dose cytarabine was associated with favourable RFS and overall survival (OS). The induction regimen including both homoharringtonine and intermediate-dose cytarabine was associated with the most favourable RFS (3-year RFS 84.7%) and OS (3-year OS 92.8%) compared to the conventional cytarabine and daunorubicin regimen (3-year RFS 27.7%, hazard ratio [HR] 0.126, 95% confidence interval [CI] 0.051-0.313, Wald p 0.001; and 3-year OS 56.4%, HR 0.179, 95% CI 0.055-0.586, Wald p = 0.005). In multivariate analyses, the induction regimen including intermediate-dose cytarabine (HR 0.364, 95% CI 0.205-0.646, Wald p 0.001) and CSF3R mutations (HR 2.667, 95% CI 1.276-5.572, Wald p = 0.009) were independently associated with RFS. Taken together, we found that induction regimen and CSF3R mutations were independent prognostic factors for AML with CEBPAdm.

Published
2022

19. A hierarchical regulatory network ensures stable albumin transcription under various pathophysiological conditions

Author

Rilu Feng, Kejia Kan, Carsten Sticht, Yujia Li, Shanshan Wang, Hui Liu, Chen Shao, Stefan Munker, Hanno Niess, Sai Wang, Christoph Meyer, Roman Liebe, Matthias P. Ebert, Steven Dooley, Huiguo Ding, and Honglei Weng

Subjects
Carcinoma, Hepatocellular, Hepatocyte Nuclear Factor 4, Liver, Hepatology, Hedgehogs, Albumins, Liver Neoplasms, Hepatocytes, CCAAT-Enhancer-Binding Protein-alpha, Humans, Animals, Liver Failure
Abstract

It remains unknown how patients with liver failure maintain essential albumin levels. Here, we delineate a hierarchical transcription regulatory network that ensures albumin expression under different disease conditions.We examined albumin levels in liver tissues and serum in 157 patients, including 84 with HCC, 38 decompensated cirrhosis, and 35 acute liver failure. Even in patients with liver failure, the average serum albumin concentrations were 30.55 g/L. In healthy subjects and patients with chronic liver diseases, albumin was expressed in hepatocytes. In patients with massive hepatocyte loss, albumin was expressed in liver progenitor cells (LPCs). The albumin gene (ALB) core promoter possesses a TATA box and nucleosome-free area, which allows constitutive RNA polymerase II binding and transcription initiation. Chromatin immunoprecipitation assays revealed that hepatocyte nuclear factor 4 alpha (HNF4α), CCAAT/enhancer-binding protein alpha (C/EBPα), and forkhead box A2 (FOXA2) bound to the ALB enhancer. Knockdown of either of these factors reduced albumin expression in hepatocytes. FOXA2 acts as a pioneer factor to support HNF4α and C/EBPα. In hepatocytes lacking HNF4α and C/EBPα expression, FOXA2 synergized with retinoic acid receptor (RAR) to maintain albumin transcription. RAR nuclear translocation was induced by retinoic acids released by activated HSCs. In patients with massive hepatocyte loss, LPCs expressed HNF4α and FOXA2. RNA sequencing and quantitative PCR analyses revealed that lack of HNF4α and C/EBPα in hepatocytes increased hedgehog ligand biosynthesis. Hedgehog up-regulates FOXA2 expression through glioblastoma family zinc finger 2 binding to the FOXA2 promoter in both hepatocytes and LPCs.A hierarchical regulatory network formed by master and pioneer transcription factors ensures essential albumin expression in various pathophysiological conditions.

Published
2022

20. Isolation of phenolic acids and tannin acids from Mangifera indica L. kernels as inhibitors of lipid accumulation in 3T3-L1 cells

Author

Takahiro Fujimaki, Chikako Sato, Rei Yamamoto, Sayo Watanabe, Hikaru Fujita, Hidehiko Kikuno, Masayuki Sue, and Yoshitaka Matsushima

Subjects
Adipogenesis, Mangifera, Plant Extracts, Organic Chemistry, food and beverages, General Medicine, Lipid Metabolism, Lipids, Applied Microbiology and Biotechnology, Biochemistry, Analytical Chemistry, PPAR gamma, Mice, 3T3-L1 Cells, CCAAT-Enhancer-Binding Protein-alpha, Animals, Tannins, Molecular Biology, Biotechnology
Abstract

Mango (Mangifera indica L.) kernels are usually discarded as waste, but they contain many pharmacological properties and bioactivities. In this study, we isolated antiobesity agents from mango kernels that inhibit intracellular lipid formation in 3T3-L1 adipocytes. Two phenolic acids, ethyl gallate and ethyl digallate, and 2 tannin acids, 1,2,3,4,6-penta-O-galloyl-β-d-glucose (PGG) and 3-O-digalloyl-1,2,4,6-tetra-O-β-d-glucose (HGG), were identified from mango kernels and were found to be suppressed lipid accumulation as evidenced by Oil Red O staining. Furthermore, ethyl digallate, PGG, and HGG significantly downregulated the mRNA expression of adipogenic transcription factors such as C/EBPα and PPARγ. However, ethyl gallate did not affect the expression of these transcription factors. Our findings reveal the presence of antiobesity compounds in mango kernels, implying its therapeutic role against obesity.

Published
2022

21. The galloyl moiety enhances inhibitory activity of polyphenols against adipogenic differentiation in 3T3-L1 preadipocytes

Author

Jinming Peng, Wenjun Wen, Ruifeng Wang, Kaikai Li, Gengsheng Xiao, and Chunmei Li

Subjects
PPAR gamma, Mice, Adipogenesis, 3T3-L1 Cells, CCAAT-Enhancer-Binding Protein-alpha, Animals, Polyphenols, Cell Differentiation, General Medicine, Food Science
Abstract

Previous studies have proved that the characteristic galloyl moiety in polyphenols is crucial for their biological activities. However, whether the presence of the galloyl moiety in the structure of polyphenols has a great contribution to their inhibition of adipogenic differentiation is not clear. Therefore, in this study, seven polyphenols with different galloylation degrees were chosen for exploring the contribution of the galloyl group to the lipid-lowering property of polyphenols and its molecular mechanism. Our results showed that the existence of the galloyl moiety in the structure of polyphenols was necessary for their inhibition of adipogenic differentiation, which could help to delay cells from entering the G2/M phase as well as to hinder the MCE process in the early stage of differentiation and the downstream PPARγ and C/EBPα related MAPK signaling pathway, probably

Published
2022

22. CEBPβ binding directly to the promoter region drives CEBPɑ transcription and improves FABP4 transcriptional activity in adipose tissue of yak (Bos grunniens)

Author

Ali Raza Jahejo, Lei Wang, Mahmoud A.O. Dawood, Linsheng Gui, Ayman H. Abd El-Aziz, Rajwali Khan, Mashael Alhumaidi Alotaibi, Boyan Ma, Ahmed A Easa, Tahani Mohamed Ibrahim Al Hazani, Mustafa Shukry, Abdullah F. Shater, Fayez Althobaiti, Khawla Hassan Alanbari, Sayed Haidar Abbas Raza, and Guobo Quan

Subjects
Adipogenesis, General Veterinary, Chemistry, CCAAT-Enhancer-Binding Protein-beta, Repressor, Promoter, Fatty Acid-Binding Proteins, Fatty acid-binding protein, Cell biology, Adipose Tissue, Transcription (biology), Enhancer binding, CCAAT-Enhancer-Binding Protein-alpha, Animals, Cattle, Promoter Regions, Genetic, Transcription factor, Chromatin immunoprecipitation
Abstract

Fatty acid binding protein 4 (FABP4) was crucial to fatty acid uptake and intracellular transport. However, the mechanisms regulating yak (Bos grunniens) FABP4 transcription were not determined. In the current study, predominant expression levels of yak FABP4 were identified in subcutaneous fat and longissimus dorsi muscles by quantitative real-time polymerase chain reactions (qPCR). The CCAAT/enhancer binding protein alpha (CEBPα) and myocyte enhancer factor 2A (MEF2A), as transcriptional activator or repressor in the promoter region of FABP4, were confirmed by both site-directed mutagenesis experiment and chromatin immunoprecipitation assay. Additionally, molecular mechanisms of CEBPɑ regulation were analyzed to explore the transcriptional regulatory property of FABP4, which indicated that transcriptional activity of CEBPɑ depended on CCAAT/ enhancer binding protein beta (CEBPβ) transcription factor. Our results demonstrated that CEBPβ binding directly to the promoter region drove CEBPɑ transcription, improving yak FABP4 transcriptional activity in adipocytes. This mechanism expanded the information on the transcriptional regulatory network of adipogenesis.

Published
2021

23. C/EBPZ modulates the differentiation and proliferation of preadipocytes

Author

Yi Zhang, Zhiwei Zhang, Qin Gao, Yuechan Chen, Zequan Li, Gao Lingyu, Jingjing Chen, Xiangqi Wu, Xuelian Pei, and Tao Lin

Subjects
medicine.medical_specialty, Bioinformatics analysis, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Adipose tissue, Development, Article, Negative regulator, In vivo, Internal medicine, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, medicine, Animals, Gene, Cell Proliferation, Adipogenesis, Nutrition and Dietetics, Chemistry, GATA2, Cell Differentiation, Metabolic syndrome, In vitro, PPAR gamma, Endocrinology, Chickens
Abstract

Background/Objectives This study investigated the functions of CCAAT/enhancer-binding protein zeta (C/EBPZ; Gene ID: 10153) in adipose tissue. Subjects/methods Bioinformatics analysis were used to study the expression pattern of C/EBPZ in human adipose tissue. The expression and function of C/EBPZ in adipose tissue were further studied using chicken as animal model in vivo and in vitro. Results The human C/EBPZ transcripts were greater and more stable in subcutaneous adipose tissue than in visceral adipose tissue (P

Published
2021

24. The anti-obesity effect of mulberry leaf (Mori Folium) extracts was increased by bioconversion with Pectinex

Author

Joo-Hui Han, Hyung-Won Lee, Sang-Hyuk Jung, Chong Woon Cho, Tae Jeong Kim, Jong Seong Kang, and Chang-Seon Myung

Subjects
Plant Leaves, Multidisciplinary, Plant Extracts, Fruit, CCAAT-Enhancer-Binding Protein-alpha, Morus, Obesity
Abstract

Mulberry leaf (Mori Folium) extract (MLE) is known to have anti-obesity effects. In this study, the enhanced effects of MLE after bioconversion treatment using Pectinex (BMLE) on obesity were explored, and the underlying mechanisms were investigated using the active components, neochlorogenic acid (5-CQA) and cryptochlorogenic acid (4-CQA), whose amounts were increased by bioconversion of MLE. Both MLE and BMLE inhibited lipid accumulation in 3T3-L1 adipocytes without cytotoxicity and suppressed the expression of CCAAT/enhancer-binding protein alpha (C/EBPα). In addition, MLE and BMLE decreased high-fat diet-induced adipose tissue mass expansion. Notably, BMLE significantly increased antiadipogenic and anti-obesity effects compared to MLE in vitro and in vivo. The active ingredients increased by bioconversion, 5-CQA and 4-CQA, inhibited the protein levels of C/EBPα and the mRNA levels of stearoyl-CoA desaturase 1 (Scd1). These findings provide new insights into the therapeutic possibility of using bioconversion of MLE, by which upregulation of 5-CQA and 4-CQA potently inhibits adipogenesis.

Published
2022

25. Plasminogen-derived peptide promotes adipogenic differentiation of preadipocytes

Author

Hea Jung, Yang, Jong-Ho, Kim, Jung Hee, Shim, and Chan Yeong, Heo

Subjects
Mice, Adipogenesis, CCAAT-Enhancer-Binding Protein-alpha, Animals, Plasminogen, Peptides, Mastectomy
Abstract

Soft tissue defects caused by adipose tissue loss can result in various conditions such as lipodystrophy in congenital diseases, trauma secondary to ageing, and mastectomy in breast cancer; fat grafting is commonly performed to restore these defects. Although various enrichment strategies have been studied, novel therapeutics that are cost-effective, safe, technologically easy to manufacture, and minimally invasive are required. In this study, we identified a novel peptide derived from plasminogen, named plasminogen-derived peptide-1 (PLP-1), which showed adipogenic differentiation potential and led to an increase in the expression levels of adiponectin, C1Q and collagen domain containing protein, fatty acid-binding protein 4, and CCAAT/enhancer-binding protein-alpha.

Published
2022

26. Inhibitory Effects of Hydrolysable Tannins on Lipid Accumulation in 3T3-L1 Cells

Author

Yasuhito Nobushi, Taira Wada, Yuzuki Koike, Hikari Kaneko, Shigeki Shimba, Taketo Uchiyama, and Yukinaga Kishikawa

Subjects
Pharmacology, Adipogenesis, Pharmaceutical Science, Cell Differentiation, General Medicine, Fatty Acid-Binding Proteins, Lipids, Hydrolyzable Tannins, PPAR gamma, Mice, Glucose, Diabetes Mellitus, Type 2, 3T3-L1 Cells, Gallic Acid, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, Peroxisome Proliferators, Obesity
Abstract

Obesity is currently the most common cause of metabolic diseases including type 2 diabetes and hyperlipidemia. Obesity results from excess lipid accumulation in adipose tissue. Several studies have investigated the inhibitory effects of natural plant-derived products on adipocyte differentiation and lipid accumulation. In this study, we examined the effect of hydrolysable tannins composed of gallic acid and glucose on adipocyte differentiation in 3T3-L1 cells. 1,2,3,4,6-Penta-O-galloyl-β-D-glucose (PGG) (1), a representative gallotannin, inhibited lipid accumulation in 3T3-L1 cells, whereas ellagitannins (tellimagrandin I, eugeniin and casuarictin) did not. The expression of adipocyte differentiation-related genes, including peroxisome proliferator activator γ2 (Pparγ2), CCAAT/enhancer binding protein α (C/EBPα) and adipocyte fatty acid binding protein (aP2), was significantly suppressed in PGG (1)-treated 3T3-L1 cells beginning at day 2 after induction of differentiation. While PGG (1) did not directly reduce Pparγ2 expression, it reduced the expression of its target genes in mature adipocytes. In addition, PGG (1) treatment inhibited mitotic clonal expansion, one of earliest events of adipocyte differentiation. These findings indicate that PGG (1) has an inhibitory effect on adipocyte differentiation through the suppression of mitotic clonal expansion.

Published
2022

27. LncRNA CEBPA-DT promotes liver cancer metastasis through DDR2/β-catenin activation via interacting with hnRNPC

Author

Yunshi Cai, Tao Lyu, Hui Li, Chang Liu, Kunlin Xie, Lin Xu, Wei Li, Hu Liu, Jiang Zhu, Yinghao Lyu, Xuping Feng, Tian Lan, Jiayin Yang, and Hong Wu

Subjects
Cancer Research, Carcinoma, Hepatocellular, Epithelial-Mesenchymal Transition, Heterogeneous-Nuclear Ribonucleoprotein Group C, Liver Neoplasms, Gene Expression Regulation, Neoplastic, Oncology, Cell Movement, Cell Line, Tumor, CCAAT-Enhancer-Binding Protein-alpha, CCAAT-Enhancer-Binding Proteins, Humans, RNA, Long Noncoding, beta Catenin, In Situ Hybridization, Fluorescence, Cell Proliferation
Abstract

Background Hepatocellular carcinoma (HCC) is the world’s third leading cause of cancer-related death; due to the fast growth and high prevalence of tumor recurrence, the prognosis of HCC patients remains dismal. Long non-coding RNA CEBPA-DT, a divergent transcript of the CCAAT Enhancer Binding Protein Alpha (CEBPA) gene, has been shown to participate in multiple tumor progression. However, no research has established its cancer-promoting mechanism in HCC yet. Methods CEBPA-DT was identified in human HCC tissues through RNA sequencing. The expression level of CEBPA-DT was assessed by quantitative real-time PCR. The biological effects of CEBPA-DT were evaluated in vitro and in vivo through gain or loss of function experiments. RNA fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were applied to investigate the downstream target of CEBPA-DT. Immunofluorescence, subcellular protein fractionation, western blot, and co-immunoprecipitation were performed to analyze the subcellular location of β-catenin and its interaction with Discoidin domain-containing receptor 2 (DDR2). Results CEBPA-DT was upregulated in human HCC tissues with postoperative distant metastasis and intimately related to the worse prognosis of HCC patients. Silencing of CEBPA-DT inhibited the growth, migration and invasion of hepatoma cells in vitro and in vivo, while enhancement of CEBPA-DT played a contrasting role. Mechanistic investigations demonstrated that CEBPA-DT could bind to heterogeneous nuclear ribonucleoprotein C (hnRNPC), which facilitated cytoplasmic translocation of hnRNPC, enhanced the interaction between hnRNPC and DDR2 mRNA, subsequently promoted the expression of DDR2. Meanwhile, CEBPA-DT induced epithelial-mesenchymal transition (EMT) process through upregulation of Snail1 via facilitating nuclear translocation of β-catenin. Using DDR2 inhibitor, we revealed that the CEBPA-DT induced the interaction between DDR2 and β-catenin, thus promoting the nuclear translocation of β-catenin to activate transcription of Snail1, contributing to EMT and HCC metastasis. Conclusions Our results suggested that CEBPA-DT promoted HCC metastasis through DDR2/β-catenin mediated activation of Snail1 via interaction with hnRNPC, indicating that the CEBPA-DT-hnRNPC-DDR2/β-catenin axis may be used as a potential therapeutic target for HCC treatment.

Published
2022

28. Notch1/Hes1信号调控CCAAT/增强子结合蛋白α表达对高氧损伤肺泡Ⅱ型上皮细胞增殖与分化的影响

Author

万峰云, 卢红艳, 万雪晴, 郝晓波, and 朱 玥

Abstract

BACKGROUND: Notch1/Hes1 signal and CCAAT/enhancer-binding protein alpha (C/EBPα) play important roles in lung development and injury. Preliminary studies have shown that hyperoxia can induce abnormal proliferation and differentiation of type II alveolar epithelial cells (AECII), which is related to C/EBPα expression. But, whether Notch1/Hes1 signal is involved remains unclear. OBJECTIVE: To investigate the effect of Notch1/Hes1 signal regulating C/EBPα on the proliferation and differentiation of AECII induced by hyperoxia. METHODS: Human AECIIs were cultured in vitro, and randomly divided into air group, air activator group (Notch pathway activator Jagged1 protein, 500 μg/L), hyperoxia group (95% O2 and 5% CO2 mixture gas administered at the speed of 3 L/minute for 10 minutes), hyperoxia activator group (500 μg/L Notch pathway activator Jagged1 protein added at 30 minutes before oxygen administration). AECIIs of each group were collected after 24 hours of intervention. The expression of Notch1, Hes1 and C/EBPα at mRNA and protein levels was determined by RT-PCR and western blot assay. The proliferation of AECII was measured by cell counting kit-8 assay. Flow cytometry labeled AQP5 was applied to detect the differentiation of AECII. RESULTS AND CONCLUSION: Compared with the air group, the mRNA and protein expression levels of Notch1, Hes1 and C/EBPα were increased significantly in the air activator group (P < 0.05), the proliferation of AECII was increased and the differentiation was reduced significantly (P < 0.05). In the hyperoxia and hyperoxia activator groups, the mRNA and protein expression levels of Notch1, Hes1 and C/EBPα were significantly decreased, the proliferation of AECII was decreased and the differentiation was increased significantly (P < 0.05). Compared with the hyperoxia group, the mRNA and protein expression levels of Notch1, Hes1 and C/EBPα were significantly increased in the hyperoxia activator group (P < 0.05), and the proliferation of AECII was increased and the differentiation was decreased significantly (P < 0.05). These results suggest that Notch1/Hes1 signal regulates the expression of C/EBPα and affects the proliferation and differentiation of AECII after exposure to hyperoxia. [ABSTRACT FROM AUTHOR]

Published
2018
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29. Cystatin F acts as a mediator of immune suppression in glioblastoma

Author

Andrej Porčnik, Jernej Mlakar, Ana Rotter, Milica Perišić Nanut, Janko Kos, Barbara Breznik, Emanuela Senjor, Ana Mitrović, and Tamara Lah Turnšek

Subjects
Cytotoxicity, Immunologic, 0301 basic medicine, Cancer Research, Cellular differentiation, urologic and male genital diseases, Monocytes, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cancer stem cell, Cell Line, Tumor, Glioma, Biomarkers, Tumor, CCAAT-Enhancer-Binding Protein-alpha, Tumor Cells, Cultured, medicine, Humans, Cytotoxic T cell, Cytotoxicity, Cells, Cultured, reproductive and urinary physiology, Microglia, Brain Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, Chemistry, General Medicine, medicine.disease, Cystatins, Immunohistochemistry, female genital diseases and pregnancy complications, Gene Expression Regulation, Neoplastic, Killer Cells, Natural, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Cancer research, Molecular Medicine, Cystatin, Glioblastoma
Abstract

Glioblastoma, the most aggressive type of brain cancer, is composed of heterogeneous populations of differentiated cells, cancer stem cells and immune cells. Cystatin F, an endogenous inhibitor of lysosomal cysteine peptidases, regulates the function of cytotoxic immune cells. The aim of this study was to determine which type of cells expresses cystatin F in glioblastoma and to determine the role of cystatin F during disease progression. RT-qPCR and immunohistochemistry were used to determine cystatin F mRNA and protein levels in glioblastoma tissue samples. The internalization of cystatin F was analyzed by Western blotting. Enzyme kinetics, real time invasion and calcein release cytotoxicity assays were used to assess the role of internalized cystatin F. We found that cystatin F was not expressed in non-cancer brain tissues, but that its expression increased with glioma progression. In tumor tissues, extensive staining was observed in cancer stem-like cells and microglia/monocytes, which secrete cystatin F into their microenvironment. In trans activity of cystatin F was confirmed using an in vitro glioblastoma cell model. Internalized cystatin F affected cathepsin L activity in glioblastoma cells and decreased their invasiveness. In addition, we found that cystatin F decreased the susceptibility of glioblastoma cells to the cytotoxic activity of natural killer (NK) cells. Our data implicate cystatin F as a mediator of immune suppression in glioblastoma. Increased cystatin F mRNA and protein levels in immune, glioblastoma and glioblastoma stem-like cells or trans internalized cystatin F may have an impact on decreased susceptibility of glioblastoma cells to NK cytotoxicity.

Published
2021

30. Artemisinin derivatives inhibit adipogenic differentiation of 3T3-L1 preadipocytes through upregulation of CHOP

Author

Na Li, Yongjuan Tong, Guoying Zhang, Peilin Li, Haotian Han, Lei Cui, Qihan Song, and Bin Yang

Subjects
0301 basic medicine, Perilipin-1, Peroxisome proliferator-activated receptor gamma, genetic structures, Biophysics, Artesunate, Down-Regulation, CHOP, Fatty Acid-Binding Proteins, Real-Time Polymerase Chain Reaction, Biochemistry, Small hairpin RNA, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, 3T3-L1 Cells, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, RNA-Seq, RNA, Small Interfering, Molecular Biology, Gene knockdown, Adipogenesis, Chemistry, 3T3-L1, Cell Biology, Lipid Metabolism, Molecular biology, Artemisinins, Up-Regulation, PPAR gamma, 030104 developmental biology, Gene Expression Regulation, 030220 oncology & carcinogenesis, CCAAT-Enhancer-Binding Proteins, Perilipin, Transcription Factor CHOP
Abstract

Artemisinin derivatives could inhibit adipogenic differentiation of 3T3-L1 preadipocytes and prevent obesity in mice. However, the molecular mechanism remains largely unclear. Our research was designed to investigate the specific molecular target of artemisinin derivatives in adipogenic differentiation of 3T3-L1 preadipocytes. Here, we revealed that in response to dihydroartemisinin (DHA) or artesunate (ATS), intracellular lipid was decreased in a concentration dependent manner as shown by BODIPY staining. Quantitative PCR analysis showed that expression of Cebpa, Pparg, Fabp4 and Plin was significantly decreased by DHA treatment in a concentration and time dependent manner. Also, DHA treatment remarkably downregulated expression of CCAAT/enhancer-binding protein α (C/EBPα) and nuclear receptor peroxisome proliferation-activated receptor γ (PPARγ) of adipogenic induced 3T3-L1 cells as assayed by western blotting. RNA-seq analysis identified thousands of differential expression genes (DEGs), among which CHOP expression was significantly improved in DHA treated cells. Upregulation of CHOP was verified by quantitative PCR and western blotting, respectively. Knockdown of CHOP by the specific shRNA revealed that the inhibition of adipogenesis by DHA was strongly blocked, resulting in restored lipid accumulation and expression of adipogenic molecules. In conclusions, the inhibitory effect of DHA on adipogenic differentiation of 3T3-L1 preadipocytes was exerted in a concentration and time dependent manner, which was mediated by expression of CHOP.

Published
2021

31. [Overexpression of

Author

Chongyang, Wang, Cheng, Luo, Hao, Zhang, Xin, Li, Yanyan, Li, Yan, Xiong, Youli, Wang, and Yaqiu, Lin

Subjects
PPAR gamma, Mice, Activating Transcription Factor 3, Adipogenesis, 3T3-L1 Cells, Goats, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, Cell Differentiation
Abstract

The aim of this study was to investigate the effect of activating transcription factor 3 (

Published
2022

32. Anti-Adipogenic Effects of Salicortin from the Twigs of Weeping Willow (

Author

Hee Jung, Kim, Da Eun, Lee, Eon Chung, Park, Moon-Jin, Ra, Sang-Mi, Jung, Jeong-Nam, Yu, Sung Hee, Um, and Ki Hyun, Kim

Subjects
PPAR gamma, Mice, Adipogenesis, Ethanol, Plant Extracts, 3T3-L1 Cells, CCAAT-Enhancer-Binding Protein-alpha, Animals, Salix, Salicylic Acid, Lipids
Published
2022

33. Inhibitory Effect of Bacterial Lysates Extracted from

Author

Han Bin, Lee and Seok-Seong, Kang

Subjects
Cell Extracts, Leptin, Pediococcus acidilactici, Adipogenesis, Cell Differentiation, Peptidoglycan, Fatty Acid-Binding Proteins, Lipid Metabolism, Lipids, Glycerides, PPAR gamma, Lipoprotein Lipase, Mice, 3T3-L1 Cells, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, RNA, Messenger
Abstract

Postbiotics, including bacterial lysates, are considered alternatives to probiotics. The aim of the current study was to investigate the effect of bacterial lysates (BLs) extracted from

Published
2022

34. C/EBPα regulates the fate of bone marrow mesenchymal stem cells and steroid-induced avascular necrosis of the femoral head by targeting the PPARγ signalling pathway

Author

Ping, Duan, Hanyu, Wang, Xinzeyu, Yi, Hao, Zhang, Hui, Chen, and Zhenyu, Pan

Subjects
Adipogenesis, Medicine (miscellaneous), Bone Marrow Cells, Cell Differentiation, Mesenchymal Stem Cells, Cell Biology, Biochemistry, Genetics and Molecular Biology (miscellaneous), Rats, Histones, PPAR gamma, Rats, Sprague-Dawley, Femur Head Necrosis, Osteogenesis, CCAAT-Enhancer-Binding Protein-alpha, Animals, Molecular Medicine, Steroids
Abstract

BackgroundThe imbalance of osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is closely related to steroid-induced avascular necrosis of the femoral head (SANFH). We aimed to investigate the epigenetic mechanism of intramedullary fat accumulation and continuous osteonecrosis after glucocorticoid (GC) withdrawal in SANFH.MethodsAn SANFH model was established in SD rats, which received an intermittent high GC dose for the first 4 weeks followed by an additional 4 weeks without GC. We explored the synergistic effects and mechanisms of C/EBPα and PPARγ on the differentiation of BMSCs by lentivirus-mediated gene knockdown and overexpression assays. A chromatin immunoprecipitation assay was performed to identify epigenetic modification sites on PPARγ in vivo and in vitro.ResultsIn the SANFH model, intramedullary fat was significantly increased, and the transcription factors C/EBPα and PPARγ were upregulated simultaneously in the femoral head. In vitro, C/EBPα promoted adipogenic differentiation of BMSCs by targeting the PPARγ signalling pathway, while overexpression of C/EBPα significantly impaired osteogenic differentiation. Further studies demonstrated that histone H3K27 acetylation of PPARγ played an important role in the epigenetic mechanism underlying SANFH. C/EBPα upregulates the histone H3K27 acetylation level in the PPARγ promoter region by inhibiting HDAC1. Additionally, inhibiting the histone acetylation level of PPARγ effectively prevented adipogenic differentiation, thus slowing the progression of SANFH.ConclusionsOur results demonstrate the molecular mechanism by which C/EBPα regulates PPARγ expression by acetylating histones and revealed the epigenetic phenomenon in SANFH for the first time.Graphical abstract

Published
2022

35. Anti-obesity Effects of Dark Tea Extracts by Down-regulation of C/EBPα and PPARγ

Author

HYEONG-JOON LIM, TAEK JOO LIM, JIN HYUN LEE, JUN HEE LEE, MYEONG-OK KIM, JI YUN PARK, JONG-TAE KIM, MIN-JEONG KIM, SEONG-HEE JANG, and SEOK HWA CHOI

Subjects
Pharmacology, Cancer Research, Tea, Plant Extracts, Down-Regulation, Diet, High-Fat, General Biochemistry, Genetics and Molecular Biology, Mice, Inbred C57BL, PPAR gamma, Mice, Cholesterol, Liver, CCAAT-Enhancer-Binding Protein-alpha, Animals, Obesity, RNA, Messenger, Triglycerides, Research Article
Abstract

Background/Aim: Dark tea, made by fermentation of tea leaves using microorganisms, is well known for its anti-obesity effect; however, studies to identify this effect have not been sufficiently conducted. Herein, the anti-obesity effects of post-fermented dark tea were studied in high-fat diet mouse. Materials and Methods: Obesity was induced through a high-fat diet in C57BL/6 mice, and then dark tea extract powder (DTP) was orally administered daily for 12 weeks to evaluate the body and organ weights. Changes in the biochemical markers of obesity were evaluated to study the mechanism of the anti-obesity effects of DTP. Results: When DTP was administered to obesity mice, the weight and food intake reduced, blood aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) decreased, whereas high-density lipoprotein cholesterol (HDL-C) increased. Histopathology showed that steatosis and inflammation scores were reduced within the liver and adipocyte sizes were reduced within epididymal adipocyte. In addition, a significant decrease in blood insulin and hepatic TG and a significant increase in blood adiponectin were also confirmed. The results of western blot and qPCR in week 12, showed a significant decrease in the mRNA and protein levels of C/EBPα, and the mRNA levels of PPARγ in the liver. Conclusion: Dark tea extracts are thought to have an anti-obesity effect by reducing the levels of the main transcription factors that promote adipocyte differentiation, such as C/EBPα, and PPARγ. Therefore, diet products using dark tea extracts could be developed.

Published
2022

36. Development and validation of a prognostic scoring model to risk stratify childhood acute myeloid leukaemia

Author

Jun Li, Lipeng Liu, Ranran Zhang, Yang Wan, Xiaowen Gong, Li Zhang, Wenyu Yang, Xiaojuan Chen, Yao Zou, Yumei Chen, Ye Guo, Min Ruan, and Xiaofan Zhu

Subjects
Leukemia, Myeloid, Acute, Myeloproliferative Disorders, fms-Like Tyrosine Kinase 3, Mutation, CCAAT-Enhancer-Binding Protein-alpha, Humans, Nuclear Proteins, Hematology, Child, Prognosis
Abstract

To create a personal prognostic model and modify the risk stratification of paediatric acute myeloid leukaemia, we downloaded the clinical data of 597 patients from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database as a training set and included 189 patients from our centre as a validation set. In the training set, age at diagnosis, -7/del(7q) or -5/del(5q), core binding factor fusion genes, FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)/nucleophosmin 1 (NPM1) status, Wilms tumour 1 (WT1) mutation, biallelic CCAAT enhancer binding protein alpha (CEBPA) mutation were strongly correlated with overall survival and included to construct the model. The prognostic model demonstrated excellent discriminative ability with the Harrell's concordance index of 0.68, 3- and 5-year area under the receiver operating characteristic curve of 0.71 and 0.72 respectively. The model was validated in the validation set and outperformed existing prognostic systems. Additionally, patients were stratified into three risk groups (low, intermediate and high risk) with significantly distinct prognosis, and the model successfully identified candidates for haematopoietic stem cell transplantation. The newly developed prognostic model showed robust ability and utility in survival prediction and risk stratification, which could be helpful in modifying treatment selection in clinical routine.

Published
2022

37. Galloyl Group in B-type Proanthocyanidin Dimers Was Responsible for Its Differential Inhibitory Activity on 3T3-L1 Preadipocytes due to the Strong Lipid Raft-Perturbing Potency

Author

Ruifeng Wang, Wei Zhu, Meizhu Dang, and Chun-mei Li

Subjects
0106 biological sciences, Dimer, 01 natural sciences, Mice, chemistry.chemical_compound, Membrane Microdomains, B type proanthocyanidin, 3T3-L1 Cells, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, Proanthocyanidins, Procyanidin B2, Lipid raft, Adipogenesis, biology, 010401 analytical chemistry, Cell Differentiation, 3T3-L1, General Chemistry, Peroxisome, 0104 chemical sciences, PPAR gamma, Fatty acid synthase, chemistry, Biophysics, biology.protein, General Agricultural and Biological Sciences, 010606 plant biology & botany
Abstract

The effects of three B-type proanthocyanidin (PA) dimers covering procyanidin B2 (B-0g), procyanidin B2 3'-O-gallate (B-1g), and procyanidin B2 3,3'-di-O-gallate (B-2g) on 3T3-L1 preadipocyte differentiation and the underlying mechanisms were investigated. The results showed that digalloylated B-type PA dimers (B-2g) strongly inhibited 3T3-L1 preadipocyte differentiation through disrupting the integrity of the lipid raft structure and inhibiting the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα) and then downregulating the expression of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) factors, followed by B-1g, while B-0g had little effect. The different inhibitory effects were mainly due to the difference in the B-type PA dimer structure and the ability to interfere with lipid rafts. The greater the galloylation degree of B-type PA dimers, the stronger the ability to disrupt the lipid raft structure and oppose 3T3-L1 preadipocyte differentiation. In addition, galloylated B-type PA dimers had greater molecular hydrophobicity and topological polarity surface area and could penetrate into the lipid rafts to form multiple hydrogen bonds with the rafts by molecular dynamics simulation. These findings highlighted that the strong lipid raft-perturbing potency of galloylated B-type PA dimers was responsible for inhibition of 3T3-L1 preadipocyte differentiation.

Published
2021

38. C/EBPα is indispensable for PML/RARα-mediated suppression of long non-coding RNA NEAT1 in acute promyelocytic leukemia cells

Author

Doudou Tang, Piao Hu, Dengqin Zhu, Yewei Wang, Mingjie Chen, Guangsen Zhang, and Yujiao Luo

Subjects
Acute promyelocytic leukemia, Transcriptional Activation, Aging, Cellular differentiation, Retinoic acid, NEAT1, Tretinoin, PML/RARα, chemistry.chemical_compound, Transactivation, Downregulation and upregulation, Leukemia, Promyelocytic, Acute, medicine, CCAAT-Enhancer-Binding Protein-alpha, Humans, transcriptional regulation, neoplasms, Chemistry, Retinoic Acid Receptor alpha, Myeloid leukemia, Cell Differentiation, Cell Biology, medicine.disease, Cell biology, Up-Regulation, APL, Retinoic acid receptor, Leukemia, C/EBPα, RNA, Long Noncoding, Research Paper
Abstract

Better understanding of the transcriptional regulatory network in acute promyelocytic leukemia (APL) cells is critical to illustrate the pathogenesis of other types of acute myeloid leukemia. Previous studies have primarily focused on the retinoic acid signaling pathway and how it is interfered with by promyelocytic leukemia/retinoic acid receptor-α (PML/RARα) fusion protein. However, this hardly explains how APL cells are blocked at the promyelocytic stage. Here, we demonstrated that C/EBPα bound and transactivated the promoter of long non-coding RNA NEAT1, an essential element for terminal differentiation of APL cells, through C/EBP binding sites. More importantly, PML/RARα repressed C/EBPα-mediated transactivation of NEAT1 through binding to NEAT1 promoter. Consistently, mutation of the C/EBP sites or deletion of retinoic acid responsive elements (RAREs) and RARE half motifs abrogated the PML/RARα-mediated repression. Moreover, silencing of C/EBPα attenuated ATRA-induced NEAT1 upregulation and APL cell differentiation. Finally, simultaneous knockdown of C/EBPα and C/EBPβ reduces ATRA-induced upregulation of C/EBPe and dramatically impaired NEAT1 activation and APL cell differentiation. In sum, C/EBPα binds and transactivates NEAT1 whereas PML/RARα represses this process. This study describes an essential role for C/EBPα in PML/RARα-mediated repression of NEAT1 and suggests that PML/RARα could contribute to the pathogenesis of APL through suppressing C/EBPα targets.

Published
2021

39. ACOX1, regulated by C/EBPα and miR-25-3p, promotes bovine preadipocyte adipogenesis

Author

Hu Tao, Li Xiaofeng, Qi Xiong, Suo Xiaojun, Feng Zhang, Mingxin Chen, Yang Qianping, Yang Liu, and Zhang Nian

Subjects
Male, 0301 basic medicine, Transcription, Genetic, Down-Regulation, 030209 endocrinology & metabolism, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, Luciferase, Promoter Regions, Genetic, 3' Untranslated Regions, Molecular Biology, Transcription factor, chemistry.chemical_classification, Adipogenesis, Base Sequence, Chemistry, Research, bovine, CEBPα, Fatty acid, Promoter, Peroxisome, Molecular biology, MicroRNAs, 030104 developmental biology, miR-25-3p, ACOX1, Cattle, Acyl-CoA Oxidase, Chromatin immunoprecipitation, Protein Binding
Abstract

Acyl-coenzyme A oxidase 1 (ACOX1) is the first and rate-limiting enzyme in peroxisomal fatty acid β-oxidation of fatty acids. Previous studies have reported that ACOX1 was correlated with the meat quality of livestock, while the role of ACOX1 in intramuscular adipogenesis of beef cattle and its transcriptional and post-transcriptional regulatory mechanisms remain unclear. In the present study, gain-of-function and loss-of-function assays demonstrated that ACOX1 positively regulated the adipogenesis of bovine intramuscular preadipocytes. The C/EBPα-binding sites in the bovine ACOX1 promoter region at −1142 to −1129 bp, −831 to −826 bp, and −303 to −298 bp were identified by promoter deletion analysis and site-directed mutagenesis. Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) further showed that these three regions are C/EBPα-binding sites, both in vitro and in vivo, indicating that C/EBPα directly interacts with the bovine ACOX1 promoter and inhibits its transcription. Furthermore, the results from bioinformatics analysis, dual luciferase assay, site-directed mutagenesis, qRT-PCR, and Western blotting demonstrated that miR-25-3p directly targeted the ACOX1 3’UTR (3’UTR). Taken together, our findings suggest that ACOX1, regulated by transcription factor C/EBPα and miR-25-3p, promotes adipogenesis of bovine intramuscular preadipocytes via regulating peroxisomal fatty acid β-oxidation.

Published
2021

40. Effects of SPARCL1 on the proliferation and differentiation of sheep preadipocytes

Author

Cheng Xiao, Hai Guo Jin, Li Chun Zhang, Jian Qiang Liu, Ming He, Hui Hai Ma, Yong Sheng Yu, and Yang Cao

Subjects
Extracellular Matrix Proteins, sheep, Adipogenesis, Histology, QH573-671, Physiology, preadipocyte, proliferation, Calcium-Binding Proteins, apoptosis, Cell Differentiation, differentiation, Cell Biology, RC648-665, Diseases of the endocrine glands. Clinical endocrinology, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, sparcl1, QP1-981, Cytology, Cell Proliferation, Research Article, Research Paper
Abstract

Important candidate genes that regulate lipid metabolism have the potential to increase the content of intramuscular fat (IMF) and improve meat quality. Secreted protein acidic and rich in cysteine like 1(SPARCL1) is a secreted glycoprotein with important physiological functions and is involved in the proliferation and differentiation of various cells. However, the role of the SPARCL1 gene in sheep preadipocytes and its regulatory mechanism is still unclear. In this study, we explored the effect of SPARCL1 on the proliferation and differentiation of sheep preadipocytes. The results showed that the expression level of the SPARCL1 gene is higher in fat tissue than in other tissues, and the gene was significantly increased on the 6th day of preadipocyte differentiation. In the preadipocyte proliferation stage, interference of SPARCL1 gene reduced cell viability and increased cell apoptosis. In preadipocyte differentiation stage, SPARCL1 overexpression significantly inhibited lipid droplets accumulation and triglyceride content by increasing Wnt10b, Fzd8, IL6, and β-catenin and inhibiting PPARγ, C/EBPα, LPL, and IGF1 genes expression, whereas SPARCL1 deficiency significantly promoted cell differentiation by inhibiting β-catenin and increasing GSK3β, PPARγ, C/EBPα, and LPL. The results of this study suggest that SPARCL1 plays a negative role during preadipocyte differentiation and may become a novel target for regulating preadipocyte differentiation and improving IMF. Abbreviations: IMF: Intramuscular fat SPARCL1: Secreted protein acidic and rich in cysteine like 1 PPARγ: Peroxisome proliferator-activated receptor γ C/EBPα: CCAAT/enhancer-binding protein-α LPL: Lipoprotein lipase IGF1: Insulin-like growth factor 1 Wnt10b: Wnt family member 10B Fzd8: Frizzled class receptor 8 IL6: Interleukin 6 β-catenin: Catenin beta interacting protein 1 GSK3β: Glycogen synthase kinase 3 beta LRP5/6: Low-density lipoprotein receptor-related protein 5/6

Published
2021

41. C/EBP

Author

Heng, Lu, Yi, Chen, Yinhai, Chen, Lingchen, Huang, and Liangwan, Chen

Subjects
Sirolimus, Transcriptional Activation, Phosphatidylinositol-4-Phosphate 3-Kinase, Muscle, Smooth, Vascular, Rats, Aortic Dissection, Phenotype, Matrix Metalloproteinase 9, Autophagy, CCAAT-Enhancer-Binding Protein-alpha, Animals, Matrix Metalloproteinase 2, Beclin-1, RNA, Small Interfering, Cells, Cultured
Abstract

To investigate the function of C/EBPAortic vascular smooth muscle cells (VSMCs) were isolated, cultured, and identified from AD rats. Then, C/EBPThe protein levels of C/EBPOur data indicated that during the development of AD, C/EBP

Published
2022

42. Derhamnosylmaysin Inhibits Adipogenesis via Inhibiting Expression of PPARγ and C/EBPα in 3T3-L1 Cells

Author

Hang-Hee Cho, Sun-Hee Jang, Chungkil Won, Chung-Hui Kim, Hong-Duck Kim, Tae Hoon Kim, and Jae-Hyeon Cho

Subjects
Flavonoids, Adipogenesis, Organic Chemistry, Insulins, Pharmaceutical Science, Cell Differentiation, Lipids, Analytical Chemistry, PPAR gamma, Mice, Glucosides, Chemistry (miscellaneous), 3T3-L1 Cells, Drug Discovery, CCAAT-Enhancer-Binding Protein-alpha, CCAAT-Enhancer-Binding Proteins, Molecular Medicine, Animals, Anti-Obesity Agents, Physical and Theoretical Chemistry, adipogenesis, Akt, derhamnosylmaysin, lipogenesis, 3T3-L1 cells, Sterol Regulatory Element Binding Protein 1, Proto-Oncogene Proteins c-akt
Abstract

We investigated the effects of derhamnosylmaysin (DM) on adipogenesis and lipid accumulation in 3T3-L1 adipocytes. Our data showed that DM inhibited lipid accumulation and adipocyte differentiation in 3T3-L1 cells. Treatment of 3T3-L1 adipocytes with DM decreased the expression of major transcription factors, such as sterol regulatory element-binding protein-1c (SREBP-1c), the CCAAT-enhancer-binding protein (CEBP) family, and peroxisome proliferator-activated receptor gamma (PPARγ), in the regulation of adipocyte differentiation. Moreover, the expression of their downstream target genes related to adipogenesis and lipogenesis, including adipocyte fatty acid-binding protein (aP2), lipoprotein lipase (LPL), stearyl-CoA-desaturase-1 (SCD-1), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS), was also decreased by treatment with DM during adipogenesis. Additionally, DM attenuated insulin-stimulated phosphorylation of Akt. These results first demonstrated that DM inhibited adipogenesis and lipogenesis through downregulation of the key adipogenic transcription factors SREBP-1c, the CEBP family, and PPARγ and inactivation of the major adipogenesis signaling factor Akt, which is intermediated in insulin. These studies demonstrated that DM is a new bioactive compound for antiadipogenic reagents for controlling overweight and obesity.

Published
2022

43. Mutant C/EBPα p30 alleviates immunosuppression of CD8

Author

Jun-Dan, Wang, Jue-Qiong, Xu, Xue-Ning, Zhang, Ze-Wei, Huang, Ling-Ling, Liu, Ling, Zhang, Xin-Xing, Lei, Man-Jie, Xue, Jian-Yu, Weng, and Zi-Jie, Long

Subjects
Immunosuppression Therapy, Leukemia, Myeloid, Acute, CCAAT-Enhancer-Binding Protein-alpha, Leukocytes, Mononuclear, Autophagy, Humans, CD8-Positive T-Lymphocytes
Abstract

Mutant C/EBPα p30 (mp30), the product of C/EBPα double mutations (DM), lacks transactivation domain 1 and has C-terminal loss-of-function mutation. Acute myeloid leukaemia (AML) patients harbouring C/EBPα DM could be classified as a distinct subgroup with favourable prognosis. However, the underlying mechanism remains elusive.Autophagy regulated by mp30 was detected by western blot and immunofluorescence. Immune infiltration analysis and GSEA were performed to investigate autophagic and inflammatory status of AML patients from the GSE14468 cohort. Flow cytometry was applied to analyse T cell activation.Mp30 inhibited autophagy by suppressing nucleus translocation of NF-κB. Autophagy-associated secretion of IL-1β was decreased in mp30-overexpressed AML cells. Bioinformatic analysis revealed that inflammatory status was attenuated, while CD8C/EBPα DM alleviates immunosuppression of CD8

Published
2022

44. MiR-144 regulates adipogenesis by mediating formation of C/EBPα-FOXO1 protein complex

Author

Weimin Lin, Xianyu Wen, Xuexin Li, Lei Chen, Wei Wei, Lifan Zhang, and Jie Chen

Subjects
Adipogenesis, Forkhead Box Protein O1, Biophysics, Cell Differentiation, Cell Biology, Biochemistry, Mice, MicroRNAs, 3T3-L1 Cells, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, RNA, Messenger, Molecular Biology
Abstract

CeRNA effect was an important regulation mode of miRNA mediated bio-activities, however, most of the researches of ceRNA were on ncRNAs synergetic with mRNAs, the exploration of ceRNA effect regulated mRNA interaction was still lack of. Besides, C/EBPα was one of the most crucial adipogenic regulators, which has been demonstrated to form a protein complex with FOXO1 to mediate AdipoQ expression. So that, we try to explore whether the ceRNA effect mediated the interaction of C/EBPα and FOXO1, and identified the key miRNAs of their ceRNA effect. In this paper, we found the ceRNA effect of C/EBPα and FOXO1 mediated their protein complex formation, furthermore regulated its transcriptional role for AdipoQ, thereby influencing pre-adipocytes adipogenesis. More importantly, we demonstrated that the miR-144 was the decisive factor that mediated the ceRNA effect of C/EBPα and FOXO1 to influence AdipoQ, thus regulated pre-adipocytes adipogenesis. This research will provide a new supplementary idea of the miRNA role in mediating coding RNA interaction that regulates pre-adipocyte adipogenesis.

Published
2022

45. C/EBPα promotes porcine pre-adipocyte proliferation and differentiation via mediating MSTRG.12568.2/FOXO3 trans-activation for STYX

Author

Weimin Lin, Lei Chen, Wenjing Meng, Kai Yang, Shengjuan Wei, Wei Wei, Jie Chen, and Lifan Zhang

Subjects
Adipogenesis, Swine, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, RNA, Long Noncoding, Cell Biology, RNA, Messenger, Molecular Biology, Cell Proliferation
Abstract

As a key adipogenic marker, C/EBPα (CCAAT/enhancer binding protein α) is also an important factor in regulating targets containing CCAAT element for transcription, whose products include coding and non-coding RNAs (ncRNAs). However, knowledge of the mechanism of C/EBPα affecting pre-adipocyte proliferation and adipogenesis through regulating ncRNA is still limited. In this study, we firstly conducted an investigation concerning the impact of C/EBPα knockdown on porcine pre-adipocytes by using RNA sequencing (RNA-Seq) to identify the role of key ncRNAs, especially lncRNAs and their correlated mRNAs in regulating proliferation and differentiation of porcine pre-adipocytes. 97 differentially expressed (DE) mRNAs and 4 DE lncRNAs were identified in si-C/EBPα groups compared with the si-NC groups. Meanwhile, we found C/EBPα directly target the promoter of a novel lncRNA, namely MSTRG.12568.2, which was trans-correlated with STYX (serine/threonine/tyrosine interacting protein), an important candidate gene for regulating cell proliferation. Moreover, FOXO3 (forkhead box O3) was identified as a co-regulator with MSTR.12568.2 for STYX. Overexpression and knockdown of any of the MSTRG.12568.2, STYX, and FOXO3 increased and decreased the levels of pre-adipocyte proliferation and differentiation, respectively, which demonstrated that they played a positive role in adipogenesis of pre-adipocytes. Furthermore, our results revealed that FOXO3 was necessary for MSTRG.12568.2 to trans-activate STYX. We revealed that C/EBPα regulated pre-adipocyte proliferation and differentiation through mediating trans-activation of MSTRG.12568.2-FOXO3 to STYX. These results provide a novel regulation signal for C/EBPα to influence porcine pre-adipocyte proliferation and differentiation and greatly benefit to our understanding of molecular mechanism regulating subcutaneous adipogenesis.

Published
2022

46. Novel

Author

Kyung Dong, Lee, Soundharrajan, Ilavenil, Muthusamy, Karnan, Chul-Ju, Yang, Dahye, Kim, and Ki Choon, Choi

Subjects
Adipogenesis, GTPase-Activating Proteins, Bacillus, Cell Differentiation, p38 Mitogen-Activated Protein Kinases, PPAR gamma, Mice, Glucose, 3T3-L1 Cells, Adipocytes, CCAAT-Enhancer-Binding Protein-alpha, Animals, Sterol Regulatory Element Binding Protein 1, Proto-Oncogene Proteins c-akt
Abstract

The health benefits of probiotics have been known for decades, but there has only been limited use of probiotics in the treatment of obesity. In this study, we describe, for the first time, the role of cell-free metabolites (CM) from

Published
2022

47. C/EBPα Epigenetically Modulates

Author

Huan, Qu, Qiufang, Zong, Haifei, Wang, Shenglong, Wu, Demin, Cai, and Wenbin, Bao

Subjects
Coronavirus, Inflammation, Jejunum, Swine, Porcine epidemic diarrhea virus, CCAAT-Enhancer-Binding Protein-alpha, Animals, Trefoil Factor-1, Coronavirus Infections, Methylation, Epigenesis, Genetic
Abstract

Porcine epidemic diarrhea virus (PEDV) is an emerging coronavirus which causes acute diarrhea and destroys gastrointestinal barrier function in neonatal pigs. Trefoil factor 1 (TFF1) is a protective peptide for maintaining the integrity of gastrointestinal mucosa and reducing intestinal inflammation. However, its role in protecting intestinal epithelium against PEDV infection is still unclear. In this study, we discovered that TFF1 expression was activated in the jejunum of pigs with PEDV infection and TFF1 is required for the growth of porcine intestinal epithelial cells. For instance, inhibited cell proliferation and cell arrest were observed when

Published
2022

48. Stevioside Enhances the Anti-Adipogenic Effect and β-Oxidation by Activating AMPK in 3T3-L1 Cells and Epididymal Adipose Tissues of db/db Mice

Author

Miey Park, Hana Baek, Jin-Young Han, and Hae-Jeung Lee

Subjects
Mice, Adipogenesis, Glucosides, 3T3-L1 Cells, CCAAT-Enhancer-Binding Protein-alpha, Animals, General Medicine, stevioside, adipogenesis, 3T3-L1 preadipocytes, differentiation, db/db mice, AMP-Activated Protein Kinases, Diterpenes, Kaurane
Abstract

Stevioside, the primary sweetener in stevia, is a glycoside with numerous beneficial biological activities. However, its anti-adipogenic effects on tissue differentiation and adipose tissues remain to be thoroughly investigated. In this study, the anti-adipogenic effects of stevioside during the differentiation of 3T3-L1 cells and epididymal adipose tissues of db/db mice were investigated by measuring the lipid droplets stained with Oil Red O and an immunoblot assay. Immunoblot analysis revealed that stevioside downregulated the expression of peroxisome proliferator-activated receptor-gamma (PPARγ), sterol regulatory element-binding protein-1c (SREBP-1c), CCAAT/enhancer-binding protein alpha (C/EBPα), and fatty acid synthase (FAS). Additionally, the protein expression of carnitine palmitoyltransferase 1 (CPT1), silent mating type information regulation 2 homolog 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) increased following treatment with stevioside. Furthermore, stevioside increased the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), both in vitro and in vivo. The activity of AMPK in stevioside-treated 3T3-L1 cells was further confirmed using agonists and antagonists of AMPK signaling. Our data indicate that stevioside ameliorates anti-adipogenic effects and promotes β-oxidation in adipocytes by activating AMPK-mediated signaling. The results of this study clearly demonstrated the inhibitory effect of stevioside on the differentiation of adipocytes and the reduction of lipid accumulation in the epididymal adipose tissues of db/db mice.

Published
2022
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49. Tentatively Identified (UPLC/T-TOF-MS/MS) Compounds in the Extract of

Author

Heba A, El Gizawy, Alaadin E, El-Haddad, Amr M, Saadeldeen, and Sylvia A, Boshra

Subjects
Saussurea, Interleukin-6, Plant Extracts, Tumor Necrosis Factor-alpha, Caspase 2, Catalase, Plant Roots, Antioxidants, Rats, MicroRNAs, Sirtuin 1, Tandem Mass Spectrometry, CCAAT-Enhancer-Binding Protein-alpha, Animals, Hepatocyte Nuclear Factor 1-alpha
Published
2022

50. ADAR1 inhibits adipogenesis and obesity by interacting with Dicer to promote the maturation of miR-155-5P

Author

Zuying Yu, Ruijie Luo, Yutian Li, Xiaoguang Li, Zhengrui Yang, Jiangtong Peng, and Kai Huang

Subjects
Ribonuclease III, Adipogenesis, Adenosine Deaminase, Cell Differentiation, Cell Biology, DEAD-box RNA Helicases, PPAR gamma, Mice, MicroRNAs, Adipose Tissue, 3T3-L1 Cells, CCAAT-Enhancer-Binding Protein-alpha, Animals, Obesity
Abstract

Adipogenesis is closely related to various metabolic diseases, such as obesity, type 2 diabetes, cardiovascular diseases and cancer. This cellular process is highly dependent on the expression and sequential activation of a diverse group of transcription factors. Here, we report that ADAR1 (also known as ADAR) could inhibit adipogenesis through binding with Dicer (also known as DICER1), resulting in enhanced production of miR-155-5p, which downregulates the adipogenic early transcription factor C/EBPβ. Consequently, the expression levels of late-stage adipogenic transcription factors (C/EBPα and PPARγ) are reduced and adipogenesis is inhibited. More importantly, in vivo studies reveal that overexpression of ADAR1 suppresses white adipose tissue expansion in high fat diet-induced obese mice, leading to improved metabolic phenotypes, such as insulin sensitivity and glucose tolerance.

Published
2022

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