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Russo R, Colantuono A, Di Gaetano S, Capasso D, Tito A, Pedone E, Pirone L. Phaseolus coccineus Seed: A Valued Resource for Bioactive Compounds Targeting Health and Tumor Cells. Int J Mol Sci 2025; 26:2189. [PMID: 40076808 PMCID: PMC11900370 DOI: 10.3390/ijms26052189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 02/19/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
Human galectin-3 (Gal-3), a β-galactoside binding lectin through its Carbohydrate Recognition Domain (CRD), is implicated in a wide range of cellular functions and is involved in critical biological processes including pathogen recognition, immune response, inflammation and fibrosis. Recently, Gal-3 has gained increasing attention for its role in pathological conditions such as cancer, where it influences cancer growth and progression, inflammatory processes and oxidative stress, opening the search for potential inhibitors. In this context, several naturally derived molecules have attracted particular interest, some of them being used in clinical trials. Here, we used the seeds of the legume Phaseolus coccineus as a green resource for bioactive compounds. The peptide-rich crude extracts were chemically characterized for their peptide and polyphenol contents, as well as their in vitro antioxidant activity, and the powerful obtained extract was tested for biological activities such as cytotoxicity and antioxidant and anti-inflammatory effects on cellular models. Furthermore, the interaction between the crude extract and the CRD of recombinant Gal-3 was verified with the aim of associating its biological effects with the inhibition of Gal-3 activity.
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Affiliation(s)
- Rita Russo
- Institute of Biostructures and Bioimaging, Via Pietro Castellino 111, 80131 Naples, Italy; (R.R.); (S.D.G.)
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
| | - Antonio Colantuono
- Arterra Bioscience S.p.A., Via Benedetto Brin 69, 80142 Napoli, Italy; (A.C.); (A.T.)
| | - Sonia Di Gaetano
- Institute of Biostructures and Bioimaging, Via Pietro Castellino 111, 80131 Naples, Italy; (R.R.); (S.D.G.)
| | - Domenica Capasso
- Department of Physics “Ettore Pancini”, University of Naples Federico II, Via Cinthia 4, 80126 Naples, Italy;
| | - Annalisa Tito
- Arterra Bioscience S.p.A., Via Benedetto Brin 69, 80142 Napoli, Italy; (A.C.); (A.T.)
| | - Emilia Pedone
- Institute of Biostructures and Bioimaging, Via Pietro Castellino 111, 80131 Naples, Italy; (R.R.); (S.D.G.)
| | - Luciano Pirone
- Institute of Biostructures and Bioimaging, Via Pietro Castellino 111, 80131 Naples, Italy; (R.R.); (S.D.G.)
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2
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MacKinnon AC, Humphries DC, Herman K, Roper JA, Holyer I, Mabbitt J, Mills R, Nilsson UJ, Leffler H, Pedersen A, Schambye H, Zetterberg F, Slack RJ. Effect of GB1107, a novel galectin-3 inhibitor on pro-fibrotic signalling in the liver. Eur J Pharmacol 2024; 985:177077. [PMID: 39528104 DOI: 10.1016/j.ejphar.2024.177077] [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: 04/24/2024] [Revised: 10/09/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND AND PURPOSE Galectin-3 (Gal-3) is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. GB1107 is a novel orally active Gal-3 small molecule inhibitor that has high affinity for Gal-3 >1000-fold selectively over other galectins. The aim of this study was to characterise GB1107 and galectin-3 in vitro and in vivo in the context of fibrosis signalling and liver disease. EXPERIMENTAL APPROACH Liver fibrosis was induced by administration of CCl4 twice weekly by intraperitoneal injection in mice for 8 weeks. GB1107 was orally administered once daily (10 mg/kg) for the last 4 weeks of CCl4 treatment. Fibrosis was assessed by picrosirius red staining of FFPE sections. Liver enzymes, Gal-3 and downstream biomarkers were assessed in liver and plasma. Paired-end sequencing was performed on the Nextseq 2000 platform. Pathway enrichment analysis was performed to determine enrichment of differentially expressed genes (DEGs) within Reactome pathways and Gene Ontology (GO) terms. KEY RESULTS GB1107 significantly reduced plasma transaminases and liver Gal-3 and reduced liver fibrosis. RNAseq analysis of whole liver showed that 1659 DEGs were identified with CCl4 treatment compared to control. Pathways enriched in up-regulated genes in the CCl4 group included those related to the extracellular matrix, collagen biosynthesis and assembly, cell cycle and the immune system. Comparing GB1107 treatment with CCl4 control 1147 DEGs were identified. GB1107 effectively reversed the majority of the CCl4 induced gene changes. CONCLUSIONS AND IMPLICATIONS GB1107 attenuated liver fibrosis and highlights Gal-3 as a therapeutic target for hepatic fibrosis.
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Affiliation(s)
- Alison C MacKinnon
- Galecto Biotech AB, Nine Edinburgh Bioquarter, 9 Little France Rd, Edinburgh, EH16 4UX, UK
| | - Duncan C Humphries
- Galecto Biotech AB, Nine Edinburgh Bioquarter, 9 Little France Rd, Edinburgh, EH16 4UX, UK
| | - Kimberley Herman
- Galecto Biotech AB, Nine Edinburgh Bioquarter, 9 Little France Rd, Edinburgh, EH16 4UX, UK
| | - James A Roper
- Galecto Biotech AB, Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, SG1 2FX, UK
| | - Ian Holyer
- Galecto Biotech AB, Nine Edinburgh Bioquarter, 9 Little France Rd, Edinburgh, EH16 4UX, UK
| | - Joseph Mabbitt
- Galecto Biotech AB, Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, SG1 2FX, UK
| | - Ross Mills
- Centre for Inflammation Research, The University of Edinburgh, Edinburgh, EH16 4TJ, UK
| | - Ulf J Nilsson
- Department of Chemistry, Lund University, 22100, Lund, Sweden
| | - Hakon Leffler
- Department of Laboratory Medicine, Lund University, 22100, Lund, Sweden
| | | | | | - Fredrik Zetterberg
- Galecto Biotech AB, Sahlgrenska Science Park, Gothenburg, S-413 46, Sweden
| | - Robert J Slack
- Galecto Biotech AB, Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, SG1 2FX, UK.
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Xie Z, Li Y, Cheng L, Huang Y, Rao W, Shi H, Li J. Potential therapeutic strategies for MASH: from preclinical to clinical development. LIFE METABOLISM 2024; 3:loae029. [PMID: 39872142 PMCID: PMC11749562 DOI: 10.1093/lifemeta/loae029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/16/2024] [Accepted: 07/05/2024] [Indexed: 01/03/2025]
Abstract
Current treatment paradigms for metabolic dysfunction-associated steatohepatitis (MASH) are based primarily on dietary restrictions and the use of existing drugs, including anti-diabetic and anti-obesity medications. Given the limited number of approved drugs specifically for MASH, recent efforts have focused on promising strategies that specifically target hepatic lipid metabolism, inflammation, fibrosis, or a combination of these processes. In this review, we examined the pathophysiology underlying the development of MASH in relation to recent advances in effective MASH therapy. Particularly, we analyzed the effects of lipogenesis inhibitors, nuclear receptor agonists, glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, fibroblast growth factor mimetics, and combinatorial therapeutic approaches. We summarize these targets along with their preclinical and clinical candidates with the ultimate goal of optimizing the therapeutic prospects for MASH.
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Affiliation(s)
- Zhifu Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yufeng Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Long Cheng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yidan Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wanglin Rao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
| | - Honglu Shi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jingya Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
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Guixé-Muntet S, Quesada-Vázquez S, Gracia-Sancho J. Pathophysiology and therapeutic options for cirrhotic portal hypertension. Lancet Gastroenterol Hepatol 2024; 9:646-663. [PMID: 38642564 DOI: 10.1016/s2468-1253(23)00438-7] [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] [Received: 10/09/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 04/22/2024]
Abstract
Portal hypertension represents the primary non-neoplastic complication of liver cirrhosis and has life-threatening consequences, such as oesophageal variceal bleeding, ascites, and hepatic encephalopathy. Portal hypertension occurs due to increased resistance of the cirrhotic liver vasculature to portal blood flow and is further aggravated by the hyperdynamic circulatory syndrome. Existing knowledge indicates that the profibrogenic phenotype acquired by sinusoidal cells is the initial factor leading to increased hepatic vascular tone and fibrosis, which cause increased vascular resistance and portal hypertension. Data also suggest that the phenotype of hepatic cells could be further impaired due to the altered mechanical properties of the cirrhotic liver itself, creating a deleterious cycle that worsens portal hypertension in the advanced stages of liver disease. In this Review, we discuss recent discoveries in the pathophysiology and treatment of cirrhotic portal hypertension, a condition with few pharmacological treatment options.
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Affiliation(s)
- Sergi Guixé-Muntet
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Sergio Quesada-Vázquez
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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5
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Leaker BD, Sojoodi M, Tanabe KK, Popov YV, Tam J, Anderson RR. Increased susceptibility to ischemia causes exacerbated response to microinjuries in the cirrhotic liver. FASEB J 2024; 38:e23585. [PMID: 38661043 DOI: 10.1096/fj.202301438rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 03/07/2024] [Accepted: 03/18/2024] [Indexed: 04/26/2024]
Abstract
Fractional laser ablation is a technique developed in dermatology to induce remodeling of skin scars by creating a dense pattern of microinjuries. Despite remarkable clinical results, this technique has yet to be tested for scars in other tissues. As a first step toward determining the suitability of this technique, we aimed to (1) characterize the response to microinjuries in the healthy and cirrhotic liver, and (2) determine the underlying cause for any differences in response. Healthy and cirrhotic rats were treated with a fractional laser then euthanized from 0 h up to 14 days after treatment. Differential expression was assessed using RNAseq with a difference-in-differences model. Spatial maps of tissue oxygenation were acquired with hyperspectral imaging and disruptions in blood supply were assessed with tomato lectin perfusion. Healthy rats showed little damage beyond the initial microinjury and healed completely by 7 days without scarring. In cirrhotic rats, hepatocytes surrounding microinjury sites died 4-6 h after ablation, resulting in enlarged and heterogeneous zones of cell death. Hepatocytes near blood vessels were spared, particularly near the highly vascularized septa. Gene sets related to ischemia and angiogenesis were enriched at 4 h. Laser-treated regions had reduced oxygen saturation and broadly disrupted perfusion of nodule microvasculature, which matched the zones of cell death. Our results demonstrate that the cirrhotic liver has an exacerbated response to microinjuries and increased susceptibility to ischemia from microvascular damage, likely related to the vascular derangements that occur during cirrhosis development. Modifications to the fractional laser tool, such as using a femtosecond laser or reducing the spot size, may be able to prevent large disruptions of perfusion and enable further development of a laser-induced microinjury treatment for cirrhosis.
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Affiliation(s)
- Ben D Leaker
- Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Mozhdeh Sojoodi
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Kenneth K Tanabe
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Yury V Popov
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Joshua Tam
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA
| | - R Rox Anderson
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA
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Sotoudeheian M. Galectin-3 and Severity of Liver Fibrosis in Metabolic Dysfunction-Associated Fatty Liver Disease. Protein Pept Lett 2024; 31:290-304. [PMID: 38715329 DOI: 10.2174/0109298665301698240404061300] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/02/2024] [Accepted: 03/21/2024] [Indexed: 08/13/2024]
Abstract
Metabolic dysfunction-associated Fatty Liver Disease (MAFLD) is a chronic liver disease characterized by the accumulation of fat in the liver and hepatic steatosis, which can progress to critical conditions, including Metabolic dysfunction-associated Steatohepatitis (MASH), liver fibrosis, hepatic cirrhosis, and hepatocellular carcinoma. Galectin-3, a member of the galectin family of proteins, has been involved in cascades that are responsible for the pathogenesis and progression of liver fibrosis in MAFLD. This review summarizes the present understanding of the role of galectin-3 in the severity of MAFLD and its associated liver fibrosis. The article assesses the underlying role of galectin-3-mediated fibrogenesis, including the triggering of hepatic stellate cells, the regulation of extracellular degradation, and the modulation of immune reactions and responses. It also highlights the assessments of the potential diagnostic and therapeutic implications of galectin-3 in liver fibrosis during MAFLD. Overall, this review provides insights into the multifaceted interaction between galectin-3 and liver fibrosis in MAFLD, which could lead to the development of novel strategies for diagnosis and treatment of this prevalent liver disease.
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7
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Abubakr S, Hazem NM, Sherif RN, Elhawary AA, Botros KG. Correlation between SDF-1α, CD34 positive hematopoietic stem cells and CXCR4 expression with liver fibrosis in CCl4 rat model. BMC Gastroenterol 2023; 23:323. [PMID: 37730560 PMCID: PMC10512633 DOI: 10.1186/s12876-023-02932-y] [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: 04/22/2023] [Accepted: 08/25/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND One of the most frequent disorders is liver fibrosis. An improved understanding of the different events during the process of liver fibrosis & its reversibility could be helpful in its staging and in finding potential therapeutic agents. AIM The goal of this research was to evaluate the relationship among CD34 + HPSCs, SDF-1α, and CXCR4 receptor expression with the percentage of the area of hepatic fibrosis. MATERIALS AND METHODS Thirty-six male Sprague-Dawley rats were separated into the control group, liver injury group & spontaneous reversion group. The liver injury was induced by using 2 ml/kg CCl4 twice a week. Flow cytometric examination of CD34 + cells in the blood & liver was performed. Bone marrow & liver samples were taken for evaluation of the SDF-1α mRNA by PCR. Liver specimens were stained for histopathological and CXCR4 immuno-expression evaluation. RESULTS In the liver injury group, the hepatic enzymes, fibrosis area percentage, CXCR4 receptor expression in the liver, CD34 + cells in the blood and bone marrow & the level SDF-1α in the liver and its concentration gradient were statistically significantly elevated with the progression of the liver fibrosis. On the contrary, SDF-1α in the bone marrow was statistically significantly reduced with the development of liver fibrosis. During the spontaneous reversion group, all the studied parameters apart from SDF-1α in the bone marrow were statistically substantially decreased compared with the liver injury group. We found a statistically substantial positive correlation between fibrosis area and all of the following: liver enzymes, CXCR4 receptor expression in the liver, CD34 + cells in the blood and liver, and SDF- 1α in the liver and its concentration gradient. In conclusion, in CCl4 rat model, the fibrosis area is significantly correlated with many parameters in the blood, bone marrow, and liver, which can be used during the process of follow-up during the therapeutic interventions.
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Affiliation(s)
- Sara Abubakr
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Noha M Hazem
- Medical Biochemistry and Molecular Biology Department, Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Algomhoria Street, Mansoura, 35516, Egypt.
- Pathological Sciences Department, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia.
| | - R N Sherif
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Adel Abdelmohdy Elhawary
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Kamal G Botros
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Davis DA, Shrestha P, Yarchoan R. Hypoxia and hypoxia-inducible factors in Kaposi sarcoma-associated herpesvirus infection and disease pathogenesis. J Med Virol 2023; 95:e29071. [PMID: 37665216 PMCID: PMC10502919 DOI: 10.1002/jmv.29071] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/05/2023]
Abstract
Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma and several other tumors and hyperproliferative diseases seen predominantly in human immunodeficiency virus-infected and other immunocompromised persons. There is an increasing body of evidence showing that hypoxia and hypoxia-inducible factors (HIFs) play important roles in the biology of KSHV and in the pathogenesis of KSHV-induced diseases. Hypoxia and HIFs can induce lytic activation of KSHV and KSHV can in turn lead to a hypoxic-like state in infected cells. In this review, we describe the complex interactions between KSHV biology, the cellular responses to hypoxia, and the pathogenesis of KSHV-induced diseases. We also describe how interference with HIFs can lead to decreased tumor growth and/or death of infected cells and KSHV-induced tumors. Finally, we show how these observations may lead to novel strategies for the treatment of KSHV-induced diseases.
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Affiliation(s)
- David A Davis
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Prabha Shrestha
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
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Bouffette S, Botez I, De Ceuninck F. Targeting galectin-3 in inflammatory and fibrotic diseases. Trends Pharmacol Sci 2023; 44:519-531. [PMID: 37391294 DOI: 10.1016/j.tips.2023.06.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 06/02/2023] [Accepted: 06/02/2023] [Indexed: 07/02/2023]
Abstract
Galectin (Gal)-3 is a β-galactoside-binding lectin emerging as a key player in cardiac, hepatic, renal, and pulmonary fibrosis and inflammation, respiratory infections caused by COVID-19, and neuroinflammatory disorders. Here, we review recent information highlighting Gal-3 as a relevant therapeutic target in these specific disease conditions. While a causal link was difficult to establish until now, we discuss how recent strategic breakthroughs allowed us to identify new-generation Gal-3 inhibitors with improved potency, selectivity, and bioavailability, and report their usefulness as valuable tools for proof-of-concept studies in various preclinical models of the aforementioned diseases, with emphasis on those actually in clinical stages. We also address critical views and suggestions intended to expand the therapeutic opportunities provided by this complex target.
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Affiliation(s)
- Selena Bouffette
- Servier, Neurology and Immuno-inflammation Therapeutic Area, Servier R&D Center, Gif-sur-Yvette, France; Université Paris-Saclay, Inserm, Inflammation Microbiome and Immunosurveillance, Orsay, France
| | - Iuliana Botez
- Servier, Drug Design Small Molecules Unit, Servier R&D Center, Gif-sur-Yvette, France
| | - Frédéric De Ceuninck
- Servier, Neurology and Immuno-inflammation Therapeutic Area, Servier R&D Center, Gif-sur-Yvette, France.
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Liu H, Hwang SY, Lee SS. Role of Galectin in Cardiovascular Conditions including Cirrhotic Cardiomyopathy. Pharmaceuticals (Basel) 2023; 16:978. [PMID: 37513890 PMCID: PMC10386075 DOI: 10.3390/ph16070978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/27/2023] [Accepted: 07/04/2023] [Indexed: 07/30/2023] Open
Abstract
Abnormal cardiac function in the setting of cirrhosis and in the absence of a primary cardiac disease is known as cirrhotic cardiomyopathy. The pathogenesis of cirrhotic cardiomyopathy is multifactorial but broadly is comprised of two pathways. The first is due to cirrhosis and synthetic liver failure with abnormal structure and function of many substances, including proteins, lipids, hormones, and carbohydrates such as lectins. The second is due to portal hypertension which invariably accompanies cirrhosis. Portal hypertension leads to a leaky, congested gut with resultant endotoxemia and systemic inflammation. This inflammatory phenotype comprises oxidative stress, cellular apoptosis, and inflammatory cell infiltration. Galectins exert all these pro-inflammatory mechanisms across many different tissues and organs, including the heart. Effective therapies for improving cardiac function in patients with cirrhosis are not available. Conventional strategies for other noncirrhotic heart diseases, including vasodilators, are not feasible because of the significant baseline vasodilation in cirrhotic patients. Therefore, exploring new treatment modalities for cirrhotic cardiomyopathy is of great importance. Galectin-3 inhibitors such as modified citrus pectin, N-acetyllactosamine, TD139 and GB0139 exert anti-apoptotic, anti-oxidative and anti-inflammatory effects and thus have potential therapeutic interest. This review briefly summarizes the physiological and pathophysiological role of galectin and specifically examines its role in cardiac disease processes. We present a more detailed discussion of galectin in cardiovascular complications of cirrhosis, particularly cirrhotic cardiomyopathy. Finally, therapeutic studies of galectin-3 inhibitors in cirrhotic cardiomyopathy are reviewed.
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Affiliation(s)
- Hongqun Liu
- Liver Unit, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada
| | - Sang-Youn Hwang
- Liver Unit, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada
- Department of Internal Medicine, Dongnam Institute of Radiological & Medical Sciences, Busan 46033, Republic of Korea
| | - Samuel S Lee
- Liver Unit, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada
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Patil VS, Harish DR, Sampat GH, Roy S, Jalalpure SS, Khanal P, Gujarathi SS, Hegde HV. System Biology Investigation Revealed Lipopolysaccharide and Alcohol-Induced Hepatocellular Carcinoma Resembled Hepatitis B Virus Immunobiology and Pathogenesis. Int J Mol Sci 2023; 24:11146. [PMID: 37446321 DOI: 10.3390/ijms241311146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 07/15/2023] Open
Abstract
Hepatitis B infection caused by the hepatitis B virus is a life-threatening cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Researchers have produced multiple in vivo models for hepatitis B virus (HBV) and, currently, there are no specific laboratory animal models available to study HBV pathogenesis or immune response; nonetheless, their limitations prevent them from being used to study HBV pathogenesis, immune response, or therapeutic methods because HBV can only infect humans and chimpanzees. The current study is the first of its kind to identify a suitable chemically induced liver cirrhosis/HCC model that parallels HBV pathophysiology. Initially, data from the peer-reviewed literature and the GeneCards database were compiled to identify the genes that HBV and seven drugs (acetaminophen, isoniazid, alcohol, D-galactosamine, lipopolysaccharide, thioacetamide, and rifampicin) regulate. Functional enrichment analysis was performed in the STRING server. The network HBV/Chemical, genes, and pathways were constructed by Cytoscape 3.6.1. About 1546 genes were modulated by HBV, of which 25.2% and 17.6% of the genes were common for alcohol and lipopolysaccharide-induced hepatitis. In accordance with the enrichment analysis, HBV activates the signaling pathways for apoptosis, cell cycle, PI3K-Akt, TNF, JAK-STAT, MAPK, chemokines, NF-kappa B, and TGF-beta. In addition, alcohol and lipopolysaccharide significantly activated these pathways more than other chemicals, with higher gene counts and lower FDR scores. In conclusion, alcohol-induced hepatitis could be a suitable model to study chronic HBV infection and lipopolysaccharide-induced hepatitis for an acute inflammatory response to HBV.
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Affiliation(s)
- Vishal S Patil
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Darasaguppe R Harish
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
| | - Ganesh H Sampat
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Subarna Roy
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
| | - Sunil S Jalalpure
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Pukar Khanal
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Swarup S Gujarathi
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Harsha V Hegde
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
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12
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Nathani RR, Bansal MB. Update on Clinical Trials for Nonalcoholic Steatohepatitis. Gastroenterol Hepatol (N Y) 2023; 19:371-381. [PMID: 37771619 PMCID: PMC10524415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2023]
Abstract
Tremendous effort has been put forth over the past 2 decades in understanding the pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH). Although multiple potential targets for drug development exist, there have been no approved therapies for NAFLD/NASH. Lipotoxicity, owing to increased delivery of fatty acids to the liver, and hepatic de novo lipogenesis are key drivers of disease pathogenesis. Moreover, genetics, environmental factors, and comorbid conditions converge to determine disease progression in individual patients. Given the complexity and heterogeneity of disease pathogenesis, numerous therapeutic targets have emerged and have been tested in clinical trials. Early trial failures have provided key lessons and foundational insights to move the field forward. Current ongoing phase 3 trials and emerging phase 2 trials are reasons for optimism, and 2 drugs, obeticholic acid and resmetirom, are being evaluated for accelerated approval by the US Food and Drug Administration this year. This article highlights key features of NASH pathophysiology and drug targets, the lessons learned from completed trials, and the current landscape of phase 2 and 3 clinical trials in NASH.
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Affiliation(s)
- Rohit R. Nathani
- Department of Medicine, Mount Sinai West and Morningside Hospital, New York, New York
| | - Meena B. Bansal
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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13
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Kim H, Weidner N, Ronin C, Klein E, Roper JA, Kahl-Knutson B, Peterson K, Leffler H, Nilsson UJ, Pedersen A, Zetterberg FR, Slack RJ. Evaluating the affinity and kinetics of small molecule glycomimetics for human and mouse galectin-3 using surface plasmon resonance. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2023; 28:233-239. [PMID: 36990319 DOI: 10.1016/j.slasd.2023.03.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/08/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023]
Abstract
Galectin-3 is a beta-galactoside-binding mammalian lectin that is one of a 15-member galectin family that can bind several cell surface glycoproteins via its carbohydrate recognition domain (CRD). As a result, it can influence a range of cellular processes including cell activation, adhesion and apoptosis. Galectin-3 has been implicated in various diseases, including fibrotic disorders and cancer, and is now being therapeutically targeted by both small and large molecules. Historically, the screening and triaging of small molecule glycomimetics that bind to the galectin-3 CRD has been completed in fluorescence polarisation (FP) assays to determine KD values. Surface plasmon resonance (SPR) has not been widely used for compound screening and in this study it was used to compare human and mouse galectin-3 affinity measures between FP and SPR, as well as investigate compound kinetics. The KD estimates for a set of compounds selected from mono- and di-saccharides with affinities across a 550-fold range, correlated well between FP and SPR assay formats for both human and mouse galectin-3. Increases in affinity for compounds binding to human galectin-3 were driven by changes in both kon and koff whilst for mouse galectin-3 this was primarily due to kon. The reduction in affinity observed between human to mouse galectin-3 was also comparable between assay formats. SPR has been shown to be a viable alternative to FP for early drug discovery screening and determining KD values. In addition, it can also provide early kinetic characterisation of small molecule galectin-3 glycomimetics with robust kon and koff values generated in a high throughput manner.
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Affiliation(s)
- Henry Kim
- NovAliX, 16 rue d'Ankara, 67000 Strasbourg, France
| | | | - Céline Ronin
- NovAliX, 16 rue d'Ankara, 67000 Strasbourg, France
| | | | - James A Roper
- Galecto Biotech AB, Stevenage Bioscience Catalyst, Stevenage, Hertfordshire, SG1 2FX United Kingdom
| | - Barbro Kahl-Knutson
- Department of Laboratory Medicine, Lund University, Box 124, SE-221 00, Lund, Sweden
| | - Kristoffer Peterson
- Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8 A, SE-413 46 Gothenburg, Sweden
| | - Hakon Leffler
- Department of Laboratory Medicine, Lund University, Box 124, SE-221 00, Lund, Sweden
| | - Ulf J Nilsson
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, SE-221 00, Lund, Sweden
| | - Anders Pedersen
- Galecto Biotech AB, Cobis Science Park, Ole Maaloes Vej 3, DK-2200, Copenhagen, Denmark
| | - Fredrik R Zetterberg
- Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8 A, SE-413 46 Gothenburg, Sweden
| | - Robert J Slack
- Galecto Biotech AB, Stevenage Bioscience Catalyst, Stevenage, Hertfordshire, SG1 2FX United Kingdom.
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14
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Mackinnon AC, Tonev D, Jacoby B, Pinzani M, Slack RJ. Galectin-3: therapeutic targeting in liver disease. Expert Opin Ther Targets 2023; 27:779-791. [PMID: 37705214 DOI: 10.1080/14728222.2023.2258280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 09/08/2023] [Indexed: 09/15/2023]
Abstract
INTRODUCTION The rising incidence of liver diseases is a worldwide healthcare concern. However, the therapeutic options to manage chronic inflammation and fibrosis, the processes at the basis of morbidity and mortality of liver diseases, are very limited. Galectin 3 (Gal-3) is a protein implicated in fibrosis in multiple organs. Several Gal-3 inhibitors are currently in clinical development. AREAS COVERED This review describes our current understanding of the role of Gal-3 in chronic liver diseases, with special emphasis on fibrosis. Also, we review therapeutic advances based on Gal-3 inhibition, describing drug properties and their current status in clinical research. EXPERT OPINION Currently, the known effects of Gal-3 point to a direct activation of the NLRP3 inflammasome leading to its activation in liver macrophages and activated macrophages play a key role in tissue fibrogenesis. However, more research is needed to elucidate the role of Gal-3 in the different activation pathways, dissecting the intracellular and extracellular mechanisms of Gal-3, and its role in pathogenesis. Gal-3 could be a target for early therapy of numerous hepatic diseases and, given the lack of therapeutic options for liver fibrosis, there is a strong pharmacologic potential for Gal-3-based therapies.
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Affiliation(s)
| | - Dimitar Tonev
- Galecto Biotech AB, Cobis Science Park, Copenhagen, Denmark
| | - Brian Jacoby
- Galecto Biotech AB, Cobis Science Park, Copenhagen, Denmark
| | - Massimo Pinzani
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Robert J Slack
- Galecto Biotech AB, Cobis Science Park, Copenhagen, Denmark
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15
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Leusmann S, Ménová P, Shanin E, Titz A, Rademacher C. Glycomimetics for the inhibition and modulation of lectins. Chem Soc Rev 2023; 52:3663-3740. [PMID: 37232696 PMCID: PMC10243309 DOI: 10.1039/d2cs00954d] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Indexed: 05/27/2023]
Abstract
Carbohydrates are essential mediators of many processes in health and disease. They regulate self-/non-self- discrimination, are key elements of cellular communication, cancer, infection and inflammation, and determine protein folding, function and life-times. Moreover, they are integral to the cellular envelope for microorganisms and participate in biofilm formation. These diverse functions of carbohydrates are mediated by carbohydrate-binding proteins, lectins, and the more the knowledge about the biology of these proteins is advancing, the more interfering with carbohydrate recognition becomes a viable option for the development of novel therapeutics. In this respect, small molecules mimicking this recognition process become more and more available either as tools for fostering our basic understanding of glycobiology or as therapeutics. In this review, we outline the general design principles of glycomimetic inhibitors (Section 2). This section is then followed by highlighting three approaches to interfere with lectin function, i.e. with carbohydrate-derived glycomimetics (Section 3.1), novel glycomimetic scaffolds (Section 3.2) and allosteric modulators (Section 3.3). We summarize recent advances in design and application of glycomimetics for various classes of lectins of mammalian, viral and bacterial origin. Besides highlighting design principles in general, we showcase defined cases in which glycomimetics have been advanced to clinical trials or marketed. Additionally, emerging applications of glycomimetics for targeted protein degradation and targeted delivery purposes are reviewed in Section 4.
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Affiliation(s)
- Steffen Leusmann
- Chemical Biology of Carbohydrates (CBCH), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123 Saarbrücken, Germany.
- Department of Chemistry, Saarland University, 66123 Saarbrücken, Germany
- Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig, Germany
| | - Petra Ménová
- University of Chemistry and Technology, Prague, Technická 5, 16628 Prague 6, Czech Republic
| | - Elena Shanin
- Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
- Department of Microbiology, Immunobiology and Genetics, Max F. Perutz Laboratories, University of Vienna, Biocenter 5, 1030 Vienna, Austria
| | - Alexander Titz
- Chemical Biology of Carbohydrates (CBCH), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123 Saarbrücken, Germany.
- Department of Chemistry, Saarland University, 66123 Saarbrücken, Germany
- Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig, Germany
| | - Christoph Rademacher
- Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
- Department of Microbiology, Immunobiology and Genetics, Max F. Perutz Laboratories, University of Vienna, Biocenter 5, 1030 Vienna, Austria
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16
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Ahmed R, Anam K, Ahmed H. Development of Galectin-3 Targeting Drugs for Therapeutic Applications in Various Diseases. Int J Mol Sci 2023; 24:8116. [PMID: 37175823 PMCID: PMC10179732 DOI: 10.3390/ijms24098116] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 04/24/2023] [Accepted: 04/29/2023] [Indexed: 05/15/2023] Open
Abstract
Galectin-3 (Gal3) is one of the most studied members of the galectin family that mediate various biological processes such as growth regulation, immune function, cancer metastasis, and apoptosis. Since Gal3 is pro-inflammatory, it is involved in many diseases that are associated with chronic inflammation such as cancer, organ fibrosis, and type 2 diabetes. As a multifunctional protein involved in multiple pathways of many diseases, Gal3 has generated significant interest in pharmaceutical industries. As a result, several Gal3-targeting therapeutic drugs are being developed to address unmet medical needs. Based on the PubMed search of Gal3 to date (1987-2023), here, we briefly describe its structure, carbohydrate-binding properties, endogenous ligands, and roles in various diseases. We also discuss its potential antagonists that are currently being investigated clinically or pre-clinically by the public and private companies. The updated knowledge on Gal3 function in various diseases could initiate new clinical or pre-clinical investigations to test therapeutic strategies, and some of these strategies could be successful and recognized as novel therapeutics for unmet medical needs.
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Affiliation(s)
| | | | - Hafiz Ahmed
- GlycoMantra Inc., Biotechnology Center, University of Maryland Baltimore County, Baltimore, MD 21250, USA
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17
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Dong J, Zhang R, Xia Y, Jiang X, Zhou K, Li J, Guo M, Cao X, Zhang S. The necroptosis related gene LGALS3 can be used as a biomarker for the adverse progression from chronic HBV infection to HCC. Front Immunol 2023; 14:1142319. [PMID: 37180150 PMCID: PMC10169569 DOI: 10.3389/fimmu.2023.1142319] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/29/2023] [Indexed: 05/15/2023] Open
Abstract
The number of patients with hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) infection remains large, despite the remarkable effectiveness of antiviral drugs and vaccines for HBV in preventing and treating HBV infection. Necroptosis is closely related to the occurrence of inflammation, clearance of viral infection, and tumor progression. Presently, little is known about the changes in necroptosis-related genes in the progression from chronic HBV infection (CHI) to HBV-related hepatic fibrosis (HBV-HF) and HBV-related hepatocellular carcinoma (HBV-HCC). In this study, Cox regression analysis was performed using GSE14520 chip data and a necroptosis-related genes survival prognosis score (NRGPS) was established for HBV-HCC patients. NRGPS was constructed using three model genes (G6PD, PINK1 and LGALS3), and verified by data sequencing in the TCGA database. The HBV-HCC cell model was established by transfection of pAAV/HBV1.2C2, constructed by homologous recombination, into HUH7 and HEPG2 cells. The expression levels of G6PD, PINK1, and LGALS3 were detected using RT-qPCR. We further analyzed the expression of the model genes in GSE83148, GSE84044, and GSE14520 and found that LGALS3 was consistently highly expressed in CHI, high fibrosis score and high NRGPS. In addition, immune microenvironment analysis showed that LGALS3 was not only associated with the infiltration of regulatory T cells in the immune microenvironment but also with expression of CCL20 and CCR6. The expression levels of model genes, FOXP3 and CCR6, were analyzed using RT-qPCR in peripheral blood mononuclear cells of 31 hepatitis B surface antibody positive patients, 30 CHI, 21 HBV-HF, and 20 HBV-HCC. In further cell-model experiments, we analyzed the expression of CCL20 by RT-qPCR and the changes in cell proliferation and migration by CCK8 and transwell assays, respectively, in HBV-HCC cell models after LGALS3 knockdown. The findings of this study suggest that LGALS3 could be a biomarker for adverse progression following chronic HBV infection and may also be involved in the regulation of the immune microenvironment, making it a potential therapeutic target.
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Affiliation(s)
- Jianming Dong
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rongzheng Zhang
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yan Xia
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xu Jiang
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Kun Zhou
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Beidahuang Industry Group General Hospital Department of Clinical Laboratory, Harbin, China
| | - Jiaqi Li
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Mengrui Guo
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinyang Cao
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shuyun Zhang
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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18
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Yu X, Qian J, Ding L, Yin S, Zhou L, Zheng S. Galectin-1: A Traditionally Immunosuppressive Protein Displays Context-Dependent Capacities. Int J Mol Sci 2023; 24:ijms24076501. [PMID: 37047471 PMCID: PMC10095249 DOI: 10.3390/ijms24076501] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/20/2023] [Accepted: 03/23/2023] [Indexed: 04/03/2023] Open
Abstract
Galectin–Carbohydrate interactions are indispensable to pathogen recognition and immune response. Galectin-1, a ubiquitously expressed 14-kDa protein with an evolutionarily conserved β-galactoside binding site, translates glycoconjugate recognition into function. That galectin-1 is demonstrated to induce T cell apoptosis has led to substantial attention to the immunosuppressive properties of this protein, such as inducing naive immune cells to suppressive phenotypes, promoting recruitment of immunosuppressing cells as well as impairing functions of cytotoxic leukocytes. However, only in recent years have studies shown that galectin-1 appears to perform a pro-inflammatory role in certain diseases. In this review, we describe the anti-inflammatory function of galectin-1 and its possible mechanisms and summarize the existing therapies and preclinical efficacy relating to these agents. In the meantime, we also discuss the potential causal factors by which galectin-1 promotes the progression of inflammation.
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19
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Singh S, Sharma N, Shukla S, Behl T, Gupta S, Anwer MK, Vargas-De-La-Cruz C, Bungau SG, Brisc C. Understanding the Potential Role of Nanotechnology in Liver Fibrosis: A Paradigm in Therapeutics. Molecules 2023; 28:molecules28062811. [PMID: 36985782 PMCID: PMC10057127 DOI: 10.3390/molecules28062811] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/15/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
The liver is a vital organ that plays a crucial role in the physiological operation of the human body. The liver controls the body's detoxification processes as well as the storage and breakdown of red blood cells, plasma protein and hormone production, and red blood cell destruction; therefore, it is vulnerable to their harmful effects, making it more prone to illness. The most frequent complications of chronic liver conditions include cirrhosis, fatty liver, liver fibrosis, hepatitis, and illnesses brought on by alcohol and drugs. Hepatic fibrosis involves the activation of hepatic stellate cells to cause persistent liver damage through the accumulation of cytosolic matrix proteins. The purpose of this review is to educate a concise discussion of the epidemiology of chronic liver disease, the pathogenesis and pathophysiology of liver fibrosis, the symptoms of liver fibrosis progression and regression, the clinical evaluation of liver fibrosis and the research into nanotechnology-based synthetic and herbal treatments for the liver fibrosis is summarized in this article. The herbal remedies summarized in this review article include epigallocathechin-3-gallate, silymarin, oxymatrine, curcumin, tetrandrine, glycyrrhetinic acid, salvianolic acid, plumbagin, Scutellaria baicalnsis Georgi, astragalosides, hawthorn extract, and andrographolides.
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Affiliation(s)
- Sukhbir Singh
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Neelam Sharma
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Saurabh Shukla
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India
| | - Tapan Behl
- School of Health Sciences &Technology, University of Petroleum and Energy Studies, Dehradun 248007, Uttarakhand, India
| | - Sumeet Gupta
- Department of Pharmacology, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Md Khalid Anwer
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Celia Vargas-De-La-Cruz
- Department of Pharmacology, Bromatology and Toxicology, Faculty of Pharmacy and Biochemistry, Universidad Nacional Mayor de San Marcos, Lima 150001, Peru
- E-Health Research Center, Universidad de Ciencias y Humanidades, Lima 15001, Peru
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Cristina Brisc
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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20
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Dai W, Guo Y, Shen Z, Wang J, Lu L, Dong H, Cai X. Identification of LBH and SPP1 involved in hepatic stellate cell activation during liver fibrogenesis. Hum Cell 2023; 36:1054-1067. [PMID: 36917392 DOI: 10.1007/s13577-023-00889-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 03/01/2023] [Indexed: 03/16/2023]
Abstract
Liver fibrosis is a pathological response driven by the activation of hepatic stellate cell (HSC). However, the mechanisms of liver fibrosis and HSC activation are complicated and far from being fully understood. We aimed to explore the candidate genes involved in HSC activation during liver fibrogenesis. Five genes (LBH, LGALS3, LOXL1, S100A6 and SPP1) were recurrent in the DEGs derived from the seven datasets. The expression of these genes gradually increased as liver fibrosis staging advanced, suggesting they might be candidate genes involved in HSC activation during hepatic fibrosis. These candidate genes were predicted to be coregulated by miRNAs such as hsa-miR-125a-5p and has-miR-125b, or by transcription factors including JUN, USF1, TP53 and TFAP2C. PPI analysis showed that LGALS3, LOXL1, S100A6 and SPP1 might interact with each other indirectly, but no interaction was found between them and LBH. The candidate genes and their interaction partners were enriched in focal adhesion, extracellular matrix organization and binding. Upregulation of LBH, S100A6 and SPP1 were further validated in TGF-β-treated LX-2 as well as in DDC or CCL4-treated mice models. Decreased LBH and SPP1 expression reduces the expression of HSC activation-related markers in TGF-β-treated LX-2. Our results indicated that LBH, LGALS3, LOXL1, S100A6 and SPP1 were candidate genes which may participate in the HSC activation during liver fibrosis.
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Affiliation(s)
- Weiming Dai
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuecheng Guo
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenyang Shen
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junjun Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lungen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Dong
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Xiaobo Cai
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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21
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Ezhilarasan D. Unraveling the pathophysiologic role of galectin-3 in chronically injured liver. J Cell Physiol 2023; 238:673-686. [PMID: 36745560 DOI: 10.1002/jcp.30956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 01/04/2023] [Accepted: 01/12/2023] [Indexed: 02/07/2023]
Abstract
Galectin-3 (Gal-3) previously referred to as S-type lectins, is a soluble protein that specifically binds to β-galactoside carbohydrates with high specificity. Gal-3 plays a pivotal role in a variety of pathophysiological processes such as cell proliferation, inflammation, differentiation, angiogenesis, transformation and apoptosis, pre-mRNA splicing, metabolic syndromes, fibrosis, and host defense. The role of Gal-3 has also been implicated in liver diseases. Gal-3 is activated upon a hepatotoxic insult to the liver and its level has been shown to be upregulated in fatty liver diseases, inflammation, nonalcoholic steatohepatitis, fibrosis, cholangitis, cirrhosis, and hepatocellular carcinoma (HCC). Gal-3 directly interacts with the NOD-like receptor family, pyrin domain containing 3, and activates the inflammasome in macrophages of the liver. In the chronically injured liver, Gal-3 secreted by injured hepatocytes and immune cells, activates hepatic stellate cells (HSCs) in a paracrine fashion to acquire a myofibroblast like collagen-producing phenotype. Activated HSCs in the fibrotic liver secrete Gal-3 which acts via autocrine signaling to exacerbate extracellular matrix synthesis and fibrogenesis. In the stromal microenvironment, Gal-3 activates cancer cell proliferation, migration, invasiveness, and metastasis. Clinically, increased serum levels and Gal-3 expression were observed in the liver tissue of nonalcoholic steatohepatitis, fibrotic/cirrhotic, and HCC patients. The pathological role of Gal-3 has been experimentally and clinically reported in the progression of chronic liver disease. Therefore, this review discusses the pathological role of Gal-3 in the progression of chronic liver diseases.
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Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
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22
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Laderach DJ, Compagno D. Inhibition of galectins in cancer: Biological challenges for their clinical application. Front Immunol 2023; 13:1104625. [PMID: 36703969 PMCID: PMC9872792 DOI: 10.3389/fimmu.2022.1104625] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 12/16/2022] [Indexed: 01/11/2023] Open
Abstract
Galectins play relevant roles in tumor development, progression and metastasis. Accordingly, galectins are certainly enticing targets for medical intervention in cancer. To date, however, clinical trials based on galectin inhibitors reported inconclusive results. This review summarizes the galectin inhibitors currently being evaluated and discusses some of the biological challenges that need to be addressed to improve these strategies for the benefit of cancer patients.
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Affiliation(s)
- Diego José Laderach
- Molecular and Functional Glyco-Oncology Laboratory, Instituto de Química Biológica de la Facutad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Buenos Aires, Argentina,Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina,Departamento de Ciencias Básicas, Universidad Nacional de Luján, Luján, Argentina,*Correspondence: Diego José Laderach,
| | - Daniel Compagno
- Molecular and Functional Glyco-Oncology Laboratory, Instituto de Química Biológica de la Facutad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Buenos Aires, Argentina,Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
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23
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Felli E, Nulan Y, Selicean S, Wang C, Gracia-Sancho J, Bosch J. Emerging Therapeutic Targets for Portal Hypertension. CURRENT HEPATOLOGY REPORTS 2023; 22:51-66. [PMID: 36908849 PMCID: PMC9988810 DOI: 10.1007/s11901-023-00598-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 01/18/2023] [Indexed: 02/13/2023]
Abstract
Purpose of Review Portal hypertension is responsible of the main complications of cirrhosis, which carries a high mortality. Recent treatments have improved prognosis, but this is still far from ideal. This paper reviews new potential therapeutic targets unveiled by advances of key pathophysiologic processes. Recent Findings Recent research highlighted the importance of suppressing etiologic factors and a safe lifestyle and outlined new mechanisms modulating portal pressure. These include intrahepatic abnormalities linked to inflammation, fibrogenesis, vascular occlusion, parenchymal extinction, and angiogenesis; impaired regeneration; increased hepatic vascular tone due to sinusoidal endothelial dysfunction with insufficient NO availability; and paracrine liver cell crosstalk. Moreover, pathways such as the gut-liver axis modulate splanchnic vasodilatation and systemic inflammation, exacerbate liver fibrosis, and are being targeted by therapy. We have summarized studies of new agents addressing these targets. Summary New agents, alone or in combination, allow acting in complementary mechanisms offering a more profound effect on portal hypertension while simultaneously limiting disease progression and favoring regression of fibrosis and of cirrhosis. Major changes in treatment paradigms are anticipated.
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Affiliation(s)
- Eric Felli
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Yelidousi Nulan
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Sonia Selicean
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Cong Wang
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Jordi Gracia-Sancho
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
- Liver Vascular Biology Research Group, CIBEREHD, IDIBAPS Research Institute, 08036 Barcelona, Spain
| | - Jaume Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
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Capasso D, Pirone L, Di Gaetano S, Russo R, Saviano M, Frisulli V, Antonacci A, Pedone E, Scognamiglio V. Galectins detection for the diagnosis of chronic diseases: An emerging biosensor approach. Trends Analyt Chem 2023. [DOI: 10.1016/j.trac.2023.116952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Fei F, Zhang M, Tarighat SS, Joo EJ, Yang L, Heisterkamp N. Galectin-1 and Galectin-3 in B-Cell Precursor Acute Lymphoblastic Leukemia. Int J Mol Sci 2022; 23:ijms232214359. [PMID: 36430839 PMCID: PMC9694201 DOI: 10.3390/ijms232214359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/09/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
Acute lymphoblastic leukemias arising from the malignant transformation of B-cell precursors (BCP-ALLs) are protected against chemotherapy by both intrinsic factors as well as by interactions with bone marrow stromal cells. Galectin-1 and Galectin-3 are lectins with overlapping specificity for binding polyLacNAc glycans. Both are expressed by bone marrow stromal cells and by hematopoietic cells but show different patterns of expression, with Galectin-3 dynamically regulated by extrinsic factors such as chemotherapy. In a comparison of Galectin-1 x Galectin-3 double null mutant to wild-type murine BCP-ALL cells, we found reduced migration, inhibition of proliferation, and increased sensitivity to drug treatment in the double knockout cells. Plant-derived carbohydrates GM-CT-01 and GR-MD-02 were used to inhibit extracellular Galectin-1/-3 binding to BCP-ALL cells in co-culture with stromal cells. Treatment with these compounds attenuated migration of the BCP-ALL cells to stromal cells and sensitized human BCP-ALL cells to vincristine and the targeted tyrosine kinase inhibitor nilotinib. Because N-glycan sialylation catalyzed by the enzyme ST6Gal1 can regulate Galectin cell-surface binding, we also compared the ability of BCP-ALL wild-type and ST6Gal1 knockdown cells to resist vincristine treatment when they were co-cultured with Galectin-1 or Galectin-3 knockout stromal cells. Consistent with previous results, stromal Galectin-3 was important for maintaining BCP-ALL fitness during chemotherapy exposure. In contrast, stromal Galectin-1 did not significantly contribute to drug resistance, and there was no clear effect of ST6Gal1-catalysed N-glycan sialylation. Taken together, our results indicate a complicated joint contribution of Galectin-1 and Galectin-3 to BCP-ALL survival, with different roles for endogenous and stromal produced Galectins. These data indicate it will be important to efficiently block both extracellular and intracellular Galectin-1 and Galectin-3 with the goal of reducing BCP-ALL persistence in the protective bone marrow niche during chemotherapy.
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Affiliation(s)
- Fei Fei
- Section of Molecular Carcinogenesis, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute of Children’s Hospital, Los Angeles, CA 90027, USA
| | - Mingfeng Zhang
- Department of Systems Biology, Beckman Research Institute City of Hope, Monrovia, CA 91016, USA
| | - Somayeh S. Tarighat
- Section of Molecular Carcinogenesis, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, The Saban Research Institute of Children’s Hospital, Los Angeles, CA 90027, USA
| | - Eun Ji Joo
- Department of Systems Biology, Beckman Research Institute City of Hope, Monrovia, CA 91016, USA
| | - Lu Yang
- Department of Systems Biology, Beckman Research Institute City of Hope, Monrovia, CA 91016, USA
| | - Nora Heisterkamp
- Department of Systems Biology, Beckman Research Institute City of Hope, Monrovia, CA 91016, USA
- Correspondence: ; Tel.: +1-626-218-7503
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Garbuzenko DV. Current strategies for targeted therapy of liver fibrosis. BULLETIN OF SIBERIAN MEDICINE 2022; 21:154-165. [DOI: 10.20538/1682-0363-2022-3-154-165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Liver fibrosis (LF) is an unfavorable event in the natural course of chronic liver diseases (CLD), therefore, early implementation and widespread use of antifibrotic therapy methods is a pressing issue in hepatology. The aim of the review was to describe current approaches to targeted therapy of LF.PubMed database, Google Scholar search engine, Cochrane Database of Systematic Reviews, eLIBRARY.RU scientific electronic library, as well as reference lists of articles were used to search for scientific articles. The publications that corresponded to the aim of the study were selected for the period from 1998 to 2021 by the terms “liver fibrosis”, “pathogenesis”, and “treatment”. Inclusion criteria were restricted to targeted therapy of LF.Despite the growing evidence for reversibility of LF, there are currently no effective or clinically approved regimens for its specific therapy. However, taking into account the relevance of the issue, scientific research in this area is necessary. Multiple drugs with a good safety profile have been studied, which, though intended for other purposes, can have a positive effect on LF. In addition, a number of innovative approaches that differ from pharmacotherapy inspire optimism about finding a solution to this problem. It is obvious that studies focused on well-characterized groups of patients with confirmed histologic, elastography, clinical, and radiological parameters are required. This is a challenging task, since the key point will be stratification of risk based on ethnicity, etiology, and clinical status, and very large samples will be required for a reliable assessment. Nevertheless, the solution will increase efficiency of treatment for patients with CLD, improve their prognosis and quality of life, and significantly reduce the need for liver transplantation, a demand for which remains extremely high worldwide.
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Exploring the Molecular Interactions of Symmetrical and Unsymmetrical Selenoglycosides with Human Galectin-1 and Galectin-3. Int J Mol Sci 2022; 23:ijms23158273. [PMID: 35955408 PMCID: PMC9368490 DOI: 10.3390/ijms23158273] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Galectins (Gals) are small cytosolic proteins that bind β-galactoside residues via their evolutionarily conserved carbohydrate recognition domain. Their dysregulation has been shown to be associated with many diseases. Consequently, targeting galectins for clinical applications has become increasingly relevant to develop tailored inhibitors selectively for one galectin. Accordingly, binding studies providing the molecular details of the interaction between galectin and inhibitor may be useful for the rational design of potent and selective antagonists. Gal-1 and Gal-3 are among the best-studied galectins, mainly for their roles in cancer progression; therefore, the molecular details of their interaction with inhibitors are demanded. This work gains more value by focusing on the interaction between Gal-1 and Gal-3 with the selenylated analogue of the Gal inhibitor thiodigalactose, characterized by a selenoglycoside bond (SeDG), and with unsymmetrical diglycosyl selenides (unsym(Se). Gal-1 and Gal-3 were produced heterologously and biophysically characterized. Interaction studies were performed by ITC, NMR spectroscopy, and MD simulation, and thermodynamic values were discussed and integrated with spectroscopic and computational results. The 3D complexes involving SeDG when interacting with Gal-1 and Gal-3 were depicted. Overall, the collected results will help identify hot spots for the design of new, better performing, and more specific Gal inhibitors.
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Thiamine pretreatment improves endotoxemia-related liver injury and cholestatic complications by regulating galactose metabolism and inhibiting macrophage activation. Int Immunopharmacol 2022; 108:108892. [DOI: 10.1016/j.intimp.2022.108892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 05/19/2022] [Accepted: 05/21/2022] [Indexed: 11/05/2022]
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Rodrigues SG, Mendoza YP, Bosch J. Investigational drugs in early clinical development for portal hypertension. Expert Opin Investig Drugs 2022; 31:825-842. [PMID: 35758843 DOI: 10.1080/13543784.2022.2095259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Advanced chronic liver disease is considered a reversible condition after removal of the primary aetiological factor. This has led to a paradigm shift in which portal hypertension (PH) is a reversible complication of cirrhosis. The pharmacologic management of PH is centered on finding targets to modify the natural history of cirrhosis and PH. AREAS COVERED This paper offers an overview of the use of pharmacological strategies in early clinical development that modify PH. Papers included were selected from searching clinical trials sites and PubMed from the last 10 years. EXPERT OPINION A paradigm shift has generated a new concept of PH in cirrhosis as a reversible complication of a potentially curable disease. Decreasing portal pressure to prevent decompensation and further complications of cirrhosis that may lead liver transplantation or death is a goal. Therapeutic strategies also aspire achieve total or partial regression of fibrosis thus eliminating the need for treatment or screening of PH.
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Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Yuly P Mendoza
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland.,Graduate School for Health Sciences (GHS), University of Bern
| | - Jaime Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
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Fibrogenic Pathways in Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD). Int J Mol Sci 2022; 23:ijms23136996. [PMID: 35805998 PMCID: PMC9266719 DOI: 10.3390/ijms23136996] [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: 04/26/2022] [Revised: 06/07/2022] [Accepted: 06/15/2022] [Indexed: 02/04/2023] Open
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD), recently also re-defined as metabolic dysfunction associated fatty liver disease (MAFLD), is rapidly increasing, affecting ~25% of the world population. MALFD/NAFLD represents a spectrum of liver pathologies including the more benign hepatic steatosis and the more advanced non-alcoholic steatohepatitis (NASH). NASH is associated with enhanced risk for liver fibrosis and progression to cirrhosis and hepatocellular carcinoma. Hepatic stellate cells (HSC) activation underlies NASH-related fibrosis. Here, we discuss the profibrogenic pathways, which lead to HSC activation and fibrogenesis, with a particular focus on the intercellular hepatocyte–HSC and macrophage–HSC crosstalk.
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Established Liposome-Coated IMB16-4 Polymeric Nanoparticles (LNPs) for Increasing Cellular Uptake and Anti-Fibrotic Effects In Vitro. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123738. [PMID: 35744862 PMCID: PMC9230879 DOI: 10.3390/molecules27123738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/06/2022] [Accepted: 06/08/2022] [Indexed: 11/17/2022]
Abstract
As a global health problem, liver fibrosis still does not have approved treatment. It was proved that N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamide) benzamide (IMB16-4) has anti-hepatic fibrosis activity. However, IMB16-4 displays poor water solubility and poor bioavailability. We are devoted to developing biodegraded liposome-coated polymeric nanoparticles (LNPs) as IMB16-4 delivery systems for improving aqueous solubility, cellular uptake, and anti-fibrotic effects. The physical states of IMB16-4−LNPs were analyzed using a transmission electron microscope (TEM), high-performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and differential scanning calorimeter (DSC). The results show that IMB16-4−LNPs increased the drug loading compared to liposomes and enhanced cellular uptake behavior compared with IMB16-4−NPs. In addition, IMB16-4−LNPs could repress the expression of hepatic fibrogenesis-associated proteins, indicating that IMB16-4−LNPs exhibited evident anti-fibrotic effects.
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32
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Cho Y, Lee YH. State-of-the-Art Overview of the Pharmacological Treatment of Non-Alcoholic Steatohepatitis. Endocrinol Metab (Seoul) 2022; 37:38-52. [PMID: 35255600 PMCID: PMC8901956 DOI: 10.3803/enm.2022.102] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 01/31/2022] [Indexed: 11/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and non-alcoholic steatohepatitis (NASH), a subtype of NAFLD, can progress to cirrhosis, hepatocellular carcinoma, and death. Nevertheless, the current treatment for NAFLD/NASH is limited to lifestyle modifications, and no drugs are currently officially approved as treatments for NASH. Many global pharmaceutical companies are pursuing the development of medications for the treatment of NASH, and results from phase 2 and 3 clinical trials have been published in recent years. Here, we review data from these recent clinical trials and reports on the efficacy of newly developed antidiabetic drugs in NASH treatment.
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Affiliation(s)
- Yongin Cho
- Department of Endocrinology and Metabolism, Inha University College of Medicine, Incheon,
Korea
| | - Yong-ho Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul,
Korea
- Department of Systems Biology, Glycosylation Network Research Center, Yonsei University, Seoul,
Korea
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Prikhodko VA, Bezborodkina NN, Okovityi SV. Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines 2022; 10:274. [PMID: 35203484 PMCID: PMC8869100 DOI: 10.3390/biomedicines10020274] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.
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Affiliation(s)
- Veronika A. Prikhodko
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
| | - Natalia N. Bezborodkina
- Zoological Institute, Russian Academy of Sciences, 1 Universitetskaya emb., 199034 St. Petersburg, Russia;
| | - Sergey V. Okovityi
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia
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Vilaseca M, Gracia-Sancho J. Drugs to Modify Liver Fibrosis Progression and Regression. PORTAL HYPERTENSION VII 2022:201-218. [DOI: 10.1007/978-3-031-08552-9_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Caligiuri A, Gentilini A, Pastore M, Gitto S, Marra F. Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression. Cells 2021; 10:cells10102759. [PMID: 34685739 PMCID: PMC8534788 DOI: 10.3390/cells10102759] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.
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He YS, Hu YQ, Xiang K, Chen Y, Feng YT, Yin KJ, Huang JX, Wang J, Wu ZD, Wang GH, Pan HF. Therapeutic potential of galectin-1 and galectin-3 in autoimmune diseases. Curr Pharm Des 2021; 28:36-45. [PMID: 34579628 DOI: 10.2174/1381612827666210927164935] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 08/24/2021] [Indexed: 11/22/2022]
Abstract
Galectins are a highly conserved protein family that binds to β-galactosides. Different members of this family play a variety of biological functions in physiological and pathological processes such as angiogenesis, regulation of immune cell activity, and cell adhesion. Galectins are widely distributed and play a vital role both inside and outside cells. It can regulate homeostasis and immune function in vivo through mechanisms such as apoptosis. Recent studies indicate that galectins exhibit pleiotropic roles in inflammation. Furthermore, emerging studies have found that galectins are involved in the occurrence and development of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D) and systemic sclerosis (SSc) by regulating cell adhesion, apoptosis, and other mechanisms. This review will briefly discuss the biological characteristics of the two most widely expressed and extensively explored members of the galectin family, galectin-1 and galectin-3, as well as their pathogenetic and therapeutic roles in autoimmune diseases. These information may provide a novel and promising therapeutic target for autoimmune diseases.
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Affiliation(s)
- Yi-Sheng He
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui. China
| | - Yu-Qian Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui. China
| | - Kun Xiang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui. China
| | - Yue Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui. China
| | - Ya-Ting Feng
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui. China
| | - Kang-Jia Yin
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui. China
| | - Ji-Xiang Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui. China
| | - Jie Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui. China
| | - Zheng-Dong Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui. China
| | - Gui-Hong Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui. China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui. China
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Abstract
Antifibrotic therapies for the treatment of liver fibrosis represent an unconquered area of drug development. The significant involvement of the gut microbiota as a driving force in a multitude of liver disease, be it pathogenesis or fibrotic progression, suggest that targeting the gut–liver axis, relevant signaling pathways, and/or manipulation of the gut’s commensal microbial composition and its metabolites may offer opportunities for biomarker discovery, novel therapies and personalized medicine development. Here, we review potential links between bacterial translocation and deficits of host-microbiome compartmentalization and liver fibrosis that occur in settings of advanced chronic liver disease. We discuss established and emerging therapeutic strategies, translated from our current knowledge of the gut–liver axis, targeted at restoring intestinal eubiosis, ameliorating hepatic fibrosis and rising portal hypertension that characterize and define the course of decompensated cirrhosis.
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Kumar V, Xin X, Ma J, Tan C, Osna N, Mahato RI. Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis. Adv Drug Deliv Rev 2021; 176:113888. [PMID: 34314787 PMCID: PMC8440458 DOI: 10.1016/j.addr.2021.113888] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/12/2021] [Accepted: 07/18/2021] [Indexed: 02/08/2023]
Abstract
Type 2 diabetes mellitus (T2DM) associated non-alcoholic fatty liver disease (NAFLD) is the fourth-leading cause of death. Hyperglycemia induces various complications, including nephropathy, cirrhosis and eventually hepatocellular carcinoma (HCC). There are several etiological factors leading to liver disease development, which involve insulin resistance and oxidative stress. Free fatty acid (FFA) accumulation in the liver exerts oxidative and endoplasmic reticulum (ER) stresses. Hepatocyte injury induces release of inflammatory cytokines from Kupffer cells (KCs), which are responsible for activating hepatic stellate cells (HSCs). In this review, we will discuss various molecular targets for treating chronic liver diseases, including homeostasis of FFA, lipid metabolism, and decrease in hepatocyte apoptosis, role of growth factors, and regulation of epithelial-to-mesenchymal transition (EMT) and HSC activation. This review will also critically assess different strategies to enhance drug delivery to different cell types. Targeting nanocarriers to specific liver cell types have the potential to increase efficacy and suppress off-target effects.
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Affiliation(s)
- Virender Kumar
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Xiaofei Xin
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jingyi Ma
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chalet Tan
- Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA
| | - Natalia Osna
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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Thapa K, Grewal AS, Kanojia N, Rani L, Sharma N, Singh S. Alcoholic and Non-Alcoholic Liver Diseases: Promising Molecular Drug Targets and their Clinical Development. Curr Drug Discov Technol 2021; 18:333-353. [PMID: 31965945 DOI: 10.2174/1570163817666200121143959] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 11/25/2019] [Accepted: 12/04/2019] [Indexed: 11/22/2022]
Abstract
Alcoholic and non-alcoholic fatty liver diseases have become a serious concern worldwide. Both these liver diseases have an identical pathology, starting from simple steatosis to cirrhosis and, ultimately to hepatocellular carcinoma. Treatment options for alcoholic liver disease (ALD) are still the same as they were 50 years ago which include corticosteroids, pentoxifylline, antioxidants, nutritional support and abstinence; and for non-alcoholic fatty liver disease (NAFLD), weight loss, insulin sensitizers, lipid-lowering agents and anti-oxidants are the only treatment options. Despite broad research in understanding the disease pathophysiology, limited treatments are available for clinical use. Some therapeutic strategies based on targeting a specific molecule have been developed to lessen the consequences of disease and are under clinical investigation. Therefore, focus on multiple molecular targets will help develop an efficient therapeutic strategy. This review comprises a brief overview of the pathogenesis of ALD and NAFLD; recent molecular drug targets explored for ALD and NAFLD that may prove to be effective for multiple therapeutic regimens and also the clinical status of these promising drug targets for liver diseases.
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Affiliation(s)
- Komal Thapa
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Ajmer Singh Grewal
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Neha Kanojia
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Lata Rani
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Xu L, Hartz RA, Beno BR, Ghosh K, Shukla JK, Kumar A, Patel D, Kalidindi N, Lemos N, Gautam SS, Kumar A, Ellsworth BA, Shah D, Sale H, Cheng D, Regueiro-Ren A. Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors. J Med Chem 2021; 64:6634-6655. [PMID: 33988358 DOI: 10.1021/acs.jmedchem.0c02001] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Galectin-3 is a member of a family of β-galactoside-binding proteins. A substantial body of literature reports that galectin-3 plays important roles in cancer, inflammation, and fibrosis. Small-molecule galectin-3 inhibitors, which are generally lactose or galactose-based derivatives, have the potential to be valuable disease-modifying agents. In our efforts to identify novel galectin-3 disaccharide mimics to improve drug-like properties, we found that one of the monosaccharide subunits can be replaced with a suitably functionalized tetrahydropyran ring. Optimization of the structure-activity relationships around the tetrahydropyran-based scaffold led to the discovery of potent galectin-3 inhibitors. Compounds 36, 40, and 45 were selected for further in vivo evaluation. The synthesis, structure-activity relationships, and in vivo evaluation of novel tetrahydropyran-based galectin-3 inhibitors are described.
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Affiliation(s)
- Li Xu
- Department of Small Molecule Drug Discovery, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States
| | - Richard A Hartz
- Department of Small Molecule Drug Discovery, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States
| | - Brett R Beno
- Department of Computer-Aided Drug Design & Molecular Analytics, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States
| | - Kaushik Ghosh
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Jinal K Shukla
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Amit Kumar
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Dipal Patel
- Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States
| | - Narasimharaju Kalidindi
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Nadine Lemos
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Shashyendra Singh Gautam
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Anoop Kumar
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Bruce A Ellsworth
- Department of Small Molecule Drug Discovery, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States
| | - Devang Shah
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Harinath Sale
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Dong Cheng
- Department of Cardiovascular and Fibrosis Discovery Biology, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States
| | - Alicia Regueiro-Ren
- Department of Small Molecule Drug Discovery, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States
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Fallowfield JA, Jimenez-Ramos M, Robertson A. Emerging synthetic drugs for the treatment of liver cirrhosis. Expert Opin Emerg Drugs 2021; 26:149-163. [PMID: 33856246 DOI: 10.1080/14728214.2021.1918099] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: The number of deaths and prevalent cases of cirrhosis are increasing worldwide, but there are no licensed antifibrotic or pro-regenerative medicines and liver transplantation is a limited resource. Cirrhosis is characterized by extreme liver fibrosis, organ dysfunction, and complications related to portal hypertension. Advances in our understanding of liver fibrosis progression and regression following successful etiological therapy betray vulnerabilities in common and disease-specific mechanisms that could be targeted pharmacologically.Area covered: This review summarizes the cellular and molecular pathogenesis of cirrhosis as a preface to discussion of the current drug development landscape. The dominant indication for global pharma R&D pipelines is cirrhosis related to nonalcoholic steatohepatitis (NASH). We searched Clinicaltrials.gov, GlobalData, Pharmaprojects and PubMed for pertinent information on emerging synthetic drugs for cirrhosis, with a focus on compounds listed in phase 2 and phase 3 trials.Expert opinion: Although cirrhosis can regress following successful etiological treatment, there are no specific antifibrotic or pro-regenerative drugs approved for this condition. Obstacles to drug development in cirrhosis include intrinsic biological factors, a heterogeneous patient population, and lack of acceptable surrogate endpoints. Nevertheless, several synthetic drugs are being evaluated in clinical trials and the NASH field is rapidly embracing a drug combination approach.
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Rockey DC, Friedman SL. Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside. Gastroenterology 2021; 160:1502-1520.e1. [PMID: 33529675 PMCID: PMC8601597 DOI: 10.1053/j.gastro.2020.09.065] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/01/2020] [Accepted: 09/06/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection and its complications have been the major cause of cirrhosis and its complications for several decades in the Western world. Until recently, treatment for HCV with interferon-based regimens was associated with moderate success but was difficult to tolerate. More recently, however, an arsenal of novel and highly effective direct-acting antiviral (DAA) drugs has transformed the landscape by curing HCV in a broad range of patients, including those with established advanced fibrosis, cirrhosis, comorbidities, and even those with complications of cirrhosis. Fibrosis is a dynamic process comprising both extracellular matrix deposition, as well as its degradation. With almost universal sustained virologic response (SVR) (ie, elimination of HCV), it is timely to explore whether HCV eradication can reverse fibrosis and cirrhosis. Indeed, fibrosis in several types of liver disease is reversible, including HCV. However, we do not know with certainty in whom fibrosis regression can be expected after HCV elimination, how quickly it occurs, and whether antifibrotic therapies will be indicated in those with persistent cirrhosis. This review summarizes the evidence for reversibility of fibrosis and cirrhosis after HCV eradication, its impact on clinical outcomes, and therapeutic prospects for directly promoting fibrosis regression in patients whose fibrosis persists after SVR.
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Affiliation(s)
- Don C Rockey
- The Medical University of South Carolina, Charleston, South Carolina.
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
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Cao N, Tang X, Gao R, Kong L, Zhang J, Qin W, Hu N, Zhang A, Ma K, Li L, Si JQ. Galectin-3 participates in PASMC migration and proliferation by interacting with TGF-β1. Life Sci 2021; 274:119347. [PMID: 33716065 DOI: 10.1016/j.lfs.2021.119347] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 02/21/2021] [Accepted: 03/05/2021] [Indexed: 11/16/2022]
Abstract
Pulmonary vascular remodelling is one of the most important factors for pulmonary hypertension (PH). Galectin-3 (Gal-3) is a β-galactoside-binding lectin. In the latest literature, Gal-3 has been reported to be involved in pulmonary vascular remodelling, and its underlying mechanism is unclear. Our research aims to prove the effect of Gal-3 on the proliferation and migration of human pulmonary artery smooth muscle cells (HPASMC) induced by transforming growth factor β1 (TGF-β1) and to study its mechanism. In vivo experiment: In Sprague-Dawley (SD) rats, monocrotaline was injected intraperitoneally to establish a PH model, and the Gal-3 inhibitor (modified citrus pectin, MCP) 28 Ds was administered in the stomach. The results indicate that Gal-3 and TGF-β1 may be involved in the occurrence and development of PH, which may be related to the Smad2/3 signalling pathway. In vitro experiment: Human pulmonary artery smooth muscle cells were pretreated with the Gal-3 inhibitor (MCP) for 24 h, then TGF-β1 or Gal-3 was administered to the cells for 24 h. The results show that exogenous TGF-β1 and Gal-3 can activate the downstream Smad2/3 signalling pathway, and increase the proliferation and migration ability of HPASMC. However, the Gal-3 inhibitor (MCP) inhibited these effects. Further results display that TGF-β1 and Gal-3 could mutually regulate the protein and mRNA expression levels. In summary, the results of this study indicate that Gal-3 regulates the Smad2/3 signalling pathway through protein interaction with TGF-β1, in turn regulates the proliferation and migration of HPASMC, thereby regulating the occurrence and development of PH.
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Affiliation(s)
- Nan Cao
- Department of Physiology, Shihezi University Medical College, Shihezi 832002, China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi 832002, China; The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University Medical College, Shihezi 832002, China
| | - Xuechun Tang
- Department of Physiology, Shihezi University Medical College, Shihezi 832002, China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi 832002, China; The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University Medical College, Shihezi 832002, China; Department of Burns department, First Affiliated Hospital of Shihezi University, Shihezi 832002, China
| | - RuiJuan Gao
- Department of Physiology, Shihezi University Medical College, Shihezi 832002, China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi 832002, China; The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University Medical College, Shihezi 832002, China
| | - Liangjingyuan Kong
- Department of Physiology, Shihezi University Medical College, Shihezi 832002, China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi 832002, China; The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University Medical College, Shihezi 832002, China
| | - Jingrong Zhang
- Department of Physiology, Shihezi University Medical College, Shihezi 832002, China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi 832002, China; The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University Medical College, Shihezi 832002, China
| | - Wenjuan Qin
- Department of Ultrasound Room, First Affiliated Hospital of Shihezi University, Shihezi 832002, China
| | - Na Hu
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University Medical College, Shihezi 832002, China
| | - Aimei Zhang
- Department of Cardiology, First Affiliated Hospital of Shihezi University, Shihezi 832002, China
| | - Ketao Ma
- Department of Physiology, Shihezi University Medical College, Shihezi 832002, China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi 832002, China; The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University Medical College, Shihezi 832002, China; Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan 430070, China; Department of Physiology, Huazhong University of Science and Technology of Basic Medical Sciences, Wuhan 430070, China
| | - Li Li
- Department of Physiology, Jiaxing University Medical College, Jiaxing 314001, China.
| | - Jun-Qiang Si
- Department of Physiology, Shihezi University Medical College, Shihezi 832002, China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi 832002, China; The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University Medical College, Shihezi 832002, China; Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan 430070, China; Department of Physiology, Huazhong University of Science and Technology of Basic Medical Sciences, Wuhan 430070, China.
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Rupcic Rubin V, Bojanic K, Smolic M, Rubin J, Tabll A, Smolic R. An Update on Efficacy and Safety of Emerging Hepatic Antifibrotic Agents. J Clin Transl Hepatol 2021. [PMID: 33604256 DOI: 10.14218/jcth.2020.00040.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Liver fibrosis represents a response to chronic liver injury. Metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis are the most common chronic liver diseases, both with increasing incidence. Therefore, there is a great impetus for development of agents targeting these conditions. Accumulating data on possible treatment options for liver fibrosis are emerging in the literature. However, despite extensive research and much effort in the field, approved agents for liver fibrosis are still lacking. In this critical review, we have summarized the main data about specific treatment options for liver fibrosis gained from ongoing clinical trials, with an emphasis on efficacy and safety of these agents.
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Affiliation(s)
- Vinka Rupcic Rubin
- Department of Gynaecology and Obstetrics, Osijek University Hospital Centre, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Kristina Bojanic
- Department of Biophysics and Radiology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia.,Department of Biophysics and Radiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia.,Department of Radiology, Health Center Osijek, Osijek, Croatia
| | - Martina Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia.,Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Jurica Rubin
- Department of Medicine, Division of Gastroenterology/Hepatology, University Hospital Osijek, Osijek, Croatia
| | - Ashraf Tabll
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, Dokki, Egypt.,Department of immunology, Egypt Center for Research and Regenerative
| | - Robert Smolic
- Department of Medicine, Division of Gastroenterology/Hepatology, University Hospital Osijek, Osijek, Croatia.,Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia.,Department of Pathophysiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
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45
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Rupcic Rubin V, Bojanic K, Smolic M, Rubin J, Tabll A, Smolic R. An Update on Efficacy and Safety of Emerging Hepatic Antifibrotic Agents. J Clin Transl Hepatol 2021; 9:60-70. [PMID: 33604256 PMCID: PMC7868700 DOI: 10.14218/jcth.2020.00040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 11/22/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023] Open
Abstract
Liver fibrosis represents a response to chronic liver injury. Metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis are the most common chronic liver diseases, both with increasing incidence. Therefore, there is a great impetus for development of agents targeting these conditions. Accumulating data on possible treatment options for liver fibrosis are emerging in the literature. However, despite extensive research and much effort in the field, approved agents for liver fibrosis are still lacking. In this critical review, we have summarized the main data about specific treatment options for liver fibrosis gained from ongoing clinical trials, with an emphasis on efficacy and safety of these agents.
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Affiliation(s)
- Vinka Rupcic Rubin
- Department of Gynaecology and Obstetrics, Osijek University Hospital Centre, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Kristina Bojanic
- Department of Biophysics and Radiology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Biophysics and Radiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Radiology, Health Center Osijek, Osijek, Croatia
| | - Martina Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Jurica Rubin
- Department of Medicine, Division of Gastroenterology/Hepatology, University Hospital Osijek, Osijek, Croatia
| | - Ashraf Tabll
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, Dokki, Egypt
- Department of immunology, Egypt Center for Research and Regenerative
| | - Robert Smolic
- Department of Medicine, Division of Gastroenterology/Hepatology, University Hospital Osijek, Osijek, Croatia
- Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pathophysiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, Croatia
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Angiotensin-I Converting Enzyme Inhibition and Antioxidant Activity of Papain-Hydrolyzed Camel Whey Protein and Its Hepato-Renal Protective Effects in Thioacetamide-Induced Toxicity. Foods 2021; 10:foods10020468. [PMID: 33672579 PMCID: PMC7924048 DOI: 10.3390/foods10020468] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/10/2021] [Accepted: 02/15/2021] [Indexed: 01/10/2023] Open
Abstract
Papain hydrolysis of camel whey protein (CWP) produced CWP hydrolysate (CWPH). Fractionation of CWPH by the size exclusion chromatography (SEC) generated fractions (i.e., SEC-F1 and SEC-F2). The angiotensin converting enzyme inhibitory activity (ACE-IA) and free radical scavenging actions were assessed for CWP, CWPH, SEC-F1, and SEC-F2. The SEC-F2 exerted the highest ACE-IA and scavenging activities, followed by CWPH. The protective effects of CWPH on thioacetamide (TAA)-induced toxicity were investigated in rats. The liver enzymes, protein profile, lipid profile, antioxidant enzyme activities, renal functions, and liver histopathological changes were assessed. Animals with TAA toxicity showed impaired hepatorenal functions, hyperlipidemia, and decreased antioxidant capacity. Treatment by CWPH counteracted the TAA-induced oxidative tissue damage as well as preserved the renal and liver functions, the antioxidative enzyme activities, and the lipid profile, compared to the untreated animals. The current findings demonstrate that the ACE-IA and antioxidative effects of CWPH and its SEC-F2 fraction are worth noting. In addition, the CWPH antioxidative properties counteracted the toxic hepatorenal dysfunctions. It is concluded that the hydrolysis of CWP generates a wide range of bioactive peptides with potent antihypertensive, antioxidant, and hepatorenal protective properties. This opens up new prospects for the therapeutic utilization of CWPH and its fractions in the treatment of oxidative stress-associated health problems, e.g., hypertension and hepatorenal failure.
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47
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Kovalevа VA, Zhevnerova NS, Antonova TV. [Disorders of carbohydrate-lipid metabolism and galectin-3 level as factors of liver fibrosis progression in chronic hepatitis C]. TERAPEVT ARKH 2021; 93:164-168. [PMID: 36286630 DOI: 10.26442/00403660.2021.02.200623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 04/05/2021] [Indexed: 11/22/2022]
Abstract
AIM To assess the effect of metabolic disorders and galectin-3 levels on the progression of liver fibrosis in chronic hepatitis C. MATERIALS AND METHODS 106 patients with HCV without decompensated liver cirrhosis were examined. EXCLUSION CRITERIA age younger than 20 and older than 65 years, diabetes, coronary heart disease, hypertension, alcoholism, drug addiction. Laboratory examination (biochemical blood test, enzyme immunoassay (ELISA) with determination of HCV-Ab antibodies, viral load) was supplemented with liver elastometry (Fibroscan) with fibrosis assessment (kPa, METAVIR scale). The body mass index of Quetelet (kg/m2), the presence of abdominal obesity, insulin resistance were evaluated. Serum levels of insulin and galectin-3 were determined by ELISA. RESULTS In 45% of patients, an increase in ITM was revealed, in 44% abdominal obesity, in 62% insulin resistance. In 75% abdominal obesity was determined in patients with liver fibrosis F3F4. Insulin resistance was found more often in patients with fibrosis F01 56.7%. Significant correlations between the level of galectin-3 and the degree of liver fibrosis (in kPa) [r=0,206, p=0,034], as well as the stage of liver fibrosis (on the METAVIR scale) [r=0,247, p=0,01] were obtained. The level of galectin-3 in liver cirrhosis was 6.32 (4.57; 9.64) ng/ml, which is significantly higher than in F0 3.96 (1.45; 5.30) ng/ml (p=0.002) and F1 3.85 (2.20; 5.83) ng/ml (p=0.002). By calculating the specificity and sensitivity of isolated for F4 stage of liver fibrosis (ROC-curve, the level of galectin-3 is 5.21 ng/ml), the level of specificity of 74.7%, sensitivity of 74% was established. CONCLUSION We found a significant relationship between the disturbances of carbohydrate-lipid metabolism and liver fibrosis, the level of galectin-3 and fibrosis stage of the liver. The prognostic value of increasing the level of galectin-3 for predicting the cirrhotic stage of liver fibrosis is substantiated.
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Affiliation(s)
- V A Kovalevа
- Pavlov First Saint Petersburg State Medical University
| | | | - T V Antonova
- Pavlov First Saint Petersburg State Medical University
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48
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Bart VMT, Pickering RJ, Taylor PR, Ipseiz N. Macrophage reprogramming for therapy. Immunology 2021; 163:128-144. [PMID: 33368269 PMCID: PMC8114216 DOI: 10.1111/imm.13300] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/02/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022] Open
Abstract
Dysfunction of the immune system underlies a plethora of human diseases, requiring the development of immunomodulatory therapeutic intervention. To date, most strategies employed have been focusing on the modification of T lymphocytes, and although remarkable improvement has been obtained, results often fall short of the intended outcome. Recent cutting-edge technologies have highlighted macrophages as potential targets for disease control. Macrophages play central roles in development, homeostasis and host defence, and their dysfunction and dysregulation have been implicated in the onset and pathogenesis of multiple disorders including cancer, neurodegeneration, autoimmunity and metabolic diseases. Recent advancements have led to a greater understanding of macrophage origin, diversity and function, in both health and disease. Over the last few years, a variety of strategies targeting macrophages have been developed and these open new therapeutic opportunities. Here, we review the progress in macrophage reprogramming in various disorders and discuss the potential implications and challenges for macrophage-targeted approaches in human disease.
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Affiliation(s)
| | - Robert J Pickering
- Immunology Network, Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, UK.,Department of Medicine, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Philip R Taylor
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK.,UK Dementia Research Institute at Cardiff, Cardiff University, Cardiff, UK
| | - Natacha Ipseiz
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
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49
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Barman SA, Bordan Z, Batori R, Haigh S, Fulton DJR. Galectin-3 Promotes ROS, Inflammation, and Vascular Fibrosis in Pulmonary Arterial Hypertension. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1303:13-32. [PMID: 33788185 DOI: 10.1007/978-3-030-63046-1_2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pulmonary Arterial Hypertension (PAH) is a progressive vascular disease arising from the narrowing of pulmonary arteries (PA) resulting in high pulmonary arterial blood pressure and ultimately right ventricular (RV) failure. A defining characteristic of PAH is the excessive remodeling of PA that includes increased proliferation, inflammation, and fibrosis. There is no cure for PAH nor interventions that effectively impede or reverse PA remodeling, and research over the past several decades has sought to identify novel molecular mechanisms of therapeutic benefit. Galectin-3 (Gal-3; Mac-2) is a carbohydrate-binding lectin that is remarkable for its chimeric structure, comprised of an N-terminal oligomerization domain and a C-terminal carbohydrate-recognition domain. Gal-3 is a regulator of changes in cell behavior that contribute to aberrant PA remodeling including cell proliferation, inflammation, and fibrosis, but its role in PAH is poorly understood. Herein, we summarize the recent literature on the role of Gal-3 in the development of PAH and provide experimental evidence supporting the ability of Gal-3 to influence reactive oxygen species (ROS) production, NOX enzyme expression, inflammation, and fibrosis, which contributes to PA remodeling. Finally, we address the clinical significance of Gal-3 as a target in the development of therapeutic agents as a treatment for PAH.
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Affiliation(s)
- Scott A Barman
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia.
| | - Zsuzsanna Bordan
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Robert Batori
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Stephen Haigh
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - David J R Fulton
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia.,Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia
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50
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Berumen J, Baglieri J, Kisseleva T, Mekeel K. Liver fibrosis: Pathophysiology and clinical implications. WIREs Mech Dis 2021; 13:e1499. [PMID: 32713091 PMCID: PMC9479486 DOI: 10.1002/wsbm.1499] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 04/30/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is a clinically significant finding that has major impacts on patient morbidity and mortality. The mechanism of fibrosis involves many different cellular pathways, but the major cell type involved appears to be hepatic stellate cells. Many liver diseases, including Hepatitis B, C, and fatty liver disease cause ongoing hepatocellular damage leading to liver fibrosis. No matter the cause of liver disease, liver-related mortality increases exponentially with increasing fibrosis. The progression to cirrhosis brings more dramatic mortality and higher incidence of hepatocellular carcinoma. Fibrosis can also affect outcomes following liver transplantation in adult and pediatric patients and require retransplantation. Drugs exist to treat Hepatitis B and C that reverse fibrosis in patients with those viral diseases, but there are currently no therapies to directly treat liver fibrosis. Several mouse models of chronic liver diseases have been successfully reversed using novel drug targets with current therapies focusing mostly on prevention of myofibroblast activation. Further research in these areas could lead to development of drugs to treat fibrosis, which will have invaluable impact on patient survival. This article is categorized under: Metabolic Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
| | - Jacopo Baglieri
- Department of Surgery, University of California, San Diego
- Department of Medicine, University of California, San Diego
| | | | - Kristin Mekeel
- Department of Surgery, University of California, San Diego
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