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Cai XX, Huang YH, Lin YCD, Huang HY, Chen YG, Zhang DP, Zhang T, Liu Y, Zuo HL, Huang HD. A comprehensive review of small molecules, targets, and pathways in ulcerative colitis treatment. Eur J Med Chem 2025; 291:117645. [PMID: 40279769 DOI: 10.1016/j.ejmech.2025.117645] [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: 02/11/2025] [Revised: 04/06/2025] [Accepted: 04/15/2025] [Indexed: 04/29/2025]
Abstract
Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), poses significant clinical challenges because of its complex pathophysiology, long-term nature, and the limited efficacy of existing treatments. Small-molecule compounds, particularly those that are able to modulate inflammation-related signaling pathways and, in many cases, occur in nature, offer a promising alternative or supplement to conventional therapies. Studies on molecules for UC therapeutics reported in 1394 publications over the past 30 years were collected from the Web of Science (WOS) database. Only studies that verified therapeutic efficacy through animal experiments were included. Through an analysis of the molecular classes, structures, common targets, and pathways using network pharmacology, we identified 14 classes of compounds, 5 direct-target modules, and 3 crucial downstream pathways. Alkaloids, phenylpropanoids, flavonoids, and terpenes (and their derivatives) appeared most frequently and mainly targeted lipid metabolism, oxidative stress, immune regulation, signaling transduction, and cancer-related pathways. Notably, there has been an increasing trend of applying naturally sourced compounds in both preclinical and clinical trials, especially flavonoids, over the last five years. Although progress in UC research has been made, the majority of studies have focused on the overall therapeutic effects and biomarker alterations, with limited emphasis on the direct targets and underlying mechanisms. These findings highlight the need to explore novel small-molecule therapeutic strategies for UC, focusing on clearly defined targets and precise modes of action.
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Affiliation(s)
- Xiao-Xuan Cai
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China; Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China
| | - Yi-Han Huang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China; Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China
| | - Yang-Chi-Dung Lin
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China; Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China; Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China
| | - Hsi-Yuan Huang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China; Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China; Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China
| | - Yi-Gang Chen
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China; Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China
| | - Da-Peng Zhang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China
| | - Tao Zhang
- R&D center, Better Way (Shanghai) Cosmetics Co., Ltd., Shanghai, 201103, PR China
| | - Yue Liu
- R&D center, Better Way (Shanghai) Cosmetics Co., Ltd., Shanghai, 201103, PR China
| | - Hua-Li Zuo
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China; Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China.
| | - Hsien-Da Huang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China; Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China; Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China; Department of Endocrinology, Key Laboratory of Endocrinology of National Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, PR China.
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Luo Y, Xue H, Gao Y, Ji G, Wu T. Sphingosine kinase 2 in cancer: A review of its expression, function, and inhibitor development. Int J Biol Macromol 2025; 306:141392. [PMID: 39988169 DOI: 10.1016/j.ijbiomac.2025.141392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
Cancer is a major public health problem facing contemporary society. Notwithstanding considerable progress in medicine in recent decades, a cure for numerous cancer kinds continues to be unattainable. Thus, the pursuit of innovative therapeutic targets and methodologies remains paramount in medical research. The advancement of lipidomics has progressively revealed the essential roles of lipid metabolic pathways. Sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) are essential molecules in sphingolipid metabolism, significantly influencing physiological functions. Two isoforms of SphK exist including SphK1 and SphK2, both of which exhibit significant expression levels within a spectrum of cancers. The involvement of SphK1 in carcinogenesis has been thoroughly documented, whereas the significance of SphK2 in cancer remains inadequately elucidated. This review retrospectively and extensively elucidates the expression and distribution of SphK2 in cancer, its methods of action, and advancements in inhibitor research, emphasizing the varied functions of the SphK2 in oncogenesis. The objective is to furnish novel insights for study and therapeutic applications concerning SphK2 in oncology.
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Affiliation(s)
- Yanqun Luo
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Haiping Xue
- Industrial Development Center, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ying Gao
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Guang Ji
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Fan Q, Gao Y, Zhou Y, Wu J, Wang H, Dong Y, Gai Z, Wu Y, Fang S, Gu S. Weizmannia coagulans BC99 Relieves Constipation Symptoms by Regulating Inflammatory, Neurotransmitter, and Lipid Metabolic Pathways: A Randomized, Double-Blind, Placebo-Controlled Trial. Foods 2025; 14:654. [PMID: 40002098 PMCID: PMC11854163 DOI: 10.3390/foods14040654] [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: 01/02/2025] [Revised: 02/03/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Probiotics have attracted increasing attention due to their benefits in terms of relieving gastrointestinal ailments, including constipation. This study evaluated the potential of Weizmannia coagulans BC99 for clinical remission of constipation in adults. In this randomized, double-blind, and placebo-controlled trial, 90 individuals with constipation were divided between a BC99 and a placebo group for an 8-week intervention duration. The spontaneous bowel movement (SBM) frequency, patient assessment of constipation symptoms (PAC-SYM), patient assessment of constipation quality of life (PAC-QOL), inflammatory cytokines, neurotransmitters, and serum metabolites were investigated before and after the intervention. The results showed that BC99 intervention significantly improved constipation symptoms and quality of life in adults with constipation, as evidenced by an increased SBM score and decreased PAC-SYM and PAC-QOL scores. Additionally, BC99 supplementation increased the levels of neurotransmitters (5-HT, MTL, AChE, and BDNF) associated with intestinal motility and alleviated inflammation in participants with constipation, as supported by higher levels of anti-inflammatory factors (IL-4, IL-10) and lower levels of pro-inflammatory factors (IL-6, IFN-γ) in the BC99 group. Furthermore, BC99 altered the abundance of 93 metabolites and affected biological pathways correlated with gastrointestinal motility, including sphingolipid metabolism, steroid hormone biosynthesis, and glycerophospholipid metabolism. This study demonstrates the effectiveness of the W. coagulans BC99 strain in relieving constipation in adults, and reveals its potential mechanism of action. These findings provide a scientific basis for BC99 as an effective and safe probiotic for constipation treatment.
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Affiliation(s)
- Qiuxia Fan
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.F.); (Y.G.); (Y.Z.); (J.W.); (H.W.); (Y.W.)
- Henan Engineering Research Center of Food Material, Henan University of Science and Technology, Luoyang 471023, China
- Henan Engineering Research Center of Food Microbiology, Luoyang 471000, China
| | - Yinyin Gao
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.F.); (Y.G.); (Y.Z.); (J.W.); (H.W.); (Y.W.)
| | - Yiqing Zhou
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.F.); (Y.G.); (Y.Z.); (J.W.); (H.W.); (Y.W.)
| | - Jinghui Wu
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.F.); (Y.G.); (Y.Z.); (J.W.); (H.W.); (Y.W.)
| | - Haotian Wang
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.F.); (Y.G.); (Y.Z.); (J.W.); (H.W.); (Y.W.)
| | - Yao Dong
- Department of Research and Development, Wecare Probiotics Co., Ltd., Suzhou 215200, China; (Y.D.); (Z.G.); (S.F.)
- Germline Stem Cells and Microenvironment Lab, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhonghui Gai
- Department of Research and Development, Wecare Probiotics Co., Ltd., Suzhou 215200, China; (Y.D.); (Z.G.); (S.F.)
| | - Ying Wu
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.F.); (Y.G.); (Y.Z.); (J.W.); (H.W.); (Y.W.)
- Henan Engineering Research Center of Food Material, Henan University of Science and Technology, Luoyang 471023, China
- Henan Engineering Research Center of Food Microbiology, Luoyang 471000, China
| | - Shuguang Fang
- Department of Research and Development, Wecare Probiotics Co., Ltd., Suzhou 215200, China; (Y.D.); (Z.G.); (S.F.)
| | - Shaobin Gu
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.F.); (Y.G.); (Y.Z.); (J.W.); (H.W.); (Y.W.)
- Henan Engineering Research Center of Food Material, Henan University of Science and Technology, Luoyang 471023, China
- Henan Engineering Research Center of Food Microbiology, Luoyang 471000, China
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Guo J, Si G, Song X, Si F. Mediating role of circulating inflammatory proteins in the effect of immune cells on esophageal cancer risk: A Mendelian randomization study. Medicine (Baltimore) 2024; 103:e40374. [PMID: 39496002 PMCID: PMC11537666 DOI: 10.1097/md.0000000000040374] [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: 08/29/2024] [Accepted: 10/16/2024] [Indexed: 11/06/2024] Open
Abstract
The immune system and inflammatory processes play crucial roles in the development of esophageal cancer (EC). This study aimed to investigate the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC, with a particular focus on the mediating role of circulating inflammatory proteins. Utilizing public genetic data, we applied a 2-sample Mendelian Randomization (MR) method to examine the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC. Comprehensive sensitivity analyses were conducted to assess the robustness, heterogeneity, and horizontal pleiotropy of the MR results. Additionally, a 2-step MR method was employed to quantify the impact and proportion of immune cell phenotypes mediated by circulating inflammatory proteins on EC. Eleven immune cell phenotypes and 1 inflammatory cytokine were found to have causal relationships with EC, with results stable across all sensitivity analyses. Mediation analyses revealed that only 2 cell phenotypes had causal relationships with EC through interleukin-10: CD3 on human leukocyte antigen-DR (HLA-DR)+ T cells (mediation effect = -0.009; mediation proportion = 12.01%) and monocytic myeloid-derived suppressor cell absolute count (mediation effect = 0.018; mediation proportion = 18.97%). This study enhances the understanding of the causal relationships between immune cells, circulating inflammatory proteins, and EC. The findings highlight the potential mediating role of interleukin-10, providing new insights into the mechanisms by which immune cells may influence esophageal tumorigenesis.
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Affiliation(s)
- Jinzhou Guo
- Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Laboratory of TCM Syndrome and Prescription Signaling, Academy of Zhongjing, Zhengzhou, Henan, China
- Henan Key Laboratory of TCM Syndrome and Prescription Signaling, Henan International Joint, Zhengzhou, Henan, China
| | - Gao Si
- Department of Orthopedic, Peking University Third Hospital, Beijing, China
| | - Xuejie Song
- Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Laboratory of TCM Syndrome and Prescription Signaling, Academy of Zhongjing, Zhengzhou, Henan, China
- Henan Key Laboratory of TCM Syndrome and Prescription Signaling, Henan International Joint, Zhengzhou, Henan, China
| | - Fuchun Si
- Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Laboratory of TCM Syndrome and Prescription Signaling, Academy of Zhongjing, Zhengzhou, Henan, China
- Henan Key Laboratory of TCM Syndrome and Prescription Signaling, Henan International Joint, Zhengzhou, Henan, China
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Nagahashi M, Miyoshi Y. Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer. Int J Mol Sci 2024; 25:3354. [PMID: 38542328 PMCID: PMC10970081 DOI: 10.3390/ijms25063354] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 03/06/2024] [Accepted: 03/12/2024] [Indexed: 01/04/2025] Open
Abstract
In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling.
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Affiliation(s)
- Masayuki Nagahashi
- Department of Surgery, Division of Breast and Endocrine Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Hyogo, Japan;
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Sun G, Wang B, Wu X, Cheng J, Ye J, Wang C, Zhu H, Liu X. How do sphingosine-1-phosphate affect immune cells to resolve inflammation? Front Immunol 2024; 15:1362459. [PMID: 38482014 PMCID: PMC10932966 DOI: 10.3389/fimmu.2024.1362459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 02/06/2024] [Indexed: 04/17/2024] Open
Abstract
Inflammation is an important immune response of the body. It is a physiological process of self-repair and defense against pathogens taken up by biological tissues when stimulated by damage factors such as trauma and infection. Inflammation is the main cause of high morbidity and mortality in most diseases and is the physiological basis of the disease. Targeted therapeutic strategies can achieve efficient toxicity clearance at the inflammatory site, reduce complications, and reduce mortality. Sphingosine-1-phosphate (S1P), a lipid signaling molecule, is involved in immune cell transport by binding to S1P receptors (S1PRs). It plays a key role in innate and adaptive immune responses and is closely related to inflammation. In homeostasis, lymphocytes follow an S1P concentration gradient from the tissues into circulation. One widely accepted mechanism is that during the inflammatory immune response, the S1P gradient is altered, and lymphocytes are blocked from entering the circulation and are, therefore, unable to reach the inflammatory site. However, the full mechanism of its involvement in inflammation is not fully understood. This review focuses on bacterial and viral infections, autoimmune diseases, and immunological aspects of the Sphks/S1P/S1PRs signaling pathway, highlighting their role in promoting intradial-adaptive immune interactions. How S1P signaling is regulated in inflammation and how S1P shapes immune responses through immune cells are explained in detail. We teased apart the immune cell composition of S1P signaling and the critical role of S1P pathway modulators in the host inflammatory immune system. By understanding the role of S1P in the pathogenesis of inflammatory diseases, we linked the genomic studies of S1P-targeted drugs in inflammatory diseases to provide a basis for targeted drug development.
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Affiliation(s)
- Gehui Sun
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Bin Wang
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xiaoyu Wu
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jiangfeng Cheng
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junming Ye
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Clinical College, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Chunli Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Hongquan Zhu
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xiaofeng Liu
- Clinical College, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of Emergency, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
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Kar SS, Gharai SR, Sahu SK, Ravichandiran V, Swain SP. The Current Landscape in the Development of Small-molecule Modulators Targeting Sphingosine-1-phosphate Receptors to Treat Neurodegenerative Diseases. Curr Top Med Chem 2024; 24:2431-2446. [PMID: 38676503 DOI: 10.2174/0115680266288509240422112839] [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: 12/13/2023] [Revised: 03/20/2024] [Accepted: 03/26/2024] [Indexed: 04/29/2024]
Abstract
Sphingosine 1-phosphate (S1P) is extensively researched as a lysophospholipid and is crucial in various physiological and pathological processes. It achieves this via signalling through five different subtypes of G protein-coupled receptors (GPCRs), namely S1PR1 to S1PR5. S1PR modulators possess the ability to traverse the blood-brain barrier, potentially leading to direct actions within the Central Nervous System (CNS). S1PR modulators specifically bind to receptors located on the surface of naive and central memory lymphocytes, causing these cells to be trapped or confined within the lymph node. The investigation of the S1P pathway has resulted in the approval of three S1PR modulators, namely fingolimod, siponimod, and ozanimod, as medications for the treatment of patients suffering from Multiple Sclerosis (MS). Additionally, new S1PR modulators, such as ponesimod and etrasimod, are currently being developed and tested in clinical trials. Research on the creation of S1P modulators in neurodegenerative illnesses is ongoing as scientists continue to explore novel possibilities for selective S1P modulators. This study provides a concise overview of sphingolipid metabolism, the mechanism by which S1P receptors are affected, and the structural characteristics of several small molecule S1P modulators, with a particular focus on their structure-activity connections.
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Affiliation(s)
- Sidhartha Sankar Kar
- Faculty of Pharmacy, C. V. Raman Global University, Mahura, Bhubaneswar, 752054, Odisha, India
| | - Soumya Ranjan Gharai
- Department of Pharmaceutical Chemistry, Institute of Pharmacy & Technology, Salipur, Cuttack, 754202, Odisha, India
| | - Sujit Kumar Sahu
- Department of Pharmaceutical Chemistry, Institute of Pharmacy & Technology, Salipur, Cuttack, 754202, Odisha, India
| | - Velayutham Ravichandiran
- Department of Medicinal Chemistry and Centre for Marine Therapeutics (CMT), National Institute of Pharmaceutical Education and Research, Kolkata, 168, Maniktala Main Road, Kolkata, 700054, India
| | - Sharada Prasanna Swain
- Department of Medicinal Chemistry and Centre for Marine Therapeutics (CMT), National Institute of Pharmaceutical Education and Research, Kolkata, 168, Maniktala Main Road, Kolkata, 700054, India
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Feng R, Liu C, Cui Z, Liu Z, Zhang Y. Sphingosine 1-phosphate combining with S1PR4 promotes regulatory T cell differentiation related to FAO through Nrf2/PPARα. Scand J Immunol 2023; 98:e13322. [PMID: 39007959 DOI: 10.1111/sji.13322] [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: 12/21/2022] [Revised: 07/01/2023] [Accepted: 08/02/2023] [Indexed: 07/16/2024]
Abstract
Metabolism and metabolic processes have long been considered to shape the tumour immunosuppressive microenvironment. Recent research has demonstrated that T regulatory cells (Tregs) display high rates of fatty acid oxidation (FAO) and a relatively low rate of glycolysis. Sphingosine 1-phosphate (S1P), which is a G protein signalling activator involved in immune regulation and FAO modulation, has been implicated in Treg differentiation. However, the precise relation between Treg differentiation and S1P remains unclear. In this study, we isolated naïve CD4+ T cells from the spleens of 6-8-week-old BALB/c mice using magnetic bead sorting, which was used in our study for Treg differentiation. S1P stimulation was performed during Treg differentiation. We examined the oxygen consumption and palmitic acid metabolism of the differentiated Tregs and evaluated the expression levels of various proteins, including Nrf2, CPT1A, Glut1, ACC1 and PPARα, through Western blotting. Our results demonstrate that S1P promotes Treg differentiation and enhances FAO, and that the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and peroxisome proliferator-activated receptor α (PPARα) is upregulated. Furthermore, Nrf2 or PPARα knockdown dampened the Treg differentiation and FAO that were promoted by S1P, confirming that S1P can bind with S1PR4 to promote Treg differentiation through the Nrf2/PPARα signalling pathway, which may be related to FAO facilitation.
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Affiliation(s)
- Rui Feng
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Chuang Liu
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Zilin Cui
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Zirong Liu
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Yamin Zhang
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
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Zhang H, Zuo L, Li J, Geng Z, Ge S, Song X, Wang Y, Zhang X, Wang L, Zhao T, Deng M, Chai D, Wang Q, Yang Z, Liu Q, Qiu Q, He X, Yang Y, Ge Y, Wu R, Zheng L, Li J, Chen R, Sun J, Hu J. Construction of a fecal immune-related protein-based biomarker panel for colorectal cancer diagnosis: a multicenter study. Front Immunol 2023; 14:1126217. [PMID: 37313408 PMCID: PMC10258350 DOI: 10.3389/fimmu.2023.1126217] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 05/09/2023] [Indexed: 06/15/2023] Open
Abstract
Purpose To explore fecal immune-related proteins that can be used for colorectal cancer (CRC) diagnosis. Patients and methods Three independent cohorts were used in present study. In the discovery cohort, which included 14 CRC patients and 6 healthy controls (HCs), label-free proteomics was applied to identify immune-related proteins in stool that could be used for CRC diagnosis. Exploring potential links between gut microbes and immune-related proteins by 16S rRNA sequencing. The abundance of fecal immune-associated proteins was verified by ELISA in two independent validation cohorts and a biomarker panel was constructed that could be used for CRC diagnosis. The validation cohort I included 192 CRC patients and 151 HCs from 6 different hospitals. The validation cohort II included 141 CRC patients, 82 colorectal adenoma (CRA) patients, and 87 HCs from another hospital. Finally, the expression of biomarkers in cancer tissues was verified by immunohistochemistry (IHC). Results In the discovery study, 436 plausible fecal proteins were identified. And among 67 differential fecal proteins (|log2 fold change| > 1, P< 0.01) that could be used for CRC diagnosis, 16 immune-related proteins with diagnostic value were identified. The 16S rRNA sequencing results showed a positive correlation between immune-related proteins and the abundance of oncogenic bacteria. In the validation cohort I, a biomarker panel consisting of five fecal immune-related proteins (CAT, LTF, MMP9, RBP4, and SERPINA3) was constructed based on the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression. The biomarker panel was found to be superior to hemoglobin in the diagnosis of CRC in both validation cohort I and validation cohort II. The IHC result showed that protein expression levels of these five immune-related proteins were significantly higher in CRC tissue than in normal colorectal tissue. Conclusion A novel biomarker panel consisting of fecal immune-related proteins can be used for the diagnosis of CRC.
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Affiliation(s)
- Hao Zhang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Lugen Zuo
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Jing Li
- Department of Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Zhijun Geng
- Department of Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Sitang Ge
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xue Song
- Department of Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yueyue Wang
- Department of Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xiaofeng Zhang
- Department of Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Lian Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Tianhao Zhao
- Department of Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Gastroenterology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Min Deng
- Department of Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Gastroenterology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Damin Chai
- Department of Pathology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Qiusheng Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Zi Yang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Quanli Liu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Quanwei Qiu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xuxu He
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yiqun Yang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yuanyuan Ge
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Rong Wu
- Department of General Surgery, Zhongda Hospital, Southeast University, Nanjing, China
| | - Lin Zheng
- Department of Clinical Laboratory, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China
| | - Jianjun Li
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Runkai Chen
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Jialiang Sun
- Department of General Surgery, Shanghai Fengxian District Central Hospital, Shanghai, China
| | - Jianguo Hu
- Department of Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
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10
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Zhang YH, Chen XL, Wang YR, Hou YW, Zhang YD, Wang KJ. Prevention of malignant digestive system tumors should focus on the control of chronic inflammation. World J Gastrointest Oncol 2023; 15:389-404. [PMID: 37009320 PMCID: PMC10052658 DOI: 10.4251/wjgo.v15.i3.389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 01/17/2023] [Accepted: 02/07/2023] [Indexed: 03/14/2023] Open
Abstract
Chronic inflammation, through a variety of mechanisms, plays a key role in the occurrence and development of digestive system malignant tumors (DSMTs). In this study, we feature and provide a comprehensive understanding of DSMT prevention strategies based on preventing or controlling chronic inflammation. The development and evaluation of cancer prevention strategies is a longstanding process. Cancer prevention, especially in the early stage of life, should be emphasized throughout the whole life course. Issues such as the time interval for colon cancer screening, the development of direct-acting antiviral drugs for liver cancer, and the Helicobacter pylori vaccine all need to be explored in long-term, large-scale experiments in the future.
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Affiliation(s)
- Yue-Hua Zhang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Henan International Joint Laboratory of Prevention and Treatment of Pediatric Diseases, Henan Children's Hospital Zhengzhou Children’s Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, Henan Province, China
| | - Xiao-Lin Chen
- Department of Prenatal Diagnosis Center, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yi-Ran Wang
- Henan International Joint Laboratory of Prevention and Treatment of Pediatric Diseases, Henan Children's Hospital Zhengzhou Children’s Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, Henan Province, China
| | - Yu-Wei Hou
- Henan International Joint Laboratory of Prevention and Treatment of Pediatric Diseases, Henan Children's Hospital Zhengzhou Children’s Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, Henan Province, China
| | - Yao-Dong Zhang
- Henan International Joint Laboratory of Prevention and Treatment of Pediatric Diseases, Henan Children's Hospital Zhengzhou Children’s Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, Henan Province, China
| | - Kai-Juan Wang
- Henan International Joint Laboratory of Prevention and Treatment of Pediatric Diseases, Henan Children's Hospital Zhengzhou Children’s Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, Henan Province, China
- Henan Children’s Hospital Zhengzhou Children’s Hospital, Children’s Hospital Affiliated to Zhengzhou University, Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450001, Henan Province, China
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11
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Tourkochristou E, Mouzaki A, Triantos C. Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases. World J Gastroenterol 2023; 29:110-125. [PMID: 36683721 PMCID: PMC9850947 DOI: 10.3748/wjg.v29.i1.110] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/16/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide. The increasing disease burden worldwide, lack of response to current biologic therapeutics, and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy. Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics. Sphingosine-1-phosphate (S1P) receptor (S1PR) modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement. S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival, differentiation, migration, proliferation, immune response, and lymphocyte trafficking. T lymphocytes play an important role in regulating inflammatory responses. In inflamed IBD tissue, an imbalance between T helper (Th) and regulatory T lymphocytes and Th cytokine levels was found. The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD. S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking, lymphocyte number, lymphocyte activity, cytokine production, and contributing to gut barrier function.
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Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
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12
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Chen H, Haddadi N, Zhu X, Hatoum D, Chen S, Nassif NT, Lin Y, McGowan EM. Expression Profile of Sphingosine Kinase 1 Isoforms in Human Cancer Tissues and Cells: Importance and Clinical Relevance of the Neglected 1b-Isoform. JOURNAL OF ONCOLOGY 2022; 2022:2250407. [PMID: 36532885 PMCID: PMC9750787 DOI: 10.1155/2022/2250407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 11/12/2022] [Accepted: 11/17/2022] [Indexed: 09/28/2023]
Abstract
Background Overexpression of sphingosine kinase 1 (SphK1) is casually associated with many types of cancer, and inhibitors of SphK1 sensitize tumors to chemotherapy. SphK1 is expressed as two major isoforms, SphK1a and SphK1b. To date, no information has been reported on the SphK1 isoform expression profile and its clinical relevance. Objective The objective is to examine the expression profile of the SphK1a and SPhK1b isoforms in human cancer and noncancer tissues and cell lines and explore their clinical relevance. Methods We used PCR to qualitatively examine the expression profile of these two isoforms in breast, liver, and prostate cancer tissues plus paired adjacent tissues and in 11 cancer and normal cell lines (breast, cervical, bone, prostate, colon, brain, mesothelioma tumor and benign, and human kidney cells). Results We found that SphK1a was ubiquitously expressed in all cancer cells and tissues tested; in contrast, SphK1b was only expressed in selective cell types in breast, prostate, and lung cancer. Conclusions Our data suggest that SphK1a is important for generic SphK1/S1P functions, and SphK1b mediates specialized and/or unique pathways in a specific type of tissue and could be a biomarker for cancer. This discovery is important for future SphK1-related cancer research and may have clinical implications in drug development associated with SphK1-directed cancer treatment.
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Affiliation(s)
- Hongjie Chen
- Department of Traditional Chinese Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Nahal Haddadi
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
| | - Xiaofeng Zhu
- Department of Transplant Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Diana Hatoum
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
- Public Health and College of Arts and Sciences, Phoenicia University, Daoudiye, Lebanon
| | - Size Chen
- Central Laboratory, First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Najah T. Nassif
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
| | - Yiguang Lin
- Department of Traditional Chinese Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
- Central Laboratory, First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Eileen M. McGowan
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
- Central Laboratory, First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, Guangdong Pharmaceutical University, Guangzhou, China
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13
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Uranbileg B, Kurano M, Kano K, Sakai E, Arita J, Hasegawa K, Nishikawa T, Ishihara S, Yamashita H, Seto Y, Ikeda H, Aoki J, Yatomi Y. Sphingosine 1-phosphate lyase facilitates cancer progression through converting sphingolipids to glycerophospholipids. Clin Transl Med 2022; 12:e1056. [PMID: 36125914 PMCID: PMC9488530 DOI: 10.1002/ctm2.1056] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 08/23/2022] [Accepted: 08/29/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND In addition to potent agonist properties for sphingosine 1-phosphate (S1P) receptors, intracellularly, S1P is an intermediate in metabolic conversion pathway from sphingolipids to glycerolysophospholipids (glyceroLPLs). We hypothesized that this S1P metabolism and its products might possess some novel roles in the pathogenesis of cancer, where S1P lyase (SPL) is a key enzyme. METHODS The mRNA levels of sphingolipid-related and other cancer-related factors were measured in human hepatocellular carcinoma (HCC), colorectal cancer, and esophageal cancer patients' tumours and in their adjacent non-tumour tissues. Phospholipids (PL) and glyceroLPLs were measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In-vitro experiments were performed in Colon 26 cell line with modulation of the SPL and GPR55 expressions. Xenograft model was used for determination of the cancer progression and for pharmacological influence. RESULTS Besides high SPL levels in human HCC and colon cancer, SPL levels were specifically and positively linked with levels of glyceroLPLs, including lysophosphatidylinositol (LPI). Overexpression of SPL in Colon 26 cells resulted in elevated levels of LPI and lysophosphatidylglycerol (LPG), which are agonists of GPR55. SPL overexpression-enhanced cell proliferation was inhibited by GPR55 silencing. Conversely, inhibition of SPL led to the opposite outcome and reversed by adding LPI, LPG, and metabolites generated during S1P degradation, which is regulated by SPL. The xenograft model results suggested the contribution of SPL and glyceroLPLs to tumour progression depending on levels of SPL and GPR55. Moreover, the pharmacological inhibition of SPL prevented the progression of cancer. The underlying mechanisms for the SPL-mediated cancer progression are the activation of p38 and mitochondrial function through the LPI, LPG-GPR55 axis and the suppression of autophagy in a GPR55-independent manner. CONCLUSION A new metabolic pathway has been proposed here in HCC and colon cancer, SPL converts S1P to glyceroLPLs, mainly to LPI and LPG, and facilitates cancer development.
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Affiliation(s)
- Baasanjav Uranbileg
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Makoto Kurano
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Eri Sakai
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junichi Arita
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Takeshi Nishikawa
- Surgical Oncology and Vascular Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Soichiro Ishihara
- Surgical Oncology and Vascular Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Hiroharu Yamashita
- Gastrointestinal Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan.,Division of Digestive Surgery, Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuyuki Seto
- Gastrointestinal Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Hitoshi Ikeda
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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14
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Meacci E, Pierucci F, Garcia-Gil M. Skeletal Muscle and COVID-19: The Potential Involvement of Bioactive Sphingolipids. Biomedicines 2022; 10:biomedicines10051068. [PMID: 35625805 PMCID: PMC9138286 DOI: 10.3390/biomedicines10051068] [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: 04/04/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 01/08/2023] Open
Abstract
SARS-CoV-2 virus infection is the cause of the coronavirus disease 2019 (COVID-19), which is still spreading over the world. The manifestation of this disease can range from mild to severe and can be limited in time (weeks) or persist for months in about 30–50% of patients. COVID-19 is considered a multiple organ dysfunction syndrome and the musculoskeletal system manifestations are beginning to be considered of absolute importance in both COVID-19 patients and in patients recovering from the SARS-CoV-2 infection. Musculoskeletal manifestations of COVID-19 and other coronavirus infections include loss of muscle mass, muscle weakness, fatigue or myalgia, and muscle injury. The molecular mechanisms by which SARS-CoV-2 can cause damage to skeletal muscle (SkM) cells are not yet well understood. Sphingolipids (SLs) represent an important class of eukaryotic lipids with structural functions as well as bioactive molecules able to modulate crucial processes, including inflammation and viral infection. In the last two decades, several reports have highlighted the role of SLs in modulating SkM cell differentiation, regeneration, aging, response to insulin, and contraction. This review summarizes the consequences of SARS-CoV-2 infection on SkM and the potential involvement of SLs in the tissue responses to virus infection. In particular, we highlight the role of sphingosine 1-phosphate signaling in order to aid the prediction of novel targets for preventing and/or treating acute and long-term musculoskeletal manifestations of virus infection in COVID-19.
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Affiliation(s)
- Elisabetta Meacci
- Unit of Biochemical Sciences and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale GB Morgagni 50, 50121 Florence, Italy;
- Interuniversity Institute of Myology, University of Florence, 50121 Florence, Italy
- Correspondence: ; Tel.: +39-055-2751231
| | - Federica Pierucci
- Unit of Biochemical Sciences and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale GB Morgagni 50, 50121 Florence, Italy;
| | - Mercedes Garcia-Gil
- Unit of Physiology, Department of Biology, University of Pisa, Via S. Zeno 31, 56127 Pisa, Italy;
- Interdepartmental Research Center “Nutraceuticals and Food for Health”, University of Pisa, 56127 Pisa, Italy
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