|
1
|
Mohamed NM, Mohamed RH, Kennedy JF, Elhefnawi MM, Hamdy NM. A comprehensive review and in silico analysis of the role of survivin (BIRC5) in hepatocellular carcinoma hallmarks: A step toward precision. Int J Biol Macromol 2025; 311:143616. [PMID: 40306500 DOI: 10.1016/j.ijbiomac.2025.143616] [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: 02/13/2025] [Revised: 04/25/2025] [Accepted: 04/27/2025] [Indexed: 05/02/2025]
Abstract
Hepatocellular carcinoma (HCC) is a complex malignancy driven by the dysregulation of multiple cellular pathways. Survivin, a key member of the inhibitor of apoptosis (IAP) family, plays a central role in HCC tumorigenesis and progression. Despite significant research, a comprehensive understanding of the contributions of survivin to the hallmarks of cancer, its molecular network, and its potential as a therapeutic target remains incomplete. In this review, we integrated bioinformatics analysis with an extensive literature review to provide deeper insights into the role of survivin in HCC. Using bioinformatics tools such as the Human Protein Atlas, GEPIA, STRING, TIMER, and Metascape, we analyzed survivin expression and its functional associations and identified the top 20 coexpressed genes in HCC. These include TK1, SPC25, SGO2, PTTG1, PRR11, PLK1, NCAPH, KPNA2, KIF2C, KIF11, HJURP, GTSE1, FOXM1, CEP55, CENPA, CDCA3, CDC45, CCNB2, CCNB1 and CTD-2510F5.4. Our findings also revealed significant protein-protein interactions among these genes, which were enriched in pathways associated with the FOXM1 oncogenic signaling cascade, and biological processes such as cell cycle regulation, mitotic checkpoints, and diseases such as liver neoplasms. We also discussed the involvement of survivin in key oncogenic pathways, including the PI3K/AKT, WNT/β-catenin, Hippo, and JAK/STAT3 pathways, and its role in modulating cell cycle checkpoints, apoptosis, and autophagy. Furthermore, we explored its interactions with the tumor microenvironment, particularly its impact on immune modulation through myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and natural killer cell function in HCC. Additionally, we highlighted its involvement in alkylglycerone phosphate synthase (AGPS)-mediated lipid reprogramming and identified important gaps in the survivin network that warrant further investigation. This review also examined the role of survivin in cancer stemness, inflammation, and virally mediated hepatocarcinogenesis. We evaluated its potential as a diagnostic, prognostic, predictive, and pharmacodynamic biomarker in HCC, emphasizing its relevance in precision medicine. Finally, we summarized emerging survivin-targeted therapeutics and ongoing clinical trials, underscoring the need for novel strategies to effectively target survivin in HCC.
Collapse
Affiliation(s)
- Nermin M Mohamed
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - Rania Hassan Mohamed
- Department of Biochemistry, Faculty of Science, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - John F Kennedy
- Chembiotech Laboratories, Kyrewood House, Tenbury Wells, Worcestershire, United Kingdom
| | - Mahmoud M Elhefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt.
| | - Nadia M Hamdy
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt.
| |
Collapse
|
|
2
|
AL-Noshokaty TM, Abdelhamid R, Abdelmaksoud NM, Khaled A, Hossam M, Ahmed R, Saber T, Khaled S, Elshaer SS, Abulsoud AI. Unlocking the multifaceted roles of GLP-1: Physiological functions and therapeutic potential. Toxicol Rep 2025; 14:101895. [PMID: 39911322 PMCID: PMC11795145 DOI: 10.1016/j.toxrep.2025.101895] [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: 11/02/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 02/07/2025] Open
Abstract
Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.
Collapse
Affiliation(s)
- Tohada M. AL-Noshokaty
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Rehab Abdelhamid
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | | | - Aya Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mariam Hossam
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Razan Ahmed
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Toka Saber
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shahd Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed I. Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11231, Egypt
- Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| |
Collapse
|
|
3
|
Lin A, Ding Y, Li Z, Jiang A, Liu Z, Wong HZH, Cheng Q, Zhang J, Luo P. Glucagon-like peptide 1 receptor agonists and cancer risk: advancing precision medicine through mechanistic understanding and clinical evidence. Biomark Res 2025; 13:50. [PMID: 40140925 PMCID: PMC11948983 DOI: 10.1186/s40364-025-00765-3] [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: 11/29/2024] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a primary first-line treatment for type 2 diabetes. This has raised concerns about their impact on cancer risk, spurring extensive research. This review systematically examines the varied effects of GLP-1RAs on the risk of different types of tumors, including overall cancer risk and specific cancers such as thyroid, pancreatic, reproductive system, liver, and colorectal cancers. The potential biological mechanisms underlying their influence on cancer risk are complex, involving metabolic regulation, direct antitumor effects, immune modulation, and epigenetic changes. A systematic comparison with other antidiabetic agents reveals notable differences in their influence on cancer risk across drug classes. Additionally, critical factors that shape the relationship between GLP-1RAs and cancer risk are thoroughly analyzed, including patient demographics, comorbidities, treatment regimens, and lifestyle factors, offering essential insights for developing individualized treatment protocols. Despite significant research progress, critical gaps remain. Future research should prioritize elucidating the molecular mechanisms behind the antitumor effects, refining individualized treatment strategies, investigating early tumor prevention applications, assessing potential benefits for non-diabetic populations, advancing the development of novel therapies, establishing robust safety monitoring frameworks, and building precision medicine decision-making platforms. These efforts aim to establish novel roles for GLP-1RAs in cancer prevention. and treatment, thereby advancing the progress of precision medicine.
Collapse
Affiliation(s)
- Anqi Lin
- Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, Jiangsu Province, 222000, China
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Yanxi Ding
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Zhengrui Li
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China
| | - Aimin Jiang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Hank Z H Wong
- Li Ka Shing, Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China.
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.
| | - Peng Luo
- Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, Jiangsu Province, 222000, China.
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.
| |
Collapse
|
|
4
|
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.
Collapse
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.
| |
Collapse
|
|
5
|
Lu C, Xu C, Yang J. The Beneficial Effects of GLP-1 Receptor Agonists Other than Their Anti-Diabetic and Anti-Obesity Properties. MEDICINA (KAUNAS, LITHUANIA) 2024; 61:17. [PMID: 39858999 PMCID: PMC11767243 DOI: 10.3390/medicina61010017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/18/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025]
Abstract
As an incretin hormone, Glucagon-like peptide-1 (GLP-1) has obvious effects on blood glucose regulation and weight loss. GLP-1 receptor (GLP-1R) agonists are synthetic products that have similar effects to GLP-1 but are less prone to degradation, and they are widely used in the treatment of type 2 diabetes and obesity. In recent years, different beneficial effects of GLP-1R agonists were discovered, such as reducing ischemia-reperfusion injury, improving the function of various organs, alleviating substance use disorder, affecting tumorigenesis, regulating bone metabolism, changing gut microbiota composition, and prolonging graft survival. Therefore, GLP-1R agonists have great potential for clinical application in various diseases. Here, we briefly summarized the beneficial effects of GLP-1R agonists other than the anti-diabetic and anti-obesity effects.
Collapse
Affiliation(s)
- Chenqi Lu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China;
| | - Cong Xu
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Jun Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China;
| |
Collapse
|
|
6
|
Misceo D, Mocciaro G, D'Amore S, Vacca M. Diverting hepatic lipid fluxes with lifestyles revision and pharmacological interventions as a strategy to tackle steatotic liver disease (SLD) and hepatocellular carcinoma (HCC). Nutr Metab (Lond) 2024; 21:112. [PMID: 39716321 DOI: 10.1186/s12986-024-00871-3] [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: 08/22/2024] [Accepted: 11/13/2024] [Indexed: 12/25/2024] Open
Abstract
Steatotic liver disease (SLD) and Hepatocellular Carcinoma (HCC) are characterised by a substantial rewiring of lipid fluxes caused by systemic metabolic unbalances and/or disrupted intracellular metabolic pathways. SLD is a direct consequence of the interaction between genetic predisposition and a chronic positive energy balance affecting whole-body energy homeostasis and the function of metabolically-competent organs. In this review, we discuss how the impairment of the cross-talk between peripheral organs and the liver stalls glucose and lipid metabolism, leading to unbalances in hepatic lipid fluxes that promote hepatic fat accumulation. We also describe how prolonged metabolic stress builds up toxic lipid species in the liver, and how lipotoxicity and metabolic disturbances drive disease progression by promoting a chronic activation of wound healing, leading to fibrosis and HCC. Last, we provide a critical overview of current state of the art (pre-clinical and clinical evidence) regarding mechanisms of action and therapeutic efficacy of candidate SLD treatment options, and their potential to interfere with SLD/HCC pathophysiology by diverting lipids away from the liver therefore improving metabolic health.
Collapse
Affiliation(s)
- Davide Misceo
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Gabriele Mocciaro
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK
| | - Simona D'Amore
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Clinica Medica "G. Baccelli", "Aldo Moro" University of Bari, 70124, Bari, Italy.
| | - Michele Vacca
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK.
| |
Collapse
|
|
7
|
Ha NB, Yao F. Alcohol and Hepatocellular Carcinoma. Clin Liver Dis 2024; 28:633-646. [PMID: 39362712 PMCID: PMC12037205 DOI: 10.1016/j.cld.2024.06.007] [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: 10/05/2024]
Abstract
Alcohol-associated liver disease (ALD) poses a significant risk for hepatocellular carcinoma (HCC), comprising various liver conditions from steatosis to cirrhosis. Despite accounting for a third of global HCC cases and deaths, ALD-related HCC lacks characterization compared to viral hepatitis-related HCC. Proposed mechanisms for ALD-related HCC include acetaldehyde toxicity, increased reactive oxygen species, and inflammation. This review examines ALD-associated HCC epidemiology, co-factors like viral hepatitis and metabolic syndrome, surveillance, and treatment challenges. Despite advances in screening and management, ALD-related HCC often presents at advanced stages, limiting treatment options and survival.
Collapse
Affiliation(s)
- Nghiem B Ha
- Hepatology, Liver Transplant, Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, 505 Parnassus Avenue, S-357, San Francisco, CA 94112, USA
| | - Francis Yao
- Hepatology, Liver Transplant, Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, 505 Parnassus Avenue, S-357, San Francisco, CA 94112, USA.
| |
Collapse
|
|
8
|
Liu Y, Lou X. The Bidirectional Association Between Metabolic Syndrome and Long-COVID-19. Diabetes Metab Syndr Obes 2024; 17:3697-3710. [PMID: 39398386 PMCID: PMC11471063 DOI: 10.2147/dmso.s484733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 09/22/2024] [Indexed: 10/15/2024] Open
Abstract
Background The rapid global spread of a new coronavirus disease known as COVID-19 has led to a significant increase in mortality rates, resulting in an unprecedented worldwide pandemic. Methods The impact of COVID-19, particularly its long-term effects, has also had a profound effect on the health and well-being of individuals.Metabolic syndrome increases the risk of heart and brain diseases, presenting a significant danger to human well-being. Purpose The prognosis of long COVID and the progression of metabolic syndrome interact with each other, but there is currently a lack of systematic reports.In this paper, the pathogenesis, related treatment and prognosis of long COVID and metabolic syndrome are systematically reviewed.
Collapse
Affiliation(s)
- Yanfen Liu
- Department of Endocrinology at Zhejiang University School of Medicine, Jinhua Hospital, Jinhua, People’s Republic of China
| | - Xueyong Lou
- Department of Endocrinology at Zhejiang University School of Medicine, Jinhua Hospital, Jinhua, People’s Republic of China
| |
Collapse
|
|
9
|
Marroncini G, Naldi L, Martinelli S, Amedei A. Gut-Liver-Pancreas Axis Crosstalk in Health and Disease: From the Role of Microbial Metabolites to Innovative Microbiota Manipulating Strategies. Biomedicines 2024; 12:1398. [PMID: 39061972 PMCID: PMC11273695 DOI: 10.3390/biomedicines12071398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/16/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
The functions of the gut are closely related to those of many other organs in the human body. Indeed, the gut microbiota (GM) metabolize several nutrients and compounds that, once released in the bloodstream, can reach distant organs, thus influencing the metabolic and inflammatory tone of the host. The main microbiota-derived metabolites responsible for the modulation of endocrine responses are short-chain fatty acids (SCFAs), bile acids and glucagon-like peptide 1 (GLP-1). These molecules can (i) regulate the pancreatic hormones (insulin and glucagon), (ii) increase glycogen synthesis in the liver, and (iii) boost energy expenditure, especially in skeletal muscles and brown adipose tissue. In other words, they are critical in maintaining glucose and lipid homeostasis. In GM dysbiosis, the imbalance of microbiota-related products can affect the proper endocrine and metabolic functions, including those related to the gut-liver-pancreas axis (GLPA). In addition, the dysbiosis can contribute to the onset of some diseases such as non-alcoholic steatohepatitis (NASH)/non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), and type 2 diabetes (T2D). In this review, we explored the roles of the gut microbiota-derived metabolites and their involvement in onset and progression of these diseases. In addition, we detailed the main microbiota-modulating strategies that could improve the diseases' development by restoring the healthy balance of the GLPA.
Collapse
Affiliation(s)
- Giada Marroncini
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (G.M.); (L.N.)
| | - Laura Naldi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (G.M.); (L.N.)
| | - Serena Martinelli
- Department of Clinical and Experimental Medicine, University of Florence, 50139 Florence, Italy
| | - Amedeo Amedei
- Department of Clinical and Experimental Medicine, University of Florence, 50139 Florence, Italy
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 50139 Florence, Italy
| |
Collapse
|
|
10
|
McFarlin BE, Duffin KL, Konkar A. Incretin and glucagon receptor polypharmacology in chronic kidney disease. Am J Physiol Endocrinol Metab 2024; 326:E747-E766. [PMID: 38477666 PMCID: PMC11551006 DOI: 10.1152/ajpendo.00374.2023] [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: 11/13/2023] [Accepted: 03/10/2024] [Indexed: 03/14/2024]
Abstract
Chronic kidney disease is a debilitating condition associated with significant morbidity and mortality. In recent years, the kidney effects of incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), have garnered substantial interest in the management of type 2 diabetes and obesity. This review delves into the intricate interactions between the kidney, GLP-1RAs, and glucagon, shedding light on their mechanisms of action and potential kidney benefits. Both GLP-1 and glucagon, known for their opposing roles in regulating glucose homeostasis, improve systemic risk factors affecting the kidney, including adiposity, inflammation, oxidative stress, and endothelial function. Additionally, these hormones and their pharmaceutical mimetics may have a direct impact on the kidney. Clinical studies have provided evidence that incretins, including those incorporating glucagon receptor agonism, are likely to exhibit improved kidney outcomes. Although further research is necessary, receptor polypharmacology holds promise for preserving kidney function through eliciting vasodilatory effects, influencing volume and electrolyte handling, and improving systemic risk factors.
Collapse
Affiliation(s)
- Brandon E McFarlin
- Lilly Research Laboratories, Lilly Corporate CenterIndianapolisIndianaUnited States
| | - Kevin L Duffin
- Lilly Research Laboratories, Lilly Corporate CenterIndianapolisIndianaUnited States
| | - Anish Konkar
- Lilly Research Laboratories, Lilly Corporate CenterIndianapolisIndianaUnited States
| |
Collapse
|
|
11
|
Yang CT, Yao WY, Yang CY, Peng ZY, Ou HT, Kuo S. Lower risks of cirrhosis and hepatocellular carcinoma with GLP-1RAs in type 2 diabetes: A nationwide cohort study using target trial emulation framework. J Intern Med 2024; 295:357-368. [PMID: 37994187 DOI: 10.1111/joim.13751] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2023]
Abstract
BACKGROUND To assess the association of cirrhosis and hepatocellular carcinoma (HCC) with the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs), which are the two commonly prescribed injectable glucose-lowering agents (GLAs) for patients with type 2 diabetes (T2D) after the failure of multiple oral GLAs. METHODS We emulated a target trial using the nationwide data of a Taiwanese cohort with T2D. Incident new users of GLP-1RAs and LAIs during 2013-2018 were identified, and propensity score (PS) matching was applied to ensure between-group comparability in baseline patient characteristics. The primary outcome was the composite liver disease including cirrhosis or HCC. Each patient was followed until the occurrence of a study outcome, death, or the end of 2019, whichever came first. Subdistribution hazard models were employed to assess the treatment-outcome association. Sensitivity (e.g., stabilized inverse probability of treatment weighting analysis, time-dependent analysis), E-value, and negative control outcome analyses were performed to examine the robustness of study findings. RESULTS We included 7171 PS-matched pairs of GLP-1RA and LAI users with no significant between-group differences at baseline. Compared with LAIs, the use of GLP-1RAs was associated with significantly reduced risks of composite liver disease (subdistribution hazard ratio [95% confidence interval]: 0.56 [0.42-0.76]), cirrhosis (0.59 [0.43-0.81]), and HCC (0.47 [0.24-0.93]). Results were consistent across sensitivity analyses and among patients with different baseline characteristics. CONCLUSION Among T2D patients who require injectable GLAs, the use of GLP-1RAs versus LAIs was associated with lower risks of cirrhosis and HCC.
Collapse
Affiliation(s)
- Chun-Ting Yang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, USA
| | - Wen-Yu Yao
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chen-Yi Yang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Zi-Yang Peng
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Huang-Tz Ou
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shihchen Kuo
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| |
Collapse
|
|
12
|
Zhang H, Liu Y, Liu J, Chen J, Wang J, Hua H, Jiang Y. cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment. J Hematol Oncol 2024; 17:5. [PMID: 38233872 PMCID: PMC10792844 DOI: 10.1186/s13045-024-01524-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/02/2024] [Indexed: 01/19/2024] Open
Abstract
Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells and angiogenesis, plays a critical role in tumor progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME. The downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), exchange protein activated by cAMP (EPAC) and ion channels. While cAMP can activate PKA or EPAC and promote cancer cell growth, it can also inhibit cell proliferation and survival in context- and cancer type-dependent manner. Tumor-associated stromal cells, such as CAF and immune cells, can release cytokines and growth factors that either stimulate or inhibit cAMP production within the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits in cancer. Small-molecule agents that inhibit adenylate cyclase and PKA have been shown to inhibit tumor growth. In addition, cAMP-elevating agents, such as forskolin, can not only induce cancer cell death, but also directly inhibit cell proliferation in some cancer types. In this review, we summarize current understanding of cAMP signaling in cancer biology and immunology and discuss the basis for its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer will be critical for the development of effective therapies. Future studies aimed at investigating the cAMP-cancer axis and its regulation in the TME may provide new insights into the underlying mechanisms of tumorigenesis and lead to the development of novel therapeutic strategies.
Collapse
Affiliation(s)
- Hongying Zhang
- Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yongliang Liu
- Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jieya Liu
- Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jinzhu Chen
- Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiao Wang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Hui Hua
- Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Yangfu Jiang
- Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| |
Collapse
|
|
13
|
Jiang H, Zang L. GLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD. Curr Pharm Des 2024; 30:100-114. [PMID: 38532322 DOI: 10.2174/0113816128283153231226103218] [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: 10/12/2023] [Accepted: 12/14/2023] [Indexed: 03/28/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a global public health concern. Currently, the cornerstone of NAFLD treatment is lifestyle modification and, if necessary, weight loss. However, compliance is a challenge, and this approach alone may not be sufficient to halt and treat the more serious disease development, so medication is urgently needed. Nevertheless, no medicines are approved to treat NAFLD. Glucagon-like peptide-1 (GLP-1) is an enteropeptide hormone that inhibits glucagon synthesis, promotes insulin secretion, and delays gastric emptying. GLP-1 has been found in recent studies to be beneficial for the management of NAFLD, and the marketed GLP-1 agonist drugs have different degrees of effectiveness for NAFLD while lowering blood glucose. In this article, we review GLP-1 and its physiological roles, the pathogenesis of NAFLD, the correlation between NAFLD and GLP-1 signaling, and potential strategies for GLP-1 treatment of NAFLD.
Collapse
Affiliation(s)
- Haoran Jiang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Linquan Zang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| |
Collapse
|
|
14
|
Hansen HH, Pors S, Andersen MW, Vyberg M, Nøhr-Meldgaard J, Nielsen MH, Oró D, Madsen MR, Lewinska M, Møllerhøj MB, Madsen AN, Feigh M. Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis. Sci Rep 2023; 13:23056. [PMID: 38155202 PMCID: PMC10754821 DOI: 10.1038/s41598-023-50328-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 12/18/2023] [Indexed: 12/30/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy with semaglutide (glucagon-like-receptor-1 receptor agonist) and lanifibranor (pan-peroxisome proliferator-activated receptor agonist) in a diet-induced obese (DIO) mouse model of NASH-HCC. Disease progression was characterized in male C57BL/6 J mice fed the GAN (Gubra Amylin NASH) diet high in fat, fructose and cholesterol for 12-72 weeks (n = 15 per group). Other GAN DIO-NASH-HCC mice fed the GAN diet for 54 weeks and with biopsy-confirmed NASH (NAFLD Activity Score ≥ 5) and advanced fibrosis (stage F3) received vehicle (n = 16), semaglutide (30 nmol/kg, s.c., n = 15), or lanifibranor (30 mg/kg, p.o., n = 15) once daily for 14 weeks. GAN DIO-NASH-HCC mice demonstrated progressive NASH, fibrosis and HCC burden. Tumors presented with histological and molecular signatures of poor prognostic HCC. Consistent with clinical trial outcomes in NASH patients, both lanifibranor and semaglutide improved NASH while only lanifibranor reduced fibrosis in GAN DIO-NASH-HCC mice. Notably, only semaglutide reduced tumor burden in GAN DIO-NASH-HCC mice. In conclusion, the GAN DIO-NASH-HCC mouse is a clinical translational model of NASH-HCC. Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC.
Collapse
Affiliation(s)
| | - Susanne Pors
- Gubra, Hørsholm Kongevej 11B, DK-2970, Hørsholm, Denmark
| | | | - Mogens Vyberg
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | | | | | - Denise Oró
- Gubra, Hørsholm Kongevej 11B, DK-2970, Hørsholm, Denmark
| | | | | | | | | | - Michael Feigh
- Gubra, Hørsholm Kongevej 11B, DK-2970, Hørsholm, Denmark
| |
Collapse
|
|
15
|
Zhan K, Yang X, Li S, Bai Y. Correlation of endoplasmic reticulum stress patterns with the immune microenvironment in hepatocellular carcinoma: a prognostic signature analysis. Front Immunol 2023; 14:1270774. [PMID: 38143739 PMCID: PMC10748430 DOI: 10.3389/fimmu.2023.1270774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/23/2023] [Indexed: 12/26/2023] Open
Abstract
Backgrounds The extended duration of endoplasmic reticulum stress (ERS) can impact the progression of hepatocellular carcinoma (HCC) and the efficacy of immunotherapies by interacting with immune cells that have infiltrated the tumor microenvironment (TME). Methods and results The study utilized a training cohort of 364 HCC patients with complete information from The Cancer Genome Atlas Program (TCGA) database, and a validation cohort of 231 HCC patients from the International Cancer Genome Consortium (ICGC) database. The genes related to ERS exhibiting a strong correlation with overall survival (OS) were identified using univariate Cox regression analysis. A 13-gene predictive signature was then produced through the least absolute shrinkage and selection operator (LASSO) regression approach. The data revealed that the ERS-associated gene signature effectively stratified patients into high- or low-risk groups regarding OS in both the training and validation cohorts (P < 0.0001 and P = 0.00029, respectively). Using the multivariate method, it is still an independent prognostic factor in both the training and validation cohorts (P < 0.001 and P = 0.008, respectively). Moreover, several metabolic pathways were identified to be enriched among the 13 genes in the predictive signature. When the ERS-associated gene signature was combined with the tumor-node-metastasis (TNM) stage, the ERS nomogram performed better than either the gene signature or the TNM stage alone (C-index values: 0.731, 0.729, and 0.573, respectively). Further analysis revealed that patients in the high-risk group exhibited increased infiltration of immune cells. Additionally, GP6 was downregulated in HCC tissues among these signature genes (P < 0.05), which was related to poor OS. Conclusions The data suggest that this novel ERS-associated gene signature could contribute to personalized cancer management for HCC. Moreover, targeting GP6 inhibition might be a potential method for HCC therapy.
Collapse
Affiliation(s)
- Ke Zhan
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xin Yang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shuang Li
- Department of Gastrointestinal Surgery, Jinshan Hospital, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yang Bai
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
16
|
Vachliotis ID, Valsamidis I, Polyzos SA. Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:5306. [PMID: 37958479 PMCID: PMC10650629 DOI: 10.3390/cancers15215306] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 10/28/2023] [Accepted: 11/01/2023] [Indexed: 11/15/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is emerging as an important risk factor for hepatocellular carcinoma (HCC), whose prevalence is rising. Although the mechanisms of progression from NAFLD to HCC are not fully elucidated, tumor necrosis factor-α (TNF-α) and adiponectin, as well as their interplay, which seems to be antagonistic, may contribute to the pathophysiology of NAFLD-associated HCC. TNF-α initially aims to protect against hepatocarcinogenesis, but during the progression of NAFLD, TNF-α is increased, thus probably inducing hepatocarcinogenesis in the long-term, when NAFLD is not resolved. On the other hand, adiponectin, which is expected to exert anti-tumorigenic effects, is decreased during the progression of the disease, a trend that may favor hepatocarcinogenesis, but is paradoxically increased at end stage disease, i.e., cirrhosis and HCC. These observations render TNF-α and adiponectin as potentially diagnostic biomarkers and appealing therapeutic targets in the setting of NAFLD-associated HCC, possibly in combination with systematic therapy. In this regard, combination strategy, including immune checkpoint inhibitors (ICIs) with anti-TNF biologics and/or adiponectin analogs or medications that increase endogenous adiponectin, may warrant investigation against NAFLD-associated HCC. This review aims to summarize evidence on the association between TNF-α and adiponectin with NAFLD-associated HCC, based on experimental and clinical studies, and to discuss relevant potential therapeutic considerations.
Collapse
Affiliation(s)
- Ilias D. Vachliotis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
- Department of Gastroenterology, 424 General Military Hospital, 56429 Thessaloniki, Greece
| | - Ioannis Valsamidis
- First Department of Internal Medicine, 424 General Military Hospital, 56429 Thessaloniki, Greece;
| | - Stergios A. Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| |
Collapse
|
|
17
|
Crane H, Gofton C, Sharma A, George J. MAFLD: an optimal framework for understanding liver cancer phenotypes. J Gastroenterol 2023; 58:947-964. [PMID: 37470858 PMCID: PMC10522746 DOI: 10.1007/s00535-023-02021-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 07/05/2023] [Indexed: 07/21/2023]
Abstract
Hepatocellular carcinoma has a substantial global mortality burden which is rising despite advancements in tackling the traditional viral risk factors. Metabolic (dysfunction) associated fatty liver disease (MAFLD) is the most prevalent liver disease, increasing in parallel with the epidemics of obesity, diabetes and systemic metabolic dysregulation. MAFLD is a major factor behind this sustained rise in HCC incidence, both as a single disease entity and often via synergistic interactions with other liver diseases. Mechanisms behind MAFLD-related HCC are complex but is crucially underpinned by systemic metabolic dysregulation with variable contributions from interacting disease modifiers related to environment, genetics, dysbiosis and immune dysregulation. MAFLD-related HCC has a distinct clinical presentation, most notably its common occurrence in non-cirrhotic liver disease. This is just one of several major challenges to effective surveillance programmes. The response of MAFLD-related HCC to immune-checkpoint therapy is currently controversial, and is further complicated by the high prevalence of MAFLD in individuals with HCC from viral aetiologies. In this review, we highlight the current data on epidemiology, clinical characteristics, outcomes and screening controversies. In addition, concepts that have arisen because of the MAFLD paradigm such as HCC in MAFLD/NAFLD non-overlapping groups, dual aetiology tumours and MAFLD sub-phenotypes is reviewed.
Collapse
Affiliation(s)
- Harry Crane
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.
- Department of Gastroenterology and Hepatology, Royal North Shore Hospital, 1 Reserve Road, St Leonards, New South Wales, Australia.
| | - Cameron Gofton
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
- Department of Gastroenterology and Hepatology, Royal North Shore Hospital, 1 Reserve Road, St Leonards, New South Wales, Australia
| | - Ankur Sharma
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, 6 Verdun Street, Nedlands, Perth, WA, 6009, Australia
- Curtin Medical School, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA, 6102, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
| |
Collapse
|
|
18
|
Polyzos SA, Chrysavgis L, Vachliotis ID, Chartampilas E, Cholongitas E. Nonalcoholic fatty liver disease and hepatocellular carcinoma:Insights in epidemiology, pathogenesis, imaging, prevention and therapy. Semin Cancer Biol 2023; 93:20-35. [PMID: 37149203 DOI: 10.1016/j.semcancer.2023.04.010] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/23/2023] [Accepted: 04/27/2023] [Indexed: 05/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is estimated to be the third leading cause of cancer-related mortality and is characterized by low survival rates. Nonalcoholic fatty liver disease (NAFLD) is emerging as a leading cause of HCC, whose rates are increasing, owing to the increasing prevalence of NAFLD. The pathogenesis of NAFLD-associated HCC is multifactorial: insulin resistance, obesity, diabetes and the low-grade hepatic inflammation, which characterizes NAFLD, seem to play key roles in the development and progression of HCC. The diagnosis of NAFLD-associated HCC is based on imaging in the presence of liver cirrhosis, preferably computerized tomography or magnetic resonance imaging, but liver biopsy for histological confirmation is usually required in the absence of liver cirrhosis. Some preventive measures have been recommended for NAFLD-associated HCC, including weight loss, cessation of even moderate alcohol drinking and smoking, as well as the use of metformin, statins and aspirin. However, these preventive measures are mainly based on observational studies, thus they need validation in trials of different design before introducing in clinical practice. The treatment of NAFLD should be tailored on an individual basis and should be ideally determined by a multidisciplinary team. In the last two decades, new medications, including tyrosine kinase inhibitors and immune checkpoints inhibitors, have improved the survival of patients with advanced HCC, but trials specifically designed for patients with NAFLD-associated HCC are scarce. The aim of this review was to overview evidence on the epidemiology and pathophysiology of NAFLD-associated HCC, then to comment on imaging tools for its appropriate screening and diagnosis, and finally to critically summarize the currently available options for its prevention and treatment.
Collapse
Affiliation(s)
- Stergios A Polyzos
- First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Lampros Chrysavgis
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, Athens, Greece
| | - Ilias D Vachliotis
- First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelos Chartampilas
- Department of Radiology, University General Hospital of Thessaloniki AHEPA, Thessaloniki, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, Athens, Greece
| |
Collapse
|
|
19
|
Mahgoub MO, Ali II, Adeghate JO, Tekes K, Kalász H, Adeghate EA. An Update on the Molecular and Cellular Basis of Pharmacotherapy in Type 2 Diabetes Mellitus. Int J Mol Sci 2023; 24:ijms24119328. [PMID: 37298274 DOI: 10.3390/ijms24119328] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 06/12/2023] Open
Abstract
Diabetes mellitus (DM) is a chronic illness with an increasing global prevalence. More than 537 million cases of diabetes were reported worldwide in 2021, and the number is steadily increasing. The worldwide number of people suffering from DM is projected to reach 783 million in 2045. In 2021 alone, more than USD 966 billion was spent on the management of DM. Reduced physical activity due to urbanization is believed to be the major cause of the increase in the incidence of the disease, as it is associated with higher rates of obesity. Diabetes poses a risk for chronic complications such as nephropathy, angiopathy, neuropathy and retinopathy. Hence, the successful management of blood glucose is the cornerstone of DM therapy. The effective management of the hyperglycemia associated with type 2 diabetes includes physical exercise, diet and therapeutic interventions (insulin, biguanides, second generation sulfonylureas, glucagon-like peptide 1 agonists, dipeptidyl-peptidase 4 inhibitors, thiazolidinediones, amylin mimetics, meglitinides, α-glucosidase inhibitors, sodium-glucose cotransporter-2 inhibitors and bile acid sequestrants). The optimal and timely treatment of DM improves the quality of life and reduces the severe burden of the disease for patients. Genetic testing, examining the roles of different genes involved in the pathogenesis of DM, may also help to achieve optimal DM management in the future by reducing the incidence of DM and by enhancing the use of individualized treatment regimens.
Collapse
Affiliation(s)
- Mohamed Omer Mahgoub
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates
- Department of Health and Medical Sciences, Khawarizmi International College, Abu Dhabi P.O. Box 25669, United Arab Emirates
| | - Ifrah Ismail Ali
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates
| | - Jennifer O Adeghate
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University, 630 W. 168th St., New York, NY 10032, USA
- Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, 635 W. 165th St., New York, NY 10032, USA
| | - Kornélia Tekes
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, 1089 Budapest, Hungary
| | - Huba Kalász
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, 1089 Budapest, Hungary
| | - Ernest A Adeghate
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates
- Zayed Centre for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| |
Collapse
|
|
20
|
Yao M, Zhou P, Qin YY, Wang L, Yao DF. Mitochondrial carnitine palmitoyltransferase-II dysfunction: A possible novel mechanism for nonalcoholic fatty liver disease in hepatocarcinogenesis. World J Gastroenterol 2023; 29:1765-1778. [PMID: 37032731 PMCID: PMC10080702 DOI: 10.3748/wjg.v29.i12.1765] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/04/2022] [Accepted: 03/09/2023] [Indexed: 03/28/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease has been characterized by the lipid accumulation with injury of hepatocytes and has become one of the most common chronic liver diseases in the world. The complex mechanisms of NAFLD formation are still under identification. Carnitine palmitoyltransferase-II (CPT-II) on inner mitochondrial membrane (IMM) regulates long chain fatty acid β-oxidation, and its abnormality has had more and more attention paid to it by basic and clinical research in NAFLD. The sequences of its peptide chain and DNA nucleotides have been identified, and the catalytic activity of CPT-II is affected on its gene mutations, deficiency, enzymatic thermal instability, circulating carnitine level and so on. Recently, the CPT-II dysfunction has been discovered in models of liver lipid accumulation. Meanwhile, the malignant transformation of hepatocyte-related CD44+ stem T cell activation, high levels of tumor-related biomarkers (AFP, GPC3) and abnormal activation of Wnt3a expression as a key signal molecule of the Wnt/β-catenin pathway run parallel to the alterations of hepatocyte pathology. This review focuses on some of the progress of CPT-II inactivity on IMM with liver fatty accumulation as a possible novel pathogenesis for NAFLD in hepatocarcinogenesis.
Collapse
Affiliation(s)
- Min Yao
- Department of Medical Immunology, Medical School of Nantong University & Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Ping Zhou
- Department of Medical Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yan-Yan Qin
- Department of Medical Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Li Wang
- Research Center for Intelligent Information Technology, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Deng-Fu Yao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| |
Collapse
|
|
21
|
Zhao D, Zhang J, Zhang L, Wu Q, Wang Y, Zhang W, Xiao Y, Chen J, Zhan Q. PAFR/Stat3 axis maintains the symbiotic ecosystem between tumor and stroma to facilitate tumor malignancy. Acta Pharm Sin B 2023; 13:694-708. [PMID: 36873192 PMCID: PMC9978919 DOI: 10.1016/j.apsb.2022.08.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 06/17/2022] [Accepted: 08/07/2022] [Indexed: 11/18/2022] Open
Abstract
Stroma surrounding the tumor cells plays crucial roles for tumor progression. However, little is known about the factors that maintain the symbiosis between stroma and tumor cells. In this study, we found that the transcriptional regulator-signal transducer and activator of transcription 3 (Stat3) was frequently activated in cancer-associated fibroblasts (CAFs), which was a potent facilitator of tumor malignancy, and formed forward feedback loop with platelet-activating factor receptor (PAFR) both in CAFs and tumor cells. Importantly, PAFR/Stat3 axis connected intercellular signaling crosstalk between CAFs and cancer cells and drove mutual transcriptional programming of these two types of cells. Two central Stat3-related cytokine signaling molecules-interleukin 6 (IL-6) and IL-11 played the critical role in the process of PAFR/Stat3 axis-mediated communication between tumor and CAFs. Pharmacological inhibition of PAFR and Stat3 activities effectively reduced tumor progression using CAFs/tumor co-culture xenograft model. Our study reveals that PAFR/Stat3 axis enhances the interaction between tumor and its associated stroma and suggests that targeting this axis can be an effective therapeutic strategy against tumor malignancy.
Collapse
Affiliation(s)
- Di Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
| | - Jing Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Lingyuan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Qingnan Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
- Peking University International Cancer Institute, Beijing 100191, China
| | - Yan Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
- Peking University International Cancer Institute, Beijing 100191, China
| | - Weimin Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
- Shenzhen Bay Laboratory, Shenzhen 518132, China
| | - Yuanfan Xiao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jie Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
- Peking University International Cancer Institute, Beijing 100191, China
- Corresponding authors.
| | - Qimin Zhan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
- Peking University International Cancer Institute, Beijing 100191, China
- Shenzhen Bay Laboratory, Shenzhen 518132, China
- Corresponding authors.
| |
Collapse
|
|
22
|
Chuanbing Z, Zhengle Z, Ruili D, Kongfan Z, Jing T. Genes Modulating Butyrate Metabolism for Assessing Clinical Prognosis and Responses to Systematic Therapies in Hepatocellular Carcinoma. Biomolecules 2022; 13:52. [PMID: 36671437 PMCID: PMC9856074 DOI: 10.3390/biom13010052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/16/2022] [Accepted: 12/21/2022] [Indexed: 12/29/2022] Open
Abstract
Butyrate, one of the major products of the gut microbiota, has played notable roles in diverse therapies for multiple tumors. Our study aimed to determine the roles of genes that modulate butyrate metabolism (BM) in predicting the clinical prognosis and responses to systemic therapies in hepatocellular carcinoma (HCC). The genes modulating BM were available from the GeneCard database, and gene expression and clinical information were obtained from TCGA-LIHC, GEO, ICGC-JP, and CCLE databases. Candidate genes from these genes that regulate BM were then identified by univariate Cox analysis. According to candidate genes, the patients in TCGA were grouped into distinct subtypes. Moreover, BM- related gene signature (BMGs) was created via the LASSO Cox algorithm. The roles of BMGs in identifying high-risk patients of HCC, assessing the prognoses, and predicting systematic therapies were determined in various datasets. The statistical analyses were fulfilled with R 4.1.3, GraphPad Prism 8.0 and Perl 5.30.0.1 software. In the TCGA cohort, most butyrate-related genes were over-expressed in the B cluster, and patients in the B cluster showed worse prognoses. BMGs constructed by LASSO were composed of eight genes. BMGs exhibited a strong performance in evaluating the prognoses of HCC patients in various datasets, which may be superior to 33 published biomarkers. Furthermore, BMGs may contribute to the early surveillance of HCC, and BMGs could play active roles in assessing the effectiveness of immunotherapy, TACE, ablation therapy, and chemotherapeutic drugs for HCC. BMGs may be served as novel promising biomarkers for early identifying high-risk groups of HCC, as well as assessing prognoses, drug sensitivity, and the responses to immunotherapy, TACE, and ablation therapy in patients with HCC.
Collapse
Affiliation(s)
- Zhao Chuanbing
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan 430061, China
| | - Zhang Zhengle
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan 430061, China
| | - Ding Ruili
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430061, China
| | - Zhu Kongfan
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan 430061, China
| | - Tao Jing
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan 430061, China
| |
Collapse
|
|
23
|
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.
Collapse
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
| |
Collapse
|
|
24
|
Razavi M, Wei YY, Rao XQ, Zhong JX. DPP-4 inhibitors and GLP-1RAs: cardiovascular safety and benefits. Mil Med Res 2022; 9:45. [PMID: 35986429 PMCID: PMC9392232 DOI: 10.1186/s40779-022-00410-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 08/08/2022] [Indexed: 11/10/2022] Open
Abstract
Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus (T2DM). Both anti-diabetic treatments function by playing key modulatory roles in the incretin system. Though these drugs have been deemed effective in treating T2DM, the Food and Drug Administration (FDA) and some members of the scientific community have questioned the safety of these therapeutics relative to important cardiovascular endpoints. As a result, since 2008, the FDA has required all new drugs for glycemic control in T2DM patients to demonstrate cardiovascular safety. The present review article strives to assess the safety and benefits of incretin-based therapy, a new class of antidiabetic drug, on the health of patient cardiovascular systems. In the process, this review will also provide a physiological overview of the incretin system and how key components function in T2DM.
Collapse
Affiliation(s)
- Michael Razavi
- Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Ying-Ying Wei
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430032, China
| | - Xiao-Quan Rao
- Department of Cardiovascular Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430032, China.
| | - Ji-Xin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430032, China.
- Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430032, China.
| |
Collapse
|
|
25
|
Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022; 77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.
Collapse
Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed M Elsharkawy
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, B15 2TH UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | - Michele Vacca
- Interdisciplinary Department of Medicine, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
| |
Collapse
|
|
26
|
Chen Y, Xu YN, Ye CY, Feng WB, Zhou QT, Yang DH, Wang MW. GLP-1 mimetics as a potential therapy for nonalcoholic steatohepatitis. Acta Pharmacol Sin 2022; 43:1156-1166. [PMID: 34934197 PMCID: PMC9061743 DOI: 10.1038/s41401-021-00836-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 11/29/2021] [Indexed: 12/14/2022]
Abstract
Nonalcoholic steatohepatitis (NASH), as a severe form of nonalcoholic fatty liver disease (NAFLD), is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis. The pathogenesis of NASH is complex and multifactorial, obesity and type 2 diabetes mellitus (T2DM) have been implicated as major risk factors. Glucagon-like peptide-1 receptor (GLP-1R) is one of the most successful drug targets of T2DM and obesity, and its peptidic ligands have been proposed as potential therapeutic agents for NASH. In this article we provide an overview of the pathophysiology and management of NASH, with a special focus on the pharmacological effects and possible mechanisms of GLP-1 mimetics in treating NAFLD/NASH, including dual and triple agonists at GLP-1R, glucose-dependent insulinotropic polypeptide receptor or glucagon receptor.
Collapse
Affiliation(s)
- Yan Chen
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Ying-Na Xu
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Chen-Yu Ye
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Wen-Bo Feng
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Qing-Tong Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - De-Hua Yang
- The CAS Key Laboratory of Receptor Research and The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Research Center for Deepsea Bioresources, Sanya, 572025, China.
| | - Ming-Wei Wang
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
- The CAS Key Laboratory of Receptor Research and The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Research Center for Deepsea Bioresources, Sanya, 572025, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
| |
Collapse
|
|
27
|
In Vitro and In Vivo Antidiabetic Potential of Monoterpenoids: An Update. MOLECULES (BASEL, SWITZERLAND) 2021; 27:molecules27010182. [PMID: 35011414 PMCID: PMC8746715 DOI: 10.3390/molecules27010182] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/20/2021] [Accepted: 12/25/2021] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus (DM) is a chronic metabolic condition characterized by persistent hyperglycemia due to insufficient insulin levels or insulin resistance. Despite the availability of several oral and injectable hypoglycemic agents, their use is associated with a wide range of side effects. Monoterpenes are compounds extracted from different plants including herbs, vegetables, and fruits and they contribute to their aroma and flavor. Based on their chemical structure, monoterpenes are classified into acyclic, monocyclic, and bicyclic monoterpenes. They have been found to exhibit numerous biological and medicinal effects such as antipruritic, antioxidant, anti-inflammatory, and analgesic activities. Therefore, monoterpenes emerged as promising molecules that can be used therapeutically to treat a vast range of diseases. Additionally, monoterpenes were found to modulate enzymes and proteins that contribute to insulin resistance and other pathological events caused by DM. In this review, we highlight the different mechanisms by which monoterpenes can be used in the pharmacological intervention of DM via the alteration of certain enzymes, proteins, and pathways involved in the pathophysiology of DM. Based on the fact that monoterpenes have multiple mechanisms of action on different targets in in vitro and in vivo studies, they can be considered as lead compounds for developing effective hypoglycemic agents. Incorporating these compounds in clinical trials is needed to investigate their actions in diabetic patients in order to confirm their ability in controlling hyperglycemia.
Collapse
|
|
28
|
Chao X, Miao F, Feng X, Shi H, Wang Y, Wu J, Zhao L, Zhang W, Jiang C. ADCY2 rs10059539 C>T polymorphism confers a decreased risk of hepatocellular carcinoma in Chinese Han women. Eur J Cancer Prev 2021; 30:351-356. [PMID: 34010241 DOI: 10.1097/cej.0000000000000638] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) poses a serious threat to human health. ADCY2 gene polymorphisms may be related to HCC susceptibility. Therefore, we investigated whether ADCY2 gene polymorphisms are correlated to the risk of HCC in a Chinese Han population. METHODS In a case-control study, we examined the associations between single nucleotide polymorphisms (SNPs) in ADCY2 and HCC risk. In 434 HCC cases and 442 healthy controls, we used the Agena MassARRAY platform to select and genotype four tag SNPs in ADCY2. We used logistic regression after adjusting for age and sex to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS The results showed that ADCY2 rs10059539 polymorphism was associated with a reduced susceptibility to HCC in women under the dominant model (TC/TT vs. CC; OR = 0.32; 95% CI = 0.13-0.83; P = 0.018) and the log-additive model (OR = 0.32; 95% CI = 0.13-0.83; P = 0.018). CONCLUSIONS Our results support the hypothesis that ADCY2 gene polymorphisms influence the genetic susceptibility to HCC.
Collapse
Affiliation(s)
- Xu Chao
- The Second Affiliated Hospital
- The College of Basic medicine, Shaanxi University of Chinese Medicine, Xianyang
| | | | - Xuesong Feng
- The College of Basic medicine, Shaanxi University of Chinese Medicine, Xianyang
| | - Hailong Shi
- The College of Basic medicine, Shaanxi University of Chinese Medicine, Xianyang
| | - Yuewen Wang
- The College of Basic medicine, Shaanxi University of Chinese Medicine, Xianyang
| | | | | | | | - Chao Jiang
- The Second Affiliated Hospital
- The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, China
| |
Collapse
|
|
29
|
Wang T, Zhang Q, Wang N, Liu Z, Zhang B, Zhao Y. Research Progresses of Targeted Therapy and Immunotherapy for Hepatocellular Carcinoma. Curr Med Chem 2021; 28:3107-3146. [PMID: 33050856 DOI: 10.2174/0929867327666201013162144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/25/2020] [Accepted: 09/01/2020] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with nearly one million new cases and deaths every year. Owing to the complex pathogenesis, hidden early symptoms, rapidly developing processes, and poor prognosis, the morbidity and mortality of HCC are increasing yearly. With the progress being made in modern medicine, the treatment of HCC is no longer limited to traditional methods. Targeted therapy and immunotherapy have emerged to treat advanced and metastatic HCC in recent years. Since Sorafenib is the first molecular targeting drug against angiogenesis, targeted drugs for HCC are continually emerging. Moreover, immunotherapy plays a vital role in clinical trials. In particular, the application of immune checkpoint inhibitors, which have received increasing attention in the field of cancer treatment, is a possible research path. Interestingly, these two therapies generally complement each other at some stages of HCC, bringing new hope for patients with advanced HCC. In this paper, we discuss the research progress of targeted therapy and immunotherapy for HCC in recent years, which will provide a reference for the further development of drugs for HCC.
Collapse
Affiliation(s)
- Tao Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Qiting Zhang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ning Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ziqi Liu
- Department of Pharmacy, the PLA Rocket Force Characteristic Medical Center, Beijing 100088, China
| | - Bin Zhang
- Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Yufen Zhao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| |
Collapse
|
|
30
|
The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet. Transl Res 2021; 227:75-88. [PMID: 32711187 DOI: 10.1016/j.trsl.2020.07.008] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 07/14/2020] [Accepted: 07/16/2020] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disorder related to type 2 diabetes (T2D). The disease can evolve toward nonalcoholic steatohepatitis (NASH), a state of hepatic inflammation and fibrosis. There is presently no drug that effectively improves and/or prevents NAFLD/NASH/fibrosis. GLP-1 receptor agonists (GLP-1Ra) are effective in treating T2D. As with the endogenous gut incretins, GLP-1Ra potentiate glucose-induced insulin secretion. In addition, GLP-1Ra limit food intake and weight gain, additional beneficial properties in the context of obesity/insulin-resistance. Nevertheless, these pleiotropic effects of GLP-1Ra complicate the elucidation of their direct action on the liver. In the present study, we used the classical methionine-choline deficient (MCD) dietary model to investigate the potential direct hepatic actions of the GLP-1Ra liraglutide. A 4-week infusion of liraglutide (570 µg/kg/day) did not impact body weight, fat accretion or glycemic control in MCD-diet fed mice, confirming the suitability of this model for avoiding confounding factors. Liraglutide treatment did not prevent lipid deposition in the liver of MCD-fed mice but limited the accumulation of C16 and C24-ceramide/sphingomyelin species. In addition, liraglutide treatment alleviated hepatic inflammation (in particular accumulation of M1 pro-inflammatory macrophages) and initiation of fibrosis. Liraglutide also influenced the composition of gut microbiota induced by the MCD-diet. This included recovery of a normal Bacteroides proportion and, among the Erysipelotrichaceae family, a shift between Allobaculum and Turicibacter genera. In conclusion, liraglutide prevents accumulation of C16 and C24-ceramides/sphingomyelins species, inflammation and initiation of fibrosis in MCD-diet-fed mice liver, suggesting beneficial hepatic actions independent of weight loss and global hepatic steatosis.
Collapse
|
|
31
|
Hepatocyte cannabinoid 1 receptor nullification alleviates toxin-induced liver damage via NF-κB signaling. Cell Death Dis 2020; 11:1044. [PMID: 33298885 PMCID: PMC7726564 DOI: 10.1038/s41419-020-03261-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 12/18/2022]
Abstract
Cannabinoid 1 receptor (CB1R) expression is upregulated in the liver with viral hepatitis, cirrhosis, and both alcoholic and non-alcoholic fatty liver disease (FLD), whereas its expression is muted under usual physiological conditions. Inhibiting CB1R has been shown to be beneficial in preserving hepatic function in FLD but it is unclear if inhibiting CB1R during an inflammatory response to an acute hepatic injury, such as toxin-induced injury, would also be beneficial. We found that intrinsic CB1R in hepatocytes regulated liver inflammation-related gene transcription. We tested if nullification of hepatocyte-specific CB1R (hCNR1−/−) in mice protects against concanavalin A (Con A)-induced liver injury. We looked for evidence of liver damage and markers of inflammation in response to Con A by measuring liver enzyme levels and proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IL-17) in serum collected from hCNR1−/− and control mice. We observed a shift to the right in the dose-response curve for liver injury and inflammation in hCNR1−/− mice. We also found less inflammatory cell infiltration and focal necrosis in livers of hCNR1−/− mice compared to controls, resulting from downregulated apoptotic markers. This anti-apoptotic mechanism results from increased activation of nuclear factor kappa B (NF-κB), especially cAMP-dependent cannabinoid signaling and membrane-bound TNF-α, via downregulated TNF-α receptor 2 (TNFR2) transcription levels. Collectively, these findings provide insight into involvement of CB1R in the pathogenesis of acute liver injury.
Collapse
|
|
32
|
Cornwell AC, Feigin ME. Unintended Effects of GPCR-Targeted Drugs on the Cancer Phenotype. Trends Pharmacol Sci 2020; 41:1006-1022. [PMID: 33198923 PMCID: PMC7672258 DOI: 10.1016/j.tips.2020.10.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/28/2020] [Accepted: 10/01/2020] [Indexed: 12/11/2022]
Abstract
G protein-coupled receptors (GPCRs) are the most common class of therapeutic targets, accounting for ~35% of all FDA-approved drugs. Cancer patients receive numerous medications not only to combat cancer but also to alleviate pain, nausea, and anxiety, many of which target GPCRs. Emerging evidence has implicated GPCRs as drivers of cancer progression, therapeutic resistance, and metastasis. Therefore, the effects of commonly prescribed GPCR-targeted drugs must be reevaluated in the context of cancer. Epidemiological and experimental evidence indicate that widely used GPCR-targeted drugs may promote or inhibit cancer progression. It is crucial that we more fully understand the indirect effects of GPCR-targeted drugs on the cancer phenotype. This review summarizes recent advances in characterizing these interactions and highlights future research opportunities.
Collapse
Affiliation(s)
- Abigail C Cornwell
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Michael E Feigin
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
| |
Collapse
|
|
33
|
Dewidar B, Kahl S, Pafili K, Roden M. Metabolic liver disease in diabetes - From mechanisms to clinical trials. Metabolism 2020; 111S:154299. [PMID: 32569680 PMCID: PMC7305712 DOI: 10.1016/j.metabol.2020.154299] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/04/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises fatty liver (steatosis), non-alcoholic steatohepatitis (NASH) and fibrosis/cirrhosis and may lead to end-stage liver failure or hepatocellular carcinoma. NAFLD is tightly associated with the most frequent metabolic disorders, such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). Both multisystem diseases share several common mechanisms. Alterations of tissue communications include excessive lipid and later cytokine release by dysfunctional adipose tissue, intestinal dysbiosis and ectopic fat deposition in skeletal muscle. On the hepatocellular level, this leads to insulin resistance due to abnormal lipid handling and mitochondrial function. Over time, cellular oxidative stress and activation of inflammatory pathways, again supported by multiorgan crosstalk, determine NAFLD progression. Recent studies show that particularly the severe insulin resistant diabetes (SIRD) subgroup (cluster) associates with NAFLD and its accelerated progression and increases the risk of diabetes-related cardiovascular and kidney diseases, underpinning the critical role of insulin resistance. Consequently, lifestyle modification and certain drug classes used to treat T2DM have demonstrated effectiveness for treating NAFLD, but also some novel therapeutic concepts may be beneficial for both NAFLD and T2DM. This review addresses the bidirectional relationship between mechanisms underlying T2DM and NAFLD, the relevance of novel biomarkers for improving the diagnostic modalities and the identification of subgroups at specific risk of disease progression. Also, the role of metabolism-related drugs in NAFLD is discussed in light of the recent clinical trials. Finally, this review highlights some challenges to be addressed by future studies on NAFLD in the context of T2DM.
Collapse
Affiliation(s)
- Bedair Dewidar
- Institute of Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Sabine Kahl
- Institute of Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany
| | - Kalliopi Pafili
- Institute of Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany
| | - Michael Roden
- Institute of Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany; Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
| |
Collapse
|
|
34
|
Kojima M, Takahashi H, Kuwashiro T, Tanaka K, Mori H, Ozaki I, Kitajima Y, Matsuda Y, Ashida K, Eguchi Y, Anzai K. Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis. Int J Mol Sci 2020; 21:ijms21165722. [PMID: 32785012 PMCID: PMC7460814 DOI: 10.3390/ijms21165722] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive β-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes.
Collapse
Affiliation(s)
- Motoyasu Kojima
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Takuya Kuwashiro
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
| | - Hitoe Mori
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
| | - Iwata Ozaki
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
| | - Yoichiro Kitajima
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Department of Radiology, Eguchi Hospital, Ogi 845-0032, Japan
| | - Yayoi Matsuda
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kenji Ashida
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Yuichiro Eguchi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Keizo Anzai
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Correspondence: ; Tel./Fax: +81-952-34-2362
| |
Collapse
|
|
35
|
Chen QF, Huang T, Si-Tu QJ, Wu P, Shen L, Li W, Huang Z. Analysis of competing endogenous RNA network identifies a poorly differentiated cancer-specific RNA signature for hepatocellular carcinoma. J Cell Biochem 2019; 121:2303-2317. [PMID: 31642123 DOI: 10.1002/jcb.29454] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 10/08/2019] [Indexed: 12/12/2022]
Abstract
Plenty of evidence has suggested that long noncoding RNAs (lncRNAs) play a vital role in competing endogenous RNA (ceRNA) networks. Poorly differentiated hepatocellular carcinoma (PDHCC) is a malignant phenotype. This paper aimed to explore the effect and the underlying regulatory mechanism of lncRNAs on PDHCC as a kind of ceRNA. Additionally, prognosis prediction was assessed. A total of 943 messenger RNAs (mRNAs), 86 miRNAs, and 468 lncRNAs that were differentially expressed between 137 PDHCCs and 235 well-differentiated HCCs were identified. Thereafter, a ceRNA network related to the dysregulated lncRNAs was established according to bioinformatic analysis and included 29 lncRNAs, 9 miRNAs, and 96 mRNAs. RNA-related overall survival (OS) curves were determined using the Kaplan-Meier method. The lncRNA ARHGEF7-AS2 was markedly correlated with OS in HCC (P = .041). Moreover, Cox regression analysis revealed that patients with low ARHGEF7-AS2 expression were associated with notably shorter survival time (P = .038). In addition, the area under the curve values of the lncRNA signature for 1-, 3-, and 5-year survival were 0.806, 0.741, and 0.701, respectively. Furthermore, a lncRNA nomogram was established, and the C-index of the internal validation was 0.717. In vitro experiments were performed to demonstrate that silencing ARHGEF7-AS2 expression significantly promoted HCC cell proliferation and migration. Taken together, our findings shed more light on the ceRNA network related to lncRNAs in PDHCC, and ARHGEF7-AS2 may be used as an independent biomarker to predict the prognosis of HCC.
Collapse
Affiliation(s)
- Qi-Feng Chen
- Department of Medical Imaging and Interventional Radiology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.,Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Tao Huang
- Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Qi-Jiao Si-Tu
- Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Peihong Wu
- Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Lujun Shen
- Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Wang Li
- Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Zilin Huang
- Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| |
Collapse
|
|
36
|
Nagy T, Fisi V, Frank D, Kátai E, Nagy Z, Miseta A. Hyperglycemia-Induced Aberrant Cell Proliferation; A Metabolic Challenge Mediated by Protein O-GlcNAc Modification. Cells 2019; 8:E999. [PMID: 31466420 PMCID: PMC6769692 DOI: 10.3390/cells8090999] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 08/26/2019] [Accepted: 08/26/2019] [Indexed: 12/13/2022] Open
Abstract
Chronic hyperglycemia has been associated with an increased prevalence of pathological conditions including cardiovascular disease, cancer, or various disorders of the immune system. In some cases, these associations may be traced back to a common underlying cause, but more often, hyperglycemia and the disturbance in metabolic balance directly facilitate pathological changes in the regular cellular functions. One such cellular function crucial for every living organism is cell cycle regulation/mitotic activity. Although metabolic challenges have long been recognized to influence cell proliferation, the direct impact of diabetes on cell cycle regulatory elements is a relatively uncharted territory. Among other "nutrient sensing" mechanisms, protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification emerged in recent years as a major contributor to the deleterious effects of hyperglycemia. An increasing amount of evidence suggest that O-GlcNAc may significantly influence the cell cycle and cellular proliferation. In our present review, we summarize the current data available on the direct impact of metabolic changes caused by hyperglycemia in pathological conditions associated with cell cycle disorders. We also review published experimental evidence supporting the hypothesis that O-GlcNAc modification may be one of the missing links between metabolic regulation and cellular proliferation.
Collapse
Affiliation(s)
- Tamás Nagy
- Department of Laboratory Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary.
| | - Viktória Fisi
- Department of Laboratory Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary
| | - Dorottya Frank
- Department of Dentistry, Oral and Maxillofacial Surgery, Medical School, University of Pécs, H-7621 Pécs, Hungary
| | - Emese Kátai
- Department of Laboratory Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary
| | - Zsófia Nagy
- Department of Laboratory Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary
| | - Attila Miseta
- Department of Laboratory Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary
| |
Collapse
|
|
37
|
Cheng F, Yuan G, He J, Shao Y, Zhang J, Guo X. Dysregulation of DPP4 Is Associated with the AMPK/JAK2/STAT3 Pathway in Adipocytes Under Insulin Resistance Status and Liraglutide Intervention. Diabetes Metab Syndr Obes 2019; 12:2635-2644. [PMID: 31849507 PMCID: PMC6911808 DOI: 10.2147/dmso.s229838] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 12/02/2019] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Dipeptidyl peptidase 4 (DPP4) is one of the newly identified adipokines, which acts as paracrine in adipose tissue and as endocrine hormones in the liver, muscles and central nervous system. Expression of DPP4 was significantly upregulated in obese patients upon insulin resistance (IR) conditions, but the mechanism underlying the dysregulation of DPP4 remains unclear. This study aimed to investigate the DPP4 expression in adipose tissue and adipocytes under IR conditions or with liraglutide intervention, and explore the potential molecular mechanisms. METHODS Obesity-associated IR animal and cell models were, respectively, constructed by using high-fat diet and palmitic acid (PA) stimulation. Expression of DPP4 in adipose tissues and adipocytes was estimated by quantitative real-time RT-PCR and Western-blot. Effects of the AMPK/JAK2/STAT3 pathway on DPP4 were examined by regulating the activity of AMPK and the JAK2/STAT signaling. The therapeutic efficacy of liraglutide in the IR models was evaluated, and its regulatory effects on DPP4 expression and the underlying molecular mechanisms were explored. RESULTS The expression of DPP4 was markedly upregulated in both the animal and cell IR models. In the adipocyte, DPP4 expression was found to be suppressed by the activation of AMPK, and this inhibition effect was mediated by the JAK2/STAT3 signaling. Moreover, liraglutide could alleviate the obesity-induced IR, and led to the downregulation of DPP4 in IR animal and cell models. Liraglutide intervention resulted in the activation of AMPK and deactivation of the JAK2/STAT3 signaling in the adipocytes. CONCLUSION Taken together, the expression of DPP4 is upregulated in adipose tissues and adipocytes upon IR conditions, but is reduced after liraglutide intervention. The dysregulation of DPP4 in the adipocytes may be performed by the AMPK/JAK2/STAT3 pathway.
Collapse
Affiliation(s)
- Fangxiao Cheng
- Department of Endocrinology, Peking University First Hospital, Beijing100034, People’s Republic of China
| | - Geheng Yuan
- Department of Endocrinology, Peking University First Hospital, Beijing100034, People’s Republic of China
- Correspondence: Geheng Yuan; Xiaohui Guo Department of Endocrinology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing100034, People’s Republic of ChinaTel\Fax +86 010 83575103 Email ;
| | - Jiao He
- Department of Endocrinology, Baoding First Central Hospital, Baoding071000, Hebei Province, People’s Republic of China
| | - Yimin Shao
- Department of Endocrinology, Peking University First Hospital, Beijing100034, People’s Republic of China
| | - Junqing Zhang
- Department of Endocrinology, Peking University First Hospital, Beijing100034, People’s Republic of China
| | - Xiaohui Guo
- Department of Endocrinology, Peking University First Hospital, Beijing100034, People’s Republic of China
| |
Collapse
|
|
38
|
Cani PD, Jordan BF. Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer. Nat Rev Gastroenterol Hepatol 2018; 15:671-682. [PMID: 29844585 DOI: 10.1038/s41575-018-0025-6] [Citation(s) in RCA: 271] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Overweight and obesity are associated with increased risk of developing metabolic disorders such as diabetes and cardiovascular diseases. However, besides these metabolic diseases, excess body weight is also associated with different cancers, including gastrointestinal cancers, such as liver, pancreatic and colon cancers. Inflammation is a common feature of both obesity and cancer; however, the origin of this inflammation has been largely debated. Over the past decade, growing evidence has shown that the composition of the gut microbiota and its activity might be associated not only with the onset of inflammation but also with metabolic disorders and cancer. Here, we review the links between the gut microbiota, gut barrier function and the onset of low-grade inflammation in the development of gastrointestinal cancer. We also describe the mechanisms by which specific microorganism-associated molecular patterns crosstalk with the immune system and how the metabolic activity of bacteria induces specific signalling pathways beyond the gut that eventually trigger carcinogenesis.
Collapse
Affiliation(s)
- Patrice D Cani
- Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium.
| | - Benedicte F Jordan
- Université catholique de Louvain, Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Brussels, Belgium
| |
Collapse
|
|
39
|
Wahlang B, McClain C, Barve S, Gobejishvili L. Role of cAMP and phosphodiesterase signaling in liver health and disease. Cell Signal 2018; 49:105-115. [PMID: 29902522 PMCID: PMC6445381 DOI: 10.1016/j.cellsig.2018.06.005] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 06/08/2018] [Accepted: 06/09/2018] [Indexed: 02/06/2023]
Abstract
Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.
Collapse
Affiliation(s)
- Banrida Wahlang
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA
| | - Craig McClain
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA; Robley Rex Louisville VAMC, Louisville, KY, USA
| | - Shirish Barve
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA
| | - Leila Gobejishvili
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA.
| |
Collapse
|
|
40
|
Peng Y, Li Y, Tian Y, Ao G. PDE4a predicts poor prognosis and promotes metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. J Cancer 2018; 9:2389-2396. [PMID: 30026835 PMCID: PMC6036708 DOI: 10.7150/jca.24079] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 03/23/2018] [Indexed: 12/12/2022] Open
Abstract
Phosphodiesterases (PDEs) was found to be involved in a variety of cancer pathologies by modulating the degradation of levels of cAMP/cGMP. However, the prognostic significance and biological effect of PDE4a in hepatocellular carcinoma (HCC) have not been understood completely. In the present study, PDE4a expression was detected in a cohort of HCC and matched adjacent liver tissues (n = 210) by immunohistochemistry staining and Western immunoblotting assay, And in vitro experiments were conducted to determine the effect of PDE4a on metastatic capacity of HCC cells. The data here displayed that the majority of HCC patients had higher PDE4a expression in tumor tissues compared to matched adjacent liver tissues and enhanced PDE4a expression in tumor tissues was associated positively with HBV infection, liver cirrhosis, higher serum AFP level, advanced TNM stage, vascular embolus, intrahepatic metastases and portal vein tumor thrombus (PVTT). Survival analyses suggested that higher PDE4a was indicated the poor prognosis of HCCs after liver resection. Ectopic expression of PDE4a in Huh7 cells leaded to significant repression of E-cadherin and up-regulated the expression of N-cadherin and Vimentin, and facilitated migration and invasion abilities. Silencing PDE4a in MHCC97h cells acquired the opposite results. Taken together, PDE4a triggered EMT in HCC cells and acted as a predictive factor candidate and a potential therapeutic target for HCC.
Collapse
Affiliation(s)
- Yanghong Peng
- Department of Radiology, the 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China
| | - Yijun Li
- Department of Gastroenterology, Xi'an Central Hospital, Xian 710010, P.R. China
| | - Yu Tian
- Department of Gastroenterology, the 6th Affiliated Hospital of Xinjiang Medical University, Urumchi 830002, P.R. China
| | - Guokun Ao
- Department of Radiology, the 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China
| |
Collapse
|
|
41
|
Hu W, Lv J, Han M, Yang Z, Li T, Jiang S, Yang Y. STAT3: The art of multi-tasking of metabolic and immune functions in obesity. Prog Lipid Res 2018; 70:17-28. [PMID: 29635003 DOI: 10.1016/j.plipres.2018.04.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 04/04/2018] [Accepted: 04/06/2018] [Indexed: 02/07/2023]
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that has recently attracted increased attention. Accumulating studies have demonstrated that STAT3 plays an important role in various diseases, such as cancer and ischemic injury. In light of the distinctive effects of STAT3 on the regulation of metabolism and immune responses, we present the elaborate network of STAT3 in obesity. In this review, we first introduce the general background of STAT3, including a discussion regarding the STAT family and the characterization and regulation of STAT3. Then, we describe the STAT3 signaling network and its pathophysiological roles in lipid and glucose metabolism and immune function. Finally, we highlight the research progress regarding STAT3 in obesity. The information presented here may be useful for the design of future studies and may highlight the potential of STAT3 as a future therapeutic target for obesity.
Collapse
Affiliation(s)
- Wei Hu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai North Road, Xi'an 710069, China; Department of Immunology, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Jianjun Lv
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Mengzhen Han
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai North Road, Xi'an 710069, China
| | - Zhi Yang
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Tian Li
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Shuai Jiang
- Department of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai North Road, Xi'an 710069, China; Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
| |
Collapse
|