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Yu Q, Xiao Y, Guan M, Zhou G, Zhang X, Yu J, Han M, Yang W, Wang Y, Li Z. Regulation of ferroptosis in osteoarthritis and osteoarthritic chondrocytes by typical MicroRNAs in chondrocytes. Front Med (Lausanne) 2024; 11:1478153. [PMID: 39564502 PMCID: PMC11573538 DOI: 10.3389/fmed.2024.1478153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 10/01/2024] [Indexed: 11/21/2024] Open
Abstract
Osteoarthritis (OA) is a progressive degenerative disorder impacting bones and joints, worsened by chronic inflammation, immune dysregulation, mechanical stress, metabolic disturbances, and various other contributing factors. The complex interplay of cartilage damage, loss, and impaired repair mechanisms remains a critical and formidable aspect of OA pathogenesis. At the genetic level, multiple genes have been implicated in the modulation of chondrocyte metabolism, displaying both promotive and inhibitory roles. Recent research has increasingly focused on the influence of non-coding RNAs in the regulation of distinct cell types within bone tissue in OA. In particular, an expanding body of evidence highlights the regulatory roles of microRNAs in OA chondrocytes. This review aims to consolidate the most relevant microRNAs associated with OA chondrocytes, as identified in recent studies, and to elucidate their involvement in chondrocyte metabolic processes and ferroptosis. Furthermore, this study explores the complex regulatory interactions between long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in OA, with an emphasis on microRNA-mediated mechanisms. Finally, critical gaps in the current research are identified, offering strategic insights to advance the understanding of OA pathophysiology and guide therapeutic developments in this field.
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Affiliation(s)
- Qingyuan Yu
- Clinical College of Integrated Traditional Chinese and Western Medicine, Changchun University of Traditional Chinese Medicine, Changchun, Jilin, China
| | - Yanan Xiao
- Clinical College of Integrated Traditional Chinese and Western Medicine, Changchun University of Traditional Chinese Medicine, Changchun, Jilin, China
| | - Mengqi Guan
- Clinical College of Integrated Traditional Chinese and Western Medicine, Changchun University of Traditional Chinese Medicine, Changchun, Jilin, China
| | - Guohui Zhou
- Clinical College of Integrated Traditional Chinese and Western Medicine, Changchun University of Traditional Chinese Medicine, Changchun, Jilin, China
| | - Xianshuai Zhang
- Clinical College of Integrated Traditional Chinese and Western Medicine, Changchun University of Traditional Chinese Medicine, Changchun, Jilin, China
| | - Jianan Yu
- Clinical College of Integrated Traditional Chinese and Western Medicine, Changchun University of Traditional Chinese Medicine, Changchun, Jilin, China
| | - Mingze Han
- Clinical College of Integrated Traditional Chinese and Western Medicine, Changchun University of Traditional Chinese Medicine, Changchun, Jilin, China
| | - Wei Yang
- Clinical College of Integrated Traditional Chinese and Western Medicine, Changchun University of Traditional Chinese Medicine, Changchun, Jilin, China
| | - Yan Wang
- Scientific Research Center, China-Japan Friendship Hospital of Jilin University, Changchun, Jilin, China
| | - Zhenhua Li
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, Jilin, China
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Liu Y, Wu Y, Wang C, Hu W, Zou S, Ren H, Zuo Y, Qu L. MiR-127-3p enhances macrophagic proliferation via disturbing fatty acid profiles and oxidative phosphorylation in atherosclerosis. J Mol Cell Cardiol 2024; 193:36-52. [PMID: 38795767 DOI: 10.1016/j.yjmcc.2024.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 05/05/2024] [Accepted: 05/21/2024] [Indexed: 05/28/2024]
Abstract
BACKGROUND Atherosclerosis is a chronic pathology, leading to acute coronary heart disease or stroke. MiR-127 has been found significantly upregulated in advanced atherosclerosis. But its function in atherosclerosis remains unexplored. We explored the role of miR-127-3p in regulating atherosclerosis development and its downstream mechanisms. METHODS The expression profile of miR-127 in carotid atherosclerotic plaques of 23 patients with severe carotid stenosis was detected by RT-qPCR and in situ hybridization. Primary bone marrow-derived macrophages (BMDM) stimulated with oxidized low-density lipoprotein were used as an in vitro model. CCK-8, EdU, RT-qPCR, and flow cytometry were used to detect the proliferative capacity and polarization of BMDM, which were infected by lentivirus-carrying plasmid to upregulate or downregulate miR-127-3p expression, respectively. RNA sequencing combined with bioinformatic analysis and targeted fatty acid metabolomics approach were used to detect the transcriptome and lipid metabolites. The association between miR-127-3p and its target was verified by dual-luciferase activity reporting and Western blotting. Oxygen consumption rate of BMDM were detected using seahorse analysis. High-cholesterol-diet-fed low density lipoprotein deficient (LDLR-/-) mice, with-or-without carotid tandem-stenosis surgery, were treated with miR-127-3p agomir or antagomir to examine its effect on plaque development and stability. RESULTS miR-127-3p, not -5p, is elevated in human advanced carotid atheroma and its expression is positively associated with macrophage accummulation in plaques. In vitro, miR-127-3p-overexpressed macrophage exhibites increased proliferation capacity and facilitates M1 polariztion whereas the contrary trend is present in miR-127-3p-inhibited macrophage. Stearoyl-CoA desaturase-1 (SCD1) is one potential target of miR-127-3p. miR-127-3p mimics decreases the activity of 3' untranslated regions of SCD-1. Furthermore, miR-127-3p downregulates SCD1 expression, and reversing the expression of SCD1 attenuates the increased proliferation induced by miR-127-3p overexpression in macrophage. miR-127-3p overexpression could also lead to decreased content of unsaturated fatty acids (UFAs), increased content of acetyl CoA and increased level of oxidative phosphorylation. In vivo, miR-127-3p agomir significantly increases atherosclerosis progression, macrophage proliferation and decreases SCD1 expression and the content of UFAs in aortic plaques of LDLR-/- mice. Conversely, miR-127-3p antagomir attenuated atherosclerosis, macrophage proliferation in LDLR-/- mice, and enhanced carotid plaque stability in mice with vulnerable plaque induced. CONCLUSION MiR-127-3p enhances proliferation in macrophages through downregulating SCD-1 expression and decreasing the content of unsaturated fatty acid, thereby promoting atherosclerosis development and decreasing plaque stability. miR-127-3p/SCD1/UFAs might provide potential therapeutic target for anti-inflammation and atherosclerosis.
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Affiliation(s)
- Yandong Liu
- Department of Geriatrics, 905th Hospital of PLA NAVY, Shanghai, China; Department of Vascular and Endovascular Surgery, Changzheng Hospital Affiliated to the Naval Medical University, Shanghai 200003, China
| | - Yicheng Wu
- Department of Vascular and Endovascular Surgery, Changzheng Hospital Affiliated to the Naval Medical University, Shanghai 200003, China
| | - Chao Wang
- Department of Vascular and Endovascular Surgery, Changzheng Hospital Affiliated to the Naval Medical University, Shanghai 200003, China
| | - Weilin Hu
- Department of Vascular and Endovascular Surgery, Changzheng Hospital Affiliated to the Naval Medical University, Shanghai 200003, China
| | - Sili Zou
- Department of Vascular and Endovascular Surgery, Changzheng Hospital Affiliated to the Naval Medical University, Shanghai 200003, China
| | - Huiqiong Ren
- Department of Geriatrics, 905th Hospital of PLA NAVY, Shanghai, China.
| | - Yong Zuo
- Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Lefeng Qu
- Department of Vascular and Endovascular Surgery, Changzheng Hospital Affiliated to the Naval Medical University, Shanghai 200003, China.
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Shrestha S, Tieu T, Wojnilowicz M, Voelcker NH, Forsythe JS, Frith JE. Delivery of miRNAs Using Porous Silicon Nanoparticles Incorporated into 3D Hydrogels Enhances MSC Osteogenesis by Modulation of Fatty Acid Signaling and Silicon Degradation. Adv Healthc Mater 2024; 13:e2400171. [PMID: 38657207 DOI: 10.1002/adhm.202400171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 04/10/2024] [Indexed: 04/26/2024]
Abstract
Strategies incorporating mesenchymal stromal cells (MSC), hydrogels and osteoinductive signals offer promise for bone repair. Osteoinductive signals such as growth factors face challenges in clinical translation due to their high cost, low stability and immunogenicity leading to interest in microRNAs as a simple, inexpensive and powerful alternative. The selection of appropriate miRNA candidates and their efficient delivery must be optimised to make this a reality. This study evaluated pro-osteogenic miRNAs and used porous silicon nanoparticles modified with polyamidoamine dendrimers (PAMAM-pSiNP) to deliver these to MSC encapsulated within gelatin-PEG hydrogels. miR-29b-3p, miR-101-3p and miR-125b-5p are strongly pro-osteogenic and are shown to target FASN and ELOVL4 in the fatty acid biosynthesis pathway to modulate MSC osteogenesis. Hydrogel delivery of miRNA:PAMAM-pSiNP complexes enhanced transfection compared to 2D. The osteogenic potential of hBMSC in hydrogels with miR125b:PAMAM-pSiNP complexes is evaluated. Importantly, a dual-effect on osteogenesis occurred, with miRNAs increasing expression of alkaline phosphatase (ALP) and Runt-related transcription factor 2 (RUNX2) whilst the pSiNPs enhanced mineralisation, likely via degradation into silicic acid. Overall, this work presents insights into the role of miRNAs and fatty acid signalling in osteogenesis, providing future targets to improve bone formation and a promising system to enhance bone tissue engineering.
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Affiliation(s)
- Surakshya Shrestha
- Department of Materials Science and Engineering, Monash University, Clayton, VIC, 3800, Australia
| | - Terence Tieu
- Melbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility, Clayton, VIC, 3168, Australia
- Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia
- Commonwealth Scientific and Industrial Research Organisation (CSIRO) Manufacturing, Bayview Avenue, Clayton, VIC, 3168, Australia
| | - Marcin Wojnilowicz
- Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia
- Commonwealth Scientific and Industrial Research Organisation (CSIRO) Manufacturing, Bayview Avenue, Clayton, VIC, 3168, Australia
| | - Nicolas H Voelcker
- Department of Materials Science and Engineering, Monash University, Clayton, VIC, 3800, Australia
- Melbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility, Clayton, VIC, 3168, Australia
- Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia
- Commonwealth Scientific and Industrial Research Organisation (CSIRO) Manufacturing, Bayview Avenue, Clayton, VIC, 3168, Australia
- ARC Training Centre for Cell and Tissue Engineering Technologies, Monash University, Clayton, VIC, 3800, Australia
| | - John S Forsythe
- Department of Materials Science and Engineering, Monash University, Clayton, VIC, 3800, Australia
- ARC Training Centre for Cell and Tissue Engineering Technologies, Monash University, Clayton, VIC, 3800, Australia
| | - Jessica E Frith
- Department of Materials Science and Engineering, Monash University, Clayton, VIC, 3800, Australia
- ARC Training Centre for Cell and Tissue Engineering Technologies, Monash University, Clayton, VIC, 3800, Australia
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, 3800, Australia
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Xie L, Ma C, Li X, Chen H, Han P, Lin L, Huang W, Xu M, Lu H, Du Z. Efficacy of Glycyrrhetinic Acid in the Treatment of Acne Vulgaris Based on Network Pharmacology and Experimental Validation. Molecules 2024; 29:2345. [PMID: 38792208 PMCID: PMC11123902 DOI: 10.3390/molecules29102345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/10/2024] [Accepted: 05/12/2024] [Indexed: 05/26/2024] Open
Abstract
Glycyrrhetinic acid (GA) is a saponin compound, isolated from licorice (Glycyrrhiza glabra), which has been wildly explored for its intriguing pharmacological and medicinal effects. GA is a triterpenoid glycoside displaying an array of pharmacological and biological activities, including anti-inflammatory, anti-bacterial, antiviral and antioxidative properties. In this study, we investigated the underlying mechanisms of GA on acne vulgaris through network pharmacology and proteomics. After the intersection of the 154 drug targets and 581 disease targets, 37 therapeutic targets for GA against acne were obtained. A protein-protein interaction (PPI) network analysis highlighted TNF, IL1B, IL6, ESR1, PPARG, NFKB1, STAT3 and TLR4 as key targets of GA against acne, which is further verified by molecular docking. The experimental results showed that GA inhibited lipid synthesis in vitro and in vivo, improved the histopathological damage of skin, prevented mast cell infiltration and decreased the level of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6. This study indicates that GA may regulate multiple pathways to improve acne symptoms, and the beneficial effects of GA against acne vulgaris might be through the regulation of sebogenesis and inflammatory responses.
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Affiliation(s)
- Lingna Xie
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China; (L.X.); (C.M.); (H.C.)
- Shenzhen Liran Cosmetics Co., Ltd., Shenzhen 518000, China (W.H.); (M.X.)
| | - Congwei Ma
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China; (L.X.); (C.M.); (H.C.)
- Shenzhen Liran Cosmetics Co., Ltd., Shenzhen 518000, China (W.H.); (M.X.)
| | - Xinyu Li
- Shenzhen Liran Cosmetics Co., Ltd., Shenzhen 518000, China (W.H.); (M.X.)
| | - Huixiong Chen
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China; (L.X.); (C.M.); (H.C.)
- Chemistry of RNA, Nucleosides, Peptides and Heterocycles, CNRS UMR8601, Université Paris Cité, 45 Rue des Saints-Pères, CEDEX 06, 75270 Paris, France
| | - Ping Han
- Foshan Allan Conney Biotechnology Co., Ltd., Foshan 528231, China; (P.H.); (L.L.)
| | - Li Lin
- Foshan Allan Conney Biotechnology Co., Ltd., Foshan 528231, China; (P.H.); (L.L.)
| | - Weiqiang Huang
- Shenzhen Liran Cosmetics Co., Ltd., Shenzhen 518000, China (W.H.); (M.X.)
| | - Menglu Xu
- Shenzhen Liran Cosmetics Co., Ltd., Shenzhen 518000, China (W.H.); (M.X.)
| | - Hailiang Lu
- Shenzhen Liran Cosmetics Co., Ltd., Shenzhen 518000, China (W.H.); (M.X.)
| | - Zhiyun Du
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China; (L.X.); (C.M.); (H.C.)
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Qi X, Yang Y, Xiong D, Wu S, Cui G, Zhang Q. ER-1 deficiency induces inflammation and lipid deposition in meibomian gland and lacrimal gland. Biochem Biophys Res Commun 2024; 696:149526. [PMID: 38241812 DOI: 10.1016/j.bbrc.2024.149526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 12/29/2023] [Accepted: 01/11/2024] [Indexed: 01/21/2024]
Abstract
PURPOSE To investigated the role of estrogen receptor-1 (ER-1) in maintaining homeostasis in ocular surface. METHODS ER-1-knockout (ER-1KO) mice were studied at 4 months of age. The ocular surface was examined using a slit lamp. Histological alterations in the meibomian gland (MG) and lacrimal gland (LG) were observed with H&E staining. Protein levels of P-ERK, peroxisome proliferator-activated receptor gamma (PPAR-γ), p-NFκB-P65, IL-1β, aquaporin 5 (AQP-5), fatty acid-binding protein 5 (Fabp5) and K10 were determined by immunofluorescence and Western blotting. Gene expressions of APO-F, APO-E, K10, ELOVL4, PPAR-γ, SCD-1, and SREBP1 were quantified by qPCR. Conjunctival (CJ) goblet cell alterations were detected by PAS staining. Lipid metabolism in MG and LG was assessed using LipidTox. Apoptosis in MG and LG was analyzed through the TUNEL assay. RESULTS Both male and female ER-1KO mice demonstrated increased corneal fluorescence staining scores. MG showed abnormal lipid metabolism and ductal dilation. LG displayed lipid deposition and reduced AQP-5 expression. CJ experienced goblet cell loss. MG, LG exhibited signs of inflammation and apoptosis. CONCLUSION ER1 is pivotal for ocular surface homeostasis in both genders of mice. ER1 deficiency induces inflammation and lipid deposition to MG and LG, culminating in dry eye-like manifestations on the ocular surface.
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Affiliation(s)
- Xiaoxuan Qi
- Department of Ophthalmology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yachun Yang
- Department of Ophthalmology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Danyu Xiong
- Department of Ophthalmology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Sainan Wu
- Department of Ophthalmology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Guoqiang Cui
- Second Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Qing Zhang
- Department of Ophthalmology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China.
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Petito G, Giacco A, Cioffi F, Mazzoli A, Magnacca N, Iossa S, Goglia F, Senese R, Lanni A. Short-term fructose feeding alters tissue metabolic pathways by modulating microRNAs expression both in young and adult rats. Front Cell Dev Biol 2023; 11:1101844. [PMID: 36875756 PMCID: PMC9977821 DOI: 10.3389/fcell.2023.1101844] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
Dietary high fructose (HFrD) is known as a metabolic disruptor contributing to the development of obesity, diabetes, and dyslipidemia. Children are more sensitive to sugar than adults due to the distinct metabolic profile, therefore it is especially relevant to study the metabolic alterations induced by HFrD and the mechanisms underlying such changes in animal models of different ages. Emerging research suggests the fundamental role of epigenetic factors such as microRNAs (miRNAs) in metabolic tissue injury. In this perspective, the aim of the present study was to investigate the involvement of miR-122-5p, miR-34a-5p, and miR-125b-5p examining the effects induced by fructose overconsumption and to evaluate whether a differential miRNA regulation exists between young and adult animals. We used young rats (30 days) and adult rats (90 days) fed on HFrD for a short period (2 weeks) as animal models. The results indicate that both young and adult rats fed on HFrD exhibit an increase in systemic oxidative stress, the establishment of an inflammatory state, and metabolic perturbations involving the relevant miRNAs and their axes. In the skeletal muscle of adult rats, HFrD impair insulin sensitivity and triglyceride accumulation affecting the miR-122-5p/PTP1B/P-IRS-1(Tyr612) axis. In liver and skeletal muscle, HFrD acts on miR-34a-5p/SIRT-1: AMPK pathway resulting in a decrease of fat oxidation and an increase in fat synthesis. In addition, liver and skeletal muscle of young and adult rats exhibit an imbalance in antioxidant enzyme. Finally, HFrD modulates miR-125b-5p expression levels in liver and white adipose tissue determining modifications in de novo lipogenesis. Therefore, miRNA modulation displays a specific tissue trend indicative of a regulatory network that contributes in targeting genes of various pathways, subsequently yielding extensive effects on cell metabolism.
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Affiliation(s)
- Giuseppe Petito
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
| | - Antonia Giacco
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Federica Cioffi
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Arianna Mazzoli
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Nunzia Magnacca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
| | - Susanna Iossa
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Fernando Goglia
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Rosalba Senese
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
| | - Antonia Lanni
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
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Feng T, Zhang W, Li Z. Potential Mechanisms of Gut-Derived Extracellular Vesicle Participation in Glucose and Lipid Homeostasis. Genes (Basel) 2022; 13:1964. [PMID: 36360201 PMCID: PMC9689624 DOI: 10.3390/genes13111964] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 01/19/2023] Open
Abstract
The intestine participates in the regulation of glucose and lipid metabolism in multiple facets. It is the major site of nutrient digestion and absorption, provides the interface as well as docking locus for gut microbiota, and harbors hormone-producing cells scattered throughout the gut epithelium. Intestinal extracellular vesicles are known to influence the local immune response, whereas their roles in glucose and lipid homeostasis have barely been explored. Hence, this current review summarizes the latest knowledge of cargo substances detected in intestinal extracellular vesicles, and connects these molecules with the fine-tuning regulation of glucose and lipid metabolism in liver, muscle, pancreas, and adipose tissue.
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Affiliation(s)
- Tiange Feng
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Ziru Li
- MaineHealth Institute for Research, MaineHealth, Scarborough, ME 04074, USA
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Chen Z, Lu Q, Zhang X, Zhang Z, Cao X, Wang K, Lu X, Yang Z, Loor JJ, Jiao P. Circ007071 Inhibits Unsaturated Fatty Acid Synthesis by Interacting with miR-103-5p to Enhance PPARγ Expression in the Dairy Goat Mammary Gland. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:13719-13729. [PMID: 36222227 DOI: 10.1021/acs.jafc.2c06174] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Understanding more precisely the mechanisms controlling the metabolism of fatty acid in the mammary gland of dairy goats is essential for future improvements in milk quality. Particularly since recent data have underscored a key role for circular RNAs (circRNAs) in the mammary gland function, high-throughput sequencing technology was used to identify expression levels of circRNAs in the mammary tissue of dairy goats during early and peak lactation in the present study. Compared with early lactation, results demonstrated that the expression level of circ007071 during peak lactation was 12.02-fold up-regulated. Subsequent studies in goat mammary epithelial cells (GMECs) revealed that circ007071 stimulated the synthesis of triglycerides (TAG) and cholesterol, as well as increased the content of saturated fatty acids (C16:0 and C18:0). More importantly, using a double luciferase reporting system allowed us to detect the circ007071 sequence at a binding site of miR-103-5p, indicating that it targeted this miRNA. Overexpression of circ007071 significantly decreased the abundance of miR-103-5p and led to inhibition of TAG synthesis. In contrast, the abundance of peroxisome proliferator-activated receptor γ (PPARγ), a target gene of miR-103-5p, was reinforced with the overexpression of circ007071. Thus, we conclude that one key function of circ007071 in the regulation of milk fat synthesis is to attenuate the inhibitory effect of miR-103-5p on PPARγ via direct interactions with miRNA. As a result, the process of TAG and saturated fatty acid is able to proceed.
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Affiliation(s)
- Zhi Chen
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, PR China
| | - Qinyue Lu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, PR China
| | - Xinlong Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, PR China
| | - Zhiyue Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, PR China
| | - Xiang Cao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, PR China
| | - Kun Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, PR China
| | - Xiaotan Lu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, PR China
| | - Zhangping Yang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, PR China
| | - Juan J Loor
- Mammalian Nutrition Physiology Genomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, Illinois 61801, United States
| | - Peixin Jiao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, PR China
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Fan Z, Chen X, Liu T, Yu Q, Song Z, Wang F, Li T. Pectin oligosaccharides improved lipid metabolism in white adipose tissue of high-fat diet fed mice. Food Sci Biotechnol 2022; 31:1197-1205. [DOI: 10.1007/s10068-022-01109-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/16/2022] [Accepted: 05/25/2022] [Indexed: 11/04/2022] Open
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Valle-Millares D, Brochado-Kith Ó, Martín-Carbonero L, Domínguez-Domínguez L, Ryan P, De los Santos I, De la Fuente S, Castro JM, Lagarde M, Cuevas G, Mayoral-Muñoz M, Matarranz M, Díez V, Gómez-Sanz A, Martínez-Román P, Crespo-Bermejo C, Palladino C, Muñoz-Muñoz M, Jiménez-Sousa MA, Resino S, Briz V, Fernández-Rodríguez A, (COVIHEP) OBOMGOVCHIV. Different HCV Exposure Drives Specific miRNA Profile in PBMCs of HIV Patients. Biomedicines 2021; 9:biomedicines9111627. [PMID: 34829855 PMCID: PMC8615810 DOI: 10.3390/biomedicines9111627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/27/2021] [Accepted: 11/01/2021] [Indexed: 12/11/2022] Open
Abstract
Micro RNAs (miRNAs) are essential players in HIV and HCV infections, as both viruses modulate cellular miRNAs and interact with the miRNA-mediated host response. We aim to analyze the miRNA profile of HIV patients with different exposure to HCV to explore specific signatures in the miRNA profile of PBMCs for each type of infection. We massively sequenced small RNAs of PBMCs from 117 HIV+ infected patients: 45 HIV+ patients chronically infected with HCV (HIV/HCV+), 36 HIV+ that spontaneously clarified HCV after acute infection (HIV/HCV-) and 36 HIV+ patients without previous HCV infection (HIV). Thirty-two healthy patients were used as healthy controls (HC). Differential expression analysis showed significantly differentially expressed (SDE) miRNAs in HIV/HCV+ (n = 153), HIV/HCV- (n = 169) and HIV (n = 153) patients. We found putative dysregulated pathways, such as infectious-related and PI3K signaling pathways, common in all contrasts. Specifically, putatively targeted genes involved in antifolate resistance (HIV/HV+), cancer-related pathways (HIV/HCV-) and HIF-signaling (HIV) were identified, among others. Our findings revealed that HCV strongly influences the expression profile of PBMCs from HIV patients through the disruption of its miRNome. Thus, different HCV exposure can be identified by specific miRNA signatures in PBMCs.
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Affiliation(s)
- Daniel Valle-Millares
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, 28220 Majadahonda, Madrid, Spain; (D.V.-M.); (Ó.B.-K.); (A.G.-S.); (P.M.-R.); (M.A.J.-S.); (S.R.)
| | - Óscar Brochado-Kith
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, 28220 Majadahonda, Madrid, Spain; (D.V.-M.); (Ó.B.-K.); (A.G.-S.); (P.M.-R.); (M.A.J.-S.); (S.R.)
| | - Luz Martín-Carbonero
- Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain; (L.M.-C.); (J.M.C.); (M.M.-M.)
| | - Lourdes Domínguez-Domínguez
- VIH Servicio de Medicina Interna Research Institute Hospital 12 de Octubre (i+12), 28041 Madrid, Spain; (L.D.-D.); (M.L.); (M.M.)
| | - Pablo Ryan
- Department of Infectious Diseases, Infanta Leonor Teaching Hospital, 28031 Madrid, Spain; (P.R.); (G.C.); (V.D.)
| | - Ignacio De los Santos
- Internal Medicine Servicie Hospital Universitario de La Princesa, 28006 Madrid, Spain;
| | - Sara De la Fuente
- Internal Medicine Service Hospital Puerta de Hierro, 28222 Madrid, Spain;
| | - Juan M. Castro
- Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain; (L.M.-C.); (J.M.C.); (M.M.-M.)
| | - María Lagarde
- VIH Servicio de Medicina Interna Research Institute Hospital 12 de Octubre (i+12), 28041 Madrid, Spain; (L.D.-D.); (M.L.); (M.M.)
| | - Guillermo Cuevas
- Department of Infectious Diseases, Infanta Leonor Teaching Hospital, 28031 Madrid, Spain; (P.R.); (G.C.); (V.D.)
| | - Mario Mayoral-Muñoz
- Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain; (L.M.-C.); (J.M.C.); (M.M.-M.)
| | - Mariano Matarranz
- VIH Servicio de Medicina Interna Research Institute Hospital 12 de Octubre (i+12), 28041 Madrid, Spain; (L.D.-D.); (M.L.); (M.M.)
| | - Victorino Díez
- Department of Infectious Diseases, Infanta Leonor Teaching Hospital, 28031 Madrid, Spain; (P.R.); (G.C.); (V.D.)
| | - Alicia Gómez-Sanz
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, 28220 Majadahonda, Madrid, Spain; (D.V.-M.); (Ó.B.-K.); (A.G.-S.); (P.M.-R.); (M.A.J.-S.); (S.R.)
| | - Paula Martínez-Román
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, 28220 Majadahonda, Madrid, Spain; (D.V.-M.); (Ó.B.-K.); (A.G.-S.); (P.M.-R.); (M.A.J.-S.); (S.R.)
| | - Celia Crespo-Bermejo
- Laboratory of Reference and Research on Viral Hepatitis, National Center for Microbiology, Institute of Health Carlos III, 28220 Majadahonda, Madrid, Spain; (C.C.-B.); (V.B.)
| | - Claudia Palladino
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal;
| | - María Muñoz-Muñoz
- Department of Animal Genetics, Instituto Nacional de Investigación y Alimentación Agraria y Alimentaria (INIA), 28040 Madrid, Spain;
| | - María A. Jiménez-Sousa
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, 28220 Majadahonda, Madrid, Spain; (D.V.-M.); (Ó.B.-K.); (A.G.-S.); (P.M.-R.); (M.A.J.-S.); (S.R.)
| | - Salvador Resino
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, 28220 Majadahonda, Madrid, Spain; (D.V.-M.); (Ó.B.-K.); (A.G.-S.); (P.M.-R.); (M.A.J.-S.); (S.R.)
| | - Verónica Briz
- Laboratory of Reference and Research on Viral Hepatitis, National Center for Microbiology, Institute of Health Carlos III, 28220 Majadahonda, Madrid, Spain; (C.C.-B.); (V.B.)
| | - Amanda Fernández-Rodríguez
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, 28220 Majadahonda, Madrid, Spain; (D.V.-M.); (Ó.B.-K.); (A.G.-S.); (P.M.-R.); (M.A.J.-S.); (S.R.)
- Faculty of Medicine, Universidad Alfonso X el Sabio, Avenida Universidad 1, 28691 Villanueva de la Cañada, Madrid, Spain
- Correspondence: ; Tel.: +34-918-223-892
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11
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Comas F, Latorre J, Ortega F, Arnoriaga Rodríguez M, Kern M, Lluch A, Ricart W, Blüher M, Gotor C, Romero LC, Fernández-Real JM, Moreno-Navarrete JM. Activation of Endogenous H 2S Biosynthesis or Supplementation with Exogenous H 2S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans. Antioxid Redox Signal 2021; 35:319-340. [PMID: 33554726 DOI: 10.1089/ars.2020.8206] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Aims: To investigate the impact of exogenous hydrogen sulfide (H2S) and its endogenous biosynthesis on human adipocytes and adipose tissue in the context of obesity and insulin resistance. Results: Experiments in human adipose tissue explants and in isolated preadipocytes demonstrated that exogenous H2S or the activation of endogenous H2S biosynthesis resulted in increased adipogenesis, insulin action, sirtuin deacetylase, and PPARγ transcriptional activity, whereas chemical inhibition and gene knockdown of each enzyme generating H2S (CTH, CBS, MPST) led to altered adipocyte differentiation, cellular senescence, and increased inflammation. In agreement with these experimental data, visceral and subcutaneous adipose tissue expression of H2S-synthesising enzymes was significantly reduced in morbidly obese subjects in association with attenuated adipogenesis and increased markers of adipose tissue inflammation and senescence. Interestingly, weight-loss interventions (including bariatric surgery or diet/exercise) improved the expression of H2S biosynthesis-related genes. In human preadipocytes, the expression of CTH, CBS, and MPST genes and H2S production were dramatically increased during adipocyte differentiation. More importantly, the adipocyte proteome exhibiting persulfidation was characterized, disclosing that different proteins involved in fatty acid and lipid metabolism, the citrate cycle, insulin signaling, several adipokines, and PPAR, experienced the most dramatic persulfidation (85-98%). Innovation: No previous studies investigated the impact of H2S on human adipose tissue. This study suggests that the potentiation of adipose tissue H2S biosynthesis is a possible therapeutic approach to improve adipose tissue dysfunction in patients with obesity and insulin resistance. Conclusion: Altogether, these data supported the relevance of H2S biosynthesis in the modulation of human adipocyte physiology. Antioxid. Redox Signal. 35, 319-340.
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Affiliation(s)
- Ferran Comas
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Jèssica Latorre
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Francisco Ortega
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - María Arnoriaga Rodríguez
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Matthias Kern
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Aina Lluch
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Wifredo Ricart
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Matthias Blüher
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Cecilia Gotor
- Instituto de Bioquímica Vegetal y Fotosíntesis, Consejo Superior de Investigaciones Científicas and Universidad de Sevilla, Seville, Spain
| | - Luis C Romero
- Instituto de Bioquímica Vegetal y Fotosíntesis, Consejo Superior de Investigaciones Científicas and Universidad de Sevilla, Seville, Spain
| | - José Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain.,Department of Medical Sciences, Universitat de Girona, Girona, Spain
| | - José María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain.,Department of Medical Sciences, Universitat de Girona, Girona, Spain
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12
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Chen X, Liu B, Li X, An TT, Zhou Y, Li G, Wu‐Smart J, Alvarez S, Naldrett MJ, Eudy J, Kubik G, Wilson RA, Kachman SD, Cui J, Yu J. Identification of anti-inflammatory vesicle-like nanoparticles in honey. J Extracell Vesicles 2021; 10:e12069. [PMID: 33613874 PMCID: PMC7879699 DOI: 10.1002/jev2.12069] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 01/05/2021] [Accepted: 01/31/2021] [Indexed: 12/11/2022] Open
Abstract
Honey has been used as a nutrient, an ointment, and a medicine worldwide for many centuries. Modern research has demonstrated that honey has many medicinal properties, reflected in its anti-microbial, anti-oxidant, and anti-inflammatory bioactivities. Honey is composed of sugars, water and a myriad of minor components, including minerals, vitamins, proteins and polyphenols. Here, we report a new bioactive component‒vesicle-like nanoparticles‒in honey (H-VLNs). These H-VLNs are membrane-bound nano-scale particles that contain lipids, proteins and small-sized RNAs. The presence of plant-originated plasma transmembrane proteins and plasma membrane-associated proteins suggests the potential vesicle-like nature of these particles. H-VLNs impede the formation and activation of the nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome, which is a crucial inflammatory signalling platform in the innate immune system. Intraperitoneal administration of H-VLNs in mice alleviates inflammation and liver damage in the experimentally induced acute liver injury. miR-4057 in H-VLNs was identified in inhibiting NLRP3 inflammasome activation. Together, our studies have identified anti-inflammatory VLNs as a new bioactive agent in honey.
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Affiliation(s)
- Xingyi Chen
- Department of Nutrition and Health SciencesUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | - Baolong Liu
- Department of Nutrition and Health SciencesUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | - Xingzhi Li
- Department of Nutrition and Health SciencesUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | - Thuy T. An
- Department of Computer Science and EngineeringUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | - You Zhou
- Center for BiotechnologyUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | - Gang Li
- Department of Plant PathologyUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | - Judy Wu‐Smart
- Department of EntomologyUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | - Sophie Alvarez
- Nebraska Center for Biotechnology, University of Nebraska‐LincolnProteomics and Metabolomics FacilityNebraskaUSA
| | - Michael J. Naldrett
- Nebraska Center for Biotechnology, University of Nebraska‐LincolnProteomics and Metabolomics FacilityNebraskaUSA
| | - James Eudy
- Department of Genetics Cell Biology and AnatomyUniversity of Nebraska Medical Center, 985915 Nebraska Medical CenterOmahaNebraskaUSA
| | - Gregory Kubik
- Genomics Core Facility, University of Nebraska Medical CenterOmahaNebraskaUSA
| | - Richard A. Wilson
- Department of Plant PathologyUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | - Stephen D. Kachman
- Department of StatisticsUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | - Juan Cui
- Department of Computer Science and EngineeringUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | - Jiujiu Yu
- Department of Nutrition and Health SciencesUniversity of Nebraska‐LincolnLincolnNebraskaUSA
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13
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Li G, Chen Y, Jin W, Zhai B, Li Y, Sun G, Li H, Kang X, Tian Y. Effects of miR-125b-5p on Preadipocyte Proliferation and Differentiation in Chicken. Mol Biol Rep 2021; 48:491-502. [PMID: 33398680 DOI: 10.1007/s11033-020-06080-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 12/10/2020] [Indexed: 12/21/2022]
Abstract
Our previous studies have shown that miR-125b-5p was highly expressed and significantly upregulated during abdominal fat deposition in chickens. However, the role of miR-125b in the regulation of adipogenesis is not clear in chickens. Therefore, we evaluated the effects of miR-125b-5p on preadipocyte proliferation and differentiation and the interaction between miR-125b-5p and the acyl-CoA synthetase bubblegum family member 2 (ACSBG2) gene in adipogenesis in chicken abdominal adipose tissue. Here, transfection tests of miR-125b-5p mimic/inhibitor were performed in preadipocytes, and the effects of miR-125b-5p on preadipocytes proliferation and differentiation were analyzed. The target site of miR-125b-5p in the 3'UTR (untranslated region) of ACSBG2 were verified by a luciferase reporter assay. Our results showed that miR-125b-5p overexpression inhibited proliferation and reduced the number of cells in S phase and G2/M phase in preadipocytes; conversely, miR-125b-5p inhibition promoted the proliferation and increased the number of cells in S phase and G2/M phase. In adipocytes after induction, miR-125b-5p overexpression led to a notable increase in the accumulation of lipid droplets as well as in the concentration of triglycerides, while miR-125b-5p inhibition had the opposite effect. Furthermore, miR-125b-5p could directly bind to the 3'UTR of ACSBG2, and its overexpression could significantly repress the mRNA and protein expression of ACSBG2. These results indicate that miR-125b-5p can inhibit preadipocyte proliferation and can promote preadipocyte differentiation to affect adipogenesis in chicken abdominal adipose tissues, at least partially by downregulating ACSBG2.
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Affiliation(s)
- Guoxi Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China.
| | - Yi Chen
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Wenjiao Jin
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Bin Zhai
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Yuanfang Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Guirong Sun
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Hong Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Xiangtao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Yadong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China.
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MiR-125b-2 knockout increases high-fat diet-induced fat accumulation and insulin resistance. Sci Rep 2020; 10:21969. [PMID: 33319811 PMCID: PMC7738482 DOI: 10.1038/s41598-020-77714-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 11/09/2020] [Indexed: 12/26/2022] Open
Abstract
Obese individuals are more susceptible to comorbidities than individuals of healthy weight, including cardiovascular disease and metabolic disorders. MicroRNAs are a class of small and noncoding RNAs that are implicated in the regulation of chronic human diseases. We previously reported that miR-125b plays a critical role in adipogenesis in vitro. However, the involvement of miR-125b-2 in fat metabolism in vivo remains unknown. In the present study, miR-125b-2 knockout mice were generated using CRISPR/CAS9 technology, resulting in mice with a 7 bp deletion in the seed sequence of miR-125b-2. MiR-125b-2 knockout increased the weight of liver tissue, epididymal white fat and inguinal white fat. MiR-125b-2 knockout also increased adipocyte volume in HFD-induced obese mice, while there were no significant differences in body weight and feed intake versus mice fed a normal diet. Additionally, qRT-PCR and western blot analysis revealed that the expression of the miR-125b-2 target gene SCD-1 and fat synthesis-associated genes, such as PPARγ and C/EBPα, were significantly up-regulated in miR-125b-2KO mice (P < 0.05). Moreover, miR-125b-2KO altered HFD-induced changes in glucose tolerance and insulin resistance. In conclusion, we show that miR-125b-2 is a novel potential target for regulating fat accumulation, and also a candidate target to develop novel treatment strategies for obesity and diabetes.
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15
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Exploration of targets regulated by miR-125b in porcine adipocytes. In Vitro Cell Dev Biol Anim 2020; 56:103-111. [PMID: 31912457 DOI: 10.1007/s11626-019-00427-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 11/25/2019] [Indexed: 12/14/2022]
Abstract
MicroRNA (miRNA) has been proved to play a key role in lipid metabolism. In our previous study, miR-125b was validated to be differentially expressed in preadipocytes and adipocytes, which was also proved to involve in lipid metabolism. To explore the comprehensive targets of miR-125b in adipocytes, isobaric tag for relative and absolute quantitation (iTRAQ) analysis was performed to obtain differentially expressed proteins in adipocytes comparing negative control (NC) and miR-125b mimic, combining with digital gene expression (DGE) profiling of mRNA incorporated into RNA-induced silencing complex (RISC) pulled down by biotinylated miR-125b mimic and targets prediction of miR-125b by three algorithms, acyl-CoA dehydrogenase short chain (ACADS) and mitochondrial trans-2-enoyl-CoA reductase (MECR) were screened out as miR-125b direct targets. Luciferase reporter assay further validated that miR-125b mimic significantly inhibited the luciferase activity by targeting wild type (WT) 3'-UTR compared with NC. qPCR analysis of ACADS and MECR mRNA from adipose tissues of miR-125b knockout (KO) mice further confirmed the inhibition of miR-125b on ACADS and MECR expressions. Here we report miR-125b play a vital role in maintaining homeostasis of fatty acid metabolism by targeting key enzyme ACADS and MECR in the process of fatty acid elongation and degradation.
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16
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Brochado-Kith Ó, Gómez Sanz A, Real LM, Crespo García J, Ryan Murúa P, Macías J, Cabezas González J, Troya J, Pineda JA, Arias Loste MT, Díez Viñas V, Jiménez-Sousa MÁ, Medrano de Dios LM, Cuesta De la Plaza I, Monzón Fernández S, Resino García S, Fernández-Rodríguez A. MicroRNA Profile of HCV Spontaneous Clarified Individuals, Denotes Previous HCV Infection. J Clin Med 2019; 8:jcm8060849. [PMID: 31207946 PMCID: PMC6617112 DOI: 10.3390/jcm8060849] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 06/03/2019] [Accepted: 06/11/2019] [Indexed: 12/12/2022] Open
Abstract
Factors involved in the spontaneous cleareance of a hepatitis C (HCV) infection are related to both HCV and the interaction with the host immune system, but little is known about the consequences after a spontaneous resolution. The main HCV extrahepatic reservoir is the peripheral blood mononuclear cells (PBMCs), and their transcriptional profile provides us information of innate and adaptive immune responses against an HCV infection. MicroRNAs regulate the innate and adaptive immune responses, and they are actively involved in the HCV cycle. High Throughput sequencing was used to analyze the miRNA profiles from PBMCs of HCV chronic naïve patients (CHC), individuals that spontaneously clarified HCV (SC), and healthy controls (HC). We did not find any differentially expressed miRNAs between SC and CHC. However, both groups showed similar expression differences (21 miRNAs) with respect to HC. This miRNA signature correctly classifies HCV-exposed (CHC and SC) vs. HC, with the has-miR-21-3p showing the best performance. The potentially targeted molecular pathways by these 21 miRNAs mainly belong to fatty acids pathways, although hippo signaling, extracellular matrix (ECM) interaction, proteoglycans-related, and steroid biosynthesis pathways were also altered. These miRNAs target host genes involved in an HCV infection. Thus, an HCV infection promotes molecular alterations in PBMCs that can be detected after an HCV spontaneous resolution, and the 21-miRNA signature is able to identify HCV-exposed patients (either CHC or SC).
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Affiliation(s)
- Óscar Brochado-Kith
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Alicia Gómez Sanz
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Luis Miguel Real
- Unidad Clínica de Enfermedades Infecciosas, Hospital Universitario de Valme, 41014 Sevilla, Spain.
| | - Javier Crespo García
- Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, 39008 Santander, Spain.
- Institute Valdecilla (IDIVAL), School of Medicine, University of Cantabria, 39005 Santander, Spain.
| | - Pablo Ryan Murúa
- Internal Medicine Service, University Hospital Infanta Leonor, School of Medicine, Complutense University of Madrid, Gregorio Marañón Health Research Institute, 28009 Madrid, Spain.
| | - Juan Macías
- Unidad Clínica de Enfermedades Infecciosas, Hospital Universitario de Valme, 41014 Sevilla, Spain.
| | - Joaquín Cabezas González
- Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, 39008 Santander, Spain.
- Institute Valdecilla (IDIVAL), School of Medicine, University of Cantabria, 39005 Santander, Spain.
| | - Jesús Troya
- Internal Medicine Service, University Hospital Infanta Leonor, School of Medicine, Complutense University of Madrid, Gregorio Marañón Health Research Institute, 28009 Madrid, Spain.
| | - Juan Antonio Pineda
- Unidad Clínica de Enfermedades Infecciosas, Hospital Universitario de Valme, 41014 Sevilla, Spain.
| | - María Teresa Arias Loste
- Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, 39008 Santander, Spain.
- Institute Valdecilla (IDIVAL), School of Medicine, University of Cantabria, 39005 Santander, Spain.
| | - Victorino Díez Viñas
- Internal Medicine Service, University Hospital Infanta Leonor, School of Medicine, Complutense University of Madrid, Gregorio Marañón Health Research Institute, 28009 Madrid, Spain.
| | - María Ángeles Jiménez-Sousa
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Luz María Medrano de Dios
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Isabel Cuesta De la Plaza
- Bioinformatics Unit, Unidades Comunes Científico Técnicas, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Sara Monzón Fernández
- Bioinformatics Unit, Unidades Comunes Científico Técnicas, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Salvador Resino García
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Amanda Fernández-Rodríguez
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
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Subramaniam S, Jeet V, Clements JA, Gunter JH, Batra J. Emergence of MicroRNAs as Key Players in Cancer Cell Metabolism. Clin Chem 2019; 65:1090-1101. [PMID: 31101638 DOI: 10.1373/clinchem.2018.299651] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 04/29/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Metabolic reprogramming is a hallmark of cancer. MicroRNAs (miRNAs) have been found to regulate cancer metabolism by regulating genes involved in metabolic pathways. Understanding this layer of complexity could lead to the development of novel therapeutic approaches. CONTENT miRNAs are noncoding RNAs that have been implicated as master regulators of gene expression. Studies have revealed the role of miRNAs in the metabolic reprogramming of tumor cells, with several miRNAs both positively and negatively regulating multiple metabolic genes. The tricarboxylic acid (TCA) cycle, aerobic glycolysis, de novo fatty acid synthesis, and altered autophagy allow tumor cells to survive under adverse conditions. In addition, major signaling molecules, hypoxia-inducible factor, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin/phosphatase and tensin homolog, and insulin signaling pathways facilitate metabolic adaptation in tumor cells and are all regulated by miRNAs. Accumulating evidence suggests that miRNA mimics or inhibitors could be used to modulate the activity of miRNAs that drive tumor progression via altering their metabolism. Currently, several clinical trials investigating the role of miRNA-based therapy for cancer have been launched that may lead to novel therapeutic interventions in the future. SUMMARY In this review, we summarize cancer-related metabolic pathways, including glycolysis, TCA cycle, pentose phosphate pathway, fatty acid metabolism, amino acid metabolism, and other metabolism-related oncogenic signaling pathways, and their regulation by miRNAs that are known to lead to tumorigenesis. Further, we discuss the current state of miRNA therapeutics in the clinic and their future potential.
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Affiliation(s)
- Sugarniya Subramaniam
- School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.,Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Varinder Jeet
- School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.,Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Judith A Clements
- School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.,Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Jennifer H Gunter
- School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.,Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Jyotsna Batra
- School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia; .,Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Translational Research Institute, Queensland University of Technology, Brisbane, Australia
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Xia Q, Li Z, Zheng J, Zhang X, Di Y, Ding J, Yu D, Yan L, Shen L, Yan D, Jia N, Chen W, Feng Y, Wang J. Identification of novel biomarkers for hepatocellular carcinoma using transcriptome analysis. J Cell Physiol 2019; 234:4851-4863. [PMID: 30272824 DOI: 10.1002/jcp.27283] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/26/2018] [Indexed: 01/01/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer in the world. To comprehensively investigate the utility of microRNAs (miRNAs) and protein-encoding transcripts (messenger RNAs [mRNAs]) in HCC as potential biomarkers for early detection and diagnosis, we exhaustively mined genomic data from three available omics datasets (GEO, Oncomine, and TCGA), analyzed the overlaps among gene expression studies from 920 hepatocellular carcinoma samples and 508 healthy (or adjacent normal) liver tissue samples available from six laboratories, and identified 178 differentially expressed genes (DEGs) associated with HCC. Paired with miRNA and lncRNA data, we identified 23 core genes that were targeted by nine differentially expressed miRNAs and 21 HCC-specific lncRNAs. We further demonstrated that alterations in these 23 genes were quite frequent, with five genes altered in over 5% of the population. Patients with high levels of YWHAZ, ENAH, and HMGN4 tended to have high-grade tumors and shorter overall survival, suggesting that these genes could be promising candidate biomarkers for disease and poor prognosis in patients with HCC. Our comprehensive mRNA, miRNA, and lncRNA omics analyses from multiple independent datasets identified robust molecules that may be used as biomarkers for early HCC detection and diagnosis.
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Affiliation(s)
- Qianlin Xia
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
| | - Zehuan Li
- Department of General Surgery, Zhong Shan Hospital, Fudan University, Shanghai, China
| | - Jianghua Zheng
- Department of Laboratory Medicine, Zhoupu Hospital Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Xu Zhang
- National Center for Liver Cancer, Shanghai, China
| | - Yang Di
- Department of Pancreatic Surgery, Pancreatic Disease Institute, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jin Ding
- Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Die Yu
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
| | - Li Yan
- Department of Severe Hepatology, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
| | - Longqiang Shen
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
| | - Dong Yan
- Department of Medical Oncology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Ning Jia
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, China
| | - Weiping Chen
- Microarray Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA
| | - Yanling Feng
- Department of Pathology, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
| | - Jin Wang
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
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Ye J, Zou M, Li P, Liu H. MicroRNA Regulation of Energy Metabolism to Induce Chemoresistance in Cancers. Technol Cancer Res Treat 2019; 17:1533033818805997. [PMID: 30444190 PMCID: PMC6243412 DOI: 10.1177/1533033818805997] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Since “Warburg effect” has been firstly uncovered in cancer cells in 1956, mounting evidence has supported the molecular mechanism underlying the energy metabolism in induced chemoresistance in cancers. MicroRNAs can mediate fine-tuning of genes in physiological process. MicroRNAs’ energy metabolic role in chemoresistance has been probed recently. In this review, we summarize 5 microRNAs in regulating glucose and lipid metabolism and other energy metabolism. They partially modulate chemoresistance to cancer treatments. Furthermore, we discuss the great therapeutic potential of metabolism-related microRNAs in novel combinatorial means to treat human cancers.
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Affiliation(s)
- Jin Ye
- 1 The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Manman Zou
- 1 The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Pei Li
- 1 The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hui Liu
- 1 The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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20
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MiR-125b-2 Knockout in Testis Is Associated with Targeting to the PAP Gene, Mitochondrial Copy Number, and Impaired Sperm Quality. Int J Mol Sci 2019; 20:ijms20010148. [PMID: 30609807 PMCID: PMC6337273 DOI: 10.3390/ijms20010148] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 12/24/2018] [Accepted: 12/27/2018] [Indexed: 01/02/2023] Open
Abstract
It has been reported that the miR-125 family plays an important role in regulating embryo development. However, the function of miR-125b-2 in spermatogenesis remains unknown. In this study, we used a model of miR-125b knockout (KO) mice to study the relationship between miR-125b-2 and spermatogenesis. Among the KO mice, the progeny test showed that the litter size decreased significantly (p = 0.0002) and the rate of non-parous females increased significantly from 10% to 38%. At the same time, the testosterone concentration increased significantly (p = 0.007), with a remarkable decrease for estradiol (p = 0.02). Moreover, the sperm count decreased obviously (p = 0.011) and the percentage of abnormal sperm increased significantly (p = 0.0002). The testicular transcriptome sequencing revealed that there were 173 up-regulated genes, including Papolb (PAP), and 151 down-regulated genes in KO mice compared with wild type (WT). The Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analysis showed that many of these genes were involved in sperm mitochondrial metabolism and other cellular biological processes. Meanwhile, the sperm mitochondria DNA (mtDNA) copy number increased significantly in the KO mice, but there were no changes observed in the mtDNA integrity and mutations of mt-Cytb, as well as the mt-ATP6 between the WT mice and KO mice. In the top 10 up-regulated genes, PAP, as a testis specific expressing gene, affect the process of spermatogenesis. Western blotting and the Luciferase assay validated that PAP was the target of miR-125b-5p. Intriguingly, we also found that both miR-125b and PAP were only highly expressed in the germ cells (GC) instead of in the Leydig cells (LC) and Sertoli cells (SC). Additionally, miR-125b-5p down regulated the secretion of testosterone in the TM3 cell by targeting PAP (p = 0.021). Our study firstly demonstrated that miR-125b-2 regulated testosterone secretion by directly targeting PAP, and increased the sperm mtDNA copy number to affect semen quality. The study indicated that miR-125b-2 had a positive influence on the reproductive performance of animals by regulating the expression of the PAP gene, and could be a potential drugs and diagnostic target for male infertility.
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21
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Transcriptomic response of breast cancer cells to anacardic acid. Sci Rep 2018; 8:8063. [PMID: 29795261 PMCID: PMC5966448 DOI: 10.1038/s41598-018-26429-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 05/10/2018] [Indexed: 02/07/2023] Open
Abstract
Anacardic acid (AnAc), a potential dietary agent for preventing and treating breast cancer, inhibited the proliferation of estrogen receptor α (ERα) positive MCF-7 and MDA-MB-231 triple negative breast cancer cells. To characterize potential regulators of AnAc action, MCF-7 and MDA-MB-231 cells were treated for 6 h with purified AnAc 24:1n5 congener followed by next generation transcriptomic sequencing (RNA-seq) and network analysis. We reported that AnAc-differentially regulated miRNA transcriptomes in each cell line and now identify AnAc-regulated changes in mRNA and lncRNA transcript expression. In MCF-7 cells, 80 AnAc-responsive genes were identified, including lncRNA MIR22HG. More AnAc-responsive genes (886) were identified in MDA-MB-231 cells. Only six genes were commonly altered by AnAc in both cell lines: SCD, INSIG1, and TGM2 were decreased and PDK4, GPR176, and ZBT20 were increased. Modeling of AnAc-induced gene changes suggests that AnAc inhibits monounsaturated fatty acid biosynthesis in both cell lines and increases endoplasmic reticulum stress in MDA-MB-231 cells. Since modeling of downregulated genes implicated NFκB in MCF-7, we confirmed that AnAc inhibited TNFα-induced NFκB reporter activity in MCF-7 cells. These data identify new targets and pathways that may account for AnAc’s anti-proliferative and pro-apoptotic activity.
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22
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Yang WC, Guo WL, Zan LS, Wang YN, Tang KQ. Bta-miR-130a regulates the biosynthesis of bovine milk fat by targeting peroxisome proliferator-activated receptor gamma. J Anim Sci 2017; 95:2898-2906. [PMID: 28727095 DOI: 10.2527/jas.2017.1504] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Milk fat determines the quality of milk and is also a main targeted trait in dairy cow breeding. Recent studies have revealed important regulatory roles of microRNAs (miRNA) in milk fat synthesis in the mammary gland. However, the role of miRNA in bovine mammary epithelial cells (BMEC) remains largely unknown. In this study, we found that the overexpression of miR-130a significantly decreased cellular triacylglycerol (TAG) levels and suppressed lipid droplet formation, whereas the inhibition of miR-130a resulted in greater lipid droplet formation and TAG accumulation in BMEC. MiR-130a also significantly affected mRNA expression related to milk fat metabolism. Specifically, the overexpression of miR-130a reduced the mRNA expression of , , , and , whereas the downregulation of miR-130a increased the mRNA expression of , , , , , and . Furthermore, western blot analysis revealed the protein level of PPARG in miR-130a mimic and inhibitor transfection groups to be consistent with the mRNA expression response. Finally, luciferase reporter assays verified that PPARG was the direct target of miR-130a. This study provides the first experimental evidence that miR-130a directly affects TAG synthesis in BMEC by targeting PPARG, suggesting that miR-130a potentially could be used to improve beneficial milk components in dairy cows.
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Liu XL, Cao HX, Wang BC, Xin FZ, Zhang RN, Zhou D, Yang RX, Zhao ZH, Pan Q, Fan JG. miR-192-5p regulates lipid synthesis in non-alcoholic fatty liver disease through SCD-1. World J Gastroenterol 2017; 23:8140-8151. [PMID: 29290651 PMCID: PMC5739921 DOI: 10.3748/wjg.v23.i46.8140] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 10/16/2017] [Accepted: 10/27/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the levels of miR-192-5p in non-alcoholic fatty liver disease (NAFLD) models and demonstrate the role of miR-192-5p in lipid accumulation. METHODS Thirty Sprague Dawley rats were randomly divided into three groups, which were given a standard diet, a high-fat diet (HFD), and an HFD with injection of liraglutide. At the end of 16 weeks, hepatic miR-192-5p and stearoyl-CoA desaturase 1 (SCD-1) levels were measured. MiR-192-5p mimic and inhibitor and SCD-1 siRNA were transfected into Huh7 cells exposed to palmitic acid (PA). Lipid accumulation was evaluated by oil red O staining and triglyceride assays. Direct interaction was validated by dual-luciferase reporter gene assays. RESULTS The HFD rats showed a 0.46-fold decrease and a 3.5-fold increase in hepatic miR-192-5p and SCD-1 protein levels compared with controls, respectively, which could be reversed after disease remission by liraglutide injection (P < 0.01). The Huh7 cells exposed to PA also showed down-regulation and up-regulation of miR-192-5p and SCD-1 protein levels, respectively (P < 0.01). Transfection with miR-192-5p mimic and inhibitor in Huh7 cells induced dramatic repression and promotion of SCD-1 protein levels, respectively (P < 0.01). Luciferase activity was suppressed and enhanced by miR-192-5p mimic and inhibitor, respectively, in wild-type SCD-1 (P < 0.01) but not in mutant SCD-1. MiR-192-5p overexpression reduced lipid accumulation significantly in PA-treated Huh7 cells, and SCD-1 siRNA transfection abrogated the lipid deposition aggravated by miR-192-5p inhibitor (P < 0.01). CONCLUSION This study demonstrates that miR-192-5p has a negative regulatory role in lipid synthesis, which is mediated through its direct regulation of SCD-1.
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Affiliation(s)
- Xiao-Lin Liu
- Qin Pan and Jian-Gao Fan, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Hai-Xia Cao
- Qin Pan and Jian-Gao Fan, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Bao-Can Wang
- Qin Pan and Jian-Gao Fan, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Feng-Zhi Xin
- Qin Pan and Jian-Gao Fan, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Rui-Nan Zhang
- Qin Pan and Jian-Gao Fan, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Da Zhou
- Qin Pan and Jian-Gao Fan, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Rui-Xu Yang
- Qin Pan and Jian-Gao Fan, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ze-Hua Zhao
- Qin Pan and Jian-Gao Fan, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
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24
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Brandão BB, Guerra BA, Mori MA. Shortcuts to a functional adipose tissue: The role of small non-coding RNAs. Redox Biol 2017; 12:82-102. [PMID: 28214707 PMCID: PMC5312655 DOI: 10.1016/j.redox.2017.01.020] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 01/30/2017] [Indexed: 12/20/2022] Open
Abstract
Metabolic diseases such as type 2 diabetes are a major public health issue worldwide. These diseases are often linked to a dysfunctional adipose tissue. Fat is a large, heterogenic, pleiotropic and rather complex tissue. It is found in virtually all cavities of the human body, shows unique plasticity among tissues, and harbors many cell types in addition to its main functional unit - the adipocyte. Adipose tissue function varies depending on the localization of the fat depot, the cell composition of the tissue and the energy status of the organism. While the white adipose tissue (WAT) serves as the main site for triglyceride storage and acts as an important endocrine organ, the brown adipose tissue (BAT) is responsible for thermogenesis. Beige adipocytes can also appear in WAT depots to sustain heat production upon certain conditions, and it is becoming clear that adipose tissue depots can switch phenotypes depending on cell autonomous and non-autonomous stimuli. To maintain such degree of plasticity and respond adequately to changes in the energy balance, three basic processes need to be properly functioning in the adipose tissue: i) adipogenesis and adipocyte turnover, ii) metabolism, and iii) signaling. Here we review the fundamental role of small non-coding RNAs (sncRNAs) in these processes, with focus on microRNAs, and demonstrate their importance in adipose tissue function and whole body metabolic control in mammals.
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Affiliation(s)
- Bruna B Brandão
- Program in Molecular Biology, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil
| | - Beatriz A Guerra
- Program in Molecular Biology, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil
| | - Marcelo A Mori
- Program in Molecular Biology, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil; Program in Genetics and Molecular Biology, Universidade Estadual de Campinas, Campinas, Brazil.
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25
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Tsiloulis T, Pike J, Powell D, Rossello FJ, Canny BJ, Meex RCR, Watt MJ. Impact of endurance exercise training on adipocyte microRNA expression in overweight men. FASEB J 2017; 31:161-171. [PMID: 27682205 DOI: 10.1096/fj.201600678r] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 09/16/2016] [Indexed: 01/05/2025]
Abstract
Adipocytes are major regulators of metabolism, and endurance exercise training improves adipocyte function; however, the molecular mechanisms that regulate chronic adaptive responses remain unresolved. microRNAs (miRNAs) influence adipocyte differentiation and metabolism. Accordingly, we aimed to determine whether adipocyte miRNA expression is responsive to exercise training and to identify exercise-responsive miRNAs that influence adipocyte metabolism. Next-generation sequencing was used to profile miRNA expression of adipocytes that were isolated from abdominal subcutaneous (ABD) and gluteofemoral (GF) adipose tissue of overweight men before and after 6 wk of endurance exercise training. Differentially expressed miRNAs were overexpressed or silenced in 3T3-L1 adipocytes, and lipid metabolism was examined. Next-generation sequencing identified 526 miRNAs in adipocytes, and there were no statistical differences in miRNA expression when comparing pre- and post-training samples for ABD and GF adipocytes. miR-10b expression was increased in ABD compared with GF adipocytes, whereas miR-204, miR-3613, and miR-4532 were more highly expressed in GF compared with ABD adipocytes. Blocking miR-10b in adipocytes suppressed β-adrenergic lipolysis but generally had a minor effect on lipid metabolism. Thus, unlike their critical role in adipogenesis, stable changes in miRNA expression do not play a prominent role in the regulation of adipocyte function in response to endurance exercise training.-Tsiloulis, T., Pike, J., Powell, D., Rossello, F. J., Canny, B. J., Meex, R. C. R., Watt, M. J. Impact of endurance exercise training on adipocyte microRNA expression in overweight men.
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Affiliation(s)
- Thomas Tsiloulis
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Department of Physiology, Monash University, Clayton, Victoria, Australia
| | - Joshua Pike
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Department of Physiology, Monash University, Clayton, Victoria, Australia
| | - David Powell
- Monash Bioinformatics Platform, Faculty of Biomedical and Psychological Sciences, Monash University, Clayton, Victoria, Australia
| | - Fernando J Rossello
- Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia; and
| | - Benedict J Canny
- Department of Physiology, Monash University, Clayton, Victoria, Australia
- School of Medicine, Faculty of Health, University of Tasmania, Hobart, Tasmania, Australia
| | - Ruth C R Meex
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Department of Physiology, Monash University, Clayton, Victoria, Australia
| | - Matthew J Watt
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia;
- Department of Physiology, Monash University, Clayton, Victoria, Australia
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Adipose tissue development and the molecular regulation of lipid metabolism. Essays Biochem 2016; 60:437-450. [DOI: 10.1042/ebc20160042] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 10/18/2016] [Accepted: 10/24/2016] [Indexed: 12/14/2022]
Abstract
The production of new adipocytes is required to maintain adipose tissue mass and involves the proliferation and differentiation of adipocyte precursor cells (APCs). In this review, we outline new developments in understanding the phenotype of APCs and provide evidence suggesting that APCs differ between distinct adipose tissue depots and are affected by obesity. Post-mitotic mature adipocytes regulate systemic lipid homeostasis by storing and releasing free fatty acids, and also modulate energy balance via the secretion of adipokines. The review highlights recent advances in understanding the cellular and molecular mechanisms regulating adipocyte metabolism, with a particular focus on lipolysis regulation and the involvement of microribonucleic acids (miRNAs).
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Porcine milk-derived exosomes promote proliferation of intestinal epithelial cells. Sci Rep 2016; 6:33862. [PMID: 27646050 PMCID: PMC5028765 DOI: 10.1038/srep33862] [Citation(s) in RCA: 141] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 09/02/2016] [Indexed: 02/07/2023] Open
Abstract
Milk-derived exosomes were identified as a novel mechanism of mother-to-child transmission of regulatory molecules, but their functions in intestinal tissues of neonates are not well-studied. Here, we characterized potential roles of porcine milk-derived exosomes in the intestinal tract. In vitro, treatment with milk-derived exosomes (27 ± 3 ng and 55 ± 5 ng total RNA) significantly promoted IPEC-J2 cell proliferation by MTT, CCK8, EdU fluorescence and EdU flow cytometry assays. The qRT-PCR and Western blot analyses indicated milk-derived exosomes (0.27 ± 0.03 μg total RNA) significantly promoted expression of CDX2, IGF-1R and PCNA, and inhibited p53 gene expression involved in intestinal proliferation. Additionally, six detected miRNAs were significantly increased in IPEC-J2 cell, while FAS and SERPINE were significantly down-regulated relative to that in control. In vivo, treated groups (0.125 μg and 0.25 μg total RNA) significantly raised mice' villus height, crypt depth and ratio of villus length to crypt depth of intestinal tissues, significantly increased CDX2, PCNA and IGF-1R' expression and significantly inhibited p53' expression. Our study demonstrated that milk-derived exosomes can facilitate intestinal cell proliferation and intestinal tract development, thus giving a new insight for milk nutrition and newborn development and health.
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