1
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Peng L, Lai W, Yu S, Li Q, Jiang X, Chen G. GLP-1 and glucagon receptor dual agonism ameliorates kidney allograft fibrosis by improving lipid metabolism. Front Immunol 2025; 16:1551136. [PMID: 40230860 PMCID: PMC11994718 DOI: 10.3389/fimmu.2025.1551136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/18/2025] [Indexed: 04/16/2025] Open
Abstract
Introduction Kidney allograft fibrosis accelerates the progression of chronic kidney disease (CKD), leads to allograft failure, and increases patient mortality. Emerging evidence suggests that metabolic syndrome in transplant recipients is associated with fibrosis development. However, it remains unclear whether targeting metabolic pathways can mitigate allograft fibrosis. This study aimed to explore the potential of targeting metabolic pathways using the GLP-1R/GCGR dual agonist TB001 for the treatment of kidney allograft fibrosis. Methods Kidney allograft fibrosis was induced in rat kidney transplant models. Histological analysis, transcriptome sequencing, and in vitro experiments were performed to investigate the efficacy of TB001 and its underlying mechanisms. Results Compared with the control group, TB001-treated recipients had significantly improved kidney allograft function, as evidenced by lower creatinine and 24-hour urine protein levels. Moreover, TB001 treatment decreased the body weight and serum total cholesterol, LDL-cholesterol, and TNF-α levels in transplant recipients, indicating metabolic improvements. Pathological analysis demonstrated that TB001 treatment reduced inflammatory cell infiltration and downregulated the expression of fibrosis markers, including TGF-β1, α-SMA, COL1A1, and Vimentin. Further transcriptome sequencing of kidney grafts revealed that TB001-treated group had a gene expression pattern similar to that of the syngeneic control group and showed significant enhancement of lipid metabolism-related pathways, particularly the PPAR pathway. In vivo and in vitro experiments further demonstrated that TB001 upregulated the expression of CPT1A, a key molecule involved in lipid metabolism, and inhibited TGF-β1/Smad2/3/Twist and PKC-α/PKC-β pathways. Conclusion Targeting metabolic pathways using the GLP-1R/GCGR dual agonist TB001 shows potential for managing kidney allograft fibrosis.
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Affiliation(s)
- Linjie Peng
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Kidney Transplantation Department II, Shenzhen Third People’s Hospital, Shenzhen, China
| | - Weijie Lai
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Shuangjin Yu
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Qihao Li
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Xianxin Jiang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Guodong Chen
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
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2
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Li M, Qi L, Huang J, Li H, Cheng W, Shi Z, Jiang X, Zhou Y, Jiang W. The Novel Long-Acting Peptide S6-FA Attenuates Liver Fibrosis In Vitro and In Vivo. ACS OMEGA 2025; 10:9661-9674. [PMID: 40092780 PMCID: PMC11904669 DOI: 10.1021/acsomega.4c10956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 02/09/2025] [Accepted: 02/13/2025] [Indexed: 03/19/2025]
Abstract
Liver fibrosis can progress to cirrhosis and hepatocellular carcinoma. Currently, there is no effective drug for liver fibrosis. The peptide 6 (T6) is an endogenous peptide derived from human intrauterine adhesion tissues and has antifibrotic potential. Here, to improve the long-term efficacy and activity of T6, we conducted the rational modified of T6 through studying structure-activity, and synthesized a series of analogues. Among them, S6 and S6-FA exhibited optimal antihepatic fibrosis activity, and S6-FA had a stronger long-acting effect than T6 and S6. The two analogues inhibited the expression of α-SMA and Collagen 1 in TGF-β-induced LX2 cells model and CCl4-induced mouse model of liver fibrosis. Besides, we discovered that S6 and S6-FA remarkably reduced the AST and ALT serum levels. Mechanistic studies have demonstrated that analogues inhibited liver fibrosis through inhibiting Erk, Smad and P65 pathways. This study provided that the novel peptide S6 and S6-FA is potential candidate compounds for treating liver fibrosis.
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Affiliation(s)
- Mingmin Li
- College
of Life Science, China Jiliang University, Hangzhou, Zhejiang 310018, China
| | - Liang Qi
- State
Key Laboratory of Anti-Infective Drug Discovery and Development, School
of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou, Guangdong 510006, China
| | - Jin Huang
- Guangzhou
Dorsay Biotechnology Co., Ltd, Guangzhou, Guangdong 510006, China
| | - Haonan Li
- State
Key Laboratory of Anti-Infective Drug Discovery and Development, School
of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou, Guangdong 510006, China
| | - Wei Cheng
- State
Key Laboratory of Anti-Infective Drug Discovery and Development, School
of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou, Guangdong 510006, China
| | - Zihan Shi
- State
Key Laboratory of Anti-Infective Drug Discovery and Development, School
of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou, Guangdong 510006, China
| | - Xianxing Jiang
- State
Key Laboratory of Anti-Infective Drug Discovery and Development, School
of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou, Guangdong 510006, China
| | - Yifeng Zhou
- College
of Life Science, China Jiliang University, Hangzhou, Zhejiang 310018, China
| | - Wanxiang Jiang
- Sichuan
Greentech Bioscience Co., Ltd, Meishan, Sichuan 620031, China
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3
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Yeo YH, Abdelmalek M, Khan S, Moylan CA, Rodriquez L, Villanueva A, Yang JD. Current and emerging strategies for the prevention of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2025; 22:173-190. [PMID: 39653784 DOI: 10.1038/s41575-024-01021-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/07/2024] [Indexed: 01/05/2025]
Abstract
Liver cancer is the third leading cause of cancer-related deaths globally, with incident cases expected to rise from 905,700 in 2020 to 1.4 million by 2040. Hepatocellular carcinoma (HCC) accounts for about 80% of all primary liver cancers. Viral hepatitis and chronic excessive alcohol consumption are major risk factors for HCC, but metabolic dysfunction-associated steatotic liver disease is also becoming a dominant cause. The increasing numbers of cases of HCC and changes in risk factors highlight the urgent need for updated and targeted prevention strategies. Preventive interventions encompass strategies to decrease the burden of chronic liver diseases and their progression to HCC. These strategies include nutritional interventions and medications that have shown promise in preclinical models. Although prevailing approaches focus on treating chronic liver disease, leveraging a wider range of interventions represents a promising area to safeguard at-risk populations. In this Review, we explore existing evidence for preventive strategies by highlighting established and potential paths to reducing HCC risk effectively and safely, especially in individuals with chronic liver diseases. We categorize the preventive strategies by the mechanism of action, including anti-inflammatory, antihyperglycaemic, lipid-lowering, nutrition and dietary, antiviral, and antifibrotic pathways. For each category, we discuss the efficacy and safety information derived from mechanistic, translational, observational and clinical trial data, pinpointing knowledge gaps and directions for future research.
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Affiliation(s)
- Yee Hui Yeo
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Manal Abdelmalek
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Seema Khan
- Robert H. Lurie Comprehensive Cancer Center, Northwestern Memorial Hospital, Chicago, IL, USA
| | - Cynthia A Moylan
- Division of Gastroenterology, Duke University Health System, Durham, NC, USA
| | - Luz Rodriquez
- Gastrointestinal & Other Cancers Research Group, NCI, Rockville, MD, USA
| | - Augusto Villanueva
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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4
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Bu T, Sun Z, Pan Y, Deng X, Yuan G. Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism. Diabetes Metab J 2024; 48:354-372. [PMID: 38650100 PMCID: PMC11140404 DOI: 10.4093/dmj.2023.0277] [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: 08/14/2023] [Accepted: 01/01/2024] [Indexed: 04/25/2024] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a 30-amino acid peptide hormone that is mainly expressed in the intestine and hypothalamus. In recent years, basic and clinical studies have shown that GLP-1 is closely related to lipid metabolism, and it can participate in lipid metabolism by inhibiting fat synthesis, promoting fat differentiation, enhancing cholesterol metabolism, and promoting adipose browning. GLP-1 plays a key role in the occurrence and development of metabolic diseases such as obesity, nonalcoholic fatty liver disease, and atherosclerosis by regulating lipid metabolism. It is expected to become a new target for the treatment of metabolic disorders. The effects of GLP-1 and dual agonists on lipid metabolism also provide a more complete treatment plan for metabolic diseases. This article reviews the recent research progress of GLP-1 in lipid metabolism.
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Affiliation(s)
- Tong Bu
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ziyan Sun
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yi Pan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xia Deng
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Guoyue Yuan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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5
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Wang Y, Xue F, Cheng W, Zhao Q, Song N, Shi Z, Liu H, Li Y, Tang Q, Liu Q, Wang Y, Zhang F, Jiang X. Design and Synthesis of Novel Ultralong-Acting Peptides as EDP-EBP Interaction Inhibitors for Pulmonary Fibrosis Treatment. J Med Chem 2024; 67:6624-6637. [PMID: 38588467 DOI: 10.1021/acs.jmedchem.4c00067] [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: 04/10/2024]
Abstract
The increased remodeling of the extracellular matrix (ECM) in pulmonary fibrosis (PF) generates bioactive ECM fragments called matricryptins, which include elastin-derived peptides (EDPs). The interaction between EDPs and their receptors, including elastin-binding protein (EBP), plays a crucial role in exacerbating fibrosis. Here, we present LXJ-02 for the first time, a novel ultralong-acting inhibitor that disrupts the EDPs/EBP peptide-protein interaction, promoting macrophages to secrete matrix metalloproteinase-12 (MMP-12), and showing great promise as a stable peptide. MMP-12 has traditionally been implicated in promoting inflammation and fibrosis in various acute and chronic diseases. However, we reveal a novel role of LXJ-02 that activates the macrophage-MMP-12 axis to increase MMP-12 expression and degrade ECM components like elastin. This leads to the preventing of PF while also improving EDP-EBP interaction. LXJ-02 effectively reverses PF in mouse models with minimal side effects, holding great promise as an excellent therapeutic agent for lung fibrosis.
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Affiliation(s)
- Yixiang Wang
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
- The First School of Clinical Medicine & The First Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Fanghan Xue
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
| | - Wei Cheng
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
| | - Qian Zhao
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
| | - Nazi Song
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
| | - Zihan Shi
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
| | - Han Liu
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
| | - Yu Li
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
| | - Qinglin Tang
- Shenzhen Turier Biotech. Co. Ltd, Shenzhen 518000, China
| | - Qi Liu
- Shenzhen Turier Biotech. Co. Ltd, Shenzhen 518000, China
| | - Yiqing Wang
- The First School of Clinical Medicine & The First Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
- Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application & Key Laboratory for Reproductive Medicine and Embryo of Gansu Province, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Fangfang Zhang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Xianxing Jiang
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
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6
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Gong B, Yao Z, Zhou C, Wang W, Sun L, Han J. Glucagon-like peptide-1 analogs: Miracle drugs are blooming? Eur J Med Chem 2024; 269:116342. [PMID: 38531211 DOI: 10.1016/j.ejmech.2024.116342] [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: 12/30/2023] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 03/28/2024]
Abstract
Glucagon-like peptide-1 (GLP-1), secreted by L cells in the small intestine, assumes a central role in managing type 2 diabetes mellitus (T2DM) and obesity. Its influence on insulin secretion and gastric emptying positions it as a therapeutic linchpin. However, the limited applicability of native GLP-1 stems from its short half-life, primarily due to glomerular filtration and the inactivating effect of dipeptidyl peptidase-IV (DPP-IV). To address this, various structural modification strategies have been developed to extend GLP-1's half-life. Despite the commendable efficacy displayed by current GLP-1 receptor agonists, inherent limitations persist. A paradigm shift emerges with the advent of unimolecular multi-agonists, such as the recently introduced tirzepatide, wherein GLP-1 is ingeniously combined with other gastrointestinal hormones. This novel approach has captured the spotlight within the diabetes and obesity research community. This review summarizes the physiological functions of GLP-1, systematically explores diverse structural modifications, delves into the realm of unimolecular multi-agonists, and provides a nuanced portrayal of the developmental prospects that lie ahead for GLP-1 analogs.
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Affiliation(s)
- Binbin Gong
- College of Medicine, Jiaxing University, Jiaxing, 314001, China; College of Pharmacy, Zhejiang University of Technology, Hangzhou, 310000, China
| | - Zhihong Yao
- College of Medicine, Jiaxing University, Jiaxing, 314001, China; College of Pharmacy, Zhejiang University of Technology, Hangzhou, 310000, China
| | - Chenxu Zhou
- College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Wenxi Wang
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, 310000, China
| | - Lidan Sun
- College of Medicine, Jiaxing University, Jiaxing, 314001, China.
| | - Jing Han
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou, 221116, China.
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7
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Chrysavgis LG, Kazanas S, Bafa K, Rozani S, Koloutsou ME, Cholongitas E. Glucagon-like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide, and Glucagon Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Medication in New Liver Disease Nomenclature. Int J Mol Sci 2024; 25:3832. [PMID: 38612640 PMCID: PMC11012092 DOI: 10.3390/ijms25073832] [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: 02/11/2024] [Revised: 03/15/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open
Abstract
Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that regulate postprandial glucose regulation, stimulating insulin secretion from pancreatic β-cells in response to food ingestion. Modified GLP-1 receptor agonists (GLP-1RAs) are being administered for the treatment of obesity and type 2 diabetes mellitus (T2DM). Strongly related to those disorders, metabolic dysfunction-associated steatotic liver disease (MASLD), especially its aggressive form, defined as metabolic dysfunction-associated steatohepatitis (MASH), is a major healthcare burden associated with high morbidity and extrahepatic complications. GLP-1RAs have been explored in MASH patients with evident improvement in liver dysfunction enzymes, glycemic control, and weight loss. Importantly, the combination of GLP-1RAs with GIP and/or glucagon RAs may be even more effective via synergistic mechanisms in amelioration of metabolic, biochemical, and histological parameters of MASLD but also has a beneficial impact on MASLD-related complications. In this current review, we aim to provide an overview of incretins' physiology, action, and signaling. Furthermore, we provide insight into the key pathophysiological mechanisms through which they impact MASLD aspects, as well as we analyze clinical data from human interventional studies. Finally, we discuss the current challenges and future perspectives pertinent to this growing area of research and clinical medicine.
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Affiliation(s)
- Lampros G. Chrysavgis
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Spyridon Kazanas
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Konstantina Bafa
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Sophia Rozani
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Maria-Evangelia Koloutsou
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece;
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
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8
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Zhao Q, Dong J, Liu H, Chen H, Yu H, Ye S, Yu S, Li Y, Qiu L, Song N, Xu H, Liu Q, Luo Z, Li Y, Wang R, Chen G, Jiang X. Design and discovery of a highly potent ultralong-acting GLP-1 and glucagon co-agonist for attenuating renal fibrosis. Acta Pharm Sin B 2024; 14:1283-1301. [PMID: 38486997 PMCID: PMC10935026 DOI: 10.1016/j.apsb.2023.11.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/09/2023] [Accepted: 11/09/2023] [Indexed: 03/17/2024] Open
Abstract
The role of co-agonists of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) in chronic kidney disease (CKD) remains unclear. Herein we found that GLP-1R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease severity. Interestingly, GLP-1R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruction (UUO). Based on the importance of GLP-1R and GCGR in CKD, we reported a novel monomeric peptide, 1907-B, with dual-agonism on both GLP-1R and GCGR. The data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys (∼2-3 fold) and exhibited better therapeutic contribution to CKD than best-in-class monoagonists, semaglutide, or glucagon, in db/db mice and UUO mice. Various lock-of-function models, including selective pharmacological activation and genetic knockdown, confirmed that 1907-B's effects on ameliorating diabetic nephropathy in db/db mice, as well as inhibiting kidney fibrosis in UUO mice, were mediated through GLP-1 and glucagon signaling. These findings highlight that 1907-B, a novel GLP-1R and GCGR co-agonist, exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment.
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Affiliation(s)
- Qian Zhao
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Jiale Dong
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Han Liu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Hui Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Huan Yu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Shuyin Ye
- Shenzhen Turier Biotech. Co., Ltd., Shenzhen 518118, China
| | - Shuangjin Yu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, China
| | - Yu Li
- Shenzhen Turier Biotech. Co., Ltd., Shenzhen 518118, China
| | - Longhui Qiu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, China
| | - Nazi Song
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Hongjiao Xu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Qi Liu
- Shenzhen Turier Biotech. Co., Ltd., Shenzhen 518118, China
| | - Zhiteng Luo
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Yuyi Li
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510006, China
| | - Rui Wang
- School of Life Sciences, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, Lanzhou University, Lanzhou 730000, China
| | - Guodong Chen
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, China
| | - Xianxing Jiang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
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9
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Jiang N, Su D, Chen D, Huang S, Tang C, Jing L, Yang C, Zhou Z, Yan Z, Han J. Discovery of a Novel Glucagon-like Peptide-1 (GLP-1) Analogue from Bullfrog and Investigation of Its Potential for Designing GLP-1-Based Multiagonists. J Med Chem 2024; 67:180-198. [PMID: 38117235 DOI: 10.1021/acs.jmedchem.3c01049] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
In this study, we aimed to discover novel GLP-1 analogues from natural sources. We investigated GLP-1 analogues from fish and amphibians, and bullfrog GLP-1 (bGLP-1) showed the highest potency. Starting with bGLP-1, we explored the structure-activity relationship and performed optimization and long-acting modifications, resulting in a potent analogue called 2f. Notably, 2f exhibited superior effects on food intake, glycemic control, and body weight compared to semaglutide. Furthermore, we explored the usefulness of bGLP-1 in designing GLP-1-based multiagonists. Using the bGLP-1 sequence, we designed novel dual GLP-1/glucagon receptor agonists and triple GLP-1/GIP/glucagon receptor agonists. The selected dual GLP-1/glucagon receptor agonist 3o and triple GLP-1/GIP/glucagon receptor agonist 4b exhibited significant therapeutic effects on lipid regulation, glycemic control, and body weight. Overall, our study highlights the potential of discovering potent GLP-1 receptor agonists from natural sources. Additionally, utilizing natural GLP-1 analogues for designing multiagonists presents a practical approach for developing antiobesity and antidiabetic agents.
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Affiliation(s)
- Neng Jiang
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China
| | - Di Su
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China
| | - De Chen
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Shutong Huang
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China
- Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi 530021, PR China
| | - Chunli Tang
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China
| | - Lin Jing
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China
| | - Caiyan Yang
- School of Pharmacy, Youjiang Medical University for Nationalities, 98 Chengxiang Road, Baise, Guangxi 533000, PR China
| | - Zhongbo Zhou
- School of Pharmacy, Youjiang Medical University for Nationalities, 98 Chengxiang Road, Baise, Guangxi 533000, PR China
| | - Zhiming Yan
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China
- Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi 530021, PR China
| | - Jing Han
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
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10
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Kim J, Chang N, Kim Y, Lee J, Oh D, Choi J, Kim O, Kim S, Choi M, Lee J, Lee J, Kim J, Cho M, Kim M, Lee K, Hwang D, Sa JK, Park S, Baek S, Im D. The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model. Pharmaceuticals (Basel) 2023; 16:1601. [PMID: 38004466 PMCID: PMC10674394 DOI: 10.3390/ph16111601] [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: 09/11/2023] [Revised: 11/08/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a complex disease resulting from chronic liver injury associated with obesity, type 2 diabetes, and inflammation. Recently, the importance of developing multi-target drugs as a strategy to address complex diseases such as NASH has been growing; however, their manufacturing processes remain time- and cost-intensive and inefficient. To overcome these limitations, we developed UniStac, a novel enzyme-mediated conjugation platform for multi-specific drug development. UniStac demonstrated high conjugation yields, optimal thermal stabilities, and robust biological activities. We designed a tetra-specific compound, C-192, targeting glucagon-like peptide 1 (GLP-1), glucagon (GCG), fibroblast growth factor 21 (FGF21), and interleukin-1 receptor antagonist (IL-1RA) simultaneously for the treatment of NASH using UniStac. The biological activity and treatment efficacy of C-192 were confirmed both in vitro and in vivo using a methionine-choline-deficient (MCD) diet-induced mouse model. C-192 exhibited profound therapeutic efficacies compared to conventional drugs, including liraglutide and dulaglutide. C-192 significantly improved alanine transaminase levels, triglyceride accumulation, and the non-alcoholic fatty liver disease activity score. In this study, we demonstrated the feasibility of UniStac in creating multi-specific drugs and confirmed the therapeutic potential of C-192, a drug that integrates multiple mechanisms into a single molecule for the treatment of NASH.
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Affiliation(s)
- Jihye Kim
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Nakho Chang
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Yunki Kim
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Jaehyun Lee
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Daeseok Oh
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Jaeyoung Choi
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Onyou Kim
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Sujin Kim
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Myongho Choi
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Junyeob Lee
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Junghwa Lee
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Jungyul Kim
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Minji Cho
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Minsu Kim
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Kwanghwan Lee
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Dukhyun Hwang
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Jason K. Sa
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Sungjin Park
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
| | - Seungjae Baek
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Daeseong Im
- Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea; (J.K.); (J.C.); (J.K.); (K.L.)
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11
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Liao X, Ruan X, Yao P, Yang D, Wu X, Zhou X, Jing J, Wei D, Liang Y, Zhang T, Qin S, Jiang H. LncRNA-Gm9866 promotes liver fibrosis by activating TGFβ/Smad signaling via targeting Fam98b. J Transl Med 2023; 21:778. [PMID: 37919785 PMCID: PMC10621198 DOI: 10.1186/s12967-023-04642-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 10/20/2023] [Indexed: 11/04/2023] Open
Abstract
OBJECTIVE The exact mechanism and target molecules of liver fibrosis have remained largely elusive. Here, we investigated the role of long noncoding RNA Gm9866(lncRNA-Gm9866) on liver fibrosis. METHODS The transcription of lncRNA-Gm9866 in activated cells and mouse fibrotic livers was determined by quantitative polymerase chain reaction (qRT-PCR). The effects of lentivirus-mediated knockdown or overexpression of lncRNA-Gm9866 in liver fibrosis were examined in vitro and in vivo. Furthermore, bioinformatics analysis, cell samples validation, fluorescence in situ hybridization (FISH) co-localization, RNA binding protein immunoprecipitation (RIP), actinomycin D test and Western blot (WB) were carried out to explore the potential mechanism of lncRNA-Gm9866. RESULTS The expression of α-smooth muscle actin (α-SMA), Collagen I (COL-1) and lncRNA-Gm9866 were significantly increased in tissues and cells. Overexpressing lncRNA-Gm9866 promoted the activation of hepatic stellate cells (HSCs). Silencing lncRNA-Gm9866 inhibited the activation of HSCs and transforming growth factor-β1 (TGFβ1) induced fibrosis. Overexpressing lncRNA-Gm9866 promoted hepatocytes (HCs) apoptosis and the expression of pro-fibrogenic genes, inhibited the proliferation and migration of HCs. Knockdown of lncRNA-Gm9866 inhibited the apoptosis of HCs, the expression of pro-fibrogenic genes, TGFβ1 induced fibrosis and the occurrence of carbon tetrachloride (CCl4)-induced liver fibrosis, and promoted the proliferation and migration of HCs. Mechanistically, lncRNA-Gm9866 may directly bine with Fam98b. Silencing Fam98b in stably overexpressing lncRNA-Gm9866 cell lines reversed the increase of pro-fibrogenic genes and pro-apoptotic genes, fibrosis related pathway protein TGFβ1, Smad2/3, p-Smad2/3 and Notch3 induced by overexpressing lncRNA-Gm9866. CONCLUSIONS LncRNA-Gm9866 may regulate TGFβ/Smad and Notch pathways by targeting Fam98b to regulate liver fibrosis. LncRNA-Gm9866 may be a new target for diagnosis and treatment of liver fibrosis.
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Affiliation(s)
- Xiaomin Liao
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Xianxian Ruan
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Peishan Yao
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Dan Yang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Xianbin Wu
- Department of Gastroenterology, The Wuming Affiliated Hospital of Guangxi Medical University, Nanning, 530000, Guangxi, China
| | - Xia Zhou
- Department of Emergency, People's Hospital of Guizhou Province, Guiyang, 550000, Guizhou, China
| | - Jie Jing
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Dafu Wei
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Yaodan Liang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Taicheng Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Shanyu Qin
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021, Guangxi, China.
| | - Haixing Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021, Guangxi, China.
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12
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Song N, Li H, Tang Q, Luo S, Shi Z, Zhao Q, Li R, Chen Y, Cai X, Jiang X. Design and Discovery of Novel Cyclic Peptides as EDPs-EBP Interaction Inhibitors for the Treatment of Liver Fibrosis. J Med Chem 2023; 66:4689-4702. [PMID: 36938613 DOI: 10.1021/acs.jmedchem.2c01764] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2023]
Abstract
Liver fibrosis is the undesirable result of excessive deposition of the extracellular matrix (ECM), and elastin is known as one of the key ECM components. Under specific pathological conditions, elastin undergoes degradation to produce elastin-derived peptides (EDPs), which bind to elastin-binding protein (EBP) to activate corresponding signal pathways, thus accelerating fibrosis progression. Herein, we describe the discovery of novel cyclic peptides that function as potent and stable inhibitors to interfere with the peptide-protein interaction between EDPs and EBP. Remarkably, CXJ-2 exhibited potent activities to inhibit the PI3K/ERK pathway and decrease hepatic stellate cell proliferation and migration. The subsequent in vivo study demonstrated that CXJ-2 possessed potent antifibrotic efficacy in ameliorating CCl4-induced liver fibrosis. This work provides a successful pharmacological strategy for the development of novel inhibitors of EDPs-EBP interaction, which sheds new light on how cyclic peptides disrupt peptide-protein interaction and may also provide new structure-oriented therapeutic candidates in liver fibrosis.
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Affiliation(s)
- Nazi Song
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
| | - Haonan Li
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
| | - Qinglin Tang
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.,Shenzhen Turier Biotech. Co. Ltd, Shenzhen 518000, China
| | - Suijia Luo
- Shenzhen Turier Biotech. Co. Ltd, Shenzhen 518000, China
| | - Zihan Shi
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
| | - Qian Zhao
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
| | - Runkai Li
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, and NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou 511400, China
| | - Yili Chen
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, and NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou 511400, China
| | - Xiaoqing Cai
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
| | - Xianxing Jiang
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
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13
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Zhao Q, Liang L, Zhai F, Ling G, Xiang R, Jiang X. A bibliometric and visualized analysis of liver fibrosis from 2002 to 2022. J Gastroenterol Hepatol 2023; 38:359-369. [PMID: 36459993 DOI: 10.1111/jgh.16081] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 11/25/2022] [Accepted: 11/29/2022] [Indexed: 12/04/2022]
Abstract
Fibrosis of the liver is a degenerative alteration that occurs in the majority of chronic liver disorders. Further progression can lead to cirrhosis, liver failure, and hepatocellular carcinoma, which can seriously affect the health and lives of patients. The field of liver fibrosis research has flourished in the last 20 years, with approximately 9000 articles retrieved from the Web of Science Core Collection database alone. In order to identify future research hotspots and potential paths in a thorough and scientifically reliable manner, it is important to organize and visualize the research on this topic from a holistic and very general perspective. This study used bibliometric analysis with CiteSpace and VOSviewer software to provide a quantitative analysis, hotspot mining, and commentary of articles published in the field of liver fibrosis over the last 20 years. This bibliometric analysis contains a total of 8994 articles with 45667 authors from 6872 institutions in 97 countries, published in 1371 journals and citing 156 309 references. The literature volume has steadily increased over the last 20 years. Research has focused on gastroenterology and hepatology, pharmacology and pharmacy, and medicine, research, and experimental areas. We found that the pathological mechanisms, diagnostic and quantitative methods, etiology, and antifibrotic strategies constitute the knowledge structure of liver fibrosis. Finding mechanisms for liver fibrosis regression, identifying precise noninvasive diagnostic and prognostic biomarkers, and creating efficient liver fibrosis patient treatments are the main goals of current research.
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Affiliation(s)
- Qianqian Zhao
- Faculty of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Luhua Liang
- School of Medical Equipment, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Fei Zhai
- School of Medical Equipment, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Guixia Ling
- School of Medical Equipment, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Rongwu Xiang
- School of Medical Equipment, Shenyang Pharmaceutical University, Shenyang, 110016, China.,Liaoning Professional Technology Innovation Center on Medical Big Data and Artificial Intelligence, Shenyang, 110016, China
| | - Xiwei Jiang
- School of Medical Equipment, Shenyang Pharmaceutical University, Shenyang, 110016, China
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14
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Zhang X, Cai Y, Yao Z, Chi H, Li Y, Shi J, Zhou Z, Sun L. Discovery of novel OXM-based glucagon-like peptide 1 (GLP-1)/glucagon receptor dual agonists. Peptides 2023; 161:170948. [PMID: 36646385 DOI: 10.1016/j.peptides.2023.170948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023]
Abstract
Novel glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have improved efficacy over GLP-1R mono-agonists in treating type 2 diabetes (T2DM) and obesity. Here, we describe the discovery of a novel oxyntomodulin (OXM) based GLP-1R/GCGR dual agonist with potent and balanced potency toward GLP-1R and GCGR. The lead peptide OXM-7 was obtained via stepwise rational design and long-acting modification. In ICR and db/db mice, OXM-7 exhibited prominent acute and long-acting hypoglycemic effects. In diet-induced obesity (DIO) mice, twice-daily administration of OXM-7 produced significant weight loss, normalized lipid metabolism, and improved glucose control. In DIO-nonalcoholic steatohepatitis (NASH) mice, OXM-7 treatment significantly reversed hepatic steatosis, and reduced serum and hepatic lipid levels. These preclinical data suggest the therapeutic potential of OXM-7 as a novel anti-diabetic, anti-steatotic and/or anti-obesity agent.
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Affiliation(s)
- Xiaolong Zhang
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Yuchen Cai
- School of Engineering, China Pharmaceutical University, Nanjing 210009, Jiangsu, PR China
| | - Zhihong Yao
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, PR China
| | - Heng Chi
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Yan Li
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Jingjing Shi
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Zhongbo Zhou
- School of Pharmacy, Youjiang Medical University for Nationalities, 98 Chengxiang Road, Baise 533000, Guangxi, PR China.
| | - Lidan Sun
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, PR China.
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15
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Yuan Y, Yan Z, Lao Q, Jiang N, Wu S, Lu Q, Han J, Zhao S. Discovery of a potent and long-acting Xenopus GLP-1-based GLP-1/glucagon/Y 2 receptor triple agonist. Eur J Med Chem 2023; 247:115036. [PMID: 36571995 DOI: 10.1016/j.ejmech.2022.115036] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/21/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
The combination of incretin-based therapies and PYY analogue has shown great potential for the treatment of type 2 diabetes (T2DM) and obesity. In this study we developed the first example of a unimolecular triple agonist peptide to simultaneously target GLP-1, glucagon and Y2 receptors, aiming for superior weight loss and better glycemic control. The strategy for constructing such a unimolecular triple agonist peptide is the conjugation of the GLP-1R/GCGR dual-agonistic moiety and PYY moiety via maleimide-thiol specific reaction. A novel triple agonist peptide, 3b, was identified via stepwise structure optimization, long-acting modification and in vitro receptor screens. Peptide 3b exhibited potent and balanced GCGR and GLP-1R activities as well as potent and highly selective Y2R activity. Peptide 3b potently reduced food intake without triggering nausea associated behavior in kaolin consumption and conditioned taste aversion assays. In diet induced obesity (DIO) mice, a lower dose of 3b achieved significantly better effects on lipid metabolism, body weight, and glycemic control than higher dose of GLP-1R mono-agonist, GLP-1R/GCGR dual agonist and GLP-1R/Y2R dual agonist counterparts. Collectively, these data support the therapeutic potential of our GLP-1R/GCGR/Y2R triple agonist 3b as a novel anti-obesity and anti-diabetic agent. Targeting GLP-1R, GCGR and Y2R with unimolecular triple agonist peptide offers a route to develop new obesity and T2DM treatments.
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Affiliation(s)
- Yongliang Yuan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China
| | - Zhiming Yan
- Pharmaceutical College, Guangxi Medical University, Nanning, 530021, PR China
| | - Qifang Lao
- Department of Critical Care Medicine, Guangxi Medical University Cancer Hospital, Nanning, 530021, PR China
| | - Neng Jiang
- Pharmaceutical College, Guangxi Medical University, Nanning, 530021, PR China
| | - Shuangmin Wu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China
| | - Qinpei Lu
- Pharmaceutical College, Guangxi Medical University, Nanning, 530021, PR China
| | - Jing Han
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou, 221116, PR China.
| | - Songfeng Zhao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China.
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16
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Targher G, Mantovani A, Byrne CD. Mechanisms and possible hepatoprotective effects of glucagon-like peptide-1 receptor agonists and other incretin receptor agonists in non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol 2023; 8:179-191. [PMID: 36620987 DOI: 10.1016/s2468-1253(22)00338-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/22/2022] [Accepted: 09/29/2022] [Indexed: 01/07/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that stimulate insulin secretion from pancreatic β cells in response to food ingestion. Modified GLP-1 and GIP peptides are potent agonists for their incretin receptors, and some evidence shows that the dual GLP-1 and GIP receptor agonist tirzepatide is effective in promoting marked weight loss. GLP-1 receptor agonists signal in the CNS to suppress appetite, increase satiety, and thereby decrease calorie intake, but many other effects of incretin signalling have been recognised that are relevant to the treatment of non-alcoholic fatty liver disease (NAFLD). This Review provides an overview of the literature supporting the notion that endogenous incretins and incretin-receptor agonist treatments are important not only for decreasing risk of developing NAFLD, but also for treating NAFLD and NAFLD-related complications. We discuss incretin signalling and related incretin-receptor agonist treatments, mechanisms in key relevant tissues affecting liver disease, and clinical data from randomised controlled trials. Finally, we present future perspectives in this rapidly developing field of research and clinical medicine.
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Affiliation(s)
- Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, UK; Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
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17
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Arvanitakis K, Koufakis T, Kotsa K, Germanidis G. How Far beyond Diabetes Can the Benefits of Glucagon-like Peptide-1 Receptor Agonists Go? A Review of the Evidence on Their Effects on Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14194651. [PMID: 36230573 PMCID: PMC9562923 DOI: 10.3390/cancers14194651] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 09/20/2022] [Accepted: 09/22/2022] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by poor survival rate and quality of life, while available treatments remain generally limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally emerged as drugs for the management of diabetes, but have also been shown to alleviate cardiorenal risk. Furthermore, they have demonstrated a wide range of extraglycemic effects that led to their evaluation as potential therapies for a variety of diseases beyond diabetes, such as obesity, neurogenerative disorders and nonalcoholic fatty liver disease. Given the presence of the GLP-1 receptor in hepatocytes, animal data suggest that GLP-1 RAs could regulate molecular pathways that are deeply involved in the genesis and progression of HCC, including inflammatory responses, tumor cell proliferation and oxidative stress, through direct and indirect effects on liver cells. However, future studies must assess several aspects of the benefit-to-risk ratio of the use of GLP-1 RAs in patients with HCC, including co-administration with approved systemic therapies, the incidence of gastrointestinal side effects in a high-risk population, and weight loss management in individuals with poor nutritional status and high rates of cancer cachexia. In this narrative review, we discuss the potential role of GLP-1 analogs in the treatment of HCC, focusing on the molecular mechanisms that could justify a possible benefit, but also referring to the potential clinical implications and areas for future research.
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Affiliation(s)
- Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
- Basic and Translational Research Unit (BTRU) of Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, AHEPA University Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, AHEPA University Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
- Basic and Translational Research Unit (BTRU) of Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
- Correspondence: ; Tel.: +30-231-330-3156; Fax: +30-231-099-4638
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