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Renu K. Exosomes derived from human adipose mesenchymal stem cells act as a therapeutic target for oral submucous fibrosis. JOURNAL OF STOMATOLOGY, ORAL AND MAXILLOFACIAL SURGERY 2025; 126:102224. [PMID: 39765310 DOI: 10.1016/j.jormas.2025.102224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 01/03/2025] [Indexed: 01/11/2025]
Abstract
Oral submucosal fibrosis is a highly malignant oral condition that necessitates the use of sophisticated therapeutic procedures. OSF is a multifactorial precancerous condition induced by areca nut chewing, deficiencies in vitamins and trace minerals, immunological aspects, and hereditary factors. Adipose tissue-derived mesenchymal stem cells possess the capability for multidirectional activation and are extensively distributed throughout the body. They have minimal immunogenicity and are extensively utilized in cancer treatment. Exosomes are extracellular vesicles produced by the intracellular route. They are biological carriers comprising microRNA, messenger RNA, lipids and proteins crucial for intercellular communication. ADSC exosomes, serving as a vehicle for miRNA, possess accessibility and little immunogenicity. They can significantly contribute to adipose tissue regrowth, angiogenesis, immunological modulation, and tissue repair. ADSC-Exo exhibits antifibrotic properties and may serve as a potential treatment for OSF. This review presents a novel therapeutic approach and clarifies the precise mechanisms involved in the clinical management of OSF using ADSC-Exo.
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Affiliation(s)
- Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai - 600077, Tamil Nadu, India.
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Kouroumalis E, Tsomidis I, Voumvouraki A. HFE-Related Hemochromatosis May Be a Primary Kupffer Cell Disease. Biomedicines 2025; 13:683. [PMID: 40149659 PMCID: PMC11940282 DOI: 10.3390/biomedicines13030683] [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: 01/14/2025] [Revised: 02/28/2025] [Accepted: 03/08/2025] [Indexed: 03/29/2025] Open
Abstract
Iron overload can lead to increased deposition of iron and cause organ damage in the liver, the pancreas, the heart and the synovium. Iron overload disorders are due to either genetic or acquired abnormalities such as excess transfusions or chronic liver diseases. The most common genetic disease of iron deposition is classic hemochromatosis (HH) type 1, which is caused by mutations of HFE. Other rare forms of HH include type 2A with mutations at the gene hemojuvelin or type 2B with mutations in HAMP that encodes hepcidin. HH type 3, is caused by mutations of the gene that encodes transferrin receptor 2. Mutations of SLC40A1 which encodes ferroportin cause either HH type 4A or HH type 4B. In the present review, an overview of iron metabolism including absorption by enterocytes and regulation of iron by macrophages, liver sinusoidal endothelial cells (LSECs) and hepatocyte production of hepcidin is presented. Hereditary Hemochromatosis and the current pathogenetic model are analyzed. Finally, a new hypothesis based on published data was suggested. The Kupffer cell is the primary defect in HFE hemochromatosis (and possibly in types 2 and 3), while the hepcidin-relative deficiency, which is the common underlying abnormality in the three types of HH, is a secondary consequence.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete Medical School, 71500 Heraklion, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece;
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Chatzikalil E, Arvanitakis K, Kalopitas G, Florentin M, Germanidis G, Koufakis T, Solomou EE. Hepatic Iron Overload and Hepatocellular Carcinoma: New Insights into Pathophysiological Mechanisms and Therapeutic Approaches. Cancers (Basel) 2025; 17:392. [PMID: 39941760 PMCID: PMC11815926 DOI: 10.3390/cancers17030392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/19/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to liver cirrhosis and HCC. Iron overload (IO), whether inherited or acquired, results in abnormal iron hepatic deposition, significantly impacting MASLD development and progression to HCC. While the pathophysiological connections between hepatic IO, MASLD, and HCC are not fully understood, dysregulation of glucose and lipid metabolism and IO-induced oxidative stress are being investigated as the primary drivers. Genomic analyses of inherited IO conditions reveal inconsistencies in the association of certain mutations with liver malignancies. Moreover, hepatic IO is also associated with hepcidin dysregulation and activation of ferroptosis, representing promising targets for HCC risk assessment and therapeutic intervention. Understanding the relationship between hepatic IO, MASLD, and HCC is essential for advancing clinical strategies against liver disease progression, particularly with recent IO-targeted therapies showing potential at improving liver biochemistry and insulin sensitivity. In this review, we summarize the current evidence on the pathophysiological association between hepatic IO and the progression of MASLD to HCC, underscoring the importance of early diagnosis, risk stratification, and targeted treatment for these interconnected conditions.
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Affiliation(s)
- Elena Chatzikalil
- Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece;
- “Aghia Sofia” Children’s Hospital ERN-PeadCan Center, 11527 Athens, Greece
| | - Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece; (K.A.); (G.K.); (G.G.)
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Georgios Kalopitas
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece; (K.A.); (G.K.); (G.G.)
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Matilda Florentin
- Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
| | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece; (K.A.); (G.K.); (G.G.)
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Theocharis Koufakis
- Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Elena E. Solomou
- Department of Internal Medicine, University of Patras Medical School, 26500 Rion, Greece
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Li C, Pang G, Zhao W, Liu Y, Huang X, Chen W, Zhao X, Liu T, Wang P, Fan X, Gao M, Cong M. Hepcidin inhibits hepatocyte apoptosis through the PERK pathway in acute liver injury and fibrosis. Hepatol Commun 2025; 9:e0604. [PMID: 39699302 PMCID: PMC11661744 DOI: 10.1097/hc9.0000000000000604] [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: 05/09/2024] [Accepted: 10/01/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Hepcidin, a peptide hormone primarily produced by the liver, regulates iron metabolism by interacting with its receptor, ferroportin. Studies have demonstrated that hepcidin participates in the progression of liver fibrosis by regulating HSC activation, but its regulatory effect on hepatocytes remains largely unknown. METHODS A carbon tetrachloride (CCl4)-induced liver fibrosis model was established in C57BL/6 wild-type (WT) and hepcidin knockout (Hamp-/-) mice. Liver injury and inflammation were assessed in WT and Hamp-/- mice at 24 and 48 hours following acute CCl4 exposure. In addition, transcriptomic sequencing of primary hepatocytes was performed to compare gene expression profiles between WT and Hamp-/- mice 24 hours after liver injury. The function of the identified molecule Eif2ak3/PERK (protein kinase R(PKR)-like endoplasmic reticulum kinase), was evaluated both in vitro and in vivo. RESULTS We found that serum hepcidin significantly increased during the progression of liver fibrosis induced by CCl4 and bile duct ligation. In addition, CCl4-treated Hamp-/- mice developed more severe liver injury, liver fibrosis, and hepatocyte apoptosis, with elevated Bax and decreased Bcl-2 expression, compared to the WT mice. Transcriptomic analysis of primary hepatocytes revealed that PERK was upregulated in Hamp-/- mice after CCl4 treatment, promoting apoptosis by regulating Bax and Bcl-2 expression. Subsequently, we demonstrated that hepcidin prevents hepatocyte apoptosis by inhibiting PERK both in vitro and in vivo. CONCLUSIONS Hepcidin inhibits hepatocyte apoptosis through suppression of the PERK pathway, highlighting its protective role in liver fibrosis and identifying a potential therapeutic target for the treatment of liver fibrosis.
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Affiliation(s)
- Changying Li
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Guojin Pang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
- Emergency Department, The First Affiliated Hospital of Tsinghua University, Beijing, China
| | - Weihua Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yingying Liu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xiaoli Huang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Wei Chen
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Tianhui Liu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Ping Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xu Fan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Ming Gao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Min Cong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
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Frascatani R, Colella M, Monteleone G. Hepcidin Is a Valuable Therapeutic Target for Colorectal Cancer. Cancers (Basel) 2024; 16:4068. [PMID: 39682254 DOI: 10.3390/cancers16234068] [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: 11/13/2024] [Revised: 11/28/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most frequent neoplasms and a major cause of cancer death worldwide. Despite recent advances in treatment approaches, the prognosis of advanced CRC remains poor, thus indicating the necessity of more effective treatments for CRC patients. CRC cells produce high levels of hepcidin, a peptide hormone that binds to the membrane-bound ferroportin and promotes its internalization and degradation, thus sequestering iron into the cancer cells with the downstream effect of enhancing tumor growth. Additionally, CRC cell-expressed hepcidin prolongs cell survival and, by targeting both CD8+ T cells and myeloid cells, restrains the induction of an efficient immune response against tumor antigens. The greatest expression of hepcidin is found in patients with metastatic CRC, and CRC patients with high hepcidin content have a worse survival rate than those with low hepcidin content. In the present article, we review the data supporting the prominent role of hepcidin in colon tumorigenesis and discuss how hepcidin inhibitors can help treat CRC patients in the metastatic setting with particular regard to the impact of hepcidin modulation on immunotherapeutic outcomes.
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Affiliation(s)
- Rachele Frascatani
- Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Marco Colella
- Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy
- Gastroenterology Unit, Fondazione Policlinico "Tor Vergata", 00133 Rome, Italy
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Tak J, An Q, Lee SG, Lee CH, Kim SG. Gα12 and endoplasmic reticulum stress-mediated pyroptosis in a single cycle of dextran sulfate-induced mouse colitis. Sci Rep 2024; 14:6335. [PMID: 38491049 PMCID: PMC10943197 DOI: 10.1038/s41598-024-56685-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 03/09/2024] [Indexed: 03/18/2024] Open
Abstract
Inflammatory bowel disease (IBD) pathogenesis involves complex inflammatory events and cell death. Although IBD involves mainly necrosis in the digestive tract, pyroptosis has also been recognized. Nonetheless, the underlying basis is elusive. Gα12/13 overexpression may affect endoplasmic reticulum (ER) stress. This study examined how Gα12/13 and ER stress affect pyroptosis using dextran sulfate sodium (DSS)-induced colitis models. Gα12/13 levels were increased in the distal and proximal colons of mice exposed to a single cycle of DSS, as accompanied by increases of IRE1α, ATF6, and p-PERK. Moreover, Il-6, Il-1β, Ym1, and Arg1 mRNA levels were increased with caspase-1 and IL-1β activation, supportive of pyroptosis. In the distal colon, RIPK1/3 levels were enhanced to a greater degree, confirming necroptosis. By contrast, the mice subjected to three cycles of DSS treatments showed decreases of Gα12/13, as accompanied by IRE1α and ATF6 suppression, but increases of RIPK1/3 and c-Cas3. AZ2 treatment, which inhibited Gα12, has an anti-pyroptotic effect against a single cycle of colitis. These results show that a single cycle of DSS-induced colitis may cause ER stress-induced pyroptosis as mediated by Gα12 overexpression in addition to necroptosis, but three cycles model induces only necroptosis, and that AZ2 may have an anti-pyroptotic effect.
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Affiliation(s)
- Jihoon Tak
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Quanxi An
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Sang Gil Lee
- Research and Development Institute, A Pharma Inc, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Sang Geon Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea.
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Ahmadi Badi S, Bereimipour A, Rohani P, Khatami S, Siadat SD. Interplay between gut microbiota and the master iron regulator, hepcidin, in the pathogenesis of liver fibrosis. Pathog Dis 2024; 82:ftae005. [PMID: 38555503 PMCID: PMC10990161 DOI: 10.1093/femspd/ftae005] [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: 10/23/2023] [Revised: 02/12/2024] [Accepted: 03/28/2024] [Indexed: 04/02/2024] Open
Abstract
INTRODUCTION There is a proven role for hepcidin and the composition of gut microbiota and its derivatives in the pathophysiology of liver fibrosis. AREA COVERED This review focuses on the literature search regarding the effect of hepcidin and gut microbiota on regulating liver physiology. We presented the regulating mechanisms of hepcidin expression and discussed the possible interaction between gut microbiota and hepcidin regulation. Furthermore, we investigated the importance of the hepcidin gene in biological processes and bacterial interactions using bioinformatics analysis. EXPERT OPINION One of the main features of liver fibrosis is iron accumulation in hepatic cells, including hepatocytes. This accumulation can induce an oxidative stress response, inflammation, and activation of hepatic stellate cells. Hepcidin is a crucial regulator of iron by targeting ferroportin expressed on hepatocytes, macrophages, and enterocytes. Various stimuli, such as iron load and inflammatory signals, control hepcidin regulation. Furthermore, a bidirectional relationship exists between iron and the composition and metabolic activity of gut microbiota. We explored the potential of gut microbiota to influence hepcidin expression and potentially manage liver fibrosis, as the regulation of iron metabolism plays a crucial role in this context.
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Affiliation(s)
- Sara Ahmadi Badi
- Biochemistry Department, Pasteur Institute of Iran, Tehran, 1963737611, Iran
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, 1416753955, Iran
| | - Ahmad Bereimipour
- Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton, TX 76203, USA
| | - Pejman Rohani
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, 1416753955, Iran
| | - Shohreh Khatami
- Biochemistry Department, Pasteur Institute of Iran, Tehran, 1963737611, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, 1963737611, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran,1963737611, Iran
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Kimura T, Iwadare T, Wakabayashi SI, Kuldeep S, Nakajima T, Yamazaki T, Aomura D, Zafar H, Iwaya M, Joshita S, Uehara T, Pydi SP, Tanaka N, Umemura T. Thrombospondin 2 is a key determinant of fibrogenesis in non-alcoholic fatty liver disease. Liver Int 2024; 44:483-496. [PMID: 38010940 DOI: 10.1111/liv.15792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 10/24/2023] [Accepted: 11/02/2023] [Indexed: 11/29/2023]
Abstract
OBJECTIVE Hepatic overexpression of the thrombospondin 2 gene (THBS2) and elevated levels of circulating thrombospondin 2 (TSP2) have been observed in patients with chronic liver disease. This study aimed to identify the specific cells expressing THBS2/TSP2 in non-alcoholic fatty liver disease (NAFLD) and investigate the underlying mechanism behind THBS2/TSP2 upregulation. DESIGN Comprehensive NAFLD liver gene datasets, including single-cell RNA sequencing (scRNA-seq), in-house NAFLD liver tissue, and LX-2 cells derived from human hepatic stellate cells (HSCs), were analysed using a combination of computational biology, genetic, immunological, and pharmacological approaches. RESULTS Analysis of the genetic dataset revealed the presence of 1433 variable genes in patients with advanced fibrosis NAFLD, with THBS2 ranked among the top 2 genes. Quantitative polymerase chain reaction (qPCR) examination of NAFLD livers showed a significant correlation between THBS2 expression and fibrosis stage (r = .349, p < .001). In support of this, scRNA-seq data and in situ hybridization demonstrated that the THBS2 gene was highly expressed in HSCs of NAFLD patients with advanced fibrosis. Pathway analysis of the gene dataset revealed THBS2 expression to be associated with the transforming growth factor beta (TGFβ) pathway and collagen gene activation. Moreover, the activation of LX-2 cells with TGFβ increased THBS2/TSP2 and collagen expression independently of the TGFβ-SMAD2/3 pathway. THBS2 gene knockdown significantly decreased collagen expression in LX-2 cells. CONCLUSIONS THBS2/TSP2 is highly expressed in HSCs and plays a role in regulating fibrogenesis in NAFLD patients. THBS2/TSP2 may therefore represent a potential target for anti-fibrotic therapy in NAFLD.
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Affiliation(s)
- Takefumi Kimura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
| | - Takanobu Iwadare
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shun-Ichi Wakabayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Seema Kuldeep
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India
| | - Tomoyuki Nakajima
- Department of Laboratory Medicine, Shinshu University School Hospital, Matsumoto, Japan
| | - Tomoo Yamazaki
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Medicine, University of California San Diego, San Diego, La Jolla, USA
| | - Daiki Aomura
- Department of Medicine, Division of Nephrology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hamim Zafar
- Department of Computer Science and Engineering and Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India
| | - Mai Iwaya
- Department of Laboratory Medicine, Shinshu University School Hospital, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School Hospital, Matsumoto, Japan
| | - Sai P Pydi
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India
| | - Naoki Tanaka
- Department of Global Medical Research Promotion, Shinshu University Graduate School of Medicine, Matsumoto, Japan
- International Relations Office, Shinshu University School of Medicine, Matsumoto, Japan
- Research Center for Social Systems, Shinshu University, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
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Olynyk JK, St. Pierre TG, Chen J, Frazer DM, Ramm LE, Ramm GA. Extrahepatic Iron Loading Associates With the Propensity to Develop Advanced Hepatic Fibrosis in Hemochromatosis. GASTRO HEP ADVANCES 2024; 3:454-460. [PMID: 39131712 PMCID: PMC11307999 DOI: 10.1016/j.gastha.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 01/22/2024] [Indexed: 08/13/2024]
Abstract
Background and Aims Hemostatic iron regulator-hemochromatosis can result in progressive iron-loading and advanced hepatic fibrosis in some individuals. We studied total body and hepatic iron loading to determine whether the distribution of iron-loading influences the risk of advanced fibrosis. Methods One hundred thirty-eight men and 66 women with hemochromatosis who underwent liver biopsy for staging of hepatic fibrosis had evaluation of hepatic iron concentration (HIC), hepatic iron index (HIC/age), total body iron stores (mobilizable iron), and mobilizable iron/HIC ratio (a marker of total body iron relative to hepatic iron). The potential impact of liver volume on mobilizable iron stores was assessed using magnetic resonance imaging in a separate cohort of 19 newly diagnosed individuals with hemochromatosis. Results Of 204 biopsied subjects, 41 had advanced fibrosis and exhibited 60% greater accumulation of mobilizable iron relative to HIC (mean 0.070 ± 0.008 g Fe/[μmol Fe/g]) compared with 163 subjects with low-grade fibrosis (mean 0.044 ± 0.002 g Fe/[μmol Fe/g], P < .0001). Linear regression modeling confirmed a discrete advanced hepatic fibrosis phenotype associated with greater mobilizable iron stores relative to HIC. The ratios of the upper to lower 95% limits of the distributions of liver volumes and the mobilizable iron/HIC ratios were 2.7 (95% confidence interval 2.3-3.0) and 9.7 (95% confidence interval 8.0-11.7), respectively, indicating that the distribution of liver volumes is not sufficiently wide to explain the variability in mobilizable iron/HIC ratios, suggesting that significant extrahepatic iron loading is present in those with advanced hepatic fibrosis. Conclusion Advanced hepatic fibrosis develops in hemostatic iron regulator-hemochromatosis individuals who also have excessive extrahepatic mobilizable iron stores.
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Affiliation(s)
- John K. Olynyk
- Curtin Medical School, Curtin University, Bentley, Western Australia, Australia
- Department of Gastroenterology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
| | - Timothy G. St. Pierre
- School of Physics, Mathematics, and Computing, University of Western Australia, Crawley, Western Australia, Australia
| | - James Chen
- Department of Gastroenterology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
| | - David M. Frazer
- Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- School of Biomedical Sciences, Queensland University of Technology, Gardens Point, Queensland, Australia
- School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia
| | - Louise E. Ramm
- Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Grant A. Ramm
- Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia
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10
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Hong YJ, Kim GH, Park Y, Jo HJ, Nam MW, Kim DG, Cho H, Shim HJ, Jin JS, Rho H, Han CY. Suaeda glauca Attenuates Liver Fibrosis in Mice by Inhibiting TGFβ1-Smad2/3 Signaling in Hepatic Stellate Cells. Nutrients 2023; 15:3740. [PMID: 37686772 PMCID: PMC10490352 DOI: 10.3390/nu15173740] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Chronic liver injury due to various hepatotoxic stimuli commonly leads to fibrosis, which is a crucial factor contributing to liver disease-related mortality. Despite the potential benefits of Suaeda glauca (S. glauca) as a natural product, its biological and therapeutic effects are barely known. This study investigated the effects of S. glauca extract (SGE), obtained from a smart farming system utilizing LED lamps, on the activation of hepatic stellate cells (HSCs) and the development of liver fibrosis. C57BL/6 mice received oral administration of either vehicle or SGE (30 or 100 mg/kg) during CCl4 treatment for 6 weeks. The supplementation of SGE significantly reduced liver fibrosis induced by CCl4 in mice as evidenced by histological changes and a decrease in collagen accumulation. SGE treatment also led to a reduction in markers of HSC activation and inflammation as well as an improvement in blood biochemical parameters. Furthermore, SGE administration diminished fibrotic responses following acute liver injury. Mechanistically, SGE treatment prevented HSC activation and inhibited the phosphorylation and nuclear translocation of Smad2/3, which are induced by transforming growth factor (TGF)-β1 in HSCs. Our findings indicate that SGE exhibits anti-fibrotic effects by inhibiting TGFβ1-Smad2/3 signaling in HSCs.
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Affiliation(s)
- You-Jung Hong
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Gil-Hwan Kim
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Yongdo Park
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Hye-Jin Jo
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Min-Woo Nam
- LED Agri-Bio Fusion Technology Research Center, Jeonbuk National University, Iksan 54596, Jeonbuk, Republic of Korea
| | - Dong-Gu Kim
- Department of Oriental Medicine Resources, Jeonbuk National University, Iksan 54596, Jeonbuk, Republic of Korea
| | - Hwangeui Cho
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Hyun-Joo Shim
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Jong-Sik Jin
- LED Agri-Bio Fusion Technology Research Center, Jeonbuk National University, Iksan 54596, Jeonbuk, Republic of Korea
- Department of Oriental Medicine Resources, Jeonbuk National University, Iksan 54596, Jeonbuk, Republic of Korea
| | - Hyunsoo Rho
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
| | - Chang-Yeob Han
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
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11
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Lin PC, Hsu WY, Lee PY, Hsu SH, Chiou SS. Insights into Hepatocellular Carcinoma in Patients with Thalassemia: From Pathophysiology to Novel Therapies. Int J Mol Sci 2023; 24:12654. [PMID: 37628834 PMCID: PMC10454908 DOI: 10.3390/ijms241612654] [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: 06/26/2023] [Revised: 08/02/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Thalassemia is a heterogeneous congenital hemoglobinopathy common in the Mediterranean region, Middle East, Indian subcontinent, and Southeast Asia with increasing incidence in Northern Europe and North America due to immigration. Iron overloading is one of the major long-term complications in patients with thalassemia and can lead to organ damage and carcinogenesis. Hepatocellular carcinoma (HCC) is one of the most common malignancies in both transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). The incidence of HCC in patients with thalassemia has increased over time, as better chelation therapy confers a sufficiently long lifespan for the development of HCC. The mechanisms of iron-overloading-associated HCC development include the increased reactive oxygen species (ROS), inflammation cytokines, dysregulated hepcidin, and ferroportin metabolism. The treatment of HCC in patients with thalassemia was basically similar to those in general population. However, due to the younger age of HCC onset in thalassemia, regular surveillance for HCC development is mandatory in TDT and NTDT. Other supplemental therapies and experiences of novel treatments for HCC in the thalassemia population were also reviewed in this article.
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Affiliation(s)
- Pei-Chin Lin
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung 807378, Taiwan; (P.-C.L.); (W.-Y.H.); (P.-Y.L.)
- School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Wan-Yi Hsu
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung 807378, Taiwan; (P.-C.L.); (W.-Y.H.); (P.-Y.L.)
| | - Po-Yi Lee
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung 807378, Taiwan; (P.-C.L.); (W.-Y.H.); (P.-Y.L.)
| | - Shih-Hsien Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Center of Applied Genomics, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Shyh-Shin Chiou
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung 807378, Taiwan; (P.-C.L.); (W.-Y.H.); (P.-Y.L.)
- Center of Applied Genomics, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Division of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807378, Taiwan
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12
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Formica V, Riondino S, Morelli C, Guerriero S, D'Amore F, Di Grazia A, Del Vecchio Blanco G, Sica G, Arkenau HT, Monteleone G, Roselli M. HIF2α, Hepcidin and their crosstalk as tumour-promoting signalling. Br J Cancer 2023; 129:222-236. [PMID: 37081189 PMCID: PMC10338631 DOI: 10.1038/s41416-023-02266-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 03/25/2023] [Accepted: 03/30/2023] [Indexed: 04/22/2023] Open
Abstract
Not all aspects of the disruption of iron homeostasis in cancer have been fully elucidated. Iron accumulation in cancer cells is frequent for many solid tumours, and this is often accompanied by the contemporary rise of two key iron regulators, HIF2α and Hepcidin. This scenario is different from what happens under physiological conditions, where Hepcidin parallels systemic iron concentrations while HIF2α levels are inversely associated to Hepcidin. The present review highlights the increasing body of evidence for the pro-tumoral effect of HIF2α and Hepcidin, discusses the possible imbalance in HIF2α, Hepcidin and iron homeostasis during cancer, and explores therapeutic options relying on these pathways as anticancer strategies.
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Affiliation(s)
- Vincenzo Formica
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy.
| | - Silvia Riondino
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Cristina Morelli
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
- PhD Program in Systems and Experimental Medicine (XXXV cycle), University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Simona Guerriero
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Federica D'Amore
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Antonio Di Grazia
- Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, Italy
| | | | - Giuseppe Sica
- Department of Surgery, University of Rome Tor Vergata, Rome, Italy
| | | | - Giovanni Monteleone
- Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Mario Roselli
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
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13
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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14
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Lin F, Tuffour A, Hao G, Peprah FA, Huang A, Zhou Y, Zhang H. Distinctive modulation of hepcidin in cancer and its therapeutic relevance. Front Oncol 2023; 13:1141603. [PMID: 36895478 PMCID: PMC9989193 DOI: 10.3389/fonc.2023.1141603] [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: 01/10/2023] [Accepted: 02/08/2023] [Indexed: 02/23/2023] Open
Abstract
Hepcidin, a short peptide synthesized primarily by hepatocytes in response to increased body iron and inflammation, is a crucial iron-regulating factor. Hepcidin regulates intestinal iron absorption and releases iron from macrophages into plasma through a negative iron feedback mechanism. The discovery of hepcidin inspired a torrent of research into iron metabolism and related problems, which have radically altered our understanding of human diseases caused by an excess of iron, an iron deficiency, or an iron disparity. It is critical to decipher how tumor cells manage hepcidin expression for their metabolic requirements because iron is necessary for cell survival, particularly for highly active cells like tumor cells. Studies show that tumor and non-tumor cells express and control hepcidin differently. These variations should be explored to produce potential novel cancer treatments. The ability to regulate hepcidin expression to deprive cancer cells of iron may be a new weapon against cancer cells.
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Affiliation(s)
- Feng Lin
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Alex Tuffour
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China.,State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Guijie Hao
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | | | - Aixia Huang
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Yang Zhou
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Haiqi Zhang
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
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15
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Panzarini E, Leporatti S, Tenuzzo BA, Quarta A, Hanafy NAN, Giannelli G, Moliterni C, Vardanyan D, Sbarigia C, Fidaleo M, Tacconi S, Dini L. Therapeutic Effect of Polymeric Nanomicelles Formulation of LY2157299-Galunisertib on CCl 4-Induced Liver Fibrosis in Rats. J Pers Med 2022; 12:jpm12111812. [PMID: 36579532 PMCID: PMC9692463 DOI: 10.3390/jpm12111812] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/21/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatic fibrosis (HF) is a major cause of liver-related disorders and together with cancer-associated fibroblasts can favor liver cancer development by modulating the tumor microenvironment. Advanced HF, characterized by an excess of extracellular matrix (ECM), is mediated by TGF- β1, that activates hepatic stellate cells (HSCs) and fibroblasts. A TGF-β1 receptor inhibitor, LY2157299 or Galunisertib (GLY), has shown promising results against chronic liver progression in animal models, and we show that it can be further improved by enhancing GLYs bioavailability through encapsulation in polymeric polygalacturonic-polyacrylic acid nanomicelles (GLY-NMs). GLY-NMs reduced HF in an in vivo rat model of liver fibrosis induced by intraperitoneal injection of CCl4 as shown by the morphological, biochemical, and molecular biology parameters of normal and fibrotic livers. Moreover, GLY-NM was able to induce recovery from HF better than free GLY. Indeed, the encapsulated drug reduces collagen deposition, hepatic stellate cells (HSCs) activation, prevents fatty degeneration and restores the correct lobular architecture of the liver as well as normalizes the serum parameters and expression of the genes involved in the onset of HF. In summary, GLY-NM improved the pharmacological activity of the free TGF- β1 inhibitor in the in vivo HF treatment and thus is a candidate as a novel therapeutic strategy.
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Affiliation(s)
- Elisa Panzarini
- Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), University of Salento, 73100 Lecce, Italy; (E.P.); (B.A.T.); (D.V.)
| | - Stefano Leporatti
- Consiglio Nazionale delle Ricerche (CNR) NANOTEC istituto di Nanotecnologia-Istituto di Nanotecnologia, 73100 Lecce, Italy; (S.L.); (A.Q.)
| | - Bernardetta Anna Tenuzzo
- Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), University of Salento, 73100 Lecce, Italy; (E.P.); (B.A.T.); (D.V.)
| | - Alessandra Quarta
- Consiglio Nazionale delle Ricerche (CNR) NANOTEC istituto di Nanotecnologia-Istituto di Nanotecnologia, 73100 Lecce, Italy; (S.L.); (A.Q.)
| | - Nemany A. N. Hanafy
- Nanomedicine Department, Institute of Nanoscience and Nanotechnology, Kafrelsheikh University, Kafr El Sheikh 6860404, Egypt;
| | - Gianluigi Giannelli
- National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, Italy;
| | - Camilla Moliterni
- Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy; (C.M.); (C.S.)
| | - Diana Vardanyan
- Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), University of Salento, 73100 Lecce, Italy; (E.P.); (B.A.T.); (D.V.)
| | - Carolina Sbarigia
- Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy; (C.M.); (C.S.)
| | - Marco Fidaleo
- Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy; (C.M.); (C.S.)
- Research Center for Nanotechnology for Engineering of Sapienza (CNIS), Sapienza University of Rome, 00185 Rome, Italy
- Correspondence: (M.F.); (S.T.); (L.D.)
| | - Stefano Tacconi
- Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy; (C.M.); (C.S.)
- Correspondence: (M.F.); (S.T.); (L.D.)
| | - Luciana Dini
- Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy; (C.M.); (C.S.)
- Research Center for Nanotechnology for Engineering of Sapienza (CNIS), Sapienza University of Rome, 00185 Rome, Italy
- Correspondence: (M.F.); (S.T.); (L.D.)
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16
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Identification of ATG7 as a Regulator of Proferroptosis and Oxidative Stress in Osteosarcoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8441676. [PMID: 36254233 PMCID: PMC9569205 DOI: 10.1155/2022/8441676] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 09/08/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022]
Abstract
Background Ferroptosis has gained significant attention from oncologists as a vital outcome of oxidative stress. The aim of this study was to develop a prognostic signature that was based on the ferroptosis-related genes (FRGs) for osteosarcoma patients and explore their specific role in osteosarcoma. Methods The training cohort dataset was extracted from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Different techniques like the univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression, multivariate Cox regression analyses, and the Kaplan-Meier (KM) survival analyses were utilized to develop a prognostic signature. Then, the intrinsic relationship between the developed gene signature and the infiltration levels of the immune cells was further investigated. An external validation dataset from the Gene Expression Omnibus (GEO) database was employed to assess the predictive ability of the developed gene signature. Subsequently, the specific function of potential FRG in affecting the oxidative stress reaction and ferroptosis of osteosarcoma cells was identified. Results A prognostic signature based on 5 FRGs (CBS, MUC1, ATG7, SOCS1, and PEBP1) was developed, and the patients were classified into the low- and high-risk groups (categories). High-risk patients displayed poor overall survival outcomes. The risk level was seen to be an independent risk factor for determining the prognosis of osteosarcoma patients (p < 0.001, hazard ratio: 7.457, 95% CI: 3.302-16.837). Additionally, the risk level was associated with immune function, which might affect the survival status of osteosarcoma patients. Moreover, the findings of the study indicated that the expression of ATG7 was related to the regulation of oxidative stress in osteosarcoma. Silencing the ATG7 gene promoted the proliferation and migration in osteosarcoma cells, suppressing the oxidative stress and ferroptosis process. Conclusions A novel FRG signature was developed in this study to predict the prognosis of osteosarcoma patients. The results indicated that ATG7 might regulate the process of oxidative stress and ferroptosis in osteosarcoma cells and could be used as a potential target to develop therapeutic strategies for treating osteosarcoma.
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17
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Chen H, Zhao W, Yan X, Huang T, Yang A. Overexpression of Hepcidin Alleviates Steatohepatitis and Fibrosis in a Diet-induced Nonalcoholic Steatohepatitis. J Clin Transl Hepatol 2022; 10:577-588. [PMID: 36062292 PMCID: PMC9396326 DOI: 10.14218/jcth.2021.00289] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 09/22/2021] [Accepted: 09/28/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Iron overload can contribute to the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). Hepcidin (Hamp), which is primarily synthesized in hepatocytes, is a key regulator of iron metabolism. However, the role of Hamp in NASH remains unclear. Therefore, we aimed to elucidate the role of Hamp in the pathophysiology of NASH. METHODS Male mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for 16 weeks to establish the mouse NASH model. A choline-supplemented amino acid-defined (CSAA) diet was used as the control diet. Recombinant adeno-associated virus genome 2 serotype 8 vector expressing Hamp (rAAV2/8-Hamp) or its negative control (rAAV2/8-NC) was administered intravenously at week 8 of either the CDAA or CSAA diet. RESULTS rAAV2/8-Hamp treatment markedly decreased liver weight and improved hepatic steatosis in the CDAA-fed mice, accompanied by changes in lipogenesis-related genes and adiponectin expression. Compared with the control group, rAAV2/8-Hamp therapy attenuated liver damage, with mice exhibiting reduced histological NAFLD inflammation and fibrosis, as well as lower levels of liver enzymes. Moreover, α-smooth muscle actin-positive activated hepatic stellate cells (HSCs) and CD68-postive macrophages increased in number in the CDAA-fed mice, which was reversed by rAAV2/8-Hamp treatment. Consistent with the in vivo findings, overexpression of Hamp increased adiponectin expression in hepatocytes and Hamp treatment inhibited HSC activation. CONCLUSIONS Overexpression of Hamp using rAAV2/8-Hamp robustly attenuated liver steatohepatitis, inflammation, and fibrosis in an animal model of NASH, suggesting a potential therapeutic role for Hamp.
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Affiliation(s)
- Hui Chen
- Digestive Department, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Correspondence to: Hui Chen, Digestive Department, Beijing Chaoyang Hospital, Capital Medical University, No. 5 Jingyuan Road, Shijingshan District, Beijing 100043, China. Tel: +86-10-51718484, Fax: +86-10-83165944, E-mail: . Aiting Yang, Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China. ORCID: https://orcid.org/0000-0002-5671-696X. Tel: +86-10-63139311, Fax: +86-10-83165944, E-mail:
| | - Wenshan Zhao
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xuzhen Yan
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Tao Huang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Aiting Yang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center of Digestive Diseases, Beijing, China
- Beijing Clinical Medicine Institute, Beijing, China
- Correspondence to: Hui Chen, Digestive Department, Beijing Chaoyang Hospital, Capital Medical University, No. 5 Jingyuan Road, Shijingshan District, Beijing 100043, China. Tel: +86-10-51718484, Fax: +86-10-83165944, E-mail: . Aiting Yang, Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China. ORCID: https://orcid.org/0000-0002-5671-696X. Tel: +86-10-63139311, Fax: +86-10-83165944, E-mail:
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18
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Sun Z, Zhan X. Myrrhone inhibits the progression of hepatic fibrosis by regulating the abnormal activation of hepatic stellate cells. J Biochem Mol Toxicol 2022; 36:e23177. [PMID: 35983967 DOI: 10.1002/jbt.23177] [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: 03/16/2022] [Revised: 06/03/2022] [Accepted: 07/21/2022] [Indexed: 11/12/2022]
Abstract
We focus on exploring the antihepatic fibrosis effect of Myrrhone (Myr), a compound extracted from myrrh, and its effective target. Mouse hepatic stellate cells (HSCs) were cultured in vitro and activated by transforming growth factor-β induction. After Myr intervention, cell viability was assessed by the Cell Counting Kit-8 assay. The α-smooth muscle actin(α-SMA) and Collagen I levels were measured by immunofluorescence, and the expressions of tumor necrosis factor-α, interleukin-6, and matrix metalloproteinase-9 were examined by enzyme-linked immunosorbent assay, and the p-Smad3 protein level in HSCs was determined by Western Blot. Small molecule-protein docking and pull-down experiments were conducted to validate the binding capacity between Nard and Smad3. In animal experiments, a mouse model of hepatic fibrosis was established with carbon tetrachloride. Myr was administered by gavage daily to determine the serum alanine aminotransferase and aspartate transaminase levels. The severity of hepatic fibrosis was evaluated by Masson staining, the α-SMA and Collagen I expressions were measured by immunohistochemistry, and the histopathological changes were examined by Sirius red and hematoxylin and eosin staining. Myr suppressed the abnormal activation of HSCs, inhibited the cell viability, downregulated the α-SMA and Collagen I, and inhibited the p-Smad3 expression. After silencing Smad3, the effect of Myr was inhibited. Molecular docking and pull-down experiments revealed the presence of a targeted binding relationship between Myr and Smad3. In mouse experiments, Myr could inhibit hepatic fibrosis. This study discovers that Myr can affect the phosphorylation of Smad3, and inhibit the activation of HSCs and the progression of hepatic fibrosis.
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Affiliation(s)
- Zhangchi Sun
- Pharmacy Department, Zhejiang Rongjun Hospital, Jiaxing, China
| | - Xiaolan Zhan
- Pharmacy Department, Zhejiang Rongjun Hospital, Jiaxing, China
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Jung HJ, Cho K, Kim SY, Seong JK, Oh SH. Ethanol extract of Pharbitis nil ameliorates liver fibrosis through regulation of the TGFβ1-SMAD2/3 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2022; 294:115370. [PMID: 35568114 DOI: 10.1016/j.jep.2022.115370] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/22/2022] [Accepted: 05/07/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pharbitis nil (L.) Choisy is a medicinal herb, and herbal remedies based on its seeds have been used to treat of obesity and liver diseases, including fatty liver and liver cirrhosis in East Asia. AIM OF THE STUDY Liver fibrosis is a major cause of morbidity and mortality in patients with chronic liver inflammation such as that caused by non-alcoholic steatohepatitis. However, no effective pharmaceutical treatment for liver fibrosis has been approved. In this study, we aimed to investigate that ethanol extract of pharbitis nil (PNE) alleviates the liver fibrosis. MATERIALS AND METHODS We studied the effects of PNE on two preclinical models. Six-week-old male C57BL/6 mice were intraperitoneally injected with CCl4 twice weekly for 6 weeks and then treated with 5 or 10 mg/kg PNE daily from week 3 for weeks. Secondly, mice were fed HFD for 41 weeks and at 35 weeks treated with 5 mg/kg PNE daily for the remaining 6 weeks. In addition, we examined the antifibrotic effects of PNE in primary mouse hepatic stellate cells and LX-2 cells. RESULTS PNE treatment ameliorated hepatocyte necrosis, inflammation, and liver fibrosis in CCl4-treated mice and inhibited the progression of liver fibrosis in mice with HFD-induced fibrosis. PNE reduced the expressions of fibrosis markers and SMAD2/3 activations in mouse livers and in TGFβ1-treated primary mouse hepatic stellate and LX-2 cells CONCLUSIONS: This study demonstrates that PNE attenuates liver fibrosis by downregulating TGFβ1-induced SMAD2/3 activation.
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Affiliation(s)
- Hyun Jin Jung
- College of Pharmacy, Gachon University, Incheon, 21936, South Korea.
| | - Kyohee Cho
- College of Pharmacy, Gachon University, Incheon, 21936, South Korea.
| | - Sun Yeou Kim
- College of Pharmacy, Gachon University, Incheon, 21936, South Korea.
| | - Je Kyung Seong
- Korea Mouse Phenotyping Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea; Laboratory of Developmental Biology and Genomics, Research Institute of Veterinary Science, BK21 Plus Program for Veterinary Science, Seoul National University, Seoul, 08826, South Korea.
| | - Seung Hyun Oh
- College of Pharmacy, Gachon University, Incheon, 21936, South Korea.
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Baboota RK, Rawshani A, Bonnet L, Li X, Yang H, Mardinoglu A, Tchkonia T, Kirkland JL, Hoffmann A, Dietrich A, Boucher J, Blüher M, Smith U. BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH. Nat Metab 2022; 4:1007-1021. [PMID: 35995996 PMCID: PMC9398907 DOI: 10.1038/s42255-022-00620-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 07/13/2022] [Indexed: 11/09/2022]
Abstract
The role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets.
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Affiliation(s)
- Ritesh K Baboota
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Aidin Rawshani
- Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Laurianne Bonnet
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Xiangyu Li
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Hong Yang
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Tamar Tchkonia
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - James L Kirkland
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Anne Hoffmann
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Arne Dietrich
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Section of Bariatric Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Jeremie Boucher
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Ulf Smith
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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21
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Fu R, Zu SJ, Liu YJ, Li JC, Dang WZ, Liao LP, Liu LP, Chen PY, Huang HM, Wu KH, Zhou B, Pan Q, Luo C, Zhang YY, Li GM. Selective bromodomain and extra-terminal bromodomain inhibitor inactivates macrophages and hepatic stellate cells to inhibit liver inflammation and fibrosis. Bioengineered 2022; 13:10914-10930. [PMID: 35499161 PMCID: PMC9278415 DOI: 10.1080/21655979.2022.2066756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Liver fibrosis occurs following inflammation triggered by the integrated actions of activated liver-resident macrophages (Kupffer cells) and hepatic stellate cells (HSCs), and the multiplicity of these mechanisms complicates drug therapy. Here, we demonstrate that the selective bromodomain and extra-terminal (BET) bromodomain inhibitor compound38 can block both the Janus kinase-signal transducer and activator of transcription and mitogen-activated protein kinase signaling pathways in macrophages, which decreased their secretion of proinflammatory cytokines in a dose-dependent manner. The inactivation of macrophages attenuated lipopolysaccharide-induced injurious inflammation concurrent with a reduction in F4/80+ cells, proinflammatory cytokine levels, and neutrophil infiltration. Moreover, compound 38 inhibited the Wnt/β-catenin and transforming growth factor-beta/SMAD signaling pathways to abolish the activation of HSCs. In vivo, compound 38 significantly decreased the collagen deposition and fibrotic area of a CCl4-induced liver fibrosis model, and restored the deficiency of activated HSCs and the upregulation of liver inflammation. These results highlight the potential role of compound 38 in treating liver fibrosis considering its simultaneous inhibitory effects on liver inflammation and related fibrosis.
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Affiliation(s)
- Rong Fu
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, Yangpu District, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Shi-Jia Zu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
- University of Chinese Academy of Sciences, Huairou District, Beijing, China
| | - Yan-Jun Liu
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, Yangpu District, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Jia-Cheng Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Wen-Zhen Dang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Li-Ping Liao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Li-Ping Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Pan-Yu Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - He-Ming Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Kang-Hui Wu
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, Yangpu District, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Bing Zhou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Qin Pan
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, Yangpu District, China
- Research center, Zhoupu Hospital affiliated to Shanghai University of Medicine and Health Sciences, Shanghai, Zhouyuan District, China
| | - Cheng Luo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
- University of Chinese Academy of Sciences, Huairou District, Beijing, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of SciencesCAS, Hangzhou, Zhejiang, China
| | - Yuan-Yuan Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
- University of Chinese Academy of Sciences, Huairou District, Beijing, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of SciencesCAS, Hangzhou, Zhejiang, China
| | - Guang-Ming Li
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, Yangpu District, China
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22
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Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis. Acta Pharm Sin B 2022; 12:2443-2461. [PMID: 35646543 PMCID: PMC9136578 DOI: 10.1016/j.apsb.2021.12.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/29/2021] [Accepted: 12/22/2021] [Indexed: 01/18/2023] Open
Abstract
Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl4, α-naphthyl-isothiocyanate (ANIT), bile duct ligation (BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix (ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl4-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of pro-inflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha (NFκB/IKBα) pathways as well as c-Jun N-terminal kinase (JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl4-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.
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23
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Xu C, Hou L, Zhao J, Wang Y, Jiang F, Jiang Q, Zhu Z, Tian L. Exosomal let-7i-5p from three-dimensional cultured human umbilical cord mesenchymal stem cells inhibits fibroblast activation in silicosis through targeting TGFBR1. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 233:113302. [PMID: 35189518 DOI: 10.1016/j.ecoenv.2022.113302] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 06/14/2023]
Abstract
Silicosis of pulmonary fibrosis (PF) is related to long-term excessive inhalation of silica. The activation of fibroblasts into myofibroblasts is the main terminal effect leading to lung fibrosis, which is of great significance to the study of the occurrence and development of silicosis fibrosis and its prevention and treatment. Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-Exos) are considered to be a potential therapy of silica-induced PF, however, their exact mechanism remains unknown. Therefore, this study aims to explore whether hucMSC-Exos affect the activation of fibroblasts to alleviate PF. In this study, a three-dimensional (3D) method was applied to culture hucMSCs and MRC-5 cells (human embryonic lung fibroblasts), and exosomes were isolated from serum-free media, identified by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and Western blotting analysis. Then, the study used an animal model of silica-induced PF to observe the effects of hucMSC-Exos and MRC-5-Exos on activation of fibroblasts. In addition, the activation of fibroblasts was analyzed by Western blotting analysis, wound healing, and migration assay with the treatment of hucMSC-Exos and MRC-5-Exos in NIH-3T3 cells (mouse embryonic fibroblasts). Furthermore, differential expression of microRNAs (DE miRNAs) was measured between hucMSCs-Exos and MRC-5-Exos by high throughput sequence. HucMSC-Exos inhibited the activation of fibroblasts in mice and NIH-3T3 cells. Let-7i-5p was significantly up-regulated in hucMSCs-Exos compared to MRC-5-Exos, which was related to silica-induced PF. Let-7i-5p of hucMSCs-Exos was responsible for the activation of fibroblasts by targeting TGFBR1. Meanwhile, Smad3 was also an important role in the activation of fibroblasts. The study demonstrates that hucMSCs-Exos act as a mediator that transfers let-7i-5p to inhibit the activation of fibroblasts, which alleviates PF through the TGFBR1/Smad3 signaling pathway. The mechanism has potential value for the treatment of silica-induced PF.
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Affiliation(s)
- Chunjie Xu
- Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Laboratory of Pharmacology/Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Lin Hou
- Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Jing Zhao
- Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Yan Wang
- Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Fuyang Jiang
- Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Qiyue Jiang
- Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Zhonghui Zhu
- Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
| | - Lin Tian
- Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
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24
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Hepcidin in hepatocellular carcinoma. Br J Cancer 2022; 127:185-192. [PMID: 35264787 PMCID: PMC9296449 DOI: 10.1038/s41416-022-01753-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/26/2022] [Accepted: 02/09/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common reasons for cancer-related deaths. Excess iron increases HCC risk. Inevitably, hepcidin, the iron hormone that maintains systemic iron homoeostasis is involved in HCC pathology. Distinct from other cancers that show high hepcidin expression, HCC patients can show low hepcidin levels. Thus, it is of immense clinical benefit to address the regulation and action of hepcidin in HCC as this may help in identifying molecular targets for diagnosis, prognosis, and therapeutics. Accordingly, this review explores hepcidin in HCC. It presents the levels of tissue and serum hepcidin and explains the mechanisms that contribute to hepcidin reduction in HCC. These include downregulation of HAMP, TfR2, HJV, ALK2 and circular RNA circ_0004913, upregulation of matriptase-2 and GDF15, inactivation of RUNX3 and mutation in TP53. The enigmas around mir-122 and the functionalities of two major hepcidin inducers BMP6 and IL6 in relation to hepcidin in HCC are discussed. Effects of hepcidin downregulation are explained, specifically, increased cancer proliferation via activation of CDK1/STAT3 pathway and increased HCC risk due to reduction in a hepcidin-mediated protective effect against hepatic stellate cell activation. Hepcidin–ferroportin axis in HCC is addressed. Finally, the role of hepcidin in the diagnosis, prognosis and therapeutics of HCC is highlighted.
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25
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Chen XL, Chen GW, Zhou P, Li H. Association of the Liver and Spleen Signal Intensity on MRI with Anemia in Gynecological Cancer. Curr Med Imaging 2022; 18:931-938. [PMID: 35255792 DOI: 10.2174/1568026622666220307123736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 11/25/2021] [Accepted: 12/20/2021] [Indexed: 11/22/2022]
Abstract
OBJECTIVE This study is to investigate the association of the liver and spleen signal intensity on MRI with anemia in patients with gynecologic cancer. METHODS 332 patients with gynecological cancer and 78 healthy women underwent MRI examination. Liver and spleen MRI parameters and laboratory tests were obtained within 1 week. The signal intensity ratios of liver and spleen to the paraspinous muscle were calculated on gradient echo T1-weighted images (T1WI) and T2-weighted images (T2WI) in both patients and healthy women, respectively. RESULTS The ratios of liver and spleen to paraspinous muscle on T1WI and T2WI were lower in patients than in the healthy women, respectively (all P<0.0001). The ratios of the liver and spleen to paraspinous muscle on T1WI and T2WI decreased with the increasing stage of anemia and decreasing of the hemoglobin levels (all P<0.001). The ratios of the liver to paraspinous muscle on T1WI, spleen to paraspinous muscle on T1WI, and the liver and spleen to paraspinous muscle on T2WI could predict anemia stage≥1 (AUC=0.576, 0.643, 0.688, and 0.756, respectively), ≥2 (AUC=0.743, 0.714, 0.891, and 0.922, respectively) and 3 (AUC=0.851, 0.822, 0.854, and 0.949, respectively). CONCLUSION T2WI-based spleen signal intensity ratios showed the highest potential for noninvasive evaluation of anemia in gynecological cancer.
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Affiliation(s)
- Xiao-Li Chen
- Department of Radiology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China
| | - Guang-Wen Chen
- Department of Radiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People\'s Hospital
| | - Peng Zhou
- Department of Radiology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China
| | - Hang Li
- Department of Radiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People\'s Hospital
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26
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Raj D, Sharma V, Upadhyaya A, Kumar N, Joshi R, Acharya V, Kumar D, Patial V. Swertia purpurascens Wall ethanolic extract mitigates hepatic fibrosis and restores hepatic hepcidin levels via inhibition of TGFβ/SMAD/NFκB signaling in rats. JOURNAL OF ETHNOPHARMACOLOGY 2022; 284:114741. [PMID: 34699946 DOI: 10.1016/j.jep.2021.114741] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/28/2021] [Accepted: 10/09/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Swertia purpurascens Wall belongs to a well-known genus in traditional systems of medicine worldwide. In folklore, it is used to treat various ailments, including hepatic disorders, as an alternative to the endangered species Swertia chirayita. However, the therapeutic potential of Swertia purpurascens Wall against hepatic fibrosis has not been validated yet. AIM OF THE STUDY The present study was planned to evaluate the efficacy of the Swertia purpurascens Wall extract (SPE) against hepatic fibrosis and elucidate the underlying mechanism of action. MATERIALS AND METHODS The metabolite profiling of the SPE was done using UHPLC-QTOF-MS/MS. The acute oral toxicity study of SPE at 2 g/kg BW dose was done in rats. Further, the liver fibrosis was induced by the CCl4 intoxication, and the efficacy of SPE at three doses (100, 200 and 400 mg/kg BW) was evaluated by studying biochemical parameters, histopathology, immunohistochemistry, qRT-PCR, western blotting and in silico analysis. RESULTS UHPLC-QTOF-MS/MS analysis revealed the presence of a total of 23 compounds in SPE. Acute oral toxicity study of SPE at 2 g/kg BW showed no harmful effects in rats. Further, the liver fibrosis was induced by the CCl4 administration, and the efficacy of SPE was evaluated at three doses (100, 200 and 400 mg/kg BW). SPE treatment significantly improved the body weight gain, the relative liver weight, serum liver injury markers and endogenous antioxidant enzyme levels in the CCl4-treated rats. SPE also recovered the altered liver histology and effectively reduced the fibrotic tissue deposition in the hepatic parenchyma. Further, SPE significantly inhibited the fibrotic (TGFβ, αSMA, SMADs and Col1A), proinflammatory markers (NFκB, TNFα and IL1β) and apoptosis in the liver tissue. Interestingly, SPE treatment also restored the altered hepcidin levels in the liver tissue. In silico study revealed the potential of various metabolites as drug candidates and their interaction with target proteins. CONCLUSION Altogether, SPE showed its therapeutic potential against CCl4-induced hepatic fibrosis by restoring the hepatic hepcidin levels and inhibiting TGFβ/SMAD/NFκB signaling in rats.
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Affiliation(s)
- Desh Raj
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; PG Department of Dravyaguna, Rajiv Gandhi Govt. Post Graduate Ayurvedic College and Hospital, Paprola, 176115, H.P, India
| | - Vinesh Sharma
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Ashwani Upadhyaya
- PG Department of Dravyaguna, Rajiv Gandhi Govt. Post Graduate Ayurvedic College and Hospital, Paprola, 176115, H.P, India
| | - Neeraj Kumar
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Robin Joshi
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Vishal Acharya
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Dinesh Kumar
- Chemical Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Vikram Patial
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India.
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27
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Liu J, Li F, Liu B, Yao Z, Li L, Liu G, Peng L, Wang Y, Huang J. Adipose-derived mesenchymal stem cell exosomes inhibit transforming growth factor-β1-induced collagen synthesis in oral mucosal fibroblasts. Exp Ther Med 2021; 22:1419. [PMID: 34707701 PMCID: PMC8543178 DOI: 10.3892/etm.2021.10854] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 05/12/2021] [Indexed: 12/20/2022] Open
Abstract
Oral submucosal fibrosis (OSF) is a potentially malignant oral disorder that requires the further development of advanced treatment strategies. TGF-β1 has been reported to be the main trigger for the increased collagen production and reduced activity of matrix degradation pathways in OSF. Exosomes are key mediators of paracrine signaling that have been proposed for direct use as therapeutic agents for tissue repair and regeneration. The present study aimed to investigate the effects of human adipose-derived mesenchymal stem cell (ADSC) exosomes (ADSC-Exos) on TGF-β1-treated oral fibroblasts in vitro and to unravel the potential underlying mechanism of action. Oral mucosal fibroblasts were obtained from the buccal tissues of patients without OSF during extraction of the third molar. ADSCs were obtained from three healthy female individuals during liposuction procedures. ADSC-Exos were isolated by ultracentrifugation and identified by electron microscopy, nanoparticle tracking and western blotting. Immunofluorescence and immunocytochemistry staining were performed to measure the expression levels of vimentin and α-smooth muscle actin in the fibroblasts. Reverse transcription-quantitative PCR and western blotting were used to determine the expression levels of mRNAs and proteins associated with collagen production. The p38 MAPK activator anisomycin was used to identify the underlying mechanisms of the effects of ADSC-Exos on TGF-β1-induced collagen synthesis in oral mucosal fibroblasts. The results of the present study revealed that ADSC-Exos exhibited a cup- or sphere-shaped morphology, with a mean diameter of 58.01±16.17 nm. ADSC-Exos were also found to be positive for CD63 and tumor susceptibility 101 expression. ADSC-Exos treatment reversed the TGF-β1-induced upregulation of collagen I and III protein expression. In addition, in the presence of TGF-β1, the expression levels of collagen type I α 1 chain and collagen type III α 1 chain mRNA were downregulated, whilst the expression levels of matrix metalloproteinase (MMP)1 and MMP3 were upregulated following ADSC-Exos treatment. The TGF-β1-induced upregulation in the phosphorylation of p38 in addition to the increased protein expression of collagens I and III were also reversed in fibroblasts following ADSC-Exos treatment. However, anisomycin treatment alleviated these ADSC-Exos-induced changes. In conclusion, findings from the present study suggest that ADSC-Exos may represent a promising strategy for OSF treatment by targeting the p38 MAPK signaling pathway.
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Affiliation(s)
- Junjie Liu
- Hunan Key Laboratory of Oral Health Research, Hunan Xiangya Stomatological Hospital, Central South University, Changsha, Hunan 410000, P.R. China.,Hunan 3D Printing Engineering Research Center, Hunan Xiangya Stomatological Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Fuxingzi Li
- Department of Endocrinology and Metabolism, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Binjie Liu
- Hunan Key Laboratory of Oral Health Research, Hunan Xiangya Stomatological Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Zhigang Yao
- Hunan Key Laboratory of Oral Health Research, Hunan Xiangya Stomatological Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Long Li
- Hunan Key Laboratory of Oral Health Research, Hunan Xiangya Stomatological Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Gui Liu
- Hunan Key Laboratory of Oral Health Research, Hunan Xiangya Stomatological Hospital, Central South University, Changsha, Hunan 410000, P.R. China.,Hunan 3D Printing Engineering Research Center, Hunan Xiangya Stomatological Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Lei Peng
- Department of Urban Palliative Home Care, Grey Nuns Community Hospital, Edmonton, AB T5J3E4, Canada
| | - Yuxin Wang
- Department of Stomatology, Changsha Central Hospital, Changsha, Hunan 410018, P.R. China
| | - Junhui Huang
- Hunan Key Laboratory of Oral Health Research, Hunan Xiangya Stomatological Hospital, Central South University, Changsha, Hunan 410000, P.R. China.,Hunan 3D Printing Engineering Research Center, Hunan Xiangya Stomatological Hospital, Central South University, Changsha, Hunan 410000, P.R. China
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28
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Bilal RM, Liu C, Zhao H, Wang Y, Farag MR, Alagawany M, Hassan FU, Elnesr SS, Elwan HAM, Qiu H, Lin Q. Olive Oil: Nutritional Applications, Beneficial Health Aspects and its Prospective Application in Poultry Production. Front Pharmacol 2021; 12:723040. [PMID: 34512350 PMCID: PMC8424077 DOI: 10.3389/fphar.2021.723040] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 07/12/2021] [Indexed: 01/18/2023] Open
Abstract
Plant polyphenols have promoting health features, including anti-mutagenic, anti-inflammatory, anti-thrombotic, anti-atherogenic, and anti-allergic effects. These polyphenols improve the immune system by affecting the white blood cell proliferation, as well as by the synthesis of cytokines and other factors, which contribute to immunological resistance. Olive trees are one of the most famous trees in the world. Whereas, olive olive oil and derivatives represent a large group of feeding resource for farm animals. In recent years, remarkable studies have been carried out to show the possible use of olive oil and derivatives for improvement of both animal performance and product quality. In vivo application of olive oil and its derived products has shown to maintain oxidative balance owing to its polyphenolic content. Consumption of extra virgin olive oil reduces the inflammation, limits the risk of liver damage, and prevents the progression of steatohepatitis through its potent antioxidant activities. Also, the monounsaturated fatty acids content of olive oil (particularly oleic acid), might have positive impacts on lipid peroxidation and hepatic protection. Therefore, this review article aims to highlight the nutritional applications and beneficial health aspects of olive oil and its effect on poultry production.
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Affiliation(s)
- Rana M. Bilal
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
- University College of Veterinary and Animal Sciences, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Chunjie Liu
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Haohan Zhao
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Yanzhou Wang
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
- Hunan Deren Husbandry Technology Co., Ltd., Changde, China
| | - Mayada R. Farag
- Forensic Medicine and Toxicology Department, Veterinary Medicine Faculty, Zagazig University, Zagazig, Egypt
| | - Mahmoud Alagawany
- Poultry Department, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | - Faiz-ul Hassan
- Institute of Animal and Dairy Sciences, Faculty of Animal Husbandry, University of Agriculture, Faisalabad, Pakistan
| | - Shaaban S. Elnesr
- Poultry Production Department, Faculty of Agriculture, Fayoum University, Fayoum, Egypt
| | - Hamada A. M. Elwan
- Animal and Poultry Production Department, Faculty of Agriculture, Minia University, El-Minya, Egypt
| | - Huajiao Qiu
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Qian Lin
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
- Hunan Deren Husbandry Technology Co., Ltd., Changde, China
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Targeted truncated TGF-β receptor type II delivery to fibrotic liver by PDGFβ receptor-binding peptide modification for improving the anti-fibrotic activity against hepatic fibrosis in vitro and in vivo. Int J Biol Macromol 2021; 188:941-949. [PMID: 34389395 DOI: 10.1016/j.ijbiomac.2021.08.055] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 07/05/2021] [Accepted: 08/06/2021] [Indexed: 01/15/2023]
Abstract
Truncated transforming growth factor-β receptor type II (tTβRII) is a promising anti-fibrotic candidate because it attenuates excessive transforming growth factor-β1 (TGF-β1) and then blocks TGF-β1 activity in hepatic fibrosis. However, its use has been greatly limited due to the fact that it is expensive to chemically synthesize and it does not specifically target to the lesion site. In this study, we describe that platelet- derived growth factor β receptor (PDGFβR)-binding peptide BiPPB modified tTβRII (BiPPB-tTβRII) was prepared from the cleavage of SUMO-BiPPB-tTβRII by digestion with SUMO-specific protease. Moreover, compared to the unmodified tTβRII, the target protein BiPPB-tTβRII not only highly specific targeted activated hepatic stellate cells (HSCs) and fibrotic liver tissue, but also significantly inhibited the protein levels of fibrosis-related genes in TGF-β1-induced HSC-T6 cells and CCl4-induced liver fibrosis in mice. Furthermore, BiPPB-tTβRII markedly ameliorated liver morphology, fibrotic responses and the damage of liver function in fibrosis animal. More importantly, BiPPB-tTβRII showed a much lesser extent in binding to quiescent HSCs and non-fibrotic liver tissue. Taken together, our results suggested that the target protein BiPPB-tTβRII, with its high specific fibrotic liver-targeting potential and its improved anti-fibrotic activity in liver fibrosis, may be a potential therapeutic agent for liver fibrosis.
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Yunna C, Mengru H, Fengling W, Lei W, Weidong C. Emerging strategies against tumor-associated fibroblast for improved the penetration of nanoparticle into desmoplastic tumor. Eur J Pharm Biopharm 2021; 165:75-83. [PMID: 33991610 DOI: 10.1016/j.ejpb.2021.05.007] [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: 12/19/2020] [Revised: 03/31/2021] [Accepted: 05/04/2021] [Indexed: 12/13/2022]
Abstract
The therapeutic effect of nanoparticles is limited in solid tumors, especially desmoplastic tumors, because the tumor matrix hinders the delivery of nanoparticles. As the most abundant cells in the tumor stroma, tumor-associated fibroblasts (TAFs) produce a dense extracellular matrix, which leads to higher tissue fluid pressure, thereby creating a physical barrier for nanoparticle delivery. Therefore, researchers focused on eliminating TAFs to combat desmoplastic tumors. In recent years, a series of methods for TAFs have been developed. In this paper, we first introduced the biological mechanism of TAFs hindering the penetration of nanoparticles. Then, the different methods of eliminating TAFs were summarized, and the mechanism of nanomedicine in eliminating TAFs was highlighted. Finally, the problems and future development directions for TAFs treatment were discussed from the perspective of the treatment of desmoplastic tumors.
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Affiliation(s)
- Chen Yunna
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui 230012, China
| | - Hu Mengru
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui 230012, China
| | - Wang Fengling
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei, Anhui 230011, China
| | - Wang Lei
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui 230012, China.
| | - Chen Weidong
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui 230012, China.
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Tsutsumi N, Nishimata S, Shimura M, Kashiwagi Y, Kawashima H. Hepcidin Levels and Pathological Characteristics in Children with Fatty Liver Disease. Pediatr Gastroenterol Hepatol Nutr 2021; 24:295-305. [PMID: 34046333 PMCID: PMC8128777 DOI: 10.5223/pghn.2021.24.3.295] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/18/2020] [Accepted: 02/02/2021] [Indexed: 12/20/2022] Open
Abstract
PURPOSE Hepcidin levels have previously been reported to be correlated with liver damage. However, the association between hepcidin levels and liver fibrosis in children with fatty liver disease remains unclear. This study therefore aimed to investigate the pathophysiology of fibrosis in children with fatty liver disease and its association with hepcidin levels. METHODS This retrospective case series included 12 boys aged 6-17 years who were diagnosed with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) at the Tokyo Medical University Hospital. Sixteen liver biopsy samples from 12 subjects were analyzed. Serum hepcidin levels were assayed using enzyme-linked immunosorbent assay. Immunostaining for hepcidin was performed, and the samples were stratified by staining intensity. RESULTS Serum hepcidin levels were higher in pediatric NAFLD/NASH patients than in controls. Conversely, a significant inverse correlation was observed between hepcidin immunostaining and Brunt grade scores and between hepcidin scores and gamma-glutamyltranspeptidase, hyaluronic acid, and leukocyte levels. We observed inverse correlations with a high correlation coefficient of >0.4 between hepcidin immunostaining and aspartate aminotransferase, alanine aminotransferase, total bile acid, and platelet count. CONCLUSION There was a significant inverse correlation between hepcidin immunoreactivity and fibrosis in pediatric NAFLD patients; however, serum hepcidin levels were significantly higher, suggesting that these patients experienced a reduction in the hepcidin-producing ability of the liver in response to iron levels, leading to subsequent fibrosis. Therefore, hepcidin levels can be used as markers to identify the progression of fibrosis in patients with NAFLD.
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Affiliation(s)
- Norito Tsutsumi
- Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, Tokyo, Japan
| | - Shigeo Nishimata
- Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, Tokyo, Japan
| | - Masaru Shimura
- Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, Tokyo, Japan.,Depatrment of Metabolism, Chiba Children's Hospital, Center for Medical Genetics, Chiba, Japan
| | - Yasuyo Kashiwagi
- Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, Tokyo, Japan
| | - Hisashi Kawashima
- Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, Tokyo, Japan
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Gammella E, Correnti M, Cairo G, Recalcati S. Iron Availability in Tissue Microenvironment: The Key Role of Ferroportin. Int J Mol Sci 2021; 22:ijms22062986. [PMID: 33804198 PMCID: PMC7999357 DOI: 10.3390/ijms22062986] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/11/2021] [Accepted: 03/12/2021] [Indexed: 12/17/2022] Open
Abstract
Body iron levels are regulated by hepcidin, a liver-derived peptide that exerts its function by controlling the presence of ferroportin (FPN), the sole cellular iron exporter, on the cell surface. Hepcidin binding leads to FPN internalization and degradation, thereby inhibiting iron release, in particular from iron-absorbing duodenal cells and macrophages involved in iron recycling. Disruption in this regulatory mechanism results in a variety of disorders associated with iron-deficiency or overload. In recent years, increasing evidence has emerged to indicate that, in addition to its role in systemic iron metabolism, FPN may play an important function in local iron control, such that its dysregulation may lead to tissue damage despite unaltered systemic iron homeostasis. In this review, we focus on recent discoveries to discuss the role of FPN-mediated iron export in the microenvironment under both physiological and pathological conditions.
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Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation. Mol Med Rep 2021; 23:305. [PMID: 33649839 PMCID: PMC7974418 DOI: 10.3892/mmr.2021.11944] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 01/08/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatic fibrosis, a common pathological manifestation of chronic liver injury, is generally considered to be the end result of an increase in extracellular matrix produced by activated hepatic stellate cells (HSCs). The aim of the present study was to target the mechanisms underlying HSC activation in order to provide a powerful therapeutic strategy for the prevention and treatment of liver fibrosis. In the present study, a high-throughput screening assay was established, and the histone deacetylase inhibitor givinostat was identified as a potent inhibitor of HSC activation in vitro. Givinostat significantly inhibited HSC activation in vivo, ameliorated carbon tetrachloride-induced mouse liver fibrosis and lowered plasma aminotransferases. Transcriptomic analysis revealed the most significantly regulated genes in the givinostat treatment group in comparison with those in the solvent group, among which, dermokine (Dmkn), mesothelin (Msln) and uroplakin-3b (Upk3b) were identified as potential regulators of HSC activation. Givinostat significantly reduced the mRNA expression of Dmkn, Msln and Upk3b in both a mouse liver fibrosis model and in HSC-LX2 cells. Knockdown of any of the aforementioned genes inhibited the TGF-β1-induced expression of α-smooth muscle actin and collagen type I, indicating that they are crucial for HSC activation. In summary, using a novel strategy targeting HSC activation, the present study identified a potential epigenetic drug for the treatment of hepatic fibrosis and revealed novel regulators of HSC activation.
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Mleczko‐Sanecka K, Silvestri L. Cell-type-specific insights into iron regulatory processes. Am J Hematol 2021; 96:110-127. [PMID: 32945012 DOI: 10.1002/ajh.26001] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/20/2020] [Accepted: 09/14/2020] [Indexed: 12/16/2022]
Abstract
Despite its essential role in many biological processes, iron is toxic when in excess due to its propensity to generate reactive oxygen species. To prevent diseases associated with iron deficiency or iron loading, iron homeostasis must be tightly controlled. Intracellular iron content is regulated by the Iron Regulatory Element-Iron Regulatory Protein (IRE-IRP) system, whereas systemic iron availability is adjusted to body iron needs chiefly by the hepcidin-ferroportin (FPN) axis. Here, we aimed to review advances in the field that shed light on cell-type-specific regulatory mechanisms that control or modify systemic and local iron balance, and how shifts in cellular iron levels may affect specialized cell functions.
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Affiliation(s)
| | - Laura Silvestri
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology IRCCS San Raffaele Scientific Institute Milan Italy
- Vita‐Salute San Raffaele University Milan Italy
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35
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Zhao Q, Zhang CL, Xiang RL, Wu LL, Li L. CTRP15 derived from cardiac myocytes attenuates TGFβ1-induced fibrotic response in cardiac fibroblasts. Cardiovasc Drugs Ther 2020; 34:591-604. [PMID: 32424654 DOI: 10.1007/s10557-020-06970-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Cardiac fibrosis is characterized by net accumulation of extracellular matrix (ECM) components in the myocardium and facilitates the development of heart failure. C1q/tumor necrosis factor-related protein 15 (CTRP15) is a novel member of the CTRP family, and its gene expression is detected in adult mouse hearts. The present study was performed to determine the effect of CTRP15 on pressure overload-induced fibrotic remodeling. METHODS Mice were subjected to transverse aortic constriction (TAC) surgery, and adeno-associated virus serotype 9 (AAV9)-carrying mouse CTRP15 gene was injected into mice to achieve CTRP15 overexpression in the myocardium. Adenovirus carrying the gene encoding CTRP15 or small interfering RNA (siRNA) of interest was infected into cultured neonatal mouse ventricular cardiomyocytes (NMVCs) or cardiac fibroblasts (CFs). Gene expression was measured by quantitative real-time PCR, and protein expression and distribution were determined by Western blotting, immunocytochemistry, and immunofluorescence staining. RESULTS CTRP15 was predominantly produced by cardiac myocytes. CTRP15 expression in the left ventricles was downregulated in mice that underwent TAC. AAV9-mediated CTRP15 overexpression alleviated ventricular remodeling and dysfunction in the pressure-overloaded mice. Treatment of CFs with recombinant CTRP15 or the conditioned medium containing CTRP15 inhibited transforming growth factor (TGF)-β1-induced Smad3 activation and myofibroblast differentiation. CTRP15 increased phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and Akt. Blockade of IR/IRS-1/Akt pathway reversed the inhibitory effect of CTRP15 on TGF-β1-induced Smad3 activation. CONCLUSION CTRP15 exerts an anti-fibrotic effect on pressure overload-induced cardiac remodeling. The activation of IR/IRS-1/Akt pathway contributes to the anti-fibrotic effect of CTRP15 through targeting Smad3.
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Affiliation(s)
- Qian Zhao
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China
| | - Cheng-Lin Zhang
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China
| | - Ruo-Lan Xiang
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China
| | - Li-Ling Wu
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China
| | - Li Li
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
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Zhang J, Li R, Liu Q, Zhou J, Huang H, Huang Y, Zhang Z, Wu T, Tang Q, Huang C, Zhao Y, Zhang G, Mo L, Li Y, He J. SB431542-Loaded Liposomes Alleviate Liver Fibrosis by Suppressing TGF-β Signaling. Mol Pharm 2020; 17:4152-4162. [PMID: 33089693 DOI: 10.1021/acs.molpharmaceut.0c00633] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Jinhang Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Rui Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jian Zhou
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Hui Huang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ya Huang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Zijing Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Tong Wu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Qin Tang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Cuiyuan Huang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yingnan Zhao
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Guorong Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Li Mo
- Center of Gerontology and Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jinhan He
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
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You E, Ko P, Jeong J, Keum S, Kim JW, Seo YJ, Song WK, Rhee S. Dynein-mediated nuclear translocation of yes-associated protein through microtubule acetylation controls fibroblast activation. Cell Mol Life Sci 2020; 77:4143-4161. [PMID: 31912196 PMCID: PMC11105004 DOI: 10.1007/s00018-019-03412-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 11/27/2019] [Accepted: 12/04/2019] [Indexed: 12/17/2022]
Abstract
Myofibroblasts are the major cell type that is responsible for increase in the mechanical stiffness in fibrotic tissues. It has well documented that the TGF-β/Smad axis is required for myofibroblast differentiation under the rigid substrate condition. However, the mechanism driving myofibroblast differentiation in soft substrates remains unknown. In this research, we demonstrated that interaction of yes-associated protein (YAP) and acetylated microtubule via dynein, a microtubule motor protein drives nuclear localization of YAP in the soft matrix, which in turn increased TGF-β1-induced transcriptional activity of Smad for myofibroblast differentiation. Pharmacological and genetical disruption of dynein impaired the nuclear translocation of YAP and decreased the TGF-β1-induced Smad activity even though phosphorylation and nuclear localization of Smad occurred normally in α-tubulin acetyltransferase 1 (α-TAT1) knockout cell. Moreover, microtubule acetylation prominently appeared in the fibroblast-like cells nearby the blood vessel in the fibrotic liver induced by CCl4 administration, which was conversely decreased by TGF-β receptor inhibitor. As a result, quantitative inhibition of microtubule acetylation may be suggested as a new target for overcoming fibrotic diseases.
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Affiliation(s)
- Eunae You
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Panseon Ko
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Jangho Jeong
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Seula Keum
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Jung-Woong Kim
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Young-Jin Seo
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Woo Keun Song
- Bio Imaging and Cell Logistics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-Gu, Gwangju, 61005, Republic of Korea.
| | - Sangmyung Rhee
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea.
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Xing L, Chang X, Shen L, Zhang C, Fan Y, Cho C, Zhang Z, Jiang H. Progress in drug delivery system for fibrosis therapy. Asian J Pharm Sci 2020; 16:47-61. [PMID: 33613729 PMCID: PMC7878446 DOI: 10.1016/j.ajps.2020.06.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/22/2020] [Accepted: 06/22/2020] [Indexed: 12/18/2022] Open
Abstract
Fibrosis is a necessary process in the progression of chronic disease to cirrhosis or even cancer, which is a serious disease threatening human health. Recent studies have shown that the early treatment of fibrosis is turning point and particularly important. Therefore, how to reverse fibrosis has become the focus and research hotspot in recent years. So far, the considerable progress has been made in the development of effective anti-fibrosis drugs and targeted drug delivery. Moreover, the existing research results will lay the foundation for more breakthrough delivery systems to achieve better anti-fibrosis effects. Herein, this review summaries anti-fibrosis delivery systems focused on three major organ fibrotic diseases such as liver, pulmonary, and renal fibrosis accompanied by the elaboration of relevant pathological mechanisms, which will provide inspiration and guidance for the design of fibrosis drugs and therapeutic systems in the future.
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Affiliation(s)
- Lei Xing
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Xin Chang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Lijun Shen
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Chenglu Zhang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Yatong Fan
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Chongsu Cho
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
- Corresponding authors.
| | - Zhiqi Zhang
- Department of General Surgery, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200081 China
- Corresponding authors.
| | - Hulin Jiang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors.
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Çam H, Yılmaz N. Serum hepcidin levels are related to serum markers for iron metabolism and fibrosis stage in patients with chronic hepatitis B: A cross-sectional study. Arab J Gastroenterol 2020; 21:85-90. [PMID: 32423859 DOI: 10.1016/j.ajg.2020.04.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 02/16/2020] [Accepted: 04/12/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND STUDY AIMS The clinical significance of serum parameters of iron metabolism and hepcidin in liver disease remains unknown. Therefore, this study aimed to evaluate the association of serum hepcidin levels with fibrosis stage and serum iron parameters in patients with chronic hepatitis B (CHB). PATIENTS AND METHODS This cross-sectional study included 126 treatment-naïve patients with CHB (median age, 39.0 years; 64.3% males) who were positive for hepatitis B surface antigen and 23 healthy controls (median age, 33.0 years; 52.2% males). Data on patient demographics, serum hepcidin levels, liver function tests and serum iron parameters and liver biopsy findings including fibrosis grade, histological activity index (HAI) and liver iron level were recorded. RESULTS The median (minimum-maximum) serum hepcidin levels were significantly lower in the CHB group than in the control group [71.2 (13.3-672.7) vs. 657.5 (201.7-2714.2) pg/mL, p < 0.001]. Higher fibrosis stage was associated with higher transferrin saturation (p = 0.029), serum ferritin level (p < 0.001) and viral load (p < 0.001). Fibrosis stage and HAI were positively correlated with ferritin (r = 0.407, p < 0.001 and r = 0.415, p < 0.001, respectively) and transferrin saturation (r = 0.219, p = 0.026 and r = 0.290, p = 0.003, respectively) levels, whereas hepcidin level was negatively correlated with fibrosis stage (r = -0.175, p = 0.051), viral load (r = -0.209, p = 0.020) and ferritin level (r = -0.244, p = 0.006) level. There were no significant differences in serum iron level, total iron binding capacity and liver iron level among patients with different stages of fibrosis. CONCLUSION Reduced hepcidin levels and elevated transferrin saturation and ferritin levels are linked to fibrosis severity and HAI in patients with CHB.
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Affiliation(s)
- Hakan Çam
- Gaziantep University Medical Faculty 27310 Gastroenterology, Gaziantep, Turkey
| | - Nimet Yılmaz
- Gaziantep University Medical Faculty 27310 Gastroenterology, Gaziantep, Turkey
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Dhar D, Baglieri J, Kisseleva T, Brenner DA. Mechanisms of liver fibrosis and its role in liver cancer. Exp Biol Med (Maywood) 2020; 245:96-108. [PMID: 31924111 PMCID: PMC7016420 DOI: 10.1177/1535370219898141] [Citation(s) in RCA: 247] [Impact Index Per Article: 49.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Hepatic fibrogenesis is a pathophysiological outcome of chronic liver injury hallmarked by excessive accumulation of extracellular matrix proteins. Fibrosis is a dynamic process that involves cross-talk between parenchymal cells (hepatocytes), hepatic stellate cells, sinusoidal endothelial cells and both resident and infiltrating immune cells. In this review, we focus on key cell-types that contribute to liver fibrosis, cytokines, and chemokines influencing this process and what it takes for fibrosis to regress. We discuss how mitochondria and metabolic changes in hepatic stellate cells modulate the fibrogenic process. We also briefly review how the presence of fibrosis affects development of hepatocellular carcinoma.
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Affiliation(s)
- Debanjan Dhar
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Jacopo Baglieri
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA
| | - David A Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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Endoplasmic Reticulum Stress Increases DUSP5 Expression via PERK-CHOP Pathway, Leading to Hepatocyte Death. Int J Mol Sci 2019; 20:ijms20184369. [PMID: 31491992 PMCID: PMC6770509 DOI: 10.3390/ijms20184369] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/03/2019] [Accepted: 09/03/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte death is critical for the pathogenesis of liver disease progression, which is closely associated with endoplasmic reticulum (ER) stress responses. However, the molecular basis for ER stress-mediated hepatocyte injury remains largely unknown. This study investigated the effect of ER stress on dual-specificity phosphatase 5 (DUSP5) expression and its role in hepatocyte death. Analysis of Gene Expression Omnibus (GEO) database showed that hepatic DUSP5 levels increased in the patients with liver fibrosis, which was verified in mouse models of liver diseases with ER stress. DUSP5 expression was elevated in both fibrotic and acutely injured liver of mice treated with liver toxicants. Treatment of ER stress inducers enhanced DUSP5 expression in hepatocytes, which was validated in vivo condition. The induction of DUSP5 by ER stress was blocked by either treatment with a chemical inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, or knockdown of C/EBP homologous protein (CHOP), whereas it was not affected by the silencing of IRE1 or ATF6. In addition, DUSP5 overexpression decreased extracellular-signal-regulated kinase (ERK) phosphorylation, but increased cleaved caspase-3 levels. Moreover, the reduction of cell viability under ER stress condition was attenuated by DUSP5 knockdown. In conclusion, DUSP5 expression is elevated in hepatocytes by ER stress through the PERK-CHOP pathway, contributing to hepatocyte death possibly through ERK inhibition.
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Czaja AJ. Review article: iron disturbances in chronic liver diseases other than haemochromatosis - pathogenic, prognostic, and therapeutic implications. Aliment Pharmacol Ther 2019; 49:681-701. [PMID: 30761559 DOI: 10.1111/apt.15173] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/08/2019] [Accepted: 01/16/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome. AIMS To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management METHODS: English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Hyperferritinemia is present in 4%-65% of patients with non-alcoholic fatty liver disease, autoimmune hepatitis, chronic viral hepatitis, or alcoholic liver disease, and hepatic iron content is increased in 11%-52%. Heterozygosity for the C282Y mutation is present in 17%-48%, but this has not uniformly distinguished patients with adverse outcomes. An inappropriately low serum hepcidin level has characterised most chronic liver diseases with the exception of non-alcoholic fatty liver disease, and the finding has been associated mainly with suppression of transcriptional activity of the hepcidin gene. Iron overload has been associated with oxidative stress, advanced fibrosis and decreased survival, and promising therapies beyond phlebotomy and oral iron chelation have included hepcidin agonists. CONCLUSIONS Iron dysregulation is common in chronic liver diseases other than hereditary haemochromatosis, and has been associated with liver toxicity and poor prognosis. Further evaluation of iron overload as a co-morbid factor should identify the key pathogenic disturbances, establish the risk threshold for iron toxicity, and promote molecular interventions.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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Mehta KJ, Farnaud SJ, Sharp PA. Iron and liver fibrosis: Mechanistic and clinical aspects. World J Gastroenterol 2019; 25:521-538. [PMID: 30774269 PMCID: PMC6371002 DOI: 10.3748/wjg.v25.i5.521] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/02/2019] [Accepted: 01/10/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.
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Affiliation(s)
- Kosha J Mehta
- School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King’s College London, London SE1 1UL, United Kingdom
- Division of Human Sciences, School of Applied Sciences, London South Bank University, London SE1 0AA, United Kingdom
| | - Sebastien Je Farnaud
- Faculty Research Centre for Sport, Exercise and Life Sciences, Coventry University, Coventry CV1 2DS, United Kingdom
| | - Paul A Sharp
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9NH, United Kingdom
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Immunonutritional consequences of different serine-type protease inhibitors in a C57BL/6 hepatocarcinoma model. Oncotarget 2019; 10:760-772. [PMID: 30774778 PMCID: PMC6366820 DOI: 10.18632/oncotarget.26605] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 01/09/2019] [Indexed: 12/21/2022] Open
Abstract
Imbalances in innate immunity and the activity of innate immune cells are implicated in the development of hepatocellular carcinoma (HCC). Plant seeds are good sources of protease inhibitors, which can have a significant influence on human health disorders, especially in the field of cancer prevention. To elucidate the impact and preventive effects of immunonutritional serine-type protease inhibitors (STPIs) on HCC, it was used an established model of chemically induced liver injury. Injured livers induced Akt as well as hepatic infiltration of NKG2D+ and CD74+ cells. Feeding STPIs reduced size and number of intrahepatic nodes of mononuclear. These animals showed an inverse association of the severity of HCC with bioactive hepcidin levels, which was significantly correlated with the hepatic myeloperoxidase activity. According to their origin, administration of STPIs significantly induce increased numbers of F4/80+ cells in injured livers that can be responsible for the biological effects detected on the parenchyma and inflammatory markers under DEN/TAA treatment. These findings can have direct implications in HCC immunotherapy where enhanced response(s) in inflammation-driven cancer patients could help promoting inflammation-driven processes and favor tumor growth. Altogether, this study demonstrates that oral administration of STPIs modulate innate immunity response influencing HCC aggressiveness and progression. These results represent a path forward to develop durable, long-lasting response against hepatocarcinoma and open a future research path in the development of coadjutant intervention strategies to pharmacological therapies.
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Gallic Acid Attenuates Dimethylnitrosamine-Induced Liver Fibrosis by Alteration of Smad Phosphoisoform Signaling in Rats. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1682743. [PMID: 30627538 PMCID: PMC6304566 DOI: 10.1155/2018/1682743] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/31/2018] [Accepted: 11/08/2018] [Indexed: 12/24/2022]
Abstract
Dimethylnitrosamine (DMN) is a potent hepatotoxin, carcinogen, and mutagen. In our previous study, a candidate gallic acid (GA) that widely exists in food and fruit was selected for its capability to alleviate DMN toxicity in vivo. We aimed to investigate the therapeutic potential of GA against DMN-induced liver fibrosis. During the first four weeks, DMN was administered to rats via intraperitoneal injection every other day, except the control group. GA or silymarin was given to rats by gavage once daily from the second to the sixth week. GA significantly reduced liver damage in serum parameters and improved the antioxidant capacity in liver and kidney tissues. Cytokines involved in liver fibrosis were measured at transcriptional and translational levels. These results indicate that GA exhibits robust antioxidant and antifibrosis effects and may be an effective candidate natural medicine for liver fibrosis treatment.
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Hepcidin Therapeutics. Pharmaceuticals (Basel) 2018; 11:ph11040127. [PMID: 30469435 PMCID: PMC6316648 DOI: 10.3390/ph11040127] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 11/15/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022] Open
Abstract
Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art.
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Kumar P, Raeman R, Chopyk DM, Smith T, Verma K, Liu Y, Anania FA. Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3537-3545. [PMID: 30293572 PMCID: PMC6529190 DOI: 10.1016/j.bbadis.2018.08.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 08/05/2018] [Accepted: 08/07/2018] [Indexed: 02/08/2023]
Abstract
Adiponectin inhibits hepatic stellate cell (HSC) activation and subsequent development of liver fibrosis via multiple mechanisms. Phosphatase and tensin homolog deletion 10 (PTEN) plays a crucial role in suppression of HSC activation, but its regulation by adiponectin is not fully understood. Here, we investigated the effect of adiponectin on PTEN in LX-2 cells, a human cell line and examined the underlying molecular mechanisms involved in adiponectin-mediated upregulation of PTEN activity during fibrosis. PTEN expression was found to be significantly reduced in the livers of mice treated with CCl4, whereas its expression was rescued by adiponectin treatment. The DNA methylation proteins DNMT1, DNMT3A, and DNMT3B are all highly expressed in activated primary HSCs compared to quiescent HSCs, and thus represent additional regulatory targets during liver fibrogenesis. Expression of DNMT proteins was significantly induced in the presence of fibrotic stimuli; however, only DNMT3B expression was reduced in the presence of adiponectin. Adiponectin-induced suppression of DNMT3B was found to be mediated by enhanced miR-29b expression. Furthermore, PTEN expression was significantly increased by overexpression of miR-29b, whereas its expression was markedly reduced by a miR-29b inhibitor in LX-2 cells. These findings suggest that adiponectin-induced upregulation of miR-29b can suppress DNMT3B transcription in LX-2 cells, thus resulting in reduced methylation of PTEN CpG islands and ultimately suppressing the PI3K/AKT pathway. Together, these data suggest a possible new explanation for the inhibitory effect of adiponectin on HSC activation and liver fibrogenesis.
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Affiliation(s)
- Pradeep Kumar
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA, USA.
| | - Reben Raeman
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Daniel M Chopyk
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA, USA
| | - Tekla Smith
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA, USA
| | - Kiran Verma
- Labratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA, USA
| | - Yunshan Liu
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA, USA
| | - Frank A Anania
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA, USA
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Qiao JB, Fan QQ, Xing L, Cui PF, He YJ, Zhu JC, Wang L, Pang T, Oh YK, Zhang C, Jiang HL. Vitamin A-decorated biocompatible micelles for chemogene therapy of liver fibrosis. J Control Release 2018; 283:113-125. [DOI: 10.1016/j.jconrel.2018.05.032] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 04/25/2018] [Accepted: 05/28/2018] [Indexed: 01/10/2023]
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Vela D. Low hepcidin in liver fibrosis and cirrhosis; a tale of progressive disorder and a case for a new biochemical marker. Mol Med 2018; 24:5. [PMID: 30134796 PMCID: PMC6016890 DOI: 10.1186/s10020-018-0008-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 02/13/2018] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a precursor of liver cirrhosis, which is associated with increased mortality. Though liver biopsy remains the gold standard for the diagnosis of fibrosis, noninvasive biochemical methods are cost-effective, practical and are not linked with major risks of complications. In this respect, serum hepcidin, has emerged as a new marker of fibrosis and cirrhosis. In this review the discussion uncovers molecular links between hepcidin disturbance and liver fibrosis/cirrhosis. The discussion also expands on clinical studies that suggest that hepcidin can potentially be used as a biochemical parameter of fibrosis/cirrhosis and target of therapeutic strategies to treat liver diseases. The debatable issues such as the complicated nature of hepcidin disturbance in non-alcoholic liver disease, serum levels of hepcidin in acute hepatitis C virus infection, cause of hepcidin disturbance in autoimmune hepatitis and hepatic insulin resistance are discussed, with potential solutions unveiled in order to be studied by future research.
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Affiliation(s)
- Driton Vela
- Department of Physiology, Faculty of Medicine, University of Prishtina, Martyr's Boulevard n.n, Prishtina, 10000, Kosovo.
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50
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Vela D. Balance of cardiac and systemic hepcidin and its role in heart physiology and pathology. J Transl Med 2018; 98:315-326. [PMID: 29058707 DOI: 10.1038/labinvest.2017.111] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 08/23/2017] [Accepted: 08/24/2017] [Indexed: 02/07/2023] Open
Abstract
Hepcidin is the main regulator of iron metabolism in tissues. Its serum levels are mostly correlated with the levels of hepcidin expression from the liver, but local hepcidin can be important for the physiology of other organs as well. There is an increasing evidence that this is the case with cardiac hepcidin. This has been confirmed by studies with models of ischemic heart disease and other heart pathologies. In this review the discussion dissects the role of cardiac hepcidin in cellular homeostasis. This review is complemented with examination of the role of systemic hepcidin in heart disease and its use as a biochemical marker. The relationship between systemic vs local hepcidin in the heart is important because it can help us understand how the fine balance between the actions of two hepcidins affects heart function. Manipulating the axis systemic/cardiac hepcidin could serve as a new therapeutic strategy in heart diseases.
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Affiliation(s)
- Driton Vela
- Department of Physiology, Faculty of Medicine, University of Prishtina, Prishtina, Kosova
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