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Zhao Q, Duan Z, Lai R, Ma P. Novel microbially transformed bile acids: Biosynthesis, structure, and function. Pharmacol Res 2025; 216:107775. [PMID: 40378940 DOI: 10.1016/j.phrs.2025.107775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/03/2025] [Accepted: 05/10/2025] [Indexed: 05/19/2025]
Abstract
The roles of gut microbiota and microbially modified bile acids in human health have become widely recognized. In the last five years, various microbially modified bile acids (e.g., proteinogenic amino-conjugated bile acids, polyamine-conjugated bile acids, neuroactive amine-conjugated bile acids, methylcysteamine-conjugated bile acids, acylated bile acids, dicarboxylic acid-conjugated bile acids, lithocholic acid (LCA) derivatives) were identified and evaluated, which greatly enriched the mammalian bile acid pool and the bioactivity of bile acids. The structure, enzyme, function, clinical reports of these bile acids, and the bacteria to produce these bile acids were summarized in this review. These novel bile acids had various functions including immunoregulation, receptor regulator, antimicrobial activity, and microbial communities regulating effect. 70, 4, 1, 11, 19, 41, 43, 9, 10 species were observed to produce proteinogenic amino-conjugated bile acids, neuroactive amine-conjugated bile acids, methylcysteamine-conjugated bile acids, acylated bile acids, dicarboxylic acid-conjugated bile acids, 3-oxoLCA, isoLCA, 3-oxoalloLCA, and isoalloLCA, respectively. The current review has shed new light on discovering new bile acid derivatives as drug candidates. These microbially modified bile acids may play important roles in disease such as sleeve gastrectomy, fatty liver, inflammatory bowel disease, cystic fibrosis, and type 2 diabetes, which may also participate in normal physiological processes such as growth of infants, longevity, and dietary habits.
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Affiliation(s)
- Qi Zhao
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), State Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan 650201, PR China
| | - Zilei Duan
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), State Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan 650201, PR China
| | - Ren Lai
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), State Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan 650201, PR China.
| | - Pengcheng Ma
- State Key Laboratory of Genetic Evolution and Animal Models, Kunming Insitute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
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Tsagkari D, Markaki M, Tavernarakis N. NHR-85 modulates mitochondrial and lipid homeostasis to protect against α-synuclein aggregation in C. elegans. J Cell Sci 2025; 138:jcs263651. [PMID: 40211924 DOI: 10.1242/jcs.263651] [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: 10/29/2024] [Accepted: 04/02/2025] [Indexed: 05/10/2025] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs), such as PPARδ, are transcription factors that play a pivotal role in energy and fat metabolism. PPARδ activates genes involved in lipid and glucose metabolism and is expressed in various human tissues, including all brain regions and especially neurons, where it regulates lipid homeostasis and contributes to neuroprotection. However, the precise molecular mechanisms underlying these protective effects remain poorly understood. Here, we identify the Caenorhabditis elegans nuclear hormone receptor NHR-85 as a putative orthologue of human PPARδ. Furthermore, we show that NHR-85 functions as an essential regulator of fat and energy metabolism, with significant impact on mitochondrial homeostasis, at least in part through modulation of mitophagy. Finally, we find that NHR-85 prevents α-synuclein aggregation in a nematode model of Parkinson's disease, suggesting that it might play a protective role in neurodegenerative diseases. Our results indicate that NHR-85 is a functional orthologue of PPARδ and support the use of C. elegans as a powerful in vivo model for dissecting PPARδ-related metabolic and neurodegenerative processes.
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Affiliation(s)
- Dikaia Tsagkari
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 70013, Crete, Greece
- Division of Basic Sciences, School of Medicine, University of Crete, Heraklion 71003, Crete, Greece
| | - Maria Markaki
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 70013, Crete, Greece
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 70013, Crete, Greece
- Division of Basic Sciences, School of Medicine, University of Crete, Heraklion 71003, Crete, Greece
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Herich R, Szabóová R, Karaffová V, Racines MP, Šefcová MA, Larrea-Álvarez M. A Narrative Review on the Impact of Probiotic Supplementation on Muscle Development, Metabolic Regulation, and Fiber Traits Related to Meat Quality in Broiler Chickens. Microorganisms 2025; 13:784. [PMID: 40284621 PMCID: PMC12029878 DOI: 10.3390/microorganisms13040784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 03/03/2025] [Accepted: 03/27/2025] [Indexed: 04/29/2025] Open
Abstract
Public concern over drug resistance has led to governmental regulations banning the use of antibiotics as growth promoters, stimulating interest in developing complementary strategies to maintain animal production, mitigate infections, and enhance muscle characteristics and quality parameters, especially in meat-producing animals. Probiotics are recognized as a potential strategy for improving growth, primarily by promoting intestinal homeostasis. These microorganisms are suggested to modulate gut microbiota, preserving their ecosystem and influencing secondary metabolite production, which can directly or indirectly regulate skeletal muscle metabolism by influencing the expression of key muscle-related genes and the activity of various signaling factors. Several studies have documented the potential benefits of various strains of Bacillus, Enterococcus, and members of the Lactobacillaceae family on muscle characteristics. These studies have shown that probiotics not only modulated myogenic factors but also influenced proteins and enzymes involved in signaling pathways related to carbon metabolism, inflammatory response, mitochondrial dynamics, and antioxidant activity. These effects have been associated with improvements in meat quality parameters and enhanced growth performance. This manuscript seeks to present a brief overview of the impact of probiotic supplementation on muscle health and the quality of meat in broiler chickens.
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Affiliation(s)
- Robert Herich
- Department of Morphological Disciplines, University of Veterinary Medicine and Pharmacy in Košice, 041 81 Košice, Slovakia (V.K.)
| | - Renáta Szabóová
- Department of Biology and Physiology, University of Veterinary Medicine and Pharmacy in Košice, 041 81 Košice, Slovakia
| | - Viera Karaffová
- Department of Morphological Disciplines, University of Veterinary Medicine and Pharmacy in Košice, 041 81 Košice, Slovakia (V.K.)
| | - Maria Paula Racines
- Facultad de Ciencias de la Salud, Carrera de Medicina, Universidad Espíritu Santo, Samborondón 092301, Ecuador
| | - Miroslava Anna Šefcová
- Facultad de Ciencias de la Salud, Carrera de Medicina, Universidad Espíritu Santo, Samborondón 092301, Ecuador
| | - Marco Larrea-Álvarez
- Facultad de Ciencias de la Salud, Carrera de Medicina, Universidad Espíritu Santo, Samborondón 092301, Ecuador
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Li WR, Zhang C, Wang J. PPARs: modulating lipotoxicity and thus inhibiting fibrosis. Hormones (Athens) 2025; 24:85-97. [PMID: 39500811 DOI: 10.1007/s42000-024-00612-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/11/2024] [Indexed: 03/18/2025]
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family of ligand-activated receptors and are known for their roles as key factors in the regulation of lipid metabolism. In the more than three decades since their discovery, most reports on PPARs have focused on their roles in lipid metabolism, and a portion of the new research has also focused on the relationship between PPARs and fibrosis. Interestingly, lipid metabolism disorders and fibrosis are also inextricably linked. This implies that PPARs, lipid metabolism and fibrosis are interrelated. On this basis, we have summarized the molecular mechanisms of PPARs regulating fibrosis through lipid metabolism and PPARγ directly regulating fibrosis, and pointed out the contradictions and enigmas that need to be further explored in the processes of PPARs regulating lipid metabolism and fibrosis. The aim of the present review is to provide new ideas for PPARs for the treatment of lipid metabolism disorders and fibrosis.
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Affiliation(s)
- Wen-Rui Li
- The Second Clinical Medical College, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Chunping Zhang
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Jing Wang
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
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Bois A, Grandela C, Gallant J, Mummery C, Menasché P. Revitalizing the heart: strategies and tools for cardiomyocyte regeneration post-myocardial infarction. NPJ Regen Med 2025; 10:6. [PMID: 39843488 PMCID: PMC11754855 DOI: 10.1038/s41536-025-00394-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 01/13/2025] [Indexed: 01/24/2025] Open
Abstract
Myocardial infarction (MI) causes the loss of millions of cardiomyocytes, and current treatments do not address this root issue. New therapies focus on stimulating cardiomyocyte division in the adult heart, inspired by the regenerative capacities of lower vertebrates and neonatal mice. This review explores strategies for heart regeneration, offers insights into cardiomyocyte proliferation, evaluates in vivo models, and discusses integrating in vitro human cardiac models to advance cardiac regeneration research.
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Affiliation(s)
- Axelle Bois
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
- Department of Cardiovascular Surgery, Université Paris Cité, INSERM U970, PARCC Hôpital Européen Georges Pompidou, 75015, Paris, France
| | - Catarina Grandela
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
| | - James Gallant
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
| | - Christine Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
| | - Philippe Menasché
- Department of Cardiovascular Surgery, Université Paris Cité, INSERM U970, PARCC Hôpital Européen Georges Pompidou, 75015, Paris, France
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Fang B, Mo R, Lin X, Huang Q, Huang R. Multi-omics analysis provides new insights into mechanism of didymin on non-alcoholic fatty liver disease in rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156016. [PMID: 39277989 DOI: 10.1016/j.phymed.2024.156016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/29/2024] [Accepted: 08/31/2024] [Indexed: 09/17/2024]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases accompanied by lipid and glucose metabolism disorder. Didymin has been reported to have various hepatoprotective effects, however, its potential effects and mechanisms on NAFLD remain unclear from the perspective of the whole. PURPOSE To investigate the underlying mechanism of didymin against NAFLD using multi-omics technologies. METHODS Rats were fed with a high-fat diet (HFD) for 8 weeks to induce NAFLD, followed by didymin treatment for 8 weeks. Next, biochemical analysis and histopathological examinations were performed to evaluate the effects of didymin. The key regulating pathways were predicted using transcriptomics, metabolomics and proteomics, and the target pathways were then verified by detecting the key genes/proteins using various experiments. RESULTS Didymin markedly mitigated liver injury and excessive lipid droplet accretion. An integrative multi-omics analysis suggested that the PPAR signaling cascade and insulin signaling pathway might serve as pivotal mechanisms underlying the modulation of lipid and glucose homeostasis by didymin. Further dissection identified five pivotal genes (PPARα, PPARβ, FABP4, ANGPTL4, and PLIN2) and four genes (HK1, HK3, GCK, and PTPN1) as potential hubs within these pathways. Subsequent validation experiments, including qPCR and Western blot, demonstrated upregulated expression of PPARα and PPARβ, indicating the activation of the PPAR pathway by didymin. Concurrently, didymin appeared to modulate the insulin signaling pathway, as evidenced by the upregulated expression of HK1 and downregulated expression of PTPN1. Notably, the manipulation of PPARα, PPARβ, and PTPN1 expression in LO2 cells through silence or overexpression confirmed that didymin significantly reduced lipid accumulation, with its molecular targets likely being the PPAR and insulin pathways. CONCLUSIONS Our findings demonstrate that didymin has a protective effect on NAFLD, and its underlying mechanism may be associated with the regulation of the PPAR and insulin signaling pathways.
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Affiliation(s)
- Bin Fang
- Guangxi Medical University, Nanning, Guangxi, 530021, PR China
| | - Rou Mo
- Guangxi Medical University, Nanning, Guangxi, 530021, PR China
| | - Xing Lin
- Guangxi Medical University, Nanning, Guangxi, 530021, PR China.
| | - Quanfang Huang
- Guangxi University of Chinese Medicine First Affiliated Hospital, Nanning, Guangxi 530023, PR China.
| | - Renbin Huang
- Guangxi Medical University, Nanning, Guangxi, 530021, PR China.
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Kytikova OY, Kovalenko IS, Novgorodtseva TP, Denisenko YK. The Role of Hydroxyeicosatetraenoic Acids in the Regulation of Inflammation in Bronchial Asthma. DOKL BIOCHEM BIOPHYS 2024; 519:512-520. [PMID: 39283556 DOI: 10.1134/s1607672924701126] [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: 07/20/2024] [Revised: 07/26/2024] [Accepted: 07/27/2024] [Indexed: 01/19/2025]
Abstract
Hydroperoxyeicosatetraenoic acids (HETEs) are metabolites of arachidonic acid that are oxidized by a family of enzymes including cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes. These enzymes are widely present in various organs and tissues, and the HETEs they synthesize perform an important function in the regulation of immune reactions and haemostasis processes under physiological and pathophysiological conditions. More researchers confirm the role of these oxidized metabolites in modulating inflammation in asthma. The high production of HETEs in allergic and severe asthma indicates their involvement in the processes of an acute inflammatory response. On the other hand, disturbance of the metabolic transformation of arachidonic acid contributes to the development of chronic inflammation due to insufficient synthesis of mediators that resolve inflammatory processes. Several HETEs have both pro-inflammatory and anti-inflammatory effects, which underscores the ongoing interest in their involvement in the pathogenesis of asthma. At the same time, research results are scarce. Based on an analysis of the literature, the pathways of metabolic transformation of 5-HETE, 12-HETE, and 15-HETE with the participation of cyclooxygenases, lipoxygenases, and cytochrome P-450, as well as their role in asthma pathogenesis, were discussed. The PubMed database was searched for information covering the last five years using selected inclusion criteria. Information queries included the following set of keywords: "bronchial asthma, hydroxyeicosatetraenoic acids, 5-HETE, 12-HETE, 15-HETE." Literature data indicate that the role of HETEs in human physiology and pathology, including the modulation of inflammation in asthma, requires comprehensive study to selectively modulate the enzymatic pathways of arachidonic acid metabolism leading to the production of these mediators.
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Affiliation(s)
- O Yu Kytikova
- Vladivostok Branch of Far Eastern Scientific Center of Physiology and Pathology of Respiration-Institute of Medical Climatology and Rehabilitative Treatment, Vladivostok, Russia.
| | - I S Kovalenko
- Vladivostok Branch of Far Eastern Scientific Center of Physiology and Pathology of Respiration-Institute of Medical Climatology and Rehabilitative Treatment, Vladivostok, Russia
| | - T P Novgorodtseva
- Vladivostok Branch of Far Eastern Scientific Center of Physiology and Pathology of Respiration-Institute of Medical Climatology and Rehabilitative Treatment, Vladivostok, Russia
| | - Yu K Denisenko
- Vladivostok Branch of Far Eastern Scientific Center of Physiology and Pathology of Respiration-Institute of Medical Climatology and Rehabilitative Treatment, Vladivostok, Russia
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Wang Z, Song X, Yin W, Shi K, Lin Y, Liu J, Li X, Tan J, Rong J, Xu K, Wang G. Exposure to High Concentrations of Tetrabromobisphenol A Slows the Process of Tissue Regeneration and Induces an Imbalance of Metabolic Homeostasis in the Regenerated Intestines of Apostichopus japonicus. Genes (Basel) 2024; 15:1448. [PMID: 39596648 PMCID: PMC11594171 DOI: 10.3390/genes15111448] [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: 09/12/2024] [Revised: 10/14/2024] [Accepted: 11/07/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Tissue regenerative capacity following evisceration, potentially influenced by environmental contaminants and intestinal microflora, is essential for the financial success of Apostichopus japonicus farming. However, the morphological structure, gut microbiome composition, and genes expression pattern of the regenerated gut after exposure to high levels of TBBPA remain poorly unclear. METHODS In this research, the effect of TBBPA exposure on tissue regeneration in A. japonicus was investigated through a comprehensive multi-omics approach. RESULTS Our results showed that the integrity, the intestinal wall thickness, and the villi length of the regenerated intestines in A. japonicus decreased after treatment with high levels of TBBPA. The findings from PCoA and NMDS analyses revealed that the microbial community composition was significantly altered following exposure to high concentrations of TBBPA in the regenerated intestines of A. japonicus. The KEGG pathway enrichment analysis indicated that the DEGs (differentially expressed genes) were predominantly enriched on metabolism and immunity-related signaling pathways after exposure to high levels of TBBPA. These included pathways involved in the PPAR signaling pathway, ECM receptor interaction, glycerolipid metabolism, and fatty acid degradation. Interestingly, the results have demonstrated that there are 77 transcript factors that were significantly different after exposure to TBBPA. CONCLUSIONS These results suggested that high levels of exposure to TBBPA induces an imbalance of the metabolic homeostasis by regulating the expression levels of transcription factors in the regenerated intestines of A. japonicus.
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Affiliation(s)
- Zi Wang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (Z.W.); (X.S.); (W.Y.); (Y.L.); (J.L.); (X.L.); (J.T.); (J.R.)
| | - Xiaojun Song
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (Z.W.); (X.S.); (W.Y.); (Y.L.); (J.L.); (X.L.); (J.T.); (J.R.)
| | - Wenhui Yin
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (Z.W.); (X.S.); (W.Y.); (Y.L.); (J.L.); (X.L.); (J.T.); (J.R.)
| | - Kuntao Shi
- Weihai Huancui District Marine Development Research Center, Weihai 264200, China;
| | - Ying Lin
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (Z.W.); (X.S.); (W.Y.); (Y.L.); (J.L.); (X.L.); (J.T.); (J.R.)
| | - Jixiang Liu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (Z.W.); (X.S.); (W.Y.); (Y.L.); (J.L.); (X.L.); (J.T.); (J.R.)
| | - Xiaohan Li
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (Z.W.); (X.S.); (W.Y.); (Y.L.); (J.L.); (X.L.); (J.T.); (J.R.)
| | - Jiabo Tan
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (Z.W.); (X.S.); (W.Y.); (Y.L.); (J.L.); (X.L.); (J.T.); (J.R.)
| | - Junjie Rong
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (Z.W.); (X.S.); (W.Y.); (Y.L.); (J.L.); (X.L.); (J.T.); (J.R.)
| | - Kefeng Xu
- Marine Science Research Institute of Shandong Province, National Oceanographic Center, Qingdao 266104, China
| | - Guodong Wang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China; (Z.W.); (X.S.); (W.Y.); (Y.L.); (J.L.); (X.L.); (J.T.); (J.R.)
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Zhu X, Zheng H, Zhang Z, Ma S, Feng Q, Wang J, Wu G, Ng HY. Cytotoxicity evaluation of organophosphorus flame retardants using electrochemical biosensors and elucidation of associated toxic mechanisms. WATER RESEARCH 2024; 265:122262. [PMID: 39167971 DOI: 10.1016/j.watres.2024.122262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 07/03/2024] [Accepted: 08/12/2024] [Indexed: 08/23/2024]
Abstract
In recent years, organophosphorus flame retardants (OPFRs) have been widely used as substitutes for brominated flame retardants with excellent properties, and their initial toxicological effects on the water ecosystem and human health have gradually emerged. However, to date, research on the cytotoxicity and health risks of OPFRs is still limited. Therefore, this study aims to systematically explore the cytotoxic effects and toxic mechanisms of OPFRs on cells. Human liver cancer (HepG2) cells were adopted as an ideal model for toxicity evaluation due to their rapid growth and metabolism. This study proposes a sensitive electrochemical cell-based sensor constructed on a graphitized multi-walled carbon nanotube/ionic liquid/gold nanoparticle-modified electrode. The sensor was used to detect the cytotoxicity of tri(2-butylxyethyl) phosphate (TBEP), tributyl phosphate (TnBP), triphenyl phosphate (TPhP), tri(1,3-dichloro-2-propyl) phosphate (TDCIPP), tri(2-chloropropyl) phosphate (TCPP) and tri(2-chloroethyl) phosphate (TCEP) in the liquid medium, providing insight into their toxicity in water environments. The half-maximal inhibitory concentration (IC50) of TBEP, TnBP, TPhP, TDCIPP, TCPP and TCEP on HepG2 cells were 179.4, 194.9, 219.8, 339.4, 511.8 and 859.0 μM, respectively. Additionally, the cytotoxic mechanism of six OPFRs was discussed from the perspective of oxidative stress and apoptosis, and four indexes were correlated with toxicity. Furthermore, transcriptome sequencing was conducted, followed by a thorough analysis of the obtained sequencing results. This analysis demonstrated a significant enrichment of the p53 and PPAR pathways, both of which are closely associated with oxidative stress and apoptosis. This study presents a simplified and efficient technique for conducting in vitro toxicity studies on organophosphorus flame retardants in a water environment. Moreover, it establishes a scientific foundation for further investigation into the mechanisms of cytotoxicity associated with these compounds.
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Affiliation(s)
- Xiaolin Zhu
- School of Environment, Northeast Normal University, Changchun 130117, PR China
| | - Huizi Zheng
- School of Environment, Northeast Normal University, Changchun 130117, PR China
| | - Zhipeng Zhang
- School of Environment, Northeast Normal University, Changchun 130117, PR China
| | - Shuang Ma
- School of Environment, Northeast Normal University, Changchun 130117, PR China
| | - Qi Feng
- School of Environment, Northeast Normal University, Changchun 130117, PR China
| | - Jinsheng Wang
- Center for Water Research, Advanced Institute of Natural Sciences, Beijing Normal University, Zhuhai, 519087, China
| | - Guanlan Wu
- School of Environment, Northeast Normal University, Changchun 130117, PR China; Center for Water Research, Advanced Institute of Natural Sciences, Beijing Normal University, Zhuhai, 519087, China.
| | - How Yong Ng
- Center for Water Research, Advanced Institute of Natural Sciences, Beijing Normal University, Zhuhai, 519087, China; Department of Civil and Environmental Engineering, National University of Singapore, 1 Engineering Drive 2, 117576, Singapore.
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Jin C, Zhao R, Hu W, Wu X, Zhou L, Shan L, Wu H. Topical hADSCs-HA Gel Promotes Skin Regeneration and Angiogenesis in Pressure Ulcers by Paracrine Activating PPARβ/δ Pathway. Drug Des Devel Ther 2024; 18:4799-4824. [PMID: 39478872 PMCID: PMC11523932 DOI: 10.2147/dddt.s474628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 10/09/2024] [Indexed: 11/02/2024] Open
Abstract
Background Pressure ulcer is common in the bedridden elderly with high mortality and lack of effective treatment. In this study, human-adipose-derived-stem-cells-hyaluronic acid gel (hADSCs-HA gel) was developed and applied topically to treat pressure ulcers, of which efficacy and paracrine mechanisms were investigated through in vivo and in vitro experiments. Methods Pressure ulcers were established on the backs of C57BL/6 mice and treated topically with hADSCs-HA gel, hADSCs, hyaluronic acid, and normal saline respectively. The rate of wound closure was observed continuously during the following 14 days and the wound samples were obtained for Western blot, histopathology, immunohistochemistry, and proteomic analysis. Human dermal fibroblasts (HDFs) and human venous endothelial cells (HUVECs) under normal or hypoxic conditions were treated with conditioned medium of human ADSCs (ADSC-CM), then CCK-8, scratch test, tube formation, and Western blot were conducted to evaluate the paracrine effects of hADSCs and to explore the underlying mechanism. Results The in vivo data demonstrated that hADSCs-HA gel significantly accelerated the healing of pressure ulcers by enhancing collagen expression, angiogenesis, and skin proliferation. The in vitro data revealed that hADSCs strengthened the proliferation and wound healing capabilities of HDFs and HUVECs, meanwhile promoted collagen secretion and tube formation through paracrine mode. ADSC-CM was also proved to exert protective effects on hypoxic HDFs and HUVECs. Besides, the results of proteomic analysis and Western blot elucidated that lipid metabolism and PPARβ/δ pathway mediated the healing effect of hADSCs-HA gel on pressure ulcers. Conclusion Our research showed that topical application of hADSCs-HA gel played an important role in dermal regeneration and angiogenesis. Therefore, hADSCs-HA gel exhibited the potential as a novel stem-cell-based therapeutic strategy of treating pressure ulcers in clinical practices.
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Affiliation(s)
- Chaoying Jin
- Department of Plastic and Aesthetic Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, People’s Republic of China
- School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310020, People’s Republic of China
| | - Ruolin Zhao
- Yichen Biotechnology Co., Ltd, Hangzhou, Zhejiang, 311200, People’s Republic of China
- Fuyang Academy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 311403, People’s Republic of China
| | - Weihang Hu
- Department of Critical Care Medicine, Zhejiang Hospital, Hangzhou, Zhejiang, 310013, People’s Republic of China
| | - Xiaolong Wu
- Fuyang Academy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 311403, People’s Republic of China
| | - Li Zhou
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310060, People’s Republic of China
| | - Letian Shan
- Fuyang Academy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 311403, People’s Republic of China
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310060, People’s Republic of China
| | - Huiling Wu
- Department of Plastic and Aesthetic Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, People’s Republic of China
- School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310020, People’s Republic of China
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11
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Warren WG, Osborn M, Duffy P, Yates A, O'Sullivan SE. Potential safety implications of fatty acid-binding protein inhibition. Toxicol Appl Pharmacol 2024; 491:117079. [PMID: 39218163 DOI: 10.1016/j.taap.2024.117079] [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: 06/07/2024] [Revised: 08/15/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
Fatty acid-binding proteins (FABPs) are small intracellular proteins that regulate fatty acid metabolism, transport, and signalling. There are ten known human isoforms, many of which are upregulated and involved in clinical pathologies. As such, FABP inhibition may be beneficial in disease states such as cancer, and those involving the cardiovascular system, metabolism, immunity, and cognition. Recently, a potent, selective FABP5 inhibitor (ART26.12), with 90-fold selectivity to FABP3 and 20-fold selectivity to FABP7, was found to be remarkably benign, with a no-observed-adverse-effect level of 1000 mg/kg in rats and dogs, showing no genotoxicity, cardiovascular, central, or respiratory toxicity. To understand the potential implication of FABP inhibition more fully, this review systematically assessed literature investigating genetic knockout, knockdown, and pharmacological inhibition of FABP3, FABP4, FABP5, or FABP7. Analysis of the literature revealed that animals bred not to express FABPs showed the most biological effects, suggesting key roles of these proteins during development. FABP ablation sometimes exacerbated symptoms of disease models, particularly those linked to metabolism, inflammatory and immune responses, cardiac contractility, neurogenesis, and cognition. However, FABP inhibition (genetic silencing or pharmacological) had a positive effect in many more disease conditions. Several polymorphisms of each FABP gene have also been linked to pathological conditions, but it was unclear how several polymorphisms affected protein function. Overall, analysis of the literature to date suggests that pharmacological inhibition of FABPs in adults is of low risk.
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Affiliation(s)
- William G Warren
- Artelo Biosciences Limited, Alderley Park, Cheshire SK10 4TG, United Kingdom.
| | - Myles Osborn
- Artelo Biosciences Limited, Alderley Park, Cheshire SK10 4TG, United Kingdom
| | - Paul Duffy
- Apconix Ltd., Alderley Park, Cheshire SK10 4TG, United Kingdom
| | - Andrew Yates
- Artelo Biosciences Limited, Alderley Park, Cheshire SK10 4TG, United Kingdom
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12
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Zubareva OE, Kharisova AR, Roginskaya AI, Kovalenko AA, Zakharova MV, Schwarz AP, Sinyak DS, Zaitsev AV. PPARβ/δ Agonist GW0742 Modulates Microglial and Astroglial Gene Expression in a Rat Model of Temporal Lobe Epilepsy. Int J Mol Sci 2024; 25:10015. [PMID: 39337503 PMCID: PMC11432388 DOI: 10.3390/ijms251810015] [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: 08/14/2024] [Revised: 09/10/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
The role of astroglial and microglial cells in the pathogenesis of epilepsy is currently under active investigation. It has been proposed that the activity of these cells may be regulated by the agonists of peroxisome proliferator-activated nuclear receptors (PPARs). This study investigated the effects of a seven-day treatment with the PPAR β/δ agonist GW0742 (Fitorine, 5 mg/kg/day) on the behavior and gene expression of the astroglial and microglial proteins involved in the regulation of epileptogenesis in the rat brain within a lithium-pilocarpine model of temporal lobe epilepsy (TLE). TLE resulted in decreased social and increased locomotor activity in the rats, increased expression of astro- and microglial activation marker genes (Gfap, Aif1), pro- and anti-inflammatory cytokine genes (Tnfa, Il1b, Il1rn), and altered expression of other microglial (Nlrp3, Arg1) and astroglial (Lcn2, S100a10) genes in the dorsal hippocampus and cerebral cortex. GW0742 attenuated, but did not completely block, some of these impairments. Specifically, the treatment affected Gfap gene expression in the dorsal hippocampus and Aif1 gene expression in the cortex. The GW0742 injections attenuated the TLE-specific enhancement of Nlrp3 and Il1rn gene expression in the cortex. These results suggest that GW0742 may affect the expression of some genes involved in the regulation of epileptogenesis.
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Affiliation(s)
| | | | | | | | | | | | | | - Aleksey V. Zaitsev
- Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, 194223 Saint Petersburg, Russia; (O.E.Z.); (A.R.K.); (A.I.R.); (A.A.K.); (M.V.Z.); (A.P.S.); (D.S.S.)
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13
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Koizumi A, Kaji K, Nishimura N, Asada S, Matsuda T, Tanaka M, Yorioka N, Tsuji Y, Kitagawa K, Sato S, Namisaki T, Akahane T, Yoshiji H. Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease. World J Gastroenterol 2024; 30:3428-3446. [PMID: 39091710 PMCID: PMC11290391 DOI: 10.3748/wjg.v30.i28.3428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 05/31/2024] [Accepted: 06/20/2024] [Indexed: 07/24/2024] Open
Abstract
BACKGROUND Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality, but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis. Peroxisome proliferator activated receptor (PPAR) α and δ play a key role in lipid metabolism and intestinal barrier homeostasis, which are major contributors to the pathological progression of ALD. Meanwhile, elafibranor (EFN), which is a dual PPARα and PPARδ agonist, has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease and primary biliary cholangitis. However, the benefits of EFN for ALD treatment is unknown. AIM To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model. METHODS ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol (EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly (1 mL/kg) for 8 weeks. EFN (3 and 10 mg/kg/day) was orally administered during the experimental period. Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis, fibrosis, and intestinal barrier integrity. The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays. RESULTS The hepatic steatosis, apoptosis, and fibrosis in the ALD mice model were significantly attenuated by EFN treatment. EFN promoted lipolysis and β-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells, primarily through PPARα activation. Moreover, EFN inhibited the Kupffer cell-mediated inflammatory response, with blunted hepatic exposure to lipopolysaccharide (LPS) and toll like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling. EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses. The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation. CONCLUSION EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis, enhancing hepatocyte autophagic and antioxidant capacities, and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.
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Affiliation(s)
- Aritoshi Koizumi
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Kosuke Kaji
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Norihisa Nishimura
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Shohei Asada
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Takuya Matsuda
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Misako Tanaka
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Nobuyuki Yorioka
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Yuki Tsuji
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Koh Kitagawa
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Shinya Sato
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Tadashi Namisaki
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Takemi Akahane
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
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14
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Santos A, Oliveira M, Lopes I, Almeida M, Venâncio C. Polyhydroxybutyrate (PHB) nanoparticles modulate metals toxicity in Hydra viridissima. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 932:172868. [PMID: 38714257 DOI: 10.1016/j.scitotenv.2024.172868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/02/2024] [Accepted: 04/27/2024] [Indexed: 05/09/2024]
Abstract
The use of bioplastics (e.g., polyhydroxybutyrate) emerged as a solution to help reduce plastic pollution caused by conventional plastics. Nevertheless, bioplastics share many characteristics with their conventional counterparts, such as degradation to nano-sized particles and the ability to sorb environmental pollutants, like metals. This study aimed to assess the potential impacts of the interaction of metals (cadmium - Cd, copper - Cu, and zinc - Zn) with polyhydroxybutyrate nanoplastics (PHB-NPLs; ~200 nm) on the freshwater cnidarian Hydra viridissima in terms of mortality rates, morphological alterations, and feeding behavior. The metal concentrations selected for the combined exposures corresponded to concentrations causing 20 %, 50 %, and 80 % of mortality (LC20, LC50, and LC80, respectively) and the PHB-NPLs concentrations ranged from 0.01 to 1000 μg/L. H. viridissima sensitivity to the metals, based on the LC50's, can be ordered as: Zn < Cd < Cu. Combined exposure to metals and PHB-NPLs yielded distinct outcomes concerning mortality, morphological changes, and feeding behavior, uncovering metal- and dose-specific responses. The interaction between Cd-LCx and PHB-NPLs progressed from no effect at LC20,96h to an ameliorative effect at Cd-LC50,96h. Cu-LCx revealed potential mitigation effects (LC20,96h and LC50,96h) but at Cu-LC80,96h the response shifts to a potentiating effect. For Zn-LCx, response patterns across the combinations with PHB-NPLs were like those induced by the metal alone. PHB-NPLs emerged as a key factor capable of modulating the toxicity of metals. This study highlights the context-dependent interactions between metals and PHB-NPLs in freshwater environments while supporting the need for further investigation of the underlying mechanisms and ecological consequences in forthcoming research.
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Affiliation(s)
- Ana Santos
- Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Miguel Oliveira
- CESAM - Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Isabel Lopes
- CESAM - Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Mónica Almeida
- Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Cátia Venâncio
- CESAM - Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal.
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Huang J, Wu S, Wang Y, Shen J, Wang C, Zheng Y, Chu PK, Liu X. Dual elemental doping activated signaling pathway of angiogenesis and defective heterojunction engineering for effective therapy of MRSA-infected wounds. Bioact Mater 2024; 37:14-29. [PMID: 38515610 PMCID: PMC10951428 DOI: 10.1016/j.bioactmat.2024.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 03/05/2024] [Accepted: 03/08/2024] [Indexed: 03/23/2024] Open
Abstract
Multi-drug resistant bacterial infections pose a significant threat to human health. Thus, the development of effective bactericidal strategies is a pressing concern. In this study, a ternary heterostructure (Zn-CN/P-GO/BiS) comprised of Zn-doped graphite phase carbon nitride (g-C3N4), phosphorous-doped graphene oxide (GO) and bismuth sulphide (Bi2S3) is constructed for efficiently treating methicillin-resistant Staphylococcus aureus (MRSA)-infected wound. Zn doping-induced defect sites in g-C3N4 results in a reduced band gap (ΔE) and a smaller energy gap (ΔEST) between the singlet state S1 and triplet state T1, which favours two-photon excitation and accelerates electron transfer. Furthermore, the formation of an internal electric field at the ternary heterogeneous interface optimizes the charge transfer pathway, inhibits the recombination of electron-hole pairs, improves the photodynamic effect of g-C3N4, and enhances its catalytic performance. Therefore, the Zn-CN/P-GO/BiS significantly augments the production of reactive oxygen species and heat under 808 nm NIR (0.67 W cm-2) irradiation, leading to the elimination of 99.60% ± 0.07% MRSA within 20 min. Additionally, the release of essential trace elements (Zn and P) promotes wound healing by activating hypoxia-inducible factor-1 (HIF-1) and peroxisome proliferator-activated receptors (PPAR) signaling pathways. This work provides unique insight into the rapid antibacterial applications of trace element doping and two-photon excitation.
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Affiliation(s)
- Jin Huang
- Biomedical Materials Engineering Research Center, Hubei Key Laboratory of Polymer Materials, Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, School of Materials Science & Engineering, Hubei University, Wuhan, 430062, China
- School of Health Science & Biomedical Engineering, Hebei University of Technology, Tianjin, 300401, China
- School of Materials Science & Engineering, Peking University, Beijing, 100871, China
| | - Shuilin Wu
- Biomedical Materials Engineering Research Center, Hubei Key Laboratory of Polymer Materials, Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, School of Materials Science & Engineering, Hubei University, Wuhan, 430062, China
- School of Materials Science & Engineering, Peking University, Beijing, 100871, China
| | - Yi Wang
- Biomedical Materials Engineering Research Center, Hubei Key Laboratory of Polymer Materials, Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, School of Materials Science & Engineering, Hubei University, Wuhan, 430062, China
- School of Health Science & Biomedical Engineering, Hebei University of Technology, Tianjin, 300401, China
- School of Materials Science & Engineering, Peking University, Beijing, 100871, China
| | - Jie Shen
- Shenzhen Key Laboratory of Spine Surgery, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Chaofeng Wang
- School of Health Science & Biomedical Engineering, Hebei University of Technology, Tianjin, 300401, China
| | - Yufeng Zheng
- School of Materials Science & Engineering, Peking University, Beijing, 100871, China
| | - Paul K. Chu
- Department of Physics and Department of Materials Science and Engineering, City University of Hong Kong, 999077, China
| | - Xiangmei Liu
- Biomedical Materials Engineering Research Center, Hubei Key Laboratory of Polymer Materials, Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, School of Materials Science & Engineering, Hubei University, Wuhan, 430062, China
- School of Health Science & Biomedical Engineering, Hebei University of Technology, Tianjin, 300401, China
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Qian J, Li Q, Song Y, Gong X, Hu K, Ge G, Sun Y. Pectolinarigenin ameliorates osteoporosis via enhancing Wnt signaling cascade in PPARβ-dependent manner. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155587. [PMID: 38608598 DOI: 10.1016/j.phymed.2024.155587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 10/03/2023] [Accepted: 04/02/2024] [Indexed: 04/14/2024]
Abstract
BACKGROUND Osteoporosis is a prevalent metabolic bone disease in older adults. Peroxisome proliferator-activated receptor β (PPARβ), the most abundant PPAR isotype expressed in bone tissues, plays a critical role in regulating the energy metabolism of osteoblasts. However, the botanical compounds targeting PPARβ for the treatment of osteoporosis remain largely unexplored. PURPOSE To discover a potent PPARβ agonist from botanical compounds, as well as to investigate the anti-osteoporosis effects and to elucidate the underlying mechanisms of the newly identified PPARβ agonist. METHODS The PPARβ agonist effects of botanical compounds were screened by an in vitro luciferase reporter gene assay. The PPARβ agonist effects of pectolinarigenin (PEC) in bone marrow mesenchymal stromal cells (BMSCs) were validated by Western blotting. RNA-seq transcriptome analyses were conducted to reveal the underlying osteoporosis mechanisms of PEC in BMSCs. The PPARβ antagonist (GSK0660) and Wnt signaling inhibitor (XAV969) were used to explore the role of the PPARβ and Wnt signaling cascade in the anti-osteoporosis effects of PEC. PEC or the PEG-PLGA nanoparticles of PEC (PEC-NP) were intraperitoneally administrated in both wild-type mice and ovariectomy-induced osteoporosis mice to examine its anti-osteoporotic effects in vivo. RESULTS PEC, a newly identified naturally occurring PPARβ agonist, significantly promotes osteogenic differentiation and up-regulates the osteogenic differentiation-related genes (Runx2, Osterix, and Bmp2) in BMSCs. RNA sequencing and functional gene enrichment analysis suggested that PEC could activate osteogenic-related signaling pathways, including Wnt and PPAR signaling pathways. Further investigations suggested that PEC could enhance Wnt/β-catenin signaling in a PPARβ-dependent manner in BMSCs. Animal tests showed that PEC-NP promoted bone mass and density, increased the bone cell matrix protein, and accelerated bone formation in wild-type mice, while PEC-NP also played a preventive role in ovariectomy-induced osteoporosis mice via maintaining the expression level of bone cell matrix protein, balancing the rate of bone formation, and slowing down bone loss. Additionally, PEC-NP did not cause any organ injury and body weight loss after long-term use (11 weeks). CONCLUSION PEC significantly promotes bone formation and reduces bone loss in both BMSCs and ovariectomy-induced osteoporosis mice via enhancing the Wnt signaling cascade in a PPARβ-dependent manner, providing a new alternative therapy for preventing estrogen deficiency-induced osteoporotic diseases.
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Affiliation(s)
- Jun Qian
- Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Oral Implantology, Stomatological Hospital and Dental School, Tongji University, Shanghai, China
| | - Qian Li
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China; School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Yangjie Song
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Xuyan Gong
- Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Oral Implantology, Stomatological Hospital and Dental School, Tongji University, Shanghai, China
| | - Kaili Hu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.
| | - Guangbo Ge
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.
| | - Yao Sun
- Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Oral Implantology, Stomatological Hospital and Dental School, Tongji University, Shanghai, China.
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Abbattista R, Feinberg NG, Snodgrass IF, Newman JW, Dandekar AM. Unveiling the "hidden quality" of the walnut pellicle: a precious source of bioactive lipids. FRONTIERS IN PLANT SCIENCE 2024; 15:1395543. [PMID: 38957599 PMCID: PMC11217525 DOI: 10.3389/fpls.2024.1395543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/30/2024] [Indexed: 07/04/2024]
Abstract
Tree nut consumption has been widely associated with various health benefits, with walnuts, in particular, being linked with improved cardiovascular and neurological health. These benefits have been attributed to walnuts' vast array of phenolic antioxidants and abundant polyunsaturated fatty acids. However, recent studies have revealed unexpected clinical outcomes related to walnut consumption, which cannot be explained simply with the aforementioned molecular hallmarks. With the goal of discovering potential molecular sources of these unexplained clinical outcomes, an exploratory untargeted metabolomics analysis of the isolated walnut pellicle was conducted. This analysis revealed a myriad of unusual lipids, including oxylipins and endocannabinoids. These lipid classes, which are likely present in the pellicle to enhance the seeds' defenses due to their antimicrobial properties, also have known potent bioactivities as mammalian signaling molecules and homeostatic regulators. Given the potential value of this tissue for human health, with respect to its "bioactive" lipid fraction, we sought to quantify the amounts of these compounds in pellicle-enriched waste by-products of mechanized walnut processing in California. An impressive repertoire of these compounds was revealed in these matrices, and in notably significant concentrations. This discovery establishes these low-value agriculture wastes promising candidates for valorization and translation into high-value, health-promoting products; as these molecules represent a potential explanation for the unexpected clinical outcomes of walnut consumption. This "hidden quality" of the walnut pellicle may encourage further consumption of walnuts, and walnut industries may benefit from a revaluation of abundant pellicle-enriched waste streams, leading to increased sustainability and profitability through waste upcycling.
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Affiliation(s)
- Ramona Abbattista
- Department of Plant Sciences, University of California, Davis, Davis, CA, United States
| | - Noah G. Feinberg
- Department of Plant Sciences, University of California, Davis, Davis, CA, United States
| | - Isabel F. Snodgrass
- West Coast Metabolomics Center, Genome Center, University of California, Davis, Davis, CA, United States
| | - John W. Newman
- Western Human Nutrition Research Center, United States Department of Agriculture, Davis, CA, United States
- West Coast Metabolomics Center, Genome Center, University of California, Davis, Davis, CA, United States
- Department of Nutrition, University of California, Davis, Davis, CA, United States
| | - Abhaya M. Dandekar
- Department of Plant Sciences, University of California, Davis, Davis, CA, United States
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18
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Liu T, Wang J, Tong Y, Wu L, Xie Y, He P, Lin S, Hu X. Integrating network pharmacology and animal experimental validation to investigate the action mechanism of oleanolic acid in obesity. J Transl Med 2024; 22:86. [PMID: 38246999 PMCID: PMC10802007 DOI: 10.1186/s12967-023-04840-x] [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: 08/30/2023] [Accepted: 12/26/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Obesity, a condition associated with the development of widespread cardiovascular disease, metabolic disorders, and other health complications, has emerged as a significant global health issue. Oleanolic acid (OA), a pentacyclic triterpenoid compound that is widely distributed in various natural plants, has demonstrated potential anti-inflammatory and anti-atherosclerotic properties. However, the mechanism by which OA fights obesity has not been well studied. METHOD Network pharmacology was utilized to search for potential targets and pathways of OA against obesity. Molecular docking and molecular dynamics simulations were utilized to validate the interaction of OA with core targets, and an animal model of obesity induced by high-fat eating was then employed to confirm the most central of these targets. RESULTS The network pharmacology study thoroughly examined 42 important OA targets for the treatment of obesity. The key biological processes (BP), cellular components (CC), and molecular functions (MF) of OA for anti-obesity were identified using GO enrichment analysis, including intracellular receptor signaling, intracellular steroid hormone receptor signaling, chromatin, nucleoplasm, receptor complex, endoplasmic reticulum membrane, and RNA polymerase II transcription Factor Activity. The KEGG/DAVID database enrichment study found that metabolic pathways, PPAR signaling pathways, cancer pathways/PPAR signaling pathways, insulin resistance, and ovarian steroidogenesis all play essential roles in the treatment of obesity and OA. The protein-protein interaction (PPI) network was used to screen nine main targets: PPARG, PPARA, MAPK3, NR3C1, PTGS2, CYP19A1, CNR1, HSD11B1, and AGTR1. Using molecular docking technology, the possible binding mechanism and degree of binding between OA and each important target were validated, demonstrating that OA has a good binding potential with each target. The molecular dynamics simulation's Root Mean Square Deviation (RMSD), and Radius of Gyration (Rg) further demonstrated that OA has strong binding stability with each target. Additional animal studies confirmed the significance of the core target PPARG and the core pathway PPAR signaling pathway in OA anti-obesity. CONCLUSION Overall, our study utilized a multifaceted approach to investigate the value and mechanisms of OA in treating obesity, thereby providing a novel foundation for the identification and development of natural drug treatments.
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Affiliation(s)
- Tianfeng Liu
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Waihuan East Road, Guangzhou, 510006, Guangdong, China
| | - Jiliang Wang
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Waihuan East Road, Guangzhou, 510006, Guangdong, China
| | - Ying Tong
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Waihuan East Road, Guangzhou, 510006, Guangdong, China
| | - Lele Wu
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Waihuan East Road, Guangzhou, 510006, Guangdong, China
| | - Ying Xie
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Waihuan East Road, Guangzhou, 510006, Guangdong, China
| | - Ping He
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Waihuan East Road, Guangzhou, 510006, Guangdong, China
| | - Shujue Lin
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Waihuan East Road, Guangzhou, 510006, Guangdong, China
| | - Xuguang Hu
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Waihuan East Road, Guangzhou, 510006, Guangdong, China.
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Changizi Z, Kajbaf F, Moslehi A. An Overview of the Role of Peroxisome Proliferator-activated Receptors in Liver Diseases. J Clin Transl Hepatol 2023; 11:1542-1552. [PMID: 38161499 PMCID: PMC10752810 DOI: 10.14218/jcth.2023.00334] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/17/2023] [Accepted: 10/09/2023] [Indexed: 01/03/2024] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a superfamily of nuclear transcription receptors, consisting of PPARα, PPARγ, and PPARβ/δ, which are highly expressed in the liver. They control and modulate the expression of a large number of genes involved in metabolism and energy homeostasis, oxidative stress, inflammation, and even apoptosis in the liver. Therefore, they have critical roles in the pathophysiology of hepatic diseases. This review provides a general insight into the role of PPARs in liver diseases and some of their agonists in the clinic.
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Affiliation(s)
- Zahra Changizi
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Forough Kajbaf
- Veterinary Department, Faculty of Agriculture, Islamic Azad University, Shoushtar Branch, Shoushtar, Iran
| | - Azam Moslehi
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
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Chen L, Chen Y, Wang B, Yang Z, Cai Z, Wang X, Sun L, Li Z, Wang G. Design, synthesis, and biological evaluation of deuterated indolepropionic acid derivatives as novel long-acting pan PPARα/γ/δ agonists. Bioorg Med Chem 2023; 96:117533. [PMID: 37976807 DOI: 10.1016/j.bmc.2023.117533] [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: 08/18/2023] [Revised: 10/17/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023]
Abstract
Metabolic syndrome is a complex disease with diverse symptoms, but current pharmacological interventions have limited efficacy. Indeglitazar, a pan-agonist targeting the three-peroxisome proliferator activated receptors (PPAR), exhibits significant therapeutic effects on both diabetic and fatty liver animal models. However, its short half-life limits the in vivo efficacy, which might be attributed to the β-oxidation of indolepropionic acid at Indeglitazar. To overcome this metabolic instability, two deuterium atoms were introduced to the α-position of indolepropionic acid to block the β-oxidation. In this study, several deuterated derivatives were found to sustain PPARs activity and extend the half-life of liver microsomes. In oral glucose tolerance tests, I-1 exhibited the strongest glucose-lowering effect on ob/ob mice in this series. In db/db mice, I-1 reduced lipid levels, liver steatosis and promoted UCP1 expression in white adipose tissue. Mechanistic studies further revealed that I-1 exerts stronger effects than Indeglitazar on the regulation of genes related to lipid metabolism, mitochondrial function, and oxidative stress. Furthermore, I-1 significantly reduced liver steatosis, hepatocellular ballooning, inflammation, and fibrosis in NASH model induced by HFD + CCl4, and even exerted better therapeutic effect than that of Indeglitazar. With the above attractive efficacy, deuterated derivative I-1 is considered as a promising treatment for metabolic syndrome.
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Affiliation(s)
- Lianru Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Ya Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Bin Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Zhongcheng Yang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Zongyu Cai
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Xuekun Wang
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong 252059, PR China
| | - Lidan Sun
- Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China.
| | - Zheng Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou 510006, PR China.
| | - Guangji Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
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Ke ZP, Tao WQ, Zhao G, Cheng K. Role of PPAR-related genes in chronic heart failure: evidence from large populations. BMC Cardiovasc Disord 2023; 23:552. [PMID: 37950149 PMCID: PMC10638691 DOI: 10.1186/s12872-023-03554-8] [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: 03/27/2023] [Accepted: 10/10/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND The role of PPAR signaling and its associated genes in the pathogenesis and progression of chronic heart failure (CHF) remains elusive. METHODS We accessed the gene expression profile and relevant baseline information of CHF samples from the Gene Expression Omnibus (GEO) database, specifically from the GSE57338 project. RESULTS From GSE57338 project, we derived the expression value of 126 PPAR-related genes. A protein-protein interaction network was then established to illustrate potential protein interactions. ClueGO analysis results revealed that these genes predominantly participate in functions such as export across plasma membrane, regulation of lipid metabolic process, fatty acid metabolism, circulatory system vascular processes, alcohol metabolism, triglyceride metabolism and regulation of lipid localization and response to nutrient. Using the cytohubba plug-in in Cytoscape, we pinpointed ACADM, PPARG and CPT2 as potential central molecules in HF pathogenesis and progression. Subsequent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis delved into the potential biological role of these three genes in CHF. Immune infiltration analysis suggested that the infiltration level of neutrophils and M2 macrophages might be notably influenced by these genes, thereby playing a role in the CHF mechanism. CONCLUSIONS Our research provides a comprehensive insight into the significance of PPAR associated genes in CHF development. Notably, the genes ACADM, PPARG and CPT2 emerged as potential targets for clinical interventions.
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Affiliation(s)
- Zun-Ping Ke
- Department of Geriatrics, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Wen-Qi Tao
- Department of Cardiology, Jing'an District Centre Hospital of Shanghai, Fudan University, Shanghai, 200040, China
| | - Gang Zhao
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China
| | - Kuan Cheng
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.
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Guan S, Hu T, Chen L, Li Z, Lin Z, Lei J, Shen J. A novel PPARβ/FFA1 dual agonist Y8 promotes diabetic wound healing. Eur J Pharmacol 2023; 958:175934. [PMID: 37562666 DOI: 10.1016/j.ejphar.2023.175934] [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: 01/17/2023] [Revised: 06/30/2023] [Accepted: 07/31/2023] [Indexed: 08/12/2023]
Abstract
BACKGROUND Diabetes ulcer is one of the leading causes of disability and death in diabetics. Y8 [(2-(2-fluoro-4-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methoxy) phenoxy)acetic acid)], a dual agonist of peroxisome proliferation activated receptorβ (PPARβ) and free fatty acid receptor 1 (FFA1/FFAR1/GPR40), a new compound molecule with the potential for diabetes ulcer treatment. OBJECTIVE To research the effect of the dual target agonist Y8 and its mechanism of action in the treatment of diabetic ulcers. METHODS We have established a wound model in diabetic mice. After treatment with Y8, wound healing was evaluated by tissue pathology, reactive oxygen species (ROS) levels, and gene expression testing. Under high sugar conditions, the mechanism of Y8 affecting fibroblasts' proliferation and keratinocytes' migration is further studied. RESULTS We found that Y8 accelerated wound healing and shortened healing time in diabetic mice. Granulation tissue generation and extracellular matrix (ECM) deposition were significantly increased in Y8-treated mice. Mechanistically, Y8 promotes keratinocyte proliferation by activating PPARβ and migration of keratinocytes by triggering FFA1 in vitro. In addition, Y8 also decreased ROS levels in fibroblasts in vitro and in vivo by activating PPARβ, reducing their release of superoxide anions. CONCLUSION Our results suggest that PPARβ/FFA1 dual agonist Y8 has the effect of promoting the healing of diabetic ulcer wounds in vivo and in vitro, and its therapeutic effect is better than that of single-target agonists.
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Affiliation(s)
- Sujuan Guan
- School of Bioscience and Biopharmaceutics, Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
| | - Tingting Hu
- School of Bioscience and Biopharmaceutics, Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
| | - Liushan Chen
- Department of Breast, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, PR China.
| | - Zheng Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
| | - Zhenming Lin
- School of Bioscience and Biopharmaceutics, Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
| | - Jinping Lei
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, PR China.
| | - Juan Shen
- School of Bioscience and Biopharmaceutics, Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
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Grzelak EM, Elshan NGRD, Shao S, Bulos ML, Joseph SB, Chatterjee AK, Chen JJ, Nguyên-Trân V, Schultz PG, Bollong MJ. Pharmacological YAP activation promotes regenerative repair of cutaneous wounds. Proc Natl Acad Sci U S A 2023; 120:e2305085120. [PMID: 37399395 PMCID: PMC10334740 DOI: 10.1073/pnas.2305085120] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 05/26/2023] [Indexed: 07/05/2023] Open
Abstract
Chronic cutaneous wounds remain a persistent unmet medical need that decreases life expectancy and quality of life. Here, we report that topical application of PY-60, a small-molecule activator of the transcriptional coactivator Yes-associated protein (YAP), promotes regenerative repair of cutaneous wounds in pig and human models. Pharmacological YAP activation enacts a reversible pro-proliferative transcriptional program in keratinocytes and dermal cells that results in accelerated re-epithelization and regranulation of the wound bed. These results demonstrate that transient topical administration of a YAP activating agent may represent a generalizable therapeutic approach to treating cutaneous wounds.
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Affiliation(s)
- Edyta M. Grzelak
- Department of Chemistry, The Scripps Research Institute, San Diego, CA92037
| | | | - Sida Shao
- Department of Chemistry, The Scripps Research Institute, San Diego, CA92037
| | - Maya L. Bulos
- Department of Chemistry, The Scripps Research Institute, San Diego, CA92037
| | - Sean B. Joseph
- Calibr, A Division of Scripps Research, San Diego, CA92037
| | | | | | | | - Peter G. Schultz
- Department of Chemistry, The Scripps Research Institute, San Diego, CA92037
- Calibr, A Division of Scripps Research, San Diego, CA92037
| | - Michael J. Bollong
- Department of Chemistry, The Scripps Research Institute, San Diego, CA92037
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24
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Wu X, Chen J, Sun W, Hart DA, Ackermann PW, Ahmed AS. Network proteomic analysis identifies inter-alpha-trypsin inhibitor heavy chain 4 during early human Achilles tendon healing as a prognostic biomarker of good long-term outcomes. Front Immunol 2023; 14:1191536. [PMID: 37483617 PMCID: PMC10358850 DOI: 10.3389/fimmu.2023.1191536] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/16/2023] [Indexed: 07/25/2023] Open
Abstract
The suboptimal or protracted regeneration of injured connective tissues often results in significant dysfunction, pain, and functional disability. Despite the prevalence of the condition, few studies have been conducted which focused on biomarkers or key molecules involved in processes governing healing outcomes. To gain insight into injured connective tissue repair, and using the Achilles tendon as a model system, we utilized quantitative proteomic and weighted co-expression network analysis of tissues acquired from Achilles tendon rupture (ATR) patients with different outcomes at 1-year postoperatively. Two modules were detected to be associated with prognosis. The initial analysis identified inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) as a biomarker or hub protein positively associated with better healing outcomes. Additional analysis identified the beneficial role of ITIH4 in inflammation, cell viability, apoptosis, proliferation, wound healing, and for the synthesis of type I collagen in cultured fibroblasts. Functionally, the effects of ITIH4 were found to be mediated by peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways. Taken together, these findings suggest that ITIH4 plays an important role in processes of connective tissue repair and advocate for the potential of ITIH4 as a therapeutic target for injured connective tissue repair. Trial registration http://clinicaltrials.gov, identifiers NCT02318472, NCT01317160.
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Affiliation(s)
- Xinjie Wu
- Division of Spine Surgery, Department of Orthopaedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Junyu Chen
- Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Wei Sun
- Department of Orthopedic Surgery, China-Japan Friendship Hospital, Beijing, China
| | - David A. Hart
- Department of Surgery, Faculty of Kinesiology and the McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, AB, Canada
| | - Paul W. Ackermann
- Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Aisha S. Ahmed
- Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Physiology, University of Helsinki, Helsinki, Finland
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25
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Kytikova OY, Denisenko YK, Novgorodtseva TP, Kovalenko IS. Cannabinoids And Cannabinoid-Like Compounds: Biochemical Characterization And Pharmacological Perspectives. RUSSIAN OPEN MEDICAL JOURNAL 2023. [DOI: 10.15275/rusomj.2023.0107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/31/2023] Open
Abstract
Publication interest in cannabinoids, including phytocannabinoids, endogenous cannabinoids, synthetic cannabinoids and cannabinomimetic compounds, is due to the therapeutic potential of these compounds in inflammatory pathology. Since recent years, scientific interest was focused on compounds with cannabinomimetic activity. The therapeutic use of phytocannabinoids and endocannabinoids is somewhat limited due to unresolved issues of dosing, toxicity and safety in humans, while cannabinoid-like compounds combine similar therapeutic effects with a high confirmed safety. Targets for endocannabinoids and phytocannabinoids are endocannabinoid receptors 1 and 2, G protein-coupled receptors (GPCRs), peroxisome proliferator-activated receptors (PPARs), and transient receptor potential ion channels (TRPs). Non-endocannabinoid N-acylethanolamines do not interact with cannabinoid receptors and exhibit agonist activity towards non-cannabinoid receptors, such as PPARs, GPCRs and TRPs. This literature review includes contemporary information on the biological activity, metabolism and pharmacological properties of cannabinoids and cannabinoid-like compounds, as well as their receptors. We established that only a few studies were devoted to the relationship of non-endocannabinoid N-acylethanolamines with non-cannabinoid receptors, such as PPARs, GPCRs, and also with TRPs. We have focused on issues that were insufficiently covered in the published sources in order to identify gaps in existing knowledge and determine the prospects for scientific research.
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26
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Lai LT, Ren YH, Huai YJ, Liu Y, Liu Y, Wang SS, Mei JH. Identification and validation of novel prognostic biomarkers and therapeutic targets for non-small cell lung cancer. Front Genet 2023; 14:1139994. [PMID: 37007961 PMCID: PMC10060803 DOI: 10.3389/fgene.2023.1139994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 03/08/2023] [Indexed: 03/18/2023] Open
Abstract
Background: Despite the significant survival benefits of anti-PD-1/PD-L1 immunotherapy, non-small cell lung cancer (NSCLC) remains one of the most common tumors and major causes of cancer-related deaths worldwide. Thus, there is an urgent need to identify new therapeutic targets for this refractory disease.Methods: In this study, microarray datasets GSE27262, GSE75037, GSE102287, and GSE21933 were integrated by Venn diagram. We performed functional clustering and pathway enrichment analyses using R. Through the STRING database and Cytoscape, we conducted protein-protein interaction (PPI) network analysis and identified the key genes, which were verified by the GEPIA2 and UALCAN portal. Validation of actin-binding protein anillin (ANLN) was performed by quantitative real-time polymerase chain reaction and Western blotting. Additionally, Kaplan-Meier methods were used to compute the survival analyses.Results: In total, 126 differentially expressed genes were identified, which were enriched in mitotic nuclear division, mitotic cell cycle G2/M transition, vasculogenesis, spindle, and peroxisome proliferator-activated receptor signaling pathway. 12 central node genes were identified in the PPI network complex. The survival analysis revealed that high transcriptional levels were associated with inferior survival in NSCLC patients. The clinical implication of ANLN was further explored; its protein expression showed a gradually increasing trend from grade I to III.Conclusion: These Key genes may be involved in the carcinogenesis and progression of NSCLC, which may serve as useful targets for NSCLC diagnosis and treatment.
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Affiliation(s)
- Li-Ting Lai
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yuan-Hui Ren
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Institute of Molecular Pathology, Nanchang University, Nanchang, Jiangxi, China
| | - Ya-Jun Huai
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yu Liu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Institute of Molecular Pathology, Nanchang University, Nanchang, Jiangxi, China
| | - Ying Liu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Institute of Molecular Pathology, Nanchang University, Nanchang, Jiangxi, China
| | - Shan-Shan Wang
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Institute of Molecular Pathology, Nanchang University, Nanchang, Jiangxi, China
- *Correspondence: Shan-Shan Wang, ; Jin-Hong Mei,
| | - Jin-Hong Mei
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Institute of Molecular Pathology, Nanchang University, Nanchang, Jiangxi, China
- *Correspondence: Shan-Shan Wang, ; Jin-Hong Mei,
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Li H, Dai H, Li J. Immunomodulatory properties of mesenchymal stromal/stem cells: The link with metabolism. J Adv Res 2023; 45:15-29. [PMID: 35659923 PMCID: PMC10006530 DOI: 10.1016/j.jare.2022.05.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/17/2022] [Accepted: 05/26/2022] [Indexed: 10/18/2022] Open
Abstract
BACKGROUND Mesenchymal stromal/stem cells (MSCs) are the most promising stem cells for the treatment of multiple inflammatory and immune diseases due to their easy acquisition and potent immuno-regulatory capacities. These immune functions mainly depend on the MSC secretion of soluble factors. Recent studies have shown that the metabolism of MSCs plays critical roles in immunomodulation, which not only provides energy and building blocks for macromolecule synthesis but is also involved in the signaling pathway regulation. AIM OF REVIEW A thorough understanding of metabolic regulation in MSC immunomodulatory properties can provide new sights to the enhancement of MSC-based therapy. KEY SCIENTIFIC CONCEPTS OF REVIEW MSC immune regulation can be affected by cellular metabolism (glucose, adenosine triphosphate, lipid and amino acid metabolism), which further mediates MSC therapy efficiency in inflammatory and immune diseases. The enhancement of glycolysis of MSCs, such as signaling molecule activation, inflammatory cytokines priming, or environmental control can promote MSC immune functions and therapeutic potential. Besides glucose metabolism, inflammatory stimuli also alter the lipid molecular profile of MSCs, but the direct link with immunomodulatory properties remains to be further explored. Arginine metabolism, glutamine-glutamate metabolism and tryptophan-kynurenine via indoleamine 2,3-dioxygenase (IDO) metabolism all contribute to the immune regulation of MSCs. In addition to the metabolism dictating the MSC immune functions, MSCs also influence the metabolism of immune cells and thus determine their behaviors. However, more direct evidence of the metabolism in MSC immune abilities as well as the underlying mechanism requires to be uncovered.
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Affiliation(s)
- Hanyue Li
- College of Stomatology, Chongqing Medical University, Chongqing 401147, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Hongwei Dai
- College of Stomatology, Chongqing Medical University, Chongqing 401147, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Jie Li
- College of Stomatology, Chongqing Medical University, Chongqing 401147, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China.
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28
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Rangasamy SB, Jana M, Dasarathi S, Kundu M, Pahan K. Treadmill workout activates PPARα in the hippocampus to upregulate ADAM10, decrease plaques and improve cognitive functions in 5XFAD mouse model of Alzheimer's disease. Brain Behav Immun 2023; 109:204-218. [PMID: 36682514 PMCID: PMC10023420 DOI: 10.1016/j.bbi.2023.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 12/26/2022] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Although liver is rich in peroxisome proliferator-activated receptor α (PPARα), recently we have described the presence of PPARα in hippocampus where it is involved in non-amyloidogenic metabolism of amyloid precursor protein (APP) via ADAM10, decreasing amyloid plaques and improving memory and learning. However, mechanisms to upregulate PPARα in vivo in the hippocampus are poorly understood. Regular exercise has multiple beneficial effects on human health and here, we describe the importance of regular mild treadmill exercise in upregulating PPARα in vivo in the hippocampus of 5XFAD mouse model of Alzheimer's disease. We also demonstrate that treadmill exercise remained unable to stimulate ADAM10, reduce plaque pathology and improve cognitive functions in 5XFADΔPPARα mice (5XFAD mice lacking PPARα). On the other hand, treadmill workout increased ADAM10, decreased plaque pathology and protected memory and learning in 5XFADΔPPARβ mice (5XFAD mice lacking PPARβ). Moreover, the other PPAR (PPARγ) also did not play any role in the transcription of ADAM10 in vivo in the hippocampus of treadmill exercised 5XFAD mice. These results underline an important role of PPARα in which treadmill exercise remains unable to exhibit neuroprotection in the hippocampus in the absence of PPARα.
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Affiliation(s)
- Suresh B Rangasamy
- Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, USA
| | - Malabendu Jana
- Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, USA
| | - Sridevi Dasarathi
- Department of Neurological Sciences, Rush University Medical Center, Chicago, USA
| | - Madhuchhanda Kundu
- Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, USA
| | - Kalipada Pahan
- Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, USA.
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Shi R, Li H, Jin X, Huang X, Ou Z, Zhang X, Luo G, Deng J. Promoting Re-epithelialization in an oxidative diabetic wound microenvironment using self-assembly of a ROS-responsive polymer and P311 peptide micelles. Acta Biomater 2022; 152:425-439. [PMID: 36113723 DOI: 10.1016/j.actbio.2022.09.017] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 08/30/2022] [Accepted: 09/08/2022] [Indexed: 11/29/2022]
Abstract
Engineering smart nano-therapeutics for re-epithelialisation of chronic wounds facilitates the wound healing process. However, due to excessive oxidative stress damage and persistent inflammation in diabetic wound microenvironment, the migration of stimulating epidermal cells in diabetic wounds represents a significant challenge. Here we synthesised P311-loaded micelles by self-assembly of P311 peptides and diblock copolymer poly (ethylene glycol)-block-poly (propylene sulfide) (PEG-b-PPS, denoted as PEPS) that have unique ability to transform an oxidative wound microenvironment into a proregenerative one while also providing cues for epidermal cell migration. The P311@PEPS showed an accelerated migration of epidermal cells via activation of the Akt signalling pathway, simultaneously suppressing the unfavourable oxidative wound microenvironment by scavenging reactive oxygen species (ROS), ultimately leading to the induction of an environment conducive to cell migration. Furthermore, the micelles were able to bypass the inhibitory effect of ROS on the Akt signalling pathway, thereby promoting epidermal cell migration. Additionally, we observed that diabetic wounds treated with P311@PEPS showed accelerated chronic wound healing, granulation tissue formation, collagen deposition and re-epithelialisation, thereby suggesting the efficacy of P311@PEPS as a promising nanoplatform for the treatment of chronic wounds. STATEMENT OF SIGNIFICANCE: Based on the unique conditions of the diabetic wound microenvironment, a smart drug delivery system with ROS-responsive nanomaterials has been widely investigated to enhance diabetic wound healing. In our previous studies, we observed that P311 promotes epidermal cell migration to induce wound re-epithelialisation. However, the application of P311 suffers from its instability. Herein, we developed a therapeutic platform with P311-loaded micelles (P311@PEPS), which were synthesized by the self-assembly of P311 peptides and diblock copolymer poly (ethylene glycol)-block-poly (propylene sulfide) (PEG-b-PPS, denoted as PEPS). These micelles provide continuous migration signals for epidermal cells by ROS-trigged P311 release. Additionally, P311@PEPS scavenges excess ROS and provides a microenvironment that reduces inflammation, which could protect P311 from enzymatic degradation and improve the bioavailability of P311.
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Affiliation(s)
- Rong Shi
- Institute of Burn Research, State Key Lab of Trauma, Burn, and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Department of Plastic Surgery, Lanzhou University Second Hospital. Lanzhou, Gansu 730000, China; Department of Breast Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730030, China
| | - Haisheng Li
- Institute of Burn Research, State Key Lab of Trauma, Burn, and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Xin Jin
- Institute of Burn Research, State Key Lab of Trauma, Burn, and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Xue Huang
- Institute of Burn Research, State Key Lab of Trauma, Burn, and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Zelin Ou
- Institute of Burn Research, State Key Lab of Trauma, Burn, and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Xuanfen Zhang
- Department of Plastic Surgery, Lanzhou University Second Hospital. Lanzhou, Gansu 730000, China.
| | - Gaoxing Luo
- Institute of Burn Research, State Key Lab of Trauma, Burn, and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
| | - Jun Deng
- Institute of Burn Research, State Key Lab of Trauma, Burn, and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
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Magadum A, Renikunta HV, Singh N, Estaras C, Kishore R, Engel FB. Live cell screening identifies glycosides as enhancers of cardiomyocyte cell cycle activity. Front Cardiovasc Med 2022; 9:901396. [PMID: 36225954 PMCID: PMC9549374 DOI: 10.3389/fcvm.2022.901396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 08/10/2022] [Indexed: 12/01/2022] Open
Abstract
Promoting cardiomyocyte proliferation is a promising strategy to regenerate the heart. Yet, so far, it is poorly understood how cardiomyocyte proliferation is regulated, and no factor identified to promote mammalian cardiomyocyte proliferation has been translated into medical practice. Therefore, finding a novel factor will be vital. Here, we established a live cell screening based on mouse embryonic stem cell-derived cardiomyocytes expressing a non-functional human geminin deletion mutant fused to Azami Green (CM7/1-hgem-derived cardiomyocytes). We screened for a subset of compounds of the small molecule library Spectrum Collection and identified 19 potential inducers of stem cell-derived cardiomyocyte proliferation. Furthermore, the pro-proliferative potential of identified candidate compounds was validated in neonatal and adult rat cardiomyocytes as well as human induced pluripotent stem cell-derived cardiomyocytes. 18 of these compounds promoted mitosis and cytokinesis in neonatal rat cardiomyocytes. Among the top four candidates were two cardiac glycosides, peruvoside and convallatoxin, the flavonoid osajin, and the selective α-adrenoceptor antagonist and imidazoline I1 receptor ligand efaroxan hydrochloride. Inhibition of PTEN and GSK-3β enhanced cell cycle re-entry and progression upon stimulation with cardiac glycosides and osajin, while inhibition of IP3 receptors inhibited the cell cycle-promoting effect of cardiac glycosides. Collectively, we established a screening system and identified potential compounds to promote cardiomyocyte proliferation. Our data suggest that modulation of calcium handling and metabolism promotes cardiomyocyte proliferation, and cardiac glycosides might, besides increasing myocardial contraction force, contribute to cardiac repair by inducing cardiomyocyte proliferation.
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Affiliation(s)
- Ajit Magadum
- Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Lewis Katz School of Medicine, Center for Translational Medicine, Temple University, Philadelphia, PA, United States
- *Correspondence: Ajit Magadum
| | - Harsha V. Renikunta
- Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
- Department of Cardiology, Charité Berlin - University Medicine, Berlin, Germany
| | - Neha Singh
- Department of Sports Biosciences, Central University of Rajasthan, Ajmer, India
| | - Conchi Estaras
- Lewis Katz School of Medicine, Center for Translational Medicine, Temple University, Philadelphia, PA, United States
| | - Raj Kishore
- Lewis Katz School of Medicine, Center for Translational Medicine, Temple University, Philadelphia, PA, United States
- Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Felix B. Engel
- Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
- Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Muscle Research Center Erlangen (MURCE), Erlangen, Germany
- Felix B. Engel
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The Use of Palmitoylethanolamide in the Treatment of Long COVID: A Real-Life Retrospective Cohort Study. Med Sci (Basel) 2022; 10:medsci10030037. [PMID: 35893119 PMCID: PMC9326613 DOI: 10.3390/medsci10030037] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 06/26/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022] Open
Abstract
COVID-19 can cause symptoms that last weeks or months after the infection has gone, with a significant impairment of quality of life. Palmitoylethanolamide (PEA) is a naturally occurring lipid mediator that has an entourage effect on the endocannabinoid system mitigating the cytokine storm. The aim of this retrospective study is to evaluate the potential efficacy of PEA in the treatment of long COVID. Patients attending the Neurological Out Clinic of the IRCCS Centro Neurolesi Bonino-Pulejo (Messina, Italy) from August 2020 to September 2021 were screened for potential inclusion in the study. We included only long COVID patients who were treated with PEA 600 mg two times daily for about 3 months. All patients performed the post-COVID-19 Functional Status (PCFS) scale. Thirty-three patients (10 males, 43.5%, mean age 47.8 ± 12.4) were enrolled in the study. Patients were divided into two groups based on hospitalization or home care observation. A substantial difference in the PCFS score between the two groups at baseline and after treatment with PEA were found. We found that smoking was a risk factor with an odds ratio of 8.13 CI 95% [0.233, 1.167]. Our findings encourage the use of PEA as a potentially effective therapy in patients with long COVID.
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Duan X, Liu X, Zhan Z. Metabolic Regulation of Cardiac Regeneration. Front Cardiovasc Med 2022; 9:933060. [PMID: 35872916 PMCID: PMC9304552 DOI: 10.3389/fcvm.2022.933060] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 06/13/2022] [Indexed: 12/16/2022] Open
Abstract
The mortality due to heart diseases remains highest in the world every year, with ischemic cardiomyopathy being the prime cause. The irreversible loss of cardiomyocytes following myocardial injury leads to compromised contractility of the remaining myocardium, adverse cardiac remodeling, and ultimately heart failure. The hearts of adult mammals can hardly regenerate after cardiac injury since adult cardiomyocytes exit the cell cycle. Nonetheless, the hearts of early neonatal mammals possess a stronger capacity for regeneration. To improve the prognosis of patients with heart failure and to find the effective therapeutic strategies for it, it is essential to promote endogenous regeneration of adult mammalian cardiomyocytes. Mitochondrial metabolism maintains normal physiological functions of the heart and compensates for heart failure. In recent decades, the focus is on the changes in myocardial energy metabolism, including glucose, fatty acid, and amino acid metabolism, in cardiac physiological and pathological states. In addition to being a source of energy, metabolites are becoming key regulators of gene expression and epigenetic patterns, which may affect heart regeneration. However, the myocardial energy metabolism during heart regeneration is majorly unknown. This review focuses on the role of energy metabolism in cardiac regeneration, intending to shed light on the strategies for manipulating heart regeneration and promoting heart repair after cardiac injury.
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Affiliation(s)
- Xuewen Duan
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Institute of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xingguang Liu
- Department of Pathogen Biology, Naval Medical University, Shanghai, China
- Xingguang Liu,
| | - Zhenzhen Zhan
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Institute of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- *Correspondence: Zhenzhen Zhan,
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Metabolism-related MOGS Gene is Dysregulated After Peripheral Nerve Injury and Negatively Regulates Schwann Cell Plasticity. J Mol Neurosci 2022; 72:1402-1412. [PMID: 35575968 PMCID: PMC9170655 DOI: 10.1007/s12031-022-02024-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 05/05/2022] [Indexed: 10/26/2022]
Abstract
Cellular metabolism is essentially linked to tissue remodeling and organ regeneration. MOGS, a gene that encodes cellular metabolism-related protein mannosyl-oligosaccharide glucosidase, was found to be upregulated in nerve segments after peripheral nerve injury. Bioinformatic analyses identified upstream regulators of MOGS and MOGS-associated genes and indicated the significant involvement of cellular metabolism in peripheral nerve regeneration. Functional assessment showed that siRNA-mediated knockdown of MOGS led to elevated proliferation, migration, and differentiation of Schwann cells, indicating the negative regulation of MOGS on Schwann cell plasticity. Schwann cells transfected with MOGS siRNA also showed lower expression of fatty acid synthase (FASN), demonstrating that dysregulated MOGS in Schwann cells may affect neuronal behavior through the metabolic coupling between Schwann cells and axons. Taken together, this study demonstrated that MOGS may be a key regulating factor of Schwann cells and neuronal phenotype during peripheral nerve regeneration.
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Su RC, Leu JG, Chen YH, Chen CY, Yang YF, Yen CC, Chou SH, Liang YJ. Topical Application of Antrodia cinnamomea Ointment in Diabetic Wound Healing. Life (Basel) 2022; 12:life12040507. [PMID: 35454998 PMCID: PMC9027955 DOI: 10.3390/life12040507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/15/2022] [Accepted: 03/28/2022] [Indexed: 11/20/2022] Open
Abstract
The number of diagnosed diabetic patients is increasing worldwide. Many people with diabetes develop wounds that are slow to, or never, heal, which can lead to serious health issues. Diabetes causes long-term excessive blood glucose buildup in human body, which leads to an over-reactive inflammatory response and excessive oxidative stress. As a result, varied wound healing effects were observed according to different circumstances and stage of healing. We used two diabetic wound animal models to analyze the wound healing effect of Antrodia cinnamomea ointment in either topical application and/or oral administration, and explored its mechanism by Western blot analysis. The results showed that topical Antrodia cinnamomea treatment can significantly promote wound healing. The increased expressions of angiopoietin 1 and angiopoietin 2 protein and reduction of CD68 expression were found around wound area. Simultaneous treatment of oral and topical Antrodia cinnamomea ointment did not show an accelerated healing effect in our animal model. This study is the first report to demonstrate the effect of topical application of Antrodia cinnamomea ointment on diabetic wounds healing, and its relationship with angiogenesis. This may also open a new field for future development and application of Taiwan Antrodia cinnamomea.
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Affiliation(s)
- Ruey-Chih Su
- Department of Life Science, Fu-Jen Catholic University, New Taipei City 242062, Taiwan; (R.-C.S.); (Y.-H.C.); (S.-H.C.)
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei City 242062, Taiwan; (C.-Y.C.); (Y.-F.Y.); (C.-C.Y.)
| | - Jyh-Gang Leu
- School of Medicine, Fu-Jen Catholic University, New Taipei City 242062, Taiwan;
- Division of Nephrology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
| | - Yuan-Hsin Chen
- Department of Life Science, Fu-Jen Catholic University, New Taipei City 242062, Taiwan; (R.-C.S.); (Y.-H.C.); (S.-H.C.)
| | - Chao-Yi Chen
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei City 242062, Taiwan; (C.-Y.C.); (Y.-F.Y.); (C.-C.Y.)
| | - Yi-Feng Yang
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei City 242062, Taiwan; (C.-Y.C.); (Y.-F.Y.); (C.-C.Y.)
| | - Chih-Cheng Yen
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei City 242062, Taiwan; (C.-Y.C.); (Y.-F.Y.); (C.-C.Y.)
| | - Shiu-Huey Chou
- Department of Life Science, Fu-Jen Catholic University, New Taipei City 242062, Taiwan; (R.-C.S.); (Y.-H.C.); (S.-H.C.)
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei City 242062, Taiwan; (C.-Y.C.); (Y.-F.Y.); (C.-C.Y.)
| | - Yao-Jen Liang
- Department of Life Science, Fu-Jen Catholic University, New Taipei City 242062, Taiwan; (R.-C.S.); (Y.-H.C.); (S.-H.C.)
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei City 242062, Taiwan; (C.-Y.C.); (Y.-F.Y.); (C.-C.Y.)
- Correspondence: ; Tel.: +886-2-2905-3593
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Albanese M, Marrone G, Paolino A, Di Lauro M, Di Daniele F, Chiaramonte C, D'Agostini C, Romani A, Cavaliere A, Guerriero C, Magrini A, Mercuri NB, Di Daniele N, Noce A. Effects of Ultramicronized Palmitoylethanolamide (um-PEA) in COVID-19 Early Stages: A Case–Control Study. Pharmaceuticals (Basel) 2022; 15:ph15020253. [PMID: 35215365 PMCID: PMC8878249 DOI: 10.3390/ph15020253] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/15/2022] [Accepted: 02/16/2022] [Indexed: 12/15/2022] Open
Abstract
Ultramicronized palmitoylethanolamide (um-PEA), a compound with antioxidant, anti-inflammatory and neuroprotective properties, appears to be a potential adjuvant treatment for early stages of Coronavirus disease 2019 (COVID-19). In our study, we enrolled 90 patients with confirmed diagnosis of COVID-19 that were randomized into two groups, homogeneous for age, gender and BMI. The first group received oral supplementation based on um-PEA at a dose of 1800 mg/day for a total of 28 days; the second group was the control group (R.S. 73.20). At baseline (T0) and after 28 days of um-PEA treatment (T1), we monitored: routine laboratory parameters, inflammatory and oxidative stress (OS) biomarkers, lymphocytes subpopulation and COVID-19 serological response. At T1, the um-PEA-treated group presented a significant reduction in inflammation compared to the control group (CRP p = 0.007; IL-6 p = 0.0001; neutrophils to lymphocytes ratio p = 0.044). At T1, the controls showed a significant increase in OS compared to the treated group (FORT p = 0.05). At T1, the um-PEA group exhibited a significant decrease in D-dimer levels (p = 0.0001) and higher levels of IgG against SARS-CoV-2 (p = 0.0001) compared to the controls. Our data demonstrated, in a randomized clinical trial, the beneficial effects of um-PEA in both asymptomatic and mild-symptomatic patients related to reductions in inflammatory state, OS and coagulative cascade alterations.
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Affiliation(s)
- Maria Albanese
- Neurology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Giulia Marrone
- UOC of Internal Medicine-Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Agostino Paolino
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Manuela Di Lauro
- UOC of Internal Medicine-Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Francesca Di Daniele
- PhD School of Applied Medical, Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
- UOSD of Dermatology, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Carlo Chiaramonte
- Department of Statistics, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Cartesio D'Agostini
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
- Laboratory of Clinical Microbiology, Policlinico Tor Vergata, 00133 Rome, Italy
| | - Annalisa Romani
- PHYTOLAB (Pharmaceutical, Cosmetic, Food Supplement, Technology and Analysis), DiSIA, University of Florence, Sesto Fiorentino, 50019 Florence, Italy
| | | | - Cristina Guerriero
- UOC of Internal Medicine-Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Andrea Magrini
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Nicola Biagio Mercuri
- Neurology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
- IRCCS Santa Lucia Foundation, 00179 Rome, Italy
| | - Nicola Di Daniele
- UOC of Internal Medicine-Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Annalisa Noce
- UOC of Internal Medicine-Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
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Zhou Z, Ren Q, Jiao S, Cai Z, Geng X, Deng L, Wang B, Hu L, Zhang L, Yang Y, Li Z. Discovery of new and highly effective quadruple FFA1 and PPARα/γ/δ agonists as potential anti-fatty liver agents. Eur J Med Chem 2022; 229:114061. [PMID: 34954593 DOI: 10.1016/j.ejmech.2021.114061] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 12/10/2021] [Accepted: 12/17/2021] [Indexed: 01/12/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common hepatic disease, while no drug was approved until now. The previous study reported that the quadruple FFA1/PPAR-α/γ/δ agonist RLA8 provided better efficacy than obeticholic acid on NASH. In the present study, two design strategies were introduced to explore better quadruple FFA1/PPAR-α/γ/δ agonists with improved metabolic stability. These efforts ultimately resulted in the identification of ZLY18, a quadruple FFA1/PPAR-α/γ/δ agonist with twice higher metabolic half-life than RLA8 in the liver microsome. In the triton-1339W-induced hyperlipidemic model, ZLY18 reversed hyperlipidemia to an almost normal level, which exhibited far stronger lipid-lowering effects than that of RLA8. Moreover, ZLY18 significantly decreased steatosis, hepatocellular ballooning, inflammation and liver fibrosis in NASH model even better than RLA8. Further mechanism studies suggested that ZLY18 exerts stronger effects than RLA8 on the regulation of the gene related to lipid synthesis, oxidative stress, inflammation and fibrosis. In addition, ZLY18 is more effective than pirfenidone in the prevention of CCl4-induced liver fibrosis. Besides, ZLY18 has an acceptable safety profile in the acute toxicity study at a high dose of 500 mg/kg. Therefore, ZLY18 represents a novel and highly promising quadruple FFA1/PPAR-α/γ/δ agonist worth of further investigation and development.
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Affiliation(s)
- Zongtao Zhou
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Qiang Ren
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Shixuan Jiao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Zongyu Cai
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Xinqian Geng
- Department of Endocrinology, The Affiliated Hospital of Yunnan University and the Second People's Hospital of Yunnan Province, Kunming, Yunnan, 650021, PR China
| | - Liming Deng
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Bin Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Lijun Hu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Luyong Zhang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, PR China.
| | - Ying Yang
- Department of Endocrinology, The Affiliated Hospital of Yunnan University and the Second People's Hospital of Yunnan Province, Kunming, Yunnan, 650021, PR China.
| | - Zheng Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
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Raciti L, Arcadi FA, Calabrò RS. Could Palmitoylethanolamide Be an Effective Treatment for Long-COVID-19? Hypothesis and Insights in Potential Mechanisms of Action and Clinical Applications. INNOVATIONS IN CLINICAL NEUROSCIENCE 2022; 19:19-25. [PMID: 35382075 PMCID: PMC8970234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
COVID-19 is highly transmissive and contagious disease with a wide spectrum of clinicopathological issues, including respiratory, vasculo-coagulative, and immune disorders. In some cases of COVID-19, patients can be characterized by clinical sequelae with mild-to-moderate symptoms that persist long after the resolution of the acute infection, known as long-COVID, potentially affecting their quality of life. The main symptoms of long-COVID include persistent dyspnea, fatigue and weakness (that are typically out of proportion, to the degree of ongoing lung damage and gas exchange impairment), persistence of anosmia and dysgeusia, neuropsychiatric symptoms, and cognitive dysfunctions (such as brain fog or memory lapses). The appropriate management and prevention of potential long-COVID sequelae is still lacking. It is also believed that long-term symptoms of COVID-19 are related to an immunity over-response, namely a cytokine storm, involving the release of pro-inflammatory interleukins, monocyte chemoattractant proteins, and tissue necrosis factors. Palmitoylethanolamide (PEA) shows affinity for vanilloid receptor 1 and for cannabinoid-like G protein-coupled receptors, enhancing anandamide activity by means of an entourage effect. Due to its anti-inflammatory properties, PEA has been recently used as an early add-on therapy for respiratory problems in patients with COVID-19. It is believed that PEA mitigates the cytokine storm modulating cell-mediated immunity, as well as counteracts pain and oxidative stress. In this article, we theorize that PEA could be a potentially effective nutraceutical to treat long-COVID, with regard to fatigue and myalgia, where a mythocondrial dysfunction is hypothesizable.
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Affiliation(s)
- Loredana Raciti
- Drs. Raciti, Arcadi, and Calabrò are with IRCCS Centro Neurolesi "Bonino Pulejo" in Messina, Italy
| | - Francesca Antonia Arcadi
- Drs. Raciti, Arcadi, and Calabrò are with IRCCS Centro Neurolesi "Bonino Pulejo" in Messina, Italy
| | - Rocco Salvatore Calabrò
- Drs. Raciti, Arcadi, and Calabrò are with IRCCS Centro Neurolesi "Bonino Pulejo" in Messina, Italy
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Cui X, Huang X, Huang M, Zhou S, Guo L, Yu W, Duan M, Jiang B, Zeng J, Zhou J, Huang X, Liang P, Zhang P. miR-24-3p obstructs the proliferation and migration of HSFs after thermal injury by targeting PPAR-β and positively regulated by NF-κB. Exp Dermatol 2021; 31:841-853. [PMID: 34932851 DOI: 10.1111/exd.14517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 12/03/2021] [Accepted: 12/19/2021] [Indexed: 11/30/2022]
Abstract
Thermal injury repair is a complex process during which the maintenance of the proliferation and migration of human skin fibroblasts (HSFs) exert a crucial role. MicroRNAs have been proven to exert an essential function in repairing skin burns. This study delves into the regulatory effects of miR-24-3p on the migration and proliferation of HSFs that have sustained a thermal injury; thereby, providing deeper insight into thermal injury repair pathogenesis. The PPAR-β protein expression level progressively increased in a time-dependent manner on the 12th , 24th , and 48th hour following the thermal injury of the HSFs. The knockdown of PPAR-β markedly suppressed the proliferation of and migration of HSF. Following thermal injury, the knockdown also promoted the inflammatory cytokine IL-6, TNF-, PTGS-2, and P65 expression. PPAR-β contrastingly exhibited an opposite trend. A targeted relationship between PPAR-β and miR-24-3p was predicted and verified. miR-24-3p inhibited thermal injured-HSFs proliferation and migration and facilitated inflammatory cytokine expression through the regulation of PPAR-β. p65 directly targeted the transcriptional precursor of miR-24 and promoted miR-24 expression. A negative correlation between miR-24-3p expression level and PPAR-β expression level in rats burnt dermal tissues was observed. Our findings reveal that miR-24-3p is conducive to rehabilitating the denatured dermis, which may be beneficial in providing effective therapy of skin burns.
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Affiliation(s)
- Xu Cui
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Xu Huang
- Department of Hyperbaric Oxygen, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Mitao Huang
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Situo Zhou
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Le Guo
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Wenchang Yu
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Mengting Duan
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Bimei Jiang
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Jizhang Zeng
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Jie Zhou
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Xiaoyuan Huang
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Pengfei Liang
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Pihong Zhang
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
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Diagnostic value of PPARδ and miRNA-17 expression levels in patients with non-small cell lung cancer. Sci Rep 2021; 11:24136. [PMID: 34921177 PMCID: PMC8683395 DOI: 10.1038/s41598-021-03312-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 11/25/2021] [Indexed: 12/25/2022] Open
Abstract
The PPARδ gene codes protein that belongs to the peroxisome proliferator-activated receptor (PPAR) family engaged in a variety of biological processes, including carcinogenesis. Specific biological and clinical roles of PPARδ in non-small cell lung cancer (NSCLC) is not fully explained. The association of PPARα with miRNA regulators (e.g. miRNA-17) has been documented, suggesting the existence of a functional relationship of all PPARs with epigenetic regulation. The aim of the study was to determine the PPARδ and miR-17 expression profiles in NSCLC and to assess their diagnostic value in lung carcinogenesis. PPARδ and miR-17 expressions was assessed by qPCR in NSCLC tissue samples (n = 26) and corresponding macroscopically unchanged lung tissue samples adjacent to the primary lesions served as control (n = 26). PPARδ and miR-17 expression were significantly lower in NSCLC than in the control (p = 0.0001 and p = 0.0178; respectively). A receiver operating characteristic (ROC) curve analysis demonstrated the diagnostic potential in discriminating NSCLC from the control with an area under the curve (AUC) of 0.914 for PPARδ and 0.692 for miR-17. Significant increase in PPARδ expression in the control for current smokers vs. former smokers (p = 0.0200) and increase in miR-17 expression in control tissue adjacent to adenocarcinoma subtype (p = 0.0422) were observed. Overexpression of miR-17 was observed at an early stage of lung carcinogenesis, which may suggest that it acts as a putative oncomiR. PPARδ and miR-17 may be markers differentiating tumour tissue from surgical margin and miR-17 may have diagnostic role in NSCLC histotypes differentiation.
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Oxidative stress-induced FABP5 S-glutathionylation protects against acute lung injury by suppressing inflammation in macrophages. Nat Commun 2021; 12:7094. [PMID: 34876574 PMCID: PMC8651733 DOI: 10.1038/s41467-021-27428-9] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 11/19/2021] [Indexed: 11/26/2022] Open
Abstract
Oxidative stress contributes to the pathogenesis of acute lung injury. Protein S-glutathionylation plays an important role in cellular antioxidant defense. Here we report that the expression of deglutathionylation enzyme Grx1 is decreased in the lungs of acute lung injury mice. The acute lung injury induced by hyperoxia or LPS is significantly relieved in Grx1 KO and Grx1fl/flLysMcre mice, confirming the protective role of Grx1-regulated S-glutathionylation in macrophages. Using a quantitative redox proteomics approach, we show that FABP5 is susceptible to S-glutathionylation under oxidative conditions. S-glutathionylation of Cys127 in FABP5 promotes its fatty acid binding ability and nuclear translocation. Further results indicate S-glutathionylation promotes the interaction of FABP5 and PPARβ/δ, activates PPARβ/δ target genes and suppresses the LPS-induced inflammation in macrophages. Our study reveals a molecular mechanism through which FABP5 S-glutathionylation regulates macrophage inflammation in the pathogenesis of acute lung injury. Redox-dependent regulation plays a key role in the pathogenesis of acute lung injury, but its mechanism is unclear. Here the authors show Grx1-regulated S-glutathionylation of FABP5 controls macrophage inflammation and alleviates acute lung injury.
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Betz IR, Qaiyumi SJ, Goeritzer M, Thiele A, Brix S, Beyhoff N, Grune J, Klopfleisch R, Greulich F, Uhlenhaut NH, Kintscher U, Foryst-Ludwig A. Cardioprotective Effects of Palmitoleic Acid (C16:1n7) in a Mouse Model of Catecholamine-Induced Cardiac Damage Are Mediated by PPAR Activation. Int J Mol Sci 2021; 22:ijms222312695. [PMID: 34884498 PMCID: PMC8657733 DOI: 10.3390/ijms222312695] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/12/2021] [Accepted: 11/17/2021] [Indexed: 01/25/2023] Open
Abstract
Palmitoleic acid (C16:1n7) has been identified as a regulator of physiological cardiac hypertrophy. In the present study, we aimed to investigate the molecular pathways involved in C16:1n7 responses in primary murine cardiomyocytes (PCM) and a mouse model of isoproterenol (ISO)-induced cardiac damage. PCMs were stimulated with C16:1n7 or a vehicle. Afterwards, RNA sequencing was performed using an Illumina HiSeq sequencer. Confirmatory analysis was performed in PCMs and HL-1 cardiomyocytes. For an in vivo study, 129 sv mice were orally treated with a vehicle or C16:1n7 for 22 days. After 5 days of pre-treatment, the mice were injected with ISO (25 mg/kg/d s. c.) for 4 consecutive days. Cardiac phenotyping was performed using echocardiography. In total, 129 genes were differentially expressed in PCMs stimulated with C16:1n7, including Angiopoietin-like factor 4 (Angptl4) and Pyruvate Dehydrogenase Kinase 4 (Pdk4). Both Angptl4 and Pdk4 are proxisome proliferator-activated receptor α/δ (PPARα/δ) target genes. Our in vivo results indicated cardioprotective and anti-fibrotic effects of C16:1n7 application in mice. This was associated with the C16:1n7-dependent regulation of the cardiac PPAR-specific signaling pathways. In conclusion, our experiments demonstrated that C16:1n7 might have protective effects on cardiac fibrosis and inflammation. Our study may help to develop future lipid-based therapies for catecholamine-induced cardiac damage.
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Affiliation(s)
- Iris Rosa Betz
- Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany; (I.R.B.); (S.J.Q.); (M.G.); (A.T.); (S.B.); (N.B.); (J.G.); (U.K.)
- Berlin Institute of Health, Emergency Department Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
| | - Sarah Julia Qaiyumi
- Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany; (I.R.B.); (S.J.Q.); (M.G.); (A.T.); (S.B.); (N.B.); (J.G.); (U.K.)
| | - Madeleine Goeritzer
- Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany; (I.R.B.); (S.J.Q.); (M.G.); (A.T.); (S.B.); (N.B.); (J.G.); (U.K.)
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
| | - Arne Thiele
- Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany; (I.R.B.); (S.J.Q.); (M.G.); (A.T.); (S.B.); (N.B.); (J.G.); (U.K.)
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
| | - Sarah Brix
- Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany; (I.R.B.); (S.J.Q.); (M.G.); (A.T.); (S.B.); (N.B.); (J.G.); (U.K.)
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
| | - Niklas Beyhoff
- Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany; (I.R.B.); (S.J.Q.); (M.G.); (A.T.); (S.B.); (N.B.); (J.G.); (U.K.)
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
| | - Jana Grune
- Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany; (I.R.B.); (S.J.Q.); (M.G.); (A.T.); (S.B.); (N.B.); (J.G.); (U.K.)
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
| | - Robert Klopfleisch
- Department of Veterinary Pathology, College of Veterinary Medicine, Freie Universität Berlin, 14163 Berlin, Germany;
| | - Franziska Greulich
- German Center for Environmental Health GmbH, Institute for Diabetes and Cancer (IDC), 85764 Munich, Germany; (F.G.); (N.H.U.)
- Metabolic Programming, School of Life Sciences Weihenstephan, Technische Universitaet Muenchen (TUM), 85354 Freising, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich, 13125 Berlin, Germany
| | - Nina Henriette Uhlenhaut
- German Center for Environmental Health GmbH, Institute for Diabetes and Cancer (IDC), 85764 Munich, Germany; (F.G.); (N.H.U.)
- Metabolic Programming, School of Life Sciences Weihenstephan, Technische Universitaet Muenchen (TUM), 85354 Freising, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich, 13125 Berlin, Germany
| | - Ulrich Kintscher
- Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany; (I.R.B.); (S.J.Q.); (M.G.); (A.T.); (S.B.); (N.B.); (J.G.); (U.K.)
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
| | - Anna Foryst-Ludwig
- Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany; (I.R.B.); (S.J.Q.); (M.G.); (A.T.); (S.B.); (N.B.); (J.G.); (U.K.)
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
- Correspondence:
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Dixit G, Prabhu A. The pleiotropic peroxisome proliferator activated receptors: Regulation and therapeutics. Exp Mol Pathol 2021; 124:104723. [PMID: 34822814 DOI: 10.1016/j.yexmp.2021.104723] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/02/2021] [Accepted: 11/15/2021] [Indexed: 02/07/2023]
Abstract
The Peroxisome proliferator-activated receptors (PPARs) are key regulators of metabolic events in our body. Owing to their implication in maintenance of homeostasis, both PPAR agonists and antagonists assume therapeutic significance. Understanding the molecular mechanisms of each of the PPAR isotypes in the healthy body and during disease is crucial to exploiting their full therapeutic potential. This article is an attempt to present a rational analysis of the multifaceted therapeutic effects and underlying mechanisms of isotype-specific PPAR agonists, dual PPAR agonists, pan PPAR agonists as well as PPAR antagonists. A holistic understanding of the mechanistic dimensions of these key metabolic regulators will guide future efforts to identify novel molecules in the realm of metabolic, inflammatory and immunotherapeutic diseases.
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Affiliation(s)
- Gargi Dixit
- Department of Pharmaceutical Chemistry & Quality Assurance, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
| | - Arati Prabhu
- Department of Pharmaceutical Chemistry & Quality Assurance, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India.
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Chen M, Jing D, Ye R, Yi J, Zhao Z. PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy. Stem Cell Res Ther 2021; 12:566. [PMID: 34736532 PMCID: PMC8567548 DOI: 10.1186/s13287-021-02628-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 10/16/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Diabetic patients are more vulnerable to skeletal complications. Peroxisome proliferators-activated receptor (PPAR) β/δ has a positive regulatory effect on bone turnover under physiologic glucose concentration; however, the regulatory effect in diabetes mellitus has not been investigated yet. Herein, we explored the effects of PPARβ/δ agonist on the regeneration of diabetic bone defects and the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) under a pathological high-glucose condition. METHODS We detected the effect of PPARβ/δ agonist on osteogenic differentiation of rBMSCs in vitro and investigated the bone healing process in diabetic rats after PPARβ/δ agonist treatment in vivo. RNA sequencing was performed to detect the differentially expressed genes and enriched pathways. Western blot was performed to detect the autophagy-related protein level. Laser confocal microscope (LSCM) and transmission electron microscope (TEM) were used to observe the formation of autophagosomes. RESULTS Our results demonstrated that the activation of PPARβ/δ can improve the osteogenic differentiation of rBMSCs in high-glucose condition and promote the bone regeneration of calvarial defects in diabetic rats, while the inhibition of PPARβ/δ alleviated the osteogenic differentiation of rBMSCs. Mechanistically, the activation of PPARβ/δ up-regulates AMPK phosphorylation, yielding mTOR suppression and resulting in enhanced autophagy activity, which further promotes the osteogenic differentiation of rBMSCs in high-glucose condition. The addition of AMPK inhibitor Compound C or autophagy inhibitor 3-MA inhibited the osteogenesis of rBMSCs in high-glucose condition, suggesting that PPARβ/δ agonist promotes osteogenic differentiation of rBMSCs through AMPK/mTOR-regulated autophagy. CONCLUSION In conclusion, our study demonstrates the potential role of PPARβ/δ as a molecular target for the treatment of impaired bone quality and delayed bone healing in diabetic patients for the first time.
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Affiliation(s)
- Miao Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section, South Renmin Road, Chengdu, 610041, Sichuan, China
| | - Dian Jing
- Department of Orthodontics, Shanghai Ninth People's Hospital, Collage of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rui Ye
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section, South Renmin Road, Chengdu, 610041, Sichuan, China
| | - Jianru Yi
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. .,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section, South Renmin Road, Chengdu, 610041, Sichuan, China.
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. .,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section, South Renmin Road, Chengdu, 610041, Sichuan, China.
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Nernpermpisooth N, Sarre C, Barrere C, Contreras R, Luz-Crawford P, Tejedor G, Vincent A, Piot C, Kumphune S, Nargeot J, Jorgensen C, Barrère-Lemaire S, Djouad F. PPARβ/δ Is Required for Mesenchymal Stem Cell Cardioprotective Effects Independently of Their Anti-inflammatory Properties in Myocardial Ischemia-Reperfusion Injury. Front Cardiovasc Med 2021; 8:681002. [PMID: 34616778 PMCID: PMC8488150 DOI: 10.3389/fcvm.2021.681002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 08/24/2021] [Indexed: 11/17/2022] Open
Abstract
Myocardial infarction ranks first for the mortality worldwide. Because the adult heart is unable to regenerate, fibrosis develops to compensate for the loss of contractile tissue after infarction, leading to cardiac remodeling and heart failure. Adult mesenchymal stem cells (MSC) regenerative properties, as well as their safety and efficacy, have been demonstrated in preclinical models. However, in clinical trials, their beneficial effects are controversial. In an experimental model of arthritis, we have previously shown that PPARβ/δ deficiency enhanced the therapeutic effect of MSC. The aim of the present study was to compare the therapeutic effects of wild-type MSC (MSC) and MSC deficient for PPARβ/δ (KO MSC) perfused in an ex vivo mouse model of ischemia-reperfusion (IR) injury. For this purpose, hearts from C57BL/6J mice were subjected ex vivo to 30 min ischemia followed by 1-h reperfusion. MSC and KO MSC were injected into the Langendorff system during reperfusion. After 1 h of reperfusion, the TTC method was used to assess infarct size. Coronary effluents collected in basal condition (before ischemia) and after ischemia at 1 h of reperfusion were analyzed for their cytokine profiles. The dose-response curve for the cardioprotection was established ex vivo using different doses of MSC (3.105, 6.105, and 24.105 cells/heart) and the dose of 6.105 MSC was found to be the optimal concentration. We showed that the cardioprotective effect of MSC was PPARβ/δ-dependent since it was lost using KO MSC. Moreover, cytokine profiling of the coronary effluents collected in the eluates after 60 min of reperfusion revealed that MSC treatment decreases CXCL1 chemokine and interleukin-6 release compared with untreated hearts. This anti-inflammatory effect of MSC was also observed when hearts were treated with PPARβ/δ-deficient MSC. In conclusion, our study revealed that the acute cardioprotective properties of MSC in an ex vivo model of IR injury, assessed by a decreased infarct size at 1 h of reperfusion, are PPARβ/δ-dependent but not related to their anti-inflammatory effects.
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Affiliation(s)
- Nitirut Nernpermpisooth
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.,Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Integrative Biomedical Research Unit, Naresuan University, Phitsanulok, Thailand
| | - Charlotte Sarre
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.,Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Montpellier, France
| | - Christian Barrere
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Rafaël Contreras
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Montpellier, France
| | - Patricia Luz-Crawford
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Montpellier, France.,Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Gautier Tejedor
- MedXCell Science, Institute for Regenerative Medicine and Biotherapy, Montpellier, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Christophe Piot
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.,Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Sarawut Kumphune
- Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Integrative Biomedical Research Unit, Naresuan University, Phitsanulok, Thailand.,Biomedical Engineering Institute, Chiang Mai University, Chiang Mai, Thailand
| | - Joel Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Christian Jorgensen
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | | | - Farida Djouad
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
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Metabolic orchestration of the wound healing response. Cell Metab 2021; 33:1726-1743. [PMID: 34384520 DOI: 10.1016/j.cmet.2021.07.017] [Citation(s) in RCA: 138] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/16/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Wound healing requires cooperation between different cell types, among which macrophages play a central role. In particular, inflammatory macrophages are engaged in the initial response to wounding, and alternatively activated macrophages are essential for wound closure and the resolution of tissue repair. The links between temporal activation-induced changes in the metabolism of such macrophages and the influence this has on their functional states, along with the realization that metabolites play both intrinsic and extrinsic roles in the cells that produce them, has focused attention on the metabolism of wound healing. Here, we discuss macrophage metabolism during distinct stages of normal healing and its related pathologic processes, such as during cancer and fibrosis. Further, we frame these insights in a broader context of the current understanding of macrophage metabolic reprogramming linked to cellular activation and function. Finally, we discuss parallels between the metabolism of macrophages and fibroblasts, the latter being a key stromal cell type in wound healing, and consider the importance of the metabolic interplay between different cell types in the wound microenvironment.
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Derrett-Smith E, Clark KEN, Shiwen X, Abraham DJ, Hoyles RK, Lacombe O, Broqua P, Junien JL, Konstantinova I, Ong VH, Denton CP. The pan-PPAR agonist lanifibranor reduces development of lung fibrosis and attenuates cardiorespiratory manifestations in a transgenic mouse model of systemic sclerosis. Arthritis Res Ther 2021; 23:234. [PMID: 34488870 PMCID: PMC8419933 DOI: 10.1186/s13075-021-02592-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 07/26/2021] [Indexed: 12/02/2022] Open
Abstract
Background The TβRII∆k-fib transgenic (TG) mouse model of scleroderma replicates key fibrotic and vasculopathic complications of systemic sclerosis through fibroblast-directed upregulation of TGFβ signalling. We have examined peroxisome proliferator-activated receptor (PPAR) pathway perturbation in this model and explored the impact of the pan-PPAR agonist lanifibranor on the cardiorespiratory phenotype. Methods PPAR pathway gene and protein expression differences from TG and WT sex-matched littermate mice were determined at baseline and following administration of one of two doses of lanifibranor (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. The prevention of bleomycin-induced lung fibrosis and SU5416-induced pulmonary hypertension by lanifibranor was explored. Results Gene expression data were consistent with the downregulation of the PPAR pathway in the TβRII∆k-fib mouse model. TG mice treated with high-dose lanifibranor demonstrated significant protection from lung fibrosis after bleomycin and from right ventricular hypertrophy following induction of pulmonary hypertension by SU5416, despite no significant change in right ventricular systolic pressure. Conclusions In the TβRII∆k-fib mouse strain, treatment with 100 mg/kg lanifibranor reduces the development of lung fibrosis and right ventricular hypertrophy induced by bleomycin or SU5416, respectively. Reduced PPAR activity may contribute to the exaggerated fibroproliferative response to tissue injury in this transgenic model of scleroderma and its pulmonary complications.
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Affiliation(s)
- Emma Derrett-Smith
- Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, Rowland Hill St., London, NW3 2PF, UK
| | - Kristina E N Clark
- Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, Rowland Hill St., London, NW3 2PF, UK
| | - Xu Shiwen
- Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, Rowland Hill St., London, NW3 2PF, UK
| | - David J Abraham
- Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, Rowland Hill St., London, NW3 2PF, UK
| | | | | | | | | | | | - Voon H Ong
- Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, Rowland Hill St., London, NW3 2PF, UK
| | - Christopher P Denton
- Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, Rowland Hill St., London, NW3 2PF, UK.
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Blunder S, Pavel P, Minzaghi D, Dubrac S. PPARdelta in Affected Atopic Dermatitis and Psoriasis: A Possible Role in Metabolic Reprograming. Int J Mol Sci 2021; 22:7354. [PMID: 34298981 PMCID: PMC8303290 DOI: 10.3390/ijms22147354] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 12/16/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors expressed in the skin. Three PPAR isotypes, α (NRC1C1), β or δ (NRC1C2) and γ (NRC1C3), have been identified. After activation through ligand binding, PPARs heterodimerize with the 9-cis-retinoic acid receptor (RXR), another nuclear hormone receptor, to bind to specific PPAR-responsive elements in regulatory regions of target genes mainly involved in organogenesis, cell proliferation, cell differentiation, inflammation and metabolism of lipids or carbohydrates. Endogenous PPAR ligands are fatty acids and fatty acid metabolites. In past years, much emphasis has been given to PPARα and γ in skin diseases. PPARβ/δ is the least studied PPAR family member in the skin despite its key role in several important pathways regulating inflammation, keratinocyte proliferation and differentiation, metabolism and the oxidative stress response. This review focuses on the role of PPARβ/δ in keratinocytes and its involvement in psoriasis and atopic dermatitis. Moreover, the relevance of targeting PPARβ/δ to alleviate skin inflammation is discussed.
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Affiliation(s)
| | | | | | - Sandrine Dubrac
- Epidermal Biology Laboratory, Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; (S.B.); (P.P.); (D.M.)
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Tejedor G, Contreras-Lopez R, Barthelaix A, Ruiz M, Noël D, De Ceuninck F, Pastoureau P, Luz-Crawford P, Jorgensen C, Djouad F. Pyrroline-5-Carboxylate Reductase 1 Directs the Cartilage Protective and Regenerative Potential of Murphy Roths Large Mouse Mesenchymal Stem Cells. Front Cell Dev Biol 2021; 9:604756. [PMID: 34277596 PMCID: PMC8284254 DOI: 10.3389/fcell.2021.604756] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 06/03/2021] [Indexed: 11/16/2022] Open
Abstract
Murphy Roths Large (MRL) mice possess outstanding capacity to regenerate several tissues. In the present study, we investigated whether this regenerative potential could be associated with the intrinsic particularities possessed by their mesenchymal stem cells (MSCs). We demonstrated that MSCs derived from MRL mice (MRL MSCs) display a superior chondrogenic potential than do C57BL/6 MSC (BL6 MSCs). This higher chondrogenic potential of MRL MSCs was associated with a higher expression level of pyrroline-5-carboxylate reductase 1 (PYCR1), an enzyme that catalyzes the biosynthesis of proline, in MRL MSCs compared with BL6 MSCs. The knockdown of PYCR1 in MRL MSCs, using a specific small interfering RNA (siRNA), abolishes their chondrogenic potential. Moreover, we showed that PYCR1 silencing in MRL MSCs induced a metabolic switch from glycolysis to oxidative phosphorylation. In two in vitro chondrocyte models that reproduce the main features of osteoarthritis (OA) chondrocytes including a downregulation of chondrocyte markers, a significant decrease of PYCR1 was observed. A downregulation of chondrocyte markers was also observed by silencing PYCR1 in freshly isolated healthy chondrocytes. Regarding MSC chondroprotective properties on chondrocytes with OA features, we showed that MSCs silenced for PYCR1 failed to protect chondrocytes from a reduced expression of anabolic markers, while MSCs overexpressing PYCR1 exhibited an increased chondroprotective potential. Finally, using the ear punch model, we demonstrated that MRL MSCs induced a regenerative response in non-regenerating BL6 mice, while BL6 and MRL MSCs deficient for PYCR1 did not. In conclusion, our results provide evidence that MRL mouse regenerative potential is, in part, attributed to its MSCs that exhibit higher PYCR1-dependent glycolytic potential, differentiation capacities, chondroprotective abilities, and regenerative potential than BL6 MSCs.
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Affiliation(s)
| | | | | | - Maxime Ruiz
- IRMB, INSERM, University Montpellier, Montpellier, France
| | - Danièle Noël
- IRMB, INSERM, University Montpellier, Montpellier, France.,CHU Montpellier, Montpellier, France
| | - Frédéric De Ceuninck
- Center for Therapeutic Innovation, Immuno-Inflammatory Disease, Institut de Recherches Servier, Croissy-sur-Seine, France
| | - Philippe Pastoureau
- Center for Therapeutic Innovation, Immuno-Inflammatory Disease, Institut de Recherches Servier, Croissy-sur-Seine, France
| | - Patricia Luz-Crawford
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Christian Jorgensen
- IRMB, INSERM, University Montpellier, Montpellier, France.,CHU Montpellier, Montpellier, France
| | - Farida Djouad
- IRMB, INSERM, University Montpellier, Montpellier, France
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Pesce M, Seguella L, Cassarano S, Aurino L, Sanseverino W, Lu J, Corpetti C, Del Re A, Vincenzi M, Sarnelli G, Esposito G. Phytotherapics in COVID19: Why palmitoylethanolamide? Phytother Res 2021; 35:2514-2522. [PMID: 33296131 DOI: 10.1002/ptr.6978] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022]
Abstract
At present, googling the search terms "COVID-19" and "Functional foods" yields nearly 500,000,000 hits, witnessing the growing interest of the scientific community and the general public in the role of nutrition and nutraceuticals during the COVID-19 pandemic. Many compounds have been proposed as phytotherapics in the prevention and/or treatment of COVID-19. The extensive interest of the general public and the enormous social media coverage on this topic urges the scientific community to address the question of whether which nutraceuticals can actually be employed in preventing and treating this newly described coronavirus-related disease. Recently, the Canadian biotech pharma company "FSD Pharma" received the green light from the Food and Drug Administration to design a proof-of-concept study evaluating the effects of ultramicronized palmitoylethanolamide (PEA) in COVID-19 patients. The story of PEA as a nutraceutical to prevent and treat infectious diseases dates back to the 1970s where the molecule was branded under the name Impulsin and was used for its immunomodulatory properties in influenza virus infection. The present paper aims at analyzing the potential of PEA as a nutraceutical and the previous evidence suggesting its anti-inflammatory and immunomodulatory properties in infectious and respiratory diseases and how these could translate to COVID-19 care.
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Affiliation(s)
- Marcella Pesce
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Luisa Seguella
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Sara Cassarano
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Laura Aurino
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | | | - Jie Lu
- Department of Human Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang City, China
| | - Chiara Corpetti
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Alessandro Del Re
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Martina Vincenzi
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Giovanni Sarnelli
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Giuseppe Esposito
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
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50
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Huang R, Zhang C, Wang X, Hu H. PPARγ in Ischemia-Reperfusion Injury: Overview of the Biology and Therapy. Front Pharmacol 2021; 12:600618. [PMID: 33995008 PMCID: PMC8117354 DOI: 10.3389/fphar.2021.600618] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) is a complex pathophysiological process that is often characterized as a blood circulation disorder caused due to various factors (such as traumatic shock, surgery, organ transplantation, burn, and thrombus). Severe metabolic dysregulation and tissue structure destruction are observed upon restoration of blood flow to the ischemic tissue. Theoretically, IRI can occur in various tissues and organs, including the kidney, liver, myocardium, and brain, among others. The advances made in research regarding restoring tissue perfusion in ischemic areas have been inadequate with regard to decreasing the mortality and infarct size associated with IRI. Hence, the clinical treatment of patients with severe IRI remains a thorny issue. Peroxisome proliferator-activated receptor γ (PPARγ) is a member of a superfamily of nuclear transcription factors activated by agonists and is a promising therapeutic target for ameliorating IRI. Therefore, this review focuses on the role of PPARγ in IRI. The protective effects of PPARγ, such as attenuating oxidative stress, inhibiting inflammatory responses, and antagonizing apoptosis, are described, envisaging certain therapeutic perspectives.
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Affiliation(s)
- Ruizhen Huang
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chiyu Zhang
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xing Wang
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Honglin Hu
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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