1
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Kouridaki ME, Gillespie J, Robinson J, Mathie T, Bain L, McArthur D, Morrison A, Greenslade DB, Papadourakis M, Maj K, Cameron K, Turner D, Webster SP, Wear MA, Doughty-Shenton D, Hulme AN, Michel J. Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments. J Med Chem 2025; 68:6815-6831. [PMID: 40074291 PMCID: PMC11956012 DOI: 10.1021/acs.jmedchem.5c00301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025]
Abstract
Cyclophilins have been implicated in the pathophysiology of metabolic dysfunction-associated steatohepatitis (MASH). Pharmacological inhibition of the cyclophilin B isoform has the potential to attenuate liver fibrosis in MASH, but current cyclophilin inhibitors in clinical trials lack isoform selectivity. We previously reported the novel tri-vector small-molecule inhibitor 1 that exhibited improved subtype selectivity by simultaneously engaging three pockets on the surface of cyclophilins. Here, we present structure-activity relationships that address genotoxicity concerns, enhance subtype selectivity, improve pharmaceutical properties, and demonstrate strong efficacy in a MASH cellular model. Lead compound 11 is a potent cyclophilin B inhibitor with an encouraging pharmacokinetic profile suitable for further development.
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Affiliation(s)
- Maria-Eleni Kouridaki
- EaStCHEM
School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, Scotland EH9 3FJ, U.K.
| | | | - John Robinson
- BioAscent
Discovery Ltd., Newhouse, Scotland Lanarkshire ML1 5UH, U.K.
| | - Tanya Mathie
- BioAscent
Discovery Ltd., Newhouse, Scotland Lanarkshire ML1 5UH, U.K.
| | - Laura Bain
- BioAscent
Discovery Ltd., Newhouse, Scotland Lanarkshire ML1 5UH, U.K.
| | - Duncan McArthur
- BioAscent
Discovery Ltd., Newhouse, Scotland Lanarkshire ML1 5UH, U.K.
| | - Angus Morrison
- BioAscent
Discovery Ltd., Newhouse, Scotland Lanarkshire ML1 5UH, U.K.
| | - Daniel B. Greenslade
- EaStCHEM
School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, Scotland EH9 3FJ, U.K.
| | - Michail Papadourakis
- EaStCHEM
School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, Scotland EH9 3FJ, U.K.
| | - Kasia Maj
- Cytochroma
Ltd., Roslin Innovation Centre, Easter Bush
Estate, Edinburgh, Scotland EH25 9RG, U.K.
| | - Kate Cameron
- Cytochroma
Ltd., Roslin Innovation Centre, Easter Bush
Estate, Edinburgh, Scotland EH25 9RG, U.K.
| | - Darryl Turner
- Concept
Life Sciences Ltd., Nine,
9 Little France Road, Edinburgh Bioquarter, Edinburgh, Scotland EH16
4UX, U.K.
| | - Scott P. Webster
- Centre for
Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland EH16
4TJ, U.K.
| | - Martin A. Wear
- The Edinburgh
Protein Production Facility (EPPF), University
of Edinburgh, Level 3
Michael Swann Building, King’s Buildings, Max Born Crescent, Edinburgh, Scotland EH9 3FF, U.K.
| | - Dahlia Doughty-Shenton
- Centre for
Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh Bioquarter, Edinburgh, Scotland EH16 4UU, U.K.
| | - Alison N. Hulme
- EaStCHEM
School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, Scotland EH9 3FJ, U.K.
| | - Julien Michel
- EaStCHEM
School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, Scotland EH9 3FJ, U.K.
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2
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Li XJ, Zhang MC, Li X, Guan LL, Liang YR, Hao EJ, Wang Y, Guo HM. Discovery of Novel Oxazolo[4,3- f]purine Derivatives as Antitumor Agents through PPIA Interaction. J Med Chem 2025; 68:5573-5596. [PMID: 40012358 DOI: 10.1021/acs.jmedchem.4c02819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
54 novel oxazolo [4,3-f]purine derivatives were designed, synthesized, and evaluated for antitumor activity, among which compound 20b exhibited potent activity against several cancer cell lines. Compound 20b inhibited cell metastasis, arrested the cell cycle in the G0/G1 phase, and induced apoptosis in HCT116 cells. Mechanistic studies revealed that 20b increased ROS levels and led to DNA damage, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction in HCT116 cells. Limited proteolysis-small molecule mapping (LiP-SMap), drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) experiments provided evidence that compound 20b bound to PPIA with a KD value of 0.52 μM. siRNA assay indicated that 20b-mediated antiproliferative and antimigration activities were abolished and that the PPIA/MAPK signaling pathway was inhibited when PPIA was silenced in HCT116 cells. Significantly, compound 20b presented significant anticolorectal cancer efficacy in vivo without obvious toxicity. These results indicate that 20b may serve as a novel anticancer agent targeting PPIA, meriting further attention in antitumor drug research.
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Affiliation(s)
- Xian-Jia Li
- State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Meng-Cheng Zhang
- State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Xiang Li
- State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Lu Lu Guan
- State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Yu-Ru Liang
- Institute of Translation Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Er-Jun Hao
- State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Yang Wang
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Hai-Ming Guo
- State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
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3
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Wan X, Ma J, Bai H, Hu X, Ma Y, Zhao M, Liu J, Duan Z. Drug Advances in NAFLD: Individual and Combination Treatment Strategies of Natural Products and Small-Synthetic-Molecule Drugs. Biomolecules 2025; 15:140. [PMID: 39858534 PMCID: PMC11764138 DOI: 10.3390/biom15010140] [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: 12/15/2024] [Revised: 01/07/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease and is closely associated with metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. However, effective treatment strategies for NAFLD are still lacking. In recent years, progress has been made in understanding the pathogenesis of NAFLD, identifying multiple therapeutic targets and providing new directions for drug development. This review summarizes the recent advances in the treatment of NAFLD, focusing on the mechanisms of action of natural products, small-synthetic-molecule drugs, and combination therapy strategies. This review aims to provide new insights and strategies in treating NAFLD.
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Affiliation(s)
- Xing Wan
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
- Institute of Integrated Traditional Chinese and Western Medicine, Dalian Medical University, Dalian 116051, China
| | - Jingyuan Ma
- The First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang 110033, China; (J.M.); (Y.M.)
| | - He Bai
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
| | - Xuyang Hu
- The Second Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang 110033, China;
| | - Yanna Ma
- The First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang 110033, China; (J.M.); (Y.M.)
| | - Mingjian Zhao
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
| | - Jifeng Liu
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
| | - Zhijun Duan
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
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4
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Katsarou A, Tsioulos G, Kassi E, Chatzigeorgiou A. Current and experimental pharmacotherapy for the management of non-alcoholic fatty liver disease. Hormones (Athens) 2024; 23:621-636. [PMID: 39112786 DOI: 10.1007/s42000-024-00588-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 07/17/2024] [Indexed: 10/29/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with its incidence increasing in parallel with the global prevalence of obesity and type 2 diabetes mellitus. Despite our steadily increasing knowledge of its pathogenesis, there is as yet no available pharmacotherapy specifically tailored for NAFLD. To define the appropriate management, it is important to clarify the context in which the disease appears. In the case of concurrent metabolic comorbidities, NAFLD patients are treated by targeting these comorbidities, such as diabetes and obesity. Thus, GLP-1 analogs, PPAR, and SGLT2 inhibitors have recently become central to the treatment of NAFLD. In parallel, randomized trials are being conducted to explore new agents targeting known pathways involved in NAFLD progression. However, there is an imperative need to intensify the effort to design new, safe drugs with biopsy-proven efficacy. Of note, the main target of the pharmacotherapy should be directed to the regression of fibrotic NASH, as this histologic stage has been correlated with increased overall as well as liver-related morbidity and mortality. Herein we discuss the drugs currently at the forefront of NAFLD treatment.
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Affiliation(s)
- Angeliki Katsarou
- 251 Hellenic Airforce General Hospital, 1 P.Kanellopoulou Str, Athens, 11525, Greece.
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str, Athens, 11527, Greece.
| | - Georgios Tsioulos
- 4th Department of Internal Medicine, Medical School, University General Hospital Attikon, National and Kapodistrian University of Athens, 1 Rimini Str, Athens, 12462, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str, Athens, 11527, Greece
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5
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Amorim R, Soares P, Chavarria D, Benfeito S, Cagide F, Teixeira J, Oliveira PJ, Borges F. Decreasing the burden of non-alcoholic fatty liver disease: From therapeutic targets to drug discovery opportunities. Eur J Med Chem 2024; 277:116723. [PMID: 39163775 DOI: 10.1016/j.ejmech.2024.116723] [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: 05/30/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/22/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) presents a pervasive global pandemic, affecting approximately 25 % of the world's population. This grave health issue not only demands urgent attention but also stands as a significant economic concern on a global scale. The genesis of NAFLD can be primarily attributed to unhealthy dietary habits and a sedentary lifestyle, albeit certain genetic factors have also been recorded to contribute to its occurrence. NAFLD is characterized by fat accumulation in more than 5 % of hepatocytes according to histological analysis, or >5.6 % of lipid volume fraction in total liver weight in patients. The pathophysiology of NAFLD/non-alcoholic steatohepatitis (NASH) is multifactorial and the mechanisms underlying the progression to advanced forms remain unclear, thereby representing a challenge to disease therapy. Despite the substantial efforts from the scientific community and the large number of pre-clinical and clinical trials performed so far, only one drug was approved by the Food and Drug Administration (FDA) to treat NAFLD/NASH specifically. This review provides an overview of available information concerning emerging molecular targets and drug candidates tested in clinical studies for the treatment of NAFLD/NASH. Improving our understanding of NAFLD pathophysiology and pharmacotherapy is crucial not only to explore new molecular targets, but also to potentiate drug discovery programs to develop new therapeutic strategies. This knowledge endeavours scientific efforts to reduce the time for achieving a specific and effective drug for NAFLD or NASH management and improve patients' quality of life.
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Affiliation(s)
- Ricardo Amorim
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Pedro Soares
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Daniel Chavarria
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Sofia Benfeito
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Fernando Cagide
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - José Teixeira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Paulo J Oliveira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal.
| | - Fernanda Borges
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
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6
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Fan W, Bradford TM, Török NJ. Metabolic dysfunction-associated liver disease and diabetes: Matrix remodeling, fibrosis, and therapeutic implications. Ann N Y Acad Sci 2024; 1538:21-33. [PMID: 38996214 DOI: 10.1111/nyas.15184] [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] [Indexed: 07/14/2024]
Abstract
Metabolic dysfunction-associated liver disease (MASLD) and steatohepatitis (MASH) are becoming the most common causes of chronic liver disease in the United States and worldwide due to the obesity and diabetes epidemics. It is estimated that by 2030 close to 100 million people might be affected and patients with type 2 diabetes are especially at high risk. Twenty to 30% of patients with MASLD can progress to MASH, which is characterized by steatosis, necroinflammation, hepatocyte ballooning, and in advanced cases, fibrosis progressing to cirrhosis. Clinically, it is recognized that disease progression in diabetic patients is accelerated and the role of various genetic and epigenetic factors, as well as cell-matrix interactions in fibrosis and stromal remodeling, have recently been recognized. While there has been great progress in drug development and clinical trials for MASLD/MASH, the complexity of these pathways highlights the need to improve diagnosis/early detection and develop more successful antifibrotic therapies that not only prevent but reverse fibrosis.
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Affiliation(s)
- Weiguo Fan
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
- Palo Alto VA Medical Center, Palo Alto, California, USA
| | - Toby M Bradford
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Natalie J Török
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
- Palo Alto VA Medical Center, Palo Alto, California, USA
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7
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Stauffer WT, Goodman AZ, Gallay PA. Cyclophilin inhibition as a strategy for the treatment of human disease. Front Pharmacol 2024; 15:1417945. [PMID: 39045055 PMCID: PMC11264201 DOI: 10.3389/fphar.2024.1417945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 06/14/2024] [Indexed: 07/25/2024] Open
Abstract
Cyclophilins (Cyps), characterized as peptidyl-prolyl cis-trans isomerases (PPIases), are highly conserved and ubiquitous, playing a crucial role in protein folding and cellular signaling. This review summarizes the biochemical pathways mediated by Cyps, including their involvement in pathological states such as viral replication, inflammation, and cancer progression, to underscore the therapeutic potential of Cyp inhibition. The exploration of Cyp inhibitors (CypI) in this review, particularly non-immunosuppressive cyclosporine A (CsA) derivatives, highlights their significance as therapeutic agents. The structural and functional nuances of CsA derivatives are examined, including their efficacy, mechanism of action, and the balance between therapeutic benefits and off-target effects. The landscape of CypI is evaluated to emphasize the clinical need for targeted approaches to exploit the complex biology of Cyps and to propose future directions for research that may enhance the utility of non-immunosuppressive CsA derivatives in treating diseases where Cyps play a key pathological role.
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Affiliation(s)
| | | | - Philippe A. Gallay
- Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, CA, United States
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8
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Fuster-Martínez I, Calatayud S. The current landscape of antifibrotic therapy across different organs: A systematic approach. Pharmacol Res 2024; 205:107245. [PMID: 38821150 DOI: 10.1016/j.phrs.2024.107245] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 06/02/2024]
Abstract
Fibrosis is a common pathological process that can affect virtually all the organs, but there are hardly any effective therapeutic options. This has led to an intense search for antifibrotic therapies over the last decades, with a great number of clinical assays currently underway. We have systematically reviewed all current and recently finished clinical trials involved in the development of new antifibrotic drugs, and the preclinical studies analyzing the relevance of each of these pharmacological strategies in fibrotic processes affecting tissues beyond those being clinically studied. We analyze and discuss this information with the aim of determining the most promising options and the feasibility of extending their therapeutic value as antifibrotic agents to other fibrotic conditions.
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Affiliation(s)
- Isabel Fuster-Martínez
- Departamento de Farmacología, Universitat de València, Valencia 46010, Spain; FISABIO (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana), Valencia 46020, Spain.
| | - Sara Calatayud
- Departamento de Farmacología, Universitat de València, Valencia 46010, Spain; CIBERehd (Centro de Investigación Biomédica en Red - Enfermedades Hepáticas y Digestivas), Spain.
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9
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Lu H. Inflammatory liver diseases and susceptibility to sepsis. Clin Sci (Lond) 2024; 138:435-487. [PMID: 38571396 DOI: 10.1042/cs20230522] [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: 09/03/2023] [Revised: 01/09/2024] [Accepted: 03/12/2024] [Indexed: 04/05/2024]
Abstract
Patients with inflammatory liver diseases, particularly alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease (MAFLD), have higher incidence of infections and mortality rate due to sepsis. The current focus in the development of drugs for MAFLD is the resolution of non-alcoholic steatohepatitis and prevention of progression to cirrhosis. In patients with cirrhosis or alcoholic hepatitis, sepsis is a major cause of death. As the metabolic center and a key immune tissue, liver is the guardian, modifier, and target of sepsis. Septic patients with liver dysfunction have the highest mortality rate compared with other organ dysfunctions. In addition to maintaining metabolic homeostasis, the liver produces and secretes hepatokines and acute phase proteins (APPs) essential in tissue protection, immunomodulation, and coagulation. Inflammatory liver diseases cause profound metabolic disorder and impairment of energy metabolism, liver regeneration, and production/secretion of APPs and hepatokines. Herein, the author reviews the roles of (1) disorders in the metabolism of glucose, fatty acids, ketone bodies, and amino acids as well as the clearance of ammonia and lactate in the pathogenesis of inflammatory liver diseases and sepsis; (2) cytokines/chemokines in inflammatory liver diseases and sepsis; (3) APPs and hepatokines in the protection against tissue injury and infections; and (4) major nuclear receptors/signaling pathways underlying the metabolic disorders and tissue injuries as well as the major drug targets for inflammatory liver diseases and sepsis. Approaches that focus on the liver dysfunction and regeneration will not only treat inflammatory liver diseases but also prevent the development of severe infections and sepsis.
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Affiliation(s)
- Hong Lu
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, U.S.A
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10
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Noureddin M. MASH clinical trials and drugs pipeline: An impending tsunami. Hepatology 2024:01515467-990000000-00811. [PMID: 38502810 DOI: 10.1097/hep.0000000000000860] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 02/24/2024] [Indexed: 03/21/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease, formerly known as NAFLD, has ascended to prominence as the predominant chronic liver disease in Western countries and now stands as a leading cause of liver transplantations. In the more advanced stage, metabolic dysfunction-associated steatohepatitis (MASH) may lead to fibrosis, a gateway to cirrhosis, liver cancer, and liver failure. Despite extensive research and exploration of various drug mechanisms, the anticipation for the inaugural approved drug to materialize by 2024 is palpable, marking a significant milestone. Numerous pathways have been investigated for MASH treatment, exploring thyroid hormone receptors, glucagon-like peptides 1, peroxisome proliferator-activated receptors, and agents influencing hepatic steatosis synthesis, inflammatory pathways, genetic components, fibrosis mechanisms, and an array of other avenues. Over time, key regulatory directions have crystallized, now manifesting in 2 primary endpoints under investigation: resolution of steatohepatitis without worsening fibrosis and/or improvement of fibrosis stage without worsening of steatohepatitis, especially used in phase 3 clinical trials, while alternative noninvasive endpoints are explored in phase 2 trials. The prospect of proving efficacy in clinical trials opens doors to combination therapies, evaluating the ideal combination of drugs to yield comprehensive benefits, extending beyond the liver to other organs. Certain combination drug trials are already underway. In this review, we discuss the forefront of MASH drug research as of 2023/2024, illuminating mechanisms, outcomes, and future trajectories. Furthermore, we tackle the challenges confronting MASH trials and propose potential strategies for surmounting them.
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Affiliation(s)
- Mazen Noureddin
- Sherrie & Alan Conover Center for Liver Disease & Transplantation, Underwood Center for Digestive Disorders Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA
- Houston Research Institute, Houston, Texas, USA
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11
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Wang Y, Yu H, Cen Z, Zhu Y, Wu W. Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis. Metabol Open 2024; 21:100267. [PMID: 38187470 PMCID: PMC10770762 DOI: 10.1016/j.metop.2023.100267] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 12/06/2023] [Accepted: 12/12/2023] [Indexed: 01/09/2024] Open
Abstract
Nonalcoholic steatohepatitis (NASH), is the advanced stage of nonalcoholic fatty liver disease (NAFLD) with rapidly rising global prevalence. It is featured with severe hepatocyte apoptosis, inflammation and hepatic lipogenesis. The drugs directly targeting the processes of steatosis, inflammation and fibrosis are currently under clinical investigation. Nevertheless, the long-term ineffectiveness and remarkable adverse effects are well documented, and new concepts are required to tackle with the root causes of NASH progression. We critically assess the recently validated drug targets that regulate the systemic metabolism to ameliorate NASH. Thermogenesis promoted by mitochondrial uncouplers restores systemic energy expenditure. Furthermore, regulation of mitochondrial proteases and proteins that are pivotal for intracellular metabolic homeostasis normalize mitochondrial function. Secreted proteins also improve systemic metabolism, and NASH is ameliorated by agonizing receptors of secreted proteins with small molecules. We analyze the drug design, the advantages and shortcomings of these novel drug candidates. Meanwhile, the structural modification of current NASH therapeutics significantly increased their selectivity, efficacy and safety. Furthermore, the arising CRISPR-Cas9 screen strategy on liver organoids has enabled the identification of new genes that mediate lipid metabolism, which may serve as promising drug targets. In summary, this article discusses the in-depth novel mechanisms and the multidisciplinary approaches, and they provide new horizons to treat NASH.
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Affiliation(s)
- Yibing Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai, 200438, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, China
| | - Hanhan Yu
- School of Kinesiology, Shanghai University of Sport, Shanghai, 200438, China
| | - Zhipeng Cen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China
| | - Yutong Zhu
- School of Kinesiology, Shanghai University of Sport, Shanghai, 200438, China
| | - Wenyi Wu
- School of Kinesiology, Shanghai University of Sport, Shanghai, 200438, China
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12
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Arnold J, Idalsoaga F, Díaz LA, Cabrera D, Barrera F, Arab JP, Arrese M. Emerging Drug Therapies for Metabolic Dysfunction-Associated Steatotic Liver Disease: A Glimpse into the Horizon. CURRENT HEPATOLOGY REPORTS 2024; 23:204-219. [DOI: 10.1007/s11901-023-00629-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/18/2023] [Indexed: 01/03/2025]
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13
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Domingues I, Leclercq IA, Beloqui A. Nonalcoholic fatty liver disease: Current therapies and future perspectives in drug delivery. J Control Release 2023; 363:415-434. [PMID: 37769817 DOI: 10.1016/j.jconrel.2023.09.040] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 08/27/2023] [Accepted: 09/20/2023] [Indexed: 10/03/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects approximately 25% of the adult population worldwide. This pathology can progress into end-stage liver disease with life-threatening complications, and yet no pharmacologic therapy has been approved. NAFLD is commonly characterized by excessive fat accumulation in the liver and is in closely associated with insulin resistance and metabolic disorders, which suggests that NAFLD is the hepatic manifestation of metabolic syndrome. Regarding treatment options, the current validated strategy relies on lifestyle modifications (exercise and diet restrictions). Although there are no approved drug-based treatments, several clinical trials are ongoing. Novel targets are being discovered, and the repurposing of drugs that show promising effects in NAFLD is starting to gain more interest. The field of nanotechnology has been growing at an increasing rate, with new and more efficient drug delivery strategies being developed for NAFLD treatment. Nanocarriers can easily encapsulate drugs that need to be better protected from the organism to exert their effect or that need help at reaching their target, thereby helping achieve a better bioavailability. Drug delivery systems can also be designed to target the site of the disease, in this case, the liver. In this review, we focus on the current knowledge of NAFLD pathology, the targets being considered for clinical trials, and the current guidelines and ongoing clinical trials, with a specific focus on potential oral treatments for NAFLD using promising drug delivery strategies.
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Affiliation(s)
- Inês Domingues
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials Group, Avenue Emmanuel Mounier 73, 1200 Brussels, Belgium
| | - Isabelle A Leclercq
- UCLouvain, Université catholique de Louvain, Institute of Experimental and Clinical Research, Laboratory of Hepato-Gastroenterology, Avenue Emmanuel Mounier 53, 1200 Brussels, Belgium.
| | - Ana Beloqui
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials Group, Avenue Emmanuel Mounier 73, 1200 Brussels, Belgium; WEL Research Institute, Avenue Pasteur, 6, 1300 Wavre, Belgium.
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14
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Stauffer W, Bobardt M, Ure D, Foster R, Gallay P. The Cyclophilin Inhibitor Rencofilstat Decreases HCV-Induced Hepatocellular Carcinoma Independently of Its Antiviral Activity. Viruses 2023; 15:2099. [PMID: 37896876 PMCID: PMC10612079 DOI: 10.3390/v15102099] [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: 09/01/2023] [Revised: 10/07/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
There is an urgent need for the identification of new drugs that inhibit HCV-induced hepatocellular carcinoma (HCC). Our work demonstrates that cyclophilin inhibitors (CypIs) represent such new drugs. We demonstrate that the nonimmunosuppressive cyclosporine A (CsA) analog (CsAa) rencofilstat possesses dual therapeutic activities for the treatment of HCV infection and HCV-induced HCC. Specifically, we show that the HCV infection of humanized mice results in the progressive development of HCC. This is true for the four genotypes tested (1 to 4). Remarkably, we demonstrate that rencofilstat inhibits the development of HCV-induced HCC in mice even when added 16 weeks after infection when HCC is well established. Importantly, we show that rencofilstat drastically reduces HCC progression independently of its anti-HCV activity. Indeed, the CypI rencofilstat inhibits HCC, while other anti-HCV agents such as NS5A (NS5Ai) and NS5B (NS5Bi) fail to reduce HCC. In conclusion, this study shows for the first time that the CypI rencofilstat represents a potent therapeutic agent for the treatment of HCV-induced HCC.
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Affiliation(s)
- Winston Stauffer
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; (W.S.); (M.B.)
| | - Michael Bobardt
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; (W.S.); (M.B.)
| | - Daren Ure
- Hepion Pharmaceuticals Inc., Edison, NJ 08837, USA; (D.U.); (R.F.)
| | - Robert Foster
- Hepion Pharmaceuticals Inc., Edison, NJ 08837, USA; (D.U.); (R.F.)
| | - Philippe Gallay
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; (W.S.); (M.B.)
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15
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Tidwell J, Balassiano N, Shaikh A, Nassar M. Emerging therapeutic options for non-alcoholic fatty liver disease: A systematic review. World J Hepatol 2023; 15:1001-1012. [PMID: 37701920 PMCID: PMC10494562 DOI: 10.4254/wjh.v15.i8.1001] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/18/2023] [Accepted: 08/07/2023] [Indexed: 08/22/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation. In the United States alone, annual medical costs are approximately 100 billion dollars. Unfortunately, there is no Federal Drug Administration (FDA)-approved medication for its treatment. However, various clinical trials are investigating several therapeutic classes that could potentially treat NAFLD. It is valuable to have a compilation of the data available on their efficacy. AIM To assess the efficacy of cyclophilin inhibitors, fibroblast growth factor 21 analogs (FGF21), and dual and pan peroxisome proliferator-activated receptor (PPAR) agonists for treating NAFLD. METHODS A comprehensive literature search using keywords including cyclophilin inhibitor, FGF agonist, pan-PPAR agonists, dual-PPAR agonist, NAFLD, non-alcoholic steatohepatitis, and fatty liver was conducted on October 29, 2022, in PubMed, EMBASE, Cochrane Library, Scopus and Web of Science. Animal and human research, case reports, and published articles in English from all countries with patients aged 18 and above were included. Only articles with a National Institutes of Health (NIH) Quality Assessment score of five or higher out of eight points were included. Articles that were narrative or systematic reviews, abstracts, not in English, focused on patients under 18 years old, did not measure outcomes of interest, were inaccessible, or had a low NIH Quality Assessment score were excluded. Each article was screened by two independent researchers evaluating relevance and quality. Resources were scored based on the NIH Quality Assessment Score; then, pertinent data was extracted in a spreadsheet and descriptively analyzed. RESULTS Of the 681 records screened, 29 met the necessary criteria and were included in this review. These records included 12 human studies and 17 animal studies. Specifically, there were four studies on cyclophilin inhibitors, four on FGF agonists/analogs, eleven on pan-PPAR agonists, and ten on dual-PPAR agonists. Different investigational products were assessed: The most common cyclophilin inhibitor was NV556; FGF agonists and analogs was Efruxifermin; pan-PPAR agonists was Lanifibranor; and dual-PPAR agonists was Saroglitazar. All classes were found to be statistically efficacious for the treatment of NAFLD, with animal studies demonstrating improvement in steatosis and/or fibrosis on biopsy and human studies evidencing improvement in different metabolic parameters and/or steatosis and fibrosis on FibroScan (P < 0.05). CONCLUSION The data analyzed in this review showed clinically significant improvement in individual histological features of NAFLD in both animal and human trials for all four classes, as well as good safety profiles (P < 0.05). We believe this compilation of information will have positive clinical implications in obtaining an FDA-approved therapy for NAFLD.
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Affiliation(s)
- Jasmine Tidwell
- Department of Internal Medicine, University of Connecticut, Farmington, CT 06032, United States
| | - Natalie Balassiano
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/NYC Health+Hospitals/Queens, New York, NY 11432, United States
| | - Anjiya Shaikh
- Department of Internal Medicine, University of Connecticut, Farmington, CT 06032, United States
| | - Mahmoud Nassar
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, NY 14221, United States.
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16
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Stauffer W, Bobardt M, Ure D, Foster R, Gallay P. The Cyclophilin Inhibitor Rencofilstat Decreases HCV-induced Hepatocellular Carcinoma Independently of Its Antiviral Activity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.19.553982. [PMID: 37645728 PMCID: PMC10462172 DOI: 10.1101/2023.08.19.553982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
There is an urgent need for the identification of new drugs that inhibit HCV-induced hepatocellular carcinoma (HCC). Our work demonstrates that cyclophilin inhibitors (CypI) represent such new drugs. We demonstrated that the non-immunosuppressive cyclosporine A (CsA) analog (CsAa) rencofilstat possesses dual therapeutic activities for the treatment of HCV infection and HCV-induced HCC. Specifically, we showed that HCV infection of humanized mice results in the progressive development of HCC. This was true for four genotypes tested (1 to 4). Remarkably, we demonstrated that rencofilstat inhibits the development of HCV-induced HCC in mice even when added 16 weeks post-infection when HCC is well established. Importantly, we showed that rencofilstat drastically reduces HCC progression independently of its anti-HCV activity. Indeed, the CypI rencofilstat inhibits HCC while other anti-HCV agents such as NS5A (NS5Ai) and NS5B (NS5Bi) fail to reduce HCC. In conclusion, this study shows for the first time that the CypI rencofilstat represents a potent therapeutic agent for the treatment of HCV-induced HCC.
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Affiliation(s)
- Winston Stauffer
- Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Michael Bobardt
- Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Daren Ure
- Hepion Pharmaceuticals Inc., Edison, New Jersey, USA
| | - Robert Foster
- Hepion Pharmaceuticals Inc., Edison, New Jersey, USA
| | - Philippe Gallay
- Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, California, USA
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17
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Gegunde S, Alfonso A, Cifuentes JM, Alvariño R, Pérez-Fuentes N, Vieytes MR, Botana LM. Cyclophilins modify their profile depending on the organ or tissue in a murine inflammatory model. Int Immunopharmacol 2023; 120:110351. [PMID: 37235965 DOI: 10.1016/j.intimp.2023.110351] [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: 02/15/2023] [Revised: 05/10/2023] [Accepted: 05/13/2023] [Indexed: 05/28/2023]
Abstract
Inflammation is the leading subjacent cause of many chronic diseases. Despite several studies in the last decades, the molecular mechanism involving its pathophysiology is not fully known. Recently, the implication of cyclophilins in inflammatory-based diseases has been demonstrated. However, the main role of cyclophilins in these processes remains elusive. Hence, a mouse model of systemic inflammation was used to better understand the relationship between cyclophilins and their tissue distribution. To induce inflammation, mice were fed with high-fat diet for 10 weeks. In these conditions, serum levels of interleukins 2 and 6, tumour necrosis factor-α, interferon-ϒ, and the monocyte chemoattractant protein 1 were elevated, evidencing a systemic inflammatory state. Then, in this inflammatory model, cyclophilins and CD147 profiles in the aorta, liver, and kidney were studied. The results demonstrate that, upon inflammatory conditions, cyclophilins A and C expression levels were increased in the aorta. Cyclophilins A and D were augmented in the liver, meanwhile, cyclophilins B and C were diminished. In the kidney, cyclophilins B and C levels were elevated. Furthermore, CD147 receptor was also increased in the aorta, liver, and kidney. In addition, when cyclophilin A was modulated, serum levels of inflammatory mediators were decreased, indicating a reduction in systemic inflammation. Besides, the expression levels of cyclophilin A and CD147 were also reduced in the aorta and liver, when cyclophilin A was modulated. Therefore, these results suggest that each cyclophilin has a different profile depending on the tissue, under inflammatory conditions.
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Affiliation(s)
- Sandra Gegunde
- Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain; Grupo de investigación Biodiscovery (IDIS), Lugo, Spain
| | - Amparo Alfonso
- Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain; Grupo de investigación Biodiscovery (IDIS), Lugo, Spain.
| | - J Manuel Cifuentes
- Departamento de Anatomía, Producción Animal y Ciencias Clínicas Veterinarias, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain
| | - Rebeca Alvariño
- Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain; Grupo de investigación Biodiscovery (IDIS), Lugo, Spain
| | - Nadia Pérez-Fuentes
- Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain; Grupo de investigación Biodiscovery (IDIS), Lugo, Spain
| | - Mercedes R Vieytes
- Departamento de Fisiología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain
| | - Luis M Botana
- Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain; Grupo de investigación Biodiscovery (IDIS), Lugo, Spain.
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18
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Géhin C, Fowler SJ, Trivedi DK. Chewing the fat: How lipidomics is changing our understanding of human health and disease in 2022. ANALYTICAL SCIENCE ADVANCES 2023; 4:104-131. [PMID: 38715925 PMCID: PMC10989624 DOI: 10.1002/ansa.202300009] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/18/2023] [Accepted: 04/18/2023] [Indexed: 11/17/2024]
Abstract
Lipids are biological molecules that play vital roles in all living organisms. They perform many cellular functions, such as 1) forming cellular and subcellular membranes, 2) storing and using energy, and 3) serving as chemical messengers during intra- and inter-cellular signal transduction. The large-scale study of the pathways and networks of cellular lipids in biological systems is called "lipidomics" and is one of the fastest-growing omics technologies of the last two decades. With state-of-the-art mass spectrometry instrumentation and sophisticated data handling, clinical studies show how human lipid composition changes in health and disease, thereby making it a valuable medium to collect for clinical applications, such as disease diagnostics, therapeutic decision-making, and drug development. This review gives a comprehensive overview of current workflows used in clinical research, from sample collection and preparation to data and clinical interpretations. This is followed by an appraisal of applications in 2022 and a perspective on the exciting future of clinical lipidomics.
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Affiliation(s)
- Caroline Géhin
- Manchester Institute of Biotechnology, Department of ChemistryUniversity of ManchesterManchesterUK
| | - Stephen J. Fowler
- Department of Respiratory MedicineManchester University Hospitals NHS Foundation TrustManchesterUK
- School of Biological Sciences, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- NIHR Manchester Biomedical Research CentreManchester University Hospitals NHS Foundation TrustManchesterUK
| | - Drupad K. Trivedi
- Manchester Institute of Biotechnology, Department of ChemistryUniversity of ManchesterManchesterUK
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