|
1
|
Navidifar T, Meftah E, Baghsheikhi H, Kazemzadeh K, Karimi H, Rezaei N. Dual role of hepcidin in response to pathogens. Microb Pathog 2025; 203:107496. [PMID: 40118299 DOI: 10.1016/j.micpath.2025.107496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 03/15/2025] [Accepted: 03/19/2025] [Indexed: 03/23/2025]
Abstract
Hepcidin is the primary regulator of vertebrate iron homeostasis. Its production is stimulated by systemic iron levels and inflammatory signals. Although the role of hepcidin in iron homeostasis is well characterized, its response to pathogenic agents is complex and diverse. In this review, we examine studies that investigate the role of hepcidin in response to infectious agents. Interleukin-6 (IL-6) is a key factor responsible for the induction of hepcidin expression. During infection, hepcidin-mediated depletion of extracellular iron serves as a protective mechanism against a variety of pathogens. However, accumulation of iron in macrophages through hepcidin-mediated pathways may increase susceptibility to intracellular pathogens such as Mycobacterium tuberculosis. Prolonged elevation of hepcidin production can lead to anemia due to reduced iron availability for erythropoiesis, a condition referred to as anemia of inflammation. In addition, we highlight the role of hepcidin upregulation in several infectious contexts, including HIV-associated anemia, iron deficiency anemia in Helicobacter pylori infection, and post-malarial anemia in pediatric patients. In addition, we show that certain infectious agents, such as hepatitis C virus (HCV), can suppress hepcidin production during both the acute and chronic phases of infection, while hepatitis B virus (HBV) exhibits similar suppression during the chronic phase.
Collapse
Affiliation(s)
- Tahereh Navidifar
- Department of Basic Sciences, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran; Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Elahe Meftah
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hediyeh Baghsheikhi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; USERN Office, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Kazemzadeh
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanie Karimi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Science, Tehran, Iran.
| |
Collapse
|
|
2
|
Liu S, Tsyplenkova S, Fillebeen C, Pantopoulos K. Hypoferremic Response to Chronic Inflammation Is Controlled via the Hemojuvelin/Hepcidin/Ferroportin Axis and Does Not Involve Hepcidin-Independent Regulation of Fpn mRNA. Am J Hematol 2025. [PMID: 40347094 DOI: 10.1002/ajh.27710] [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: 12/16/2024] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/12/2025]
Abstract
The iron regulatory hormone hepcidin contributes to the pathogenesis of anemia of inflammation (AI) by inhibiting the iron exporter ferroportin in target cells, causing hypoferremia. Under acute inflammation, hepcidin induction requires hemojuvelin (Hjv), a bone morphogenetic protein co-receptor, while Fpn mRNA is also suppressed in a hepcidin-independent manner. However, it is unclear whether, during chronic inflammation, Hjv and hepcidin-independent Fpn mRNA regulation are critical for hypoferremia and AI. To address these questions, wild type and Hjv-/- mice, a model of hemochromatosis, were fed for 8 weeks an adenine-rich diet to develop chronic kidney disease (CKD). Renal inflammation, accessed by increased Il6 mRNA expression, did not differ among genotypes. Hjv disruption did not mitigate the severity of kidney injury but suppressed the inflammatory induction of liver hepcidin. CKD triggered hypoferremia and mild anemia in wild type mice; however, Hjv-/- littermates maintained high serum iron and normal hemoglobin, consistent with a protective effect of Hjv/hepcidin deficiency. Notably, tissue Fpn mRNA levels were not affected by the inflammatory milieu of CKD. Following injection of wild type or Hjv-/- mice with heat-killed Brucella abortus, Fpn mRNA was suppressed during the acute phase of inflammation but quickly recovered and persisted in the chronic phase. We conclude that Hjv deficiency reduces hepcidin levels and mitigates anemia in the CKD model, providing further support for pharmacological targeting of Hjv for the treatment of AI. Moreover, our data demonstrate that Fpn mRNA suppression only occurs under acute but not chronic inflammatory conditions and therefore cannot substantially contribute to AI pathogenesis.
Collapse
Affiliation(s)
- Siqi Liu
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Sofiya Tsyplenkova
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Carine Fillebeen
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Kostas Pantopoulos
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada
| |
Collapse
|
|
3
|
Kobayashi N, Okazaki Y, Iwane A, Hara K, Horikoshi M, Awazawa M, Soeda K, Matsushita M, Sasako T, Yoshimura K, Itoh N, Kobayashi K, Seto Y, Yamauchi T, Aburatani H, Blüher M, Kadowaki T, Ueki K. Activin B improves glucose metabolism via induction of Fgf21 and hepatic glucagon resistance. Nat Commun 2025; 16:3678. [PMID: 40246973 PMCID: PMC12006358 DOI: 10.1038/s41467-025-58836-w] [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: 08/07/2024] [Accepted: 04/03/2025] [Indexed: 04/19/2025] Open
Abstract
Orchestrated hormonal interactions in response to feeding and fasting play a pivotal role in regulating glucose homeostasis. Here, we show that in obesity, the production of follistatin-like 3 (FSTL3), an endogenous inhibitor of Activin B, in adipose tissue is increased in both mice and humans. The knockdown of FSTL3 improves insulin sensitivity and glucose tolerance in diabetic obese db/db mice. Notably, the overexpression of Activin B, a member of the TGFβ superfamily that is induced in liver sinusoidal endothelial cells by fasting, exerts multiple metabolically beneficial effects, including improvement of insulin sensitivity, suppression of hepatic glucose production, and enhancement of glucose-stimulated insulin secretion, all of which are attenuated by the overexpression of FSTL3. Activin B increases insulin sensitivity and reduces fat by inducing fibroblast growth factor 21 (FGF21) while suppressing glucagon action in the liver by increasing phosphodiesterase 4 B (PDE4B), leading to hepatic glucagon resistance and resultant hyperglucagonemia. Activin B-induced hyperglucagonemia enhances glucose-stimulated insulin secretion by stimulating glucagon-like peptide-1 (GLP-1) receptor in pancreatic β-cells. Thus, enhancing the action of Activin B which improves multiple components of the pathogenesis of diabetes may be a promising strategy for diabetes treatment.
Collapse
Affiliation(s)
- Naoki Kobayashi
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yukiko Okazaki
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Aya Iwane
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuo Hara
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Momoko Horikoshi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Motoharu Awazawa
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kotaro Soeda
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Maya Matsushita
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Takayoshi Sasako
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kotaro Yoshimura
- Department of Plastic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuyuki Itoh
- Department of Genetic Biochemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Kenta Kobayashi
- Section of Viral Vector Development, National Institute for Physiological Sciences, Aichi, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Aburatani
- Research Center for Advanced Science and Technology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Matthias Blüher
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Toranomon Hospital, Tokyo, Japan
| | - Kohjiro Ueki
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan.
- Department of Molecular Diabetology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| |
Collapse
|
|
4
|
Fu S, Huang J, Feng Z, Wang H, Xu H, Wu M, Ma F, Xu Z. Inflammatory indexes and anemia in chronic kidney disease: correlation and survival analysis of the National Health and Nutrition Examination Survey 2005-2018. Ren Fail 2024; 46:2399314. [PMID: 39248404 PMCID: PMC11385632 DOI: 10.1080/0886022x.2024.2399314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 08/17/2024] [Accepted: 08/23/2024] [Indexed: 09/10/2024] Open
Abstract
BACKGROUND There is currently no research on the correlation between novel inflammatory indexes systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and the risk of anemia in chronic kidney disease (CKD) population, as well as survival analysis in CKD with anemia. METHODS This investigation encompassed 4444 adult subjects out of the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018. The study utilized multi-variable logistic regression to assess the relationship between SII, NLR, PLR, and anemia risk occurrence in CKD population. Survival differences in CKD patients with anemia, based on varying levels of SII, NLR, and PLR were evaluated employing Kaplan-Meier and Cox proportional hazards models. RESULTS The adjusted logistic regression model demonstrates that SII, NLR, and PLR are associated with the risk of anemia occurrence in CKD population. Kaplan-Meier's analysis reveals significant differences in survival rates among CKD patients with anemia stratified by NLR levels. The adjusted Cox proportional hazards model shows that the higher NLR group has a 30% elevated risk of all-cause mortality contrasted with lower group (hazard ratio, HR: 1.30, confidence interval (CI) [1.01, 1.66], p value <.04). Restricted cubic spline (RCS) demonstrates no nonlinear relationship between NLR and all-cause mortality. Lastly, sub-cohort analysis indicates that in populations with diabetes, hypertension, and hyperuricemia, NLR levels have a greater impact on all-cause mortality. CONCLUSIONS Controlling inflammation may reduce the occurrence of anemia in CKD populations, with NLR serving to be a potential prognostic indicator for survival results within CKD patients suffering from co-morbid anemia.
Collapse
Affiliation(s)
- Shaojie Fu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Jingda Huang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Zhenbang Feng
- Center of Oncology, The First Hospital of Jilin University, Changchun, China
| | - Haitao Wang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Hongzhao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Meiyan Wu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Fuzhe Ma
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Zhonggao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
5
|
Liu Y, Zhou Q, Zou G, Zhang W. Inhibin subunit beta B (INHBB): an emerging role in tumor progression. J Physiol Biochem 2024; 80:775-793. [PMID: 39183219 DOI: 10.1007/s13105-024-01041-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 07/30/2024] [Indexed: 08/27/2024]
Abstract
The gene inhibin subunit beta B (INHBB) encodes the inhibin βB subunit, which is involved in forming protein members of the transforming growth factor-β (TGF-β) superfamily. The TGF-β superfamily is extensively involved in cell proliferation, differentiation, adhesion, movement, metabolism, communication, and death. Activins and inhibins, which belong to the TGF-β superfamily, were first discovered in ovarian follicular fluid. They were initially described as regulators of pituitary follicle-stimulating hormone (FSH) secretion both in vivo and in vitro. Later studies found that INHBB is expressed not only in reproductive organs such as the ovary, uterus, and testis but also in numerous other organs, including the brain, spinal cord, liver, kidneys, and adrenal glands. This wide distribution implies its involvement in the normal physiological functions of various organs; however, the mechanisms underlying these functions have not yet been fully elucidated. Recent studies suggest that INHBB plays a significant, yet complex role in tumorigenesis. It appears to have dual effects, promoting tumor progression in some contexts while inhibiting it in others, although these roles are not yet fully understood. In this paper, we review the different expression patterns, functions, and mechanisms of INHBB in normal and tumor tissues to illustrate the research prospects of INHBB in tumor progression.
Collapse
Affiliation(s)
- Ying Liu
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Tongzipo Road 172, Yuelu District, Changsha, 410013, Hunan Province, People's Republic of China
- Department of Clinical Laboratory, Zhengzhou Orthopedic Hospital, Zhengzhou, Henan, People's Republic of China
- Department of Medical Laboratory Science, Xiangya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China
| | - Qing Zhou
- Department of Clinical Laboratory, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, People's Republic of China
| | - Guoying Zou
- Department of Clinical Laboratory, Brain Hospital of Hunan Province, Changsha, Hunan, People's Republic of China
| | - Wenling Zhang
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Tongzipo Road 172, Yuelu District, Changsha, 410013, Hunan Province, People's Republic of China.
- Department of Medical Laboratory Science, Xiangya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China.
| |
Collapse
|
|
6
|
Davaanyam D, Seol SI, Oh SA, Lee H, Lee JK. Hepatocyte activation and liver injury following cerebral ischemia promote HMGB1-mediated hepcidin upregulation in hepatocytes and regulation of systemic iron levels. Exp Mol Med 2024; 56:2171-2183. [PMID: 39349828 PMCID: PMC11541749 DOI: 10.1038/s12276-024-01314-y] [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: 12/26/2023] [Accepted: 06/24/2024] [Indexed: 10/03/2024] Open
Abstract
We previously reported that high mobility group box 1 (HMGB1), a danger-associated molecular pattern (DAMP), increases intracellular iron levels in the postischemic brain by upregulating hepcidin, a key regulator of iron homeostasis, triggering ferroptosis. Since hepatocytes are the primary cells that produce hepcidin and control systemic iron levels, we investigated whether cerebral ischemia induces hepcidin upregulation in hepatocytes. Following middle cerebral artery occlusion (MCAO) in a rodent model, significant liver injury was observed. This injury was evidenced by significantly elevated Eckhoff's scores and increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, total iron levels were significantly elevated in the liver, with intracellular iron accumulation detected in hepatocytes. Hepcidin expression in the liver, which is primarily localized in hepatocytes, increased significantly starting at 3 h after MCAO and continued to increase rapidly, reaching a peak at 24 h. Interestingly, HMGB1 levels in the liver were also significantly elevated after MCAO, with the disulfide form of HMGB1 being the major subtype. In vitro experiments using AML12 hepatocytes showed that recombinant disulfide HMGB1 significantly upregulated hepcidin expression in a Toll-like receptor 4 (TLR4)- and RAGE-dependent manner. Furthermore, treatment with a ROS scavenger and a peptide HMGB1 antagonist revealed that both ROS generation and HMGB1 induction contributed to hepatocyte activation and liver damage following MCAO-reperfusion. In conclusion, this study revealed that cerebral ischemia triggers hepatocyte activation and liver injury. HMGB1 potently induces hepcidin not only in the brain but also in the liver, thereby influencing systemic iron homeostasis following ischemic stroke.
Collapse
Affiliation(s)
- Dashdulam Davaanyam
- Department of Anatomy, Inha University School of Medicine, Incheon, 22212, Korea
| | - Song-I Seol
- Department of Anatomy, Inha University School of Medicine, Incheon, 22212, Korea
| | - Sang-A Oh
- Department of Anatomy, Inha University School of Medicine, Incheon, 22212, Korea
| | - Hahnbi Lee
- Department of Anatomy, Inha University School of Medicine, Incheon, 22212, Korea
| | - Ja-Kyeong Lee
- Department of Anatomy, Inha University School of Medicine, Incheon, 22212, Korea.
| |
Collapse
|
|
7
|
Du R, Wen L, Niu M, Zhao L, Guan X, Yang J, Zhang C, Liu H. Activin receptors in human cancer: Functions, mechanisms, and potential clinical applications. Biochem Pharmacol 2024; 222:116061. [PMID: 38369212 DOI: 10.1016/j.bcp.2024.116061] [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: 11/06/2023] [Revised: 01/18/2024] [Accepted: 02/15/2024] [Indexed: 02/20/2024]
Abstract
Activins are members of the transforming growth factor-β (TGF-β) superfamily and act as key regulators in various physiological processes, such as follicle and embryonic development, as well as in multiple human diseases, including cancer. They have been established to signal through three type I and two type II serine/threonine kinase receptors, which, upon ligand binding, form a final signal-transducing receptor complex that activates downstream signaling and governs gene expression. Recent research highlighted the dysregulation of the expression or activity of activin receptors in multiple human cancers and their critical involvement in cancer progression. Furthermore, expression levels of activin receptors have been associated with clinicopathological features and patient outcomes across different cancers. However, there is currently a paucity of comprehensive systematic reviews of activin receptors in cancer. Thus, this review aimed to consolidate existing knowledge concerning activin receptors, with a primary emphasis on their signaling cascade and emerging biological functions, regulatory mechanisms, and potential clinical applications in human cancers in order to provide novel perspectives on cancer prognosis and targeted therapy.
Collapse
Affiliation(s)
- Ruochen Du
- First Clinical Medical College of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Department of Laboratory Animal Center, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Liqi Wen
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Min Niu
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Liting Zhao
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Xiaoya Guan
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Jiao Yang
- Department of Anatomy, the Basic Medical School of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Chunming Zhang
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
| | - Hongliang Liu
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; First Clinical Medical College of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Department of Cell Biology and Genetics, the Basic Medical School of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
| |
Collapse
|
|
8
|
Saadh MJ, Allela OQB, Sattay ZJ, Al Zuhairi RAH, Ahmad H, Eldesoky GE, Adil M, Ali MS. Deciphering the functional landscape and therapeutic implications of noncoding RNAs in the TGF-β signaling pathway in colorectal cancer: A comprehensive review. Pathol Res Pract 2024; 255:155158. [PMID: 38320438 DOI: 10.1016/j.prp.2024.155158] [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: 12/21/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 02/08/2024]
Abstract
Colorectal cancer (CRC) remains a major global health concern, necessitating an in-depth exploration of the intricate molecular mechanisms underlying its progression and potential therapeutic interventions. Transforming Growth Factor-β (TGF-β) signaling, a pivotal pathway implicated in CRC plays a dual role as a tumor suppressor in the early stages and a promoter of tumor progression in later stages. Recent research has shed light on the critical involvement of noncoding RNAs (ncRNAs) in modulating the TGF-β signaling pathway, introducing a new layer of complexity to our understanding of CRC pathogenesis. This comprehensive review synthesizes the current state of knowledge regarding the function and therapeutic potential of various classes of ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), in the context of TGF-β signaling in CRC. The intricate interplay between these ncRNAs and key components of the TGF-β pathway is dissected, revealing regulatory networks that contribute to the dynamic balance between tumor suppression and promotion. Emphasis is placed on how dysregulation of specific ncRNAs can disrupt this delicate equilibrium, fostering CRC initiation, progression, and metastasis. Moreover, the review provides a critical appraisal of the emerging therapeutic strategies targeting ncRNAs associated with TGF-β signaling in CRC. The potential of these ncRNAs as diagnostic and prognostic biomarkers is discussed, highlighting their clinical relevance. Additionally, the challenges and prospects of developing RNA-based therapeutics, such as RNA interference and CRISPR/Cas-based approaches, are explored in the context of modulating TGF-β signaling for CRC treatment. In conclusion, this review offers a comprehensive overview of the intricate interplay between ncRNAs and the TGF-β signaling pathway in CRC. By unraveling the functional significance of these regulatory elements, we gain valuable insights into the molecular landscape of CRC, paving the way for the development of novel and targeted therapeutic interventions aimed at modulating the TGF-β signaling cascade through the manipulation of ncRNAs.
Collapse
Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan
| | | | - Zahraa Jasim Sattay
- Department of Medical Laboratory Technology l, University of imam Jaafar Al-Sadiq, Iraq
| | | | - Hijaz Ahmad
- Section of Mathematics, International Telematic University Uninettuno, Corso Vittorio Emanuele II, 39, Rome 00186, Italy; Center for Applied Mathematics and Bioinformatics, Gulf University for Science and Technology, Kuwait; Department of Computer Science and Mathematics, Lebanese American University, Beirut, Lebanon
| | - Gaber E Eldesoky
- Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | | | | |
Collapse
|
|
9
|
Ganz T, Nemeth E. Hypoferremia of inflammation: Innate host defense against infections. Blood Cells Mol Dis 2024; 104:102777. [PMID: 37391347 DOI: 10.1016/j.bcmd.2023.102777] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/18/2023] [Accepted: 06/19/2023] [Indexed: 07/02/2023]
Abstract
Iron is an essential nutrient for microbes, plants and animals. Multicellular organisms have evolved multiple strategies to control invading microbes by restricting microbial access to iron. Hypoferremia of inflammation is a rapidly-acting organismal response that prevents the formation of iron species that would be readily accessible to microbes. This review takes an evolutionary perspective to explore the mechanisms and host defense function of hypoferremia of inflammation and its clinical implications.
Collapse
Affiliation(s)
- Tomas Ganz
- Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1690, USA; Department of Pathology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1690, USA.
| | - Elizabeta Nemeth
- Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1690, USA
| |
Collapse
|
|
10
|
Xin X, Chang HM, Leung PCK, Dong L, Li J, Lian F, Wu H. Bone morphogenetic protein 6 induces downregulation of pentraxin 3 expression in human granulosa lutein cells in women with polycystic ovary syndrome. J Assist Reprod Genet 2024; 41:31-48. [PMID: 37930517 PMCID: PMC10789681 DOI: 10.1007/s10815-023-02972-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: 08/30/2023] [Accepted: 10/09/2023] [Indexed: 11/07/2023] Open
Abstract
PURPOSE To evaluate whether PTX3 is differentially expressed in the granulosa lutein cells derived from women with PCOS and whether BMP6 can regulate the expression of PTX3 in hGL cells. METHODS The expression levels of BMP6 and PTX3 in granulosa lutein cells were evaluated by RT-qPCR. The correlation between the expression levels of BMP6 /PTX3 and oocyte quality indexes were analyzed using clinical samples. The cells were incubated with BMP6 at different concentrations and times to check the expression of PTX3 in KGN cells. TGF-β type I inhibitors and small interfering RNA targeting ALK2/3/6,SMAD1/5/8 and SMAD4 were used to study the involvement of SMAD dependent pathways in KGN cells. RESULTS The levels of BMP6 in hGL cells were negatively correlated with the corresponding oocyte maturation rate and high-quality embryo rate, whereas the levels of PTX3 were positively correlated with the corresponding oocyte maturation rate in PCOS. Additionally, the in vitro cell cultured results showed BMP6 significantly inhibited the expression of PTX3 in KGN cells. Furthermore, using a dual inhibition approach (kinase inhibitors and small interfering RNAs), we identified the ALK2/ALK3 type I receptors and BMPR2/ACVR2A type II receptors and the downstream SMAD1/SMAD5-SMAD4 signaling pathway were responsible for the BMP6-induced cellular activities in KGN cells. CONCLUSIONS The suppressive effect of BMP6 on PTX3 was mediated by ALK2/ALK3 type I receptors and BMPR2/ACVR2A type II receptors in granulosa cells through the SMAD1/5-SMAD4 dependent signaling pathway in PCOS.Our findings provides new insights into the understanding of the pathogenesis of PCOS-related ovulatory disorders.
Collapse
Affiliation(s)
- Xin Xin
- First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250011, China
| | - Hsun-Ming Chang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
| | - Peter C K Leung
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Li Dong
- First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250011, China
| | - Jiaxi Li
- First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250011, China
| | - Fang Lian
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
| | - Haicui Wu
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
| |
Collapse
|
|
11
|
Walter S, Mertens C, Muckenthaler MU, Ott C. Cardiac iron metabolism during aging - Role of inflammation and proteolysis. Mech Ageing Dev 2023; 215:111869. [PMID: 37678569 DOI: 10.1016/j.mad.2023.111869] [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: 07/26/2023] [Revised: 09/01/2023] [Accepted: 09/03/2023] [Indexed: 09/09/2023]
Abstract
Iron is the most abundant trace element in the human body. Since iron can switch between its 2-valent and 3-valent form it is essential in various physiological processes such as energy production, proliferation or DNA synthesis. Especially high metabolic organs such as the heart rely on iron-associated iron-sulfur and heme proteins. However, due to switches in iron oxidation state, iron overload exhibits high toxicity through formation of reactive oxygen species, underlining the importance of balanced iron levels. Growing evidence demonstrates disturbance of this balance during aging. While age-associated cardiovascular diseases are often related to iron deficiency, in physiological aging cardiac iron accumulates. To understand these changes, we focused on inflammation and proteolysis, two hallmarks of aging, and their role in iron metabolism. Via the IL-6-hepcidin axis, inflammation and iron status are strongly connected often resulting in anemia accompanied by infiltration of macrophages. This tight connection between anemia and inflammation highlights the importance of the macrophage iron metabolism during inflammation. Age-related decrease in proteolytic activity additionally affects iron balance due to impaired degradation of iron metabolism proteins. Therefore, this review accentuates alterations in iron metabolism during aging with regards to inflammation and proteolysis to draw attention to their implications and associations.
Collapse
Affiliation(s)
- Sophia Walter
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Molecular Toxicology, Nuthetal, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Wuppertal, Germany; DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany
| | - Christina Mertens
- Center for Translational Biomedical Iron Research, Department of Pediatric Oncology, Immunology, and Hematology, University of Heidelberg, Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), Heidelberg, Mannheim, Germany
| | - Martina U Muckenthaler
- Center for Translational Biomedical Iron Research, Department of Pediatric Oncology, Immunology, and Hematology, University of Heidelberg, Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), Heidelberg, Mannheim, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany
| | - Christiane Ott
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Molecular Toxicology, Nuthetal, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Wuppertal, Germany; DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
| |
Collapse
|
|
12
|
Inactivating the Uninhibited: The Tale of Activins and Inhibins in Pulmonary Arterial Hypertension. Int J Mol Sci 2023; 24:ijms24043332. [PMID: 36834742 PMCID: PMC9963072 DOI: 10.3390/ijms24043332] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/10/2023] Open
Abstract
Advances in technology and biomedical knowledge have led to the effective diagnosis and treatment of an increasing number of rare diseases. Pulmonary arterial hypertension (PAH) is a rare disorder of the pulmonary vasculature that is associated with high mortality and morbidity rates. Although significant progress has been made in understanding PAH and its diagnosis and treatment, numerous unanswered questions remain regarding pulmonary vascular remodeling, a major factor contributing to the increase in pulmonary arterial pressure. Here, we discuss the role of activins and inhibins, both of which belong to the TGF-β superfamily, in PAH development. We examine how these relate to signaling pathways implicated in PAH pathogenesis. Furthermore, we discuss how activin/inhibin-targeting drugs, particularly sotatercep, affect pathophysiology, as these target the afore-mentioned specific pathway. We highlight activin/inhibin signaling as a critical mediator of PAH development that is to be targeted for therapeutic gain, potentially improving patient outcomes in the future.
Collapse
|
|
13
|
Evans ET, Horst B, Arend RC, Mythreye K. Evolving roles of activins and inhibins in ovarian cancer pathophysiology. Am J Physiol Cell Physiol 2023; 324:C428-C437. [PMID: 36622068 PMCID: PMC9902228 DOI: 10.1152/ajpcell.00178.2022] [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: 04/27/2022] [Revised: 12/14/2022] [Accepted: 12/15/2022] [Indexed: 01/10/2023]
Abstract
Activins and inhibins are unique members of the transforming growth factor-β (TGFβ) family of growth factors, with the ability to exert autocrine, endocrine, and paracrine effects in a wide range of complex physiologic and pathologic processes. Although first isolated within the pituitary, emerging evidence suggests broader influence beyond reproductive development and function. Known roles of activin and inhibin in angiogenesis and immunity along with correlations between gene expression and cancer prognosis suggest potential roles in tumorigenesis. Here, we present a review of the current understanding of the biological role of activins and inhibins as it relates to ovarian cancers, summarizing the underlying signaling mechanisms and physiologic influence, followed by detailing their roles in cancer progression, diagnosis, and treatment.
Collapse
Affiliation(s)
- Elizabeth T Evans
- Department of Gynecologic Oncology, Heersink School of Medicine, University of Alabama School of Medicine, Birmingham, Alabama
| | - Ben Horst
- Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Rebecca C Arend
- Department of Gynecologic Oncology, Heersink School of Medicine, University of Alabama School of Medicine, Birmingham, Alabama
| | - Karthikeyan Mythreye
- Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| |
Collapse
|
|
14
|
Tupý J. Anemia of inflammatory: does eiderr knowledge mean better diagnosis and treatment? VNITRNI LEKARSTVI 2023; 69:10-18. [PMID: 37072261 DOI: 10.36290/vnl.2023.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
Abstract
Anemia, which is a manifestation of the deterioration of patients' health and performance, is a common concomitant condition in diseases with signs of inflammation activation. This anemia - anemia of inflammation, is caused by disturbances of iron metabolism that lead to iron retention within macrophages, cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation, and a reduced erytrocyte half-life. Anemia is usually mild to moderate, normocytic and normochromic. It is characterized by low iron circulation, but normal to increased levels of stored ferritin and the hormone hepcidin. The primary therapeutic approach is the treatment of the underlying inflammatory disease. In case of failure, iron supplementation and / or treatment with erythropoietin stimulating agents may be used. Blood transfusions are just an emergency treatment for life-threatening anemia. A new treatment modalities with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors is emerging. However, their therapeutic efficacy needs to be verified and evaluated in clinical trials.
Collapse
|
|
15
|
Ham SY, Jun JH, Kim HB, Shim JK, Lee G, Kwak YL. Regulators impeding erythropoiesis following iron supplementation in a clinically relevant rat model of iron deficiency anemia with inflammation. Life Sci 2022; 310:121124. [DOI: 10.1016/j.lfs.2022.121124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/14/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022]
|
|
16
|
Wang Y, Hamang M, Culver A, Jiang H, Yanum J, Garcia V, Lee J, White E, Kusumanchi P, Chalasani N, Liangpunsakul S, Yaden BC, Dai G. Activin B promotes the initiation and progression of liver fibrosis. Hepatol Commun 2022; 6:2812-2826. [PMID: 35866567 PMCID: PMC9512478 DOI: 10.1002/hep4.2037] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/01/2022] [Accepted: 06/14/2022] [Indexed: 11/09/2022] Open
Abstract
The role of activin B, a transforming growth factor β (TGFβ) superfamily cytokine, in liver health and disease is largely unknown. We aimed to investigate whether activin B modulates liver fibrogenesis. Liver and serum activin B, along with its analog activin A, were analyzed in patients with liver fibrosis from different etiologies and in mouse acute and chronic liver injury models. Activin B, activin A, or both was immunologically neutralized in mice with progressive or established carbon tetrachloride (CCl4 )-induced liver fibrosis. Hepatic and circulating activin B was increased in human patients with liver fibrosis caused by several liver diseases. In mice, hepatic and circulating activin B exhibited persistent elevation following the onset of several types of liver injury, whereas activin A displayed transient increases. The results revealed a close correlation of activin B with liver injury regardless of etiology and species. Injured hepatocytes produced excessive activin B. Neutralizing activin B largely prevented, as well as improved, CCl4 -induced liver fibrosis, which was augmented by co-neutralizing activin A. Mechanistically, activin B mediated the activation of c-Jun-N-terminal kinase (JNK), the induction of inducible nitric oxide synthase (iNOS) expression, and the maintenance of poly (ADP-ribose) polymerase 1 (PARP1) expression in injured livers. Moreover, activin B directly induced a profibrotic expression profile in hepatic stellate cells (HSCs) and stimulated these cells to form a septa structure. Conclusions: We demonstrate that activin B, cooperating with activin A, mediates the activation or expression of JNK, iNOS, and PARP1 and the activation of HSCs, driving the initiation and progression of liver fibrosis.
Collapse
Affiliation(s)
- Yan Wang
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Matthew Hamang
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Alexander Culver
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Huaizhou Jiang
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Jennifer Yanum
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Veronica Garcia
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Joonyong Lee
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Emily White
- College of ScienceDepartment of Biological SciencesPurdue UniversityWest LafayetteIndianaUSA
| | - Praveen Kusumanchi
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Naga Chalasani
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
- Department of Biochemistry and Molecular BiologyIndiana University School of MedicineIndianapolisIndianaUSA
- Roudebush Veterans Administration Medical CenterIndianapolisIndianaUSA
| | - Benjamin C. Yaden
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Guoli Dai
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| |
Collapse
|
|
17
|
Matsumura M, Murakami M, Funaba M. Transcriptional activation of hepcidin by the microphthalmia/transcription factor E family. Cell Biochem Funct 2022; 40:742-749. [PMID: 36062805 DOI: 10.1002/cbf.3739] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 08/10/2022] [Accepted: 08/17/2022] [Indexed: 12/30/2022]
Abstract
Hepcidin negatively regulates the circulating iron levels by inhibiting the intestinal absorption of iron as well as iron release from macrophages. Hepcidin activity is largely determined by its expression, which is regulated at the transcriptional level. Hepcidin transcription is induced not only by the iron status-related bone morphogenetic protein (BMP)-2/6, but also by inflammatory cytokines, such as interleukin (IL)-1β and IL-6. The present study reveals that the microphthalmia (MiT)/transcription factor E (TFE) family members are novel regulators of hepcidin transcription. Melanocyte-inducing transcription factor (MITF)-A, a member of the MiT/TFE family, was identified as a positive regulator of hepcidin transcription via stimulus screening for transcription regulators. An E-box (5'-CATGTG-3') spanning nt-645 to nt-640 of the murine hepcidin promoter was identified as an MITF-A-responsive element. Responsiveness to MITF-A on hepcidin transcription decreased when the cells were stimulated with BMP2 or IL-1β. These results suggest a functional interaction between the MITF pathway and BMP- or IL-1β-mediated signaling. TFEB and TFE3, members of the MiT/TFE family, also stimulated hepcidin transcription, but the main region responsible for hepcidin transcription was distinct from that induced by MITF-A. The region spanning nt-581 to nt-526 was involved in TFEB/TFE3-mediated hepcidin transcription. Considering that members of the MiT/TFE family act as regulators of starvation-induced lysosomal biogenesis, hepcidin expression may be controlled by additional pathways apart from those identified so far.
Collapse
Affiliation(s)
- Manami Matsumura
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Masaru Murakami
- Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara, Japan
| | - Masayuki Funaba
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| |
Collapse
|
|
18
|
Shonibare Z, Monavarian M, O’Connell K, Altomare D, Shelton A, Mehta S, Jaskula-Sztul R, Phaeton R, Starr MD, Whitaker R, Berchuck A, Nixon AB, Arend RC, Lee NY, Miller CR, Hempel N, Mythreye K. Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer. Cell Rep 2022; 40:111066. [PMID: 35905726 PMCID: PMC9899501 DOI: 10.1016/j.celrep.2022.111066] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 05/05/2022] [Accepted: 06/16/2022] [Indexed: 02/07/2023] Open
Abstract
Growth factors in tumor environments are regulators of cell survival and metastasis. Here, we reveal the dichotomy between TGF-β superfamily growth factors BMP and TGF-β/activin and their downstream SMAD effectors. Gene expression profiling uncovers SOX2 as a key contextual signaling node regulated in an opposing manner by BMP2, -4, and -9 and TGF-β and activin A to impact anchorage-independent cell survival. We find that SOX2 is repressed by BMPs, leading to a reduction in intraperitoneal tumor burden and improved survival of tumor-bearing mice. Repression of SOX2 is driven by SMAD1-dependent histone H3K27me3 recruitment and DNA methylation at SOX2's promoter. Conversely, TGF-β, which is elevated in patient ascites, and activin A can promote SOX2 expression and anchorage-independent survival by SMAD3-dependent histone H3K4me3 recruitment. Our findings identify SOX2 as a contextual and contrastingly regulated node downstream of TGF-β members controlling anchorage-independent survival and metastasis in ovarian cancers.
Collapse
Affiliation(s)
- Zainab Shonibare
- Department of Pathology, O’Neal Comprehensive Cancer Center, University of Alabama School of Medicine, Birmingham, AL, USA,Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
| | - Mehri Monavarian
- Department of Pathology, O’Neal Comprehensive Cancer Center, University of Alabama School of Medicine, Birmingham, AL, USA
| | - Kathleen O’Connell
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
| | - Diego Altomare
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Abigail Shelton
- Department of Pathology, O’Neal Comprehensive Cancer Center, Comprehensive Neuroscience Center, University of Alabama School of Medicine, Birmingham, AL, USA
| | - Shubham Mehta
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
| | - Renata Jaskula-Sztul
- Department of Surgery, University of Alabama School of Medicine, Birmingham, AL, USA
| | - Rebecca Phaeton
- Department of Obstetrics and Gynecology, and Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Mark D. Starr
- Department of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Regina Whitaker
- Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA
| | - Andrew Berchuck
- Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA
| | - Andrew B. Nixon
- Department of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Rebecca C. Arend
- Department of Gynecology Oncology, University of Alabama School of Medicine, Birmingham, AL, USA
| | - Nam Y. Lee
- Department of Chemistry and Biochemistry, Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA
| | - C. Ryan Miller
- Department of Pathology, O’Neal Comprehensive Cancer Center, Comprehensive Neuroscience Center, University of Alabama School of Medicine, Birmingham, AL, USA
| | - Nadine Hempel
- Department of Pharmacology, and Obstetrics and Gynecology, College of Medicine, Pennsylvania State University, Hershey, PA, USA; Department of Medicine, Division of Hematology Oncology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
| | - Karthikeyan Mythreye
- Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama School of Medicine, Birmingham, AL, USA; Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA.
| |
Collapse
|
|
19
|
Abstract
The liver is the major target organ of continued alcohol consumption at risk and resulting alcoholic liver disease (ALD) is the most common liver disease worldwide. The underlying molecular mechanisms are still poorly understood despite decades of scientific effort limiting our abilities to identify those individuals who are at risk to develop the disease, to develop appropriate screening strategies and, in addition, to develop targeted therapeutic approaches. ALD is predestined for the newly evolving translational medicine, as conventional clinical and health care structures seem to be constrained to fully appreciate this disease. This concept paper aims at summarizing the 15 years translational experience at the Center of Alcohol Research in Heidelberg, namely based on the long-term prospective and detailed characterization of heavy drinkers with mortality data. In addition, novel experimental findings will be presented. A special focus will be the long-known hepatic iron accumulation, the somewhat overlooked role of the hematopoietic system and novel insights into iron sensing and the role of hepcidin. Our preliminary work indicates that enhanced red blood cell (RBC) turnover is critical for survival in ALD patients. RBC turnover is not primarily due to vitamin deficiency but rather to ethanol toxicity directly targeted to erythrocytes but also to the bone marrow stem cell compartment. These novel insights also help to explain long-known aspects of ALD such as mean corpuscular volume of erythrocytes (MCV) and elevated aspartate transaminase (GOT/AST) levels. This work also aims at identifying future projects, naming unresolved observations, and presenting novel hypothetical concepts still requiring future validation.
Collapse
|
|
20
|
Yamamoto T, Diao Z, Murakami M, Shimokawa F, Matsui T, Funaba M. Factors affecting the induction of uncoupling protein 1 in C2C12 myogenic cells. Cytokine 2022; 157:155936. [PMID: 35738051 DOI: 10.1016/j.cyto.2022.155936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/26/2022] [Accepted: 06/03/2022] [Indexed: 11/03/2022]
Abstract
Brown/beige adipocytes, which are derived from skeletal muscle/smooth muscle-lineage cells, consume excess energy as heat through the expression of mitochondrial uncoupling protein 1 (UCP1). Previous studies have shown that forced expression of PR/SET domain (PRDM)-16 or early B-cell factor (EBF)-2 induced UCP1-positive adipocytes in C2C12 myogenic cells. Here, we explored the culture conditions to induce Ucp1 expression in C2C12 cells without introducing exogenous genes. Treatment with rosiglitazone (a peroxisome proliferator-activated receptor (PPAR)-γ agonist), GW501516 (a PPARδ agonist), and bone morphogenetic protein (BMP)-7 for 8 days efficiently increased Ucp1 expression in response to treatment with forskolin, an activator of the protein kinase A pathway. BMP7 dose-dependently increased forskolin-induced Ucp1 expression in the presence of rosiglitazone and GW501516; however, GW501516 was not required for Ucp1 induction. Additionally, the structurally related proteins, BMP6 and BMP9, efficiently increased forskolin-induced Ucp1 expression in rosiglitazone-treated cells. UCP1 protein was localized in cells with lipid droplets, but adipocytes were not always positive for UCP1. Continuous treatment with BMP7 was needed for the efficient induction of Ucp1 by forskolin treatment. Significant expression of Prdm16 was not detected, irrespective of the treatment, and treatment with rosiglitazone, GW501516, and BMP7 did not affect the expression levels of Ebf2. Fibroblast growth factor receptor (Fgfr)-3 expression levels were increased by BMP9 in rosiglitazone-treated cells, and molecules that upregulate Fgfr3 transcription partly overlapped with those that stimulate Ucp1 transcription. The present results provide basic information on the practical differentiation of myogenic cells to brown adipocytes.
Collapse
Affiliation(s)
- Takehiro Yamamoto
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
| | - Zhicheng Diao
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
| | - Masaru Murakami
- Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara 252-5201, Japan
| | - Fumie Shimokawa
- Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara 252-5201, Japan
| | - Tohru Matsui
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
| | - Masayuki Funaba
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
| |
Collapse
|
|
21
|
Correnti M, Gammella E, Cairo G, Recalcati S. Iron Mining for Erythropoiesis. Int J Mol Sci 2022; 23:ijms23105341. [PMID: 35628152 PMCID: PMC9140467 DOI: 10.3390/ijms23105341] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/05/2022] [Accepted: 05/09/2022] [Indexed: 01/27/2023] Open
Abstract
Iron is necessary for essential processes in every cell of the body, but the erythropoietic compartment is a privileged iron consumer. In fact, as a necessary component of hemoglobin and myoglobin, iron assures oxygen distribution; therefore, a considerable amount of iron is required daily for hemoglobin synthesis and erythroid cell proliferation. Therefore, a tight link exists between iron metabolism and erythropoiesis. The liver-derived hormone hepcidin, which controls iron homeostasis via its interaction with the iron exporter ferroportin, coordinates erythropoietic activity and iron homeostasis. When erythropoiesis is enhanced, iron availability to the erythron is mainly ensured by inhibiting hepcidin expression, thereby increasing ferroportin-mediated iron export from both duodenal absorptive cells and reticuloendothelial cells that process old and/or damaged red blood cells. Erythroferrone, a factor produced and secreted by erythroid precursors in response to erythropoietin, has been identified and characterized as a suppressor of hepcidin synthesis to allow iron mobilization and facilitate erythropoiesis.
Collapse
|
|
22
|
Fisher AL, Babitt JL. Coordination of iron homeostasis by bone morphogenetic proteins: Current understanding and unanswered questions. Dev Dyn 2022; 251:26-46. [PMID: 33993583 PMCID: PMC8594283 DOI: 10.1002/dvdy.372] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/15/2021] [Accepted: 05/07/2021] [Indexed: 01/19/2023] Open
Abstract
Iron homeostasis is tightly regulated to balance the iron requirement for erythropoiesis and other vital cellular functions, while preventing cellular injury from iron excess. The liver hormone hepcidin is the master regulator of systemic iron balance by controlling the degradation and function of the sole known mammalian iron exporter ferroportin. Liver hepcidin expression is coordinately regulated by several signals that indicate the need for more or less iron, including plasma and tissue iron levels, inflammation, and erythropoietic drive. Most of these signals regulate hepcidin expression by modulating the activity of the bone morphogenetic protein (BMP)-SMAD pathway, which controls hepcidin transcription. Genetic disorders of iron overload and iron deficiency have identified several hepatocyte membrane proteins that play a critical role in mediating the BMP-SMAD and hepcidin regulatory response to iron. However, the precise molecular mechanisms by which serum and tissue iron levels are sensed to regulate BMP ligand production and promote the physical and/or functional interaction of these proteins to modulate SMAD signaling and hepcidin expression remain uncertain. This critical commentary will focus on the current understanding and key unanswered questions regarding how the liver senses iron levels to regulate BMP-SMAD signaling and thereby hepcidin expression to control systemic iron homeostasis.
Collapse
Affiliation(s)
| | - Jodie L Babitt
- Corresponding author: Jodie L Babitt, Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Mailing address: 185 Cambridge St., CPZN-8208, Boston, MA 02114. Telephone: +1 (617) 643-3181.
| |
Collapse
|
|
23
|
Refaat B, Zekri J, Aslam A, Ahmad J, Baghdadi MA, Meliti A, Idris S, Sultan S, Alardati H, Saimeh HA, Alsaegh A, Alhadrami M, Hamid T, Naeem ME, Elsamany SA. Profiling Activins and Follistatin in Colorectal Cancer According to Clinical Stage, Tumour Sidedness and Smad4 Status. Pathol Oncol Res 2021; 27:1610032. [PMID: 34867090 PMCID: PMC8634429 DOI: 10.3389/pore.2021.1610032] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/12/2021] [Indexed: 01/10/2023]
Abstract
This study explored the roles of activins and follistatin in colorectal cancers. Paired malignant and normal colonic tissues were collected from archived paraffin-embedded (n = 90 patients) alongside fresh (n = 40 patients) specimen cohorts. Activin β-subunits, follistatin and Smad4 mRNAs and proteins were measured by real-time PCR and immunohistochemistry (IHC). Mature activin-A, -B, -AB and follistatin proteins were measured by ELISA. Cancer tissues having ≤ the 20th percentile of the Smad4 IHC score were considered as low (L-S4) group. The Smad4-intact SW480 and Smad4-null HT29 colon cancer cell lines were treated with activins and follistatin, and cell cycle was analysed by flow cytometry. The cell cycle inducing (CCND1/CCND3) and inhibitory (p21/p27) proteins alongside the survival (survivin/BCL2) and pro-apoptosis (Casp-8/Casp-3) markers were measured by immunofluorescence. Thirty-nine patients had right-sided cancers (30%) and showed higher rates of L-S4 tumours (n = 17; 13.1%) alongside worse clinicopathological characteristics relative to left-sided cancers. The βA-subunit and activin-A increased, whilst βB-subunit and activin-AB decreased, in malignant sites and the late-stage cancers revealed the greatest abnormalities. Interestingly, follistatin declined markedly in early-stage malignant tissues, whilst increased significantly in the advanced stages. All activin molecules were comparable between the early stage right- and left-sided tumours, whereas the late-stage right-sided cancers and L-S4 tumours showed more profound deregulations. In vitro, activin-A increased the numbers of the SW480 cells in sub-G1 and G0/G1-phases, whereas reduced the HT29 cell numbers in the sub-G1 phase with simultaneous increases in the G0/G1 and S phases. The p21/p27/Casp-8/Casp-3 proteins escalated, whilst CCND1/CCND3/BCL2/survivin declined in the SW480 cells following activin-A, whereas activin-A only promoted p21 and p27 alongside reduced CCND3 in the HT29 cells. By contrast, activin-AB increased the numbers of SW480 and HT29 cells in Sub-G1 and G0/G1-phases and promoted the anti-cancer and reduced the oncogenic proteins in both cell lines. In conclusion, activins and follistatin displayed stage-dependent dysregulations and were markedly altered during the advanced stages of right-sided and L-S4 cancers. Moreover, the activin-A actions in CRC could be Smad4-dependent, whereas activin-AB may act as a Smad4-independent tumour suppressor protein.
Collapse
Affiliation(s)
- Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Jamal Zekri
- Oncology Department, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia.,College of Medicine, Alfaisal University, Jeddah, Saudi Arabia
| | - Akhmed Aslam
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Jawwad Ahmad
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mohammed A Baghdadi
- Research Centre, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
| | - Abdelrazak Meliti
- Pathology Department, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia.,Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Shakir Idris
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Sufian Sultan
- Department of Surgery, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
| | - Hosam Alardati
- Pathology Department, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
| | - Haitham Akram Saimeh
- Department of Surgery, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
| | - Aiman Alsaegh
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mai Alhadrami
- Pathology Department, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Tahira Hamid
- Histopathology Department, King Abdullah Medical City, Makkah, Saudi Arabia
| | - Mohammed E Naeem
- Histopathology Department, King Abdullah Medical City, Makkah, Saudi Arabia
| | - Shereef Ahmed Elsamany
- Medical Oncology Department, Oncology Centre, King Abdullah Medical City, Makkah, Saudi Arabia.,Medical Oncology Department, Oncology Centre, Mansoura University, Mansoura, Egypt
| |
Collapse
|
|
24
|
Luo M, Liu Q, Ye S, Liu S, Hu Y, Lv D, Wang G, Li M, Jian C, Huang B. RNA-seq of buffalo fibroblasts over-expressed pluripotent-related genes to investigate characteristics of its preliminarily reprogrammed stage. Res Vet Sci 2021; 144:164-174. [PMID: 34839950 DOI: 10.1016/j.rvsc.2021.11.008] [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: 07/08/2021] [Revised: 10/19/2021] [Accepted: 11/16/2021] [Indexed: 01/10/2023]
Abstract
Induced pluripotent stem cells (iPSCs) can enhance the efficiency of buffalo genetic improvements because of their differentiation potential and proliferation ability, which are similar to those of embryonic stem cells. However, very few studies have focussed on buffalo iPSCs, and a stable induction system has not been established for buffalo somatic cell reprogramming. In this study, we constructed a PiggyBac transposon vector co-expressing buffalo OCT4, C-MYC, KLF4 and SOX2 genes (PB_OMKS) separated by the nucleotide sequence of three 2A peptides and established the buffalo foetal skin fibroblast (BFSF) cell line BFSF_OMKS. RNA-seq technology and bioinformatics analysis methods were mainly employed to perform a transcriptome analysis between BFSF and BFSF_OMKS. The results revealed that over-expression of OCT4, C-MYC, KLF4 and SOX2 in BFSFs led to the activation of reprogramming-related LIF, activin, BMP4, SMAD1/5/9 and Wnt signals. These results increased our understanding of buffalo somatic cell reprogramming mechanisms and could provide a possible theory for the selection of small-molecule cocktails to promote reprogramming.
Collapse
Affiliation(s)
- Man Luo
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, Guangxi 530004, China; College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China
| | - Quanhui Liu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, Guangxi 530004, China; College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China
| | - Sheng Ye
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, Guangxi 530004, China; College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China
| | - Shulin Liu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, Guangxi 530004, China; College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China
| | - Yanan Hu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, Guangxi 530004, China; College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China
| | - Danwei Lv
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, Guangxi 530004, China; College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China
| | - Guodong Wang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, Guangxi 530004, China; College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China
| | - Mengmei Li
- College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China.
| | - Chongdong Jian
- Department of Neurology, The Affiliated Hospital of Youjiang Medical for Nationalities, Baise, Guangxi 533000, China.
| | - Ben Huang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, Guangxi 530004, China; College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China.
| |
Collapse
|
|
25
|
Rana S, Prabhakar N. Iron disorders and hepcidin. Clin Chim Acta 2021; 523:454-468. [PMID: 34755647 DOI: 10.1016/j.cca.2021.10.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 12/13/2022]
Abstract
Iron is an essential element due to its role in a wide variety of physiological processes. Iron homeostasis is crucial to prevent iron overload disorders as well as iron deficiency anemia. The liver synthesized peptide hormone hepcidin is a master regulator of systemic iron metabolism. Given its role in overall health, measurement of hepcidin can be used as a predictive marker in disease states. In addition, hepcidin-targeting drugs appear beneficial as therapeutic agents. This review emphasizes recent development on analytical techniques (immunochemical, mass spectrometry and biosensors) and therapeutic approaches (hepcidin agonists, stimulators and antagonists). These insights highlight hepcidin as a potential biomarker as well as an aid in the development of new drugs for iron disorders.
Collapse
Affiliation(s)
- Shilpa Rana
- Department of Biochemistry, Sector-25, Panjab University, Chandigarh 160014, India
| | - Nirmal Prabhakar
- Department of Biochemistry, Sector-25, Panjab University, Chandigarh 160014, India.
| |
Collapse
|
|
26
|
Patel V, Joharapurkar A, Kshirsagar S, Patel M, Patel H, Savsani H, Jain M. Hepcidin inhibition improves iron homeostasis in ferrous sulfate and LPS treatment model in mice. Drug Res (Stuttg) 2021; 71:528-534. [PMID: 34311475 DOI: 10.1055/a-1542-8531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Hepcidin, a liver-derived peptide, regulates the absorption, distribution, and circulation of iron in the body. Inflammation or iron overload stimulates hepcidin release, which causes the accumulation of iron in tissues. The inadequate levels of iron in circulation impair erythropoiesis. Inhibition of hepcidin may increase iron in circulation and improve efficient erythropoiesis. Activin-like kinase (ALK) inhibitors decrease hepcidin. METHODS In this work, we have investigated an ALK inhibitor LDN193189 for its efficacy in iron homeostasis. The effect of LDN193189 treatment was assessed in C57BL6/J mice, in which hepcidin was induced by either ferrous sulfate or lipopolysaccharide (LPS) injection. RESULTS After two hours of treatment, ferrous sulfate increased serum and liver iron, serum hepcidin, and liver hepcidin expression. On the other hand, LPS reduced serum iron in a dose-related manner after six hours of treatment. LDN193189 treatment increased serum iron, decreased spleen and liver iron, decreased serum hepcidin and liver hepcidin expression in ferrous sulfate-treated mice, and increased serum iron in LPS-induced hypoferremia. We observed that ferrous sulfate caused a significantly higher increase in liver iron, serum hepcidin, and liver hepcidin than turpentine oil or LPS in mice. Iron dextran (intraperitoneal or intravenous) increased serum iron, but LDN193189 did not show hyperferremia with iron dextran stimulus. CONCLUSION Ferrous sulfate-induced hyperferremia can be a valuable and rapid screening model for assessing the efficacy of hepcidin inhibitors.
Collapse
Affiliation(s)
- Vishal Patel
- Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
| | - Amit Joharapurkar
- Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
| | | | - Maulik Patel
- Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
| | - Hiren Patel
- Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
| | | | - Mukul Jain
- Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
| |
Collapse
|
|
27
|
Lanser L, Fuchs D, Kurz K, Weiss G. Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis-Mechanistic Insights into Anemia of Inflammation and Its Treatment. Nutrients 2021; 13:3732. [PMID: 34835988 PMCID: PMC8619077 DOI: 10.3390/nu13113732] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 02/07/2023] Open
Abstract
Anemia is very common in patients with inflammatory disorders. Its prevalence is associated with severity of the underlying disease, and it negatively affects quality of life and cardio-vascular performance of patients. Anemia of inflammation (AI) is caused by disturbances of iron metabolism resulting in iron retention within macrophages, a reduced erythrocyte half-life, and cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation. AI is mostly mild to moderate, normochromic and normocytic, and characterized by low circulating iron, but normal and increased levels of the storage protein ferritin and the iron hormone hepcidin. The primary therapeutic approach for AI is treatment of the underlying inflammatory disease which mostly results in normalization of hemoglobin levels over time unless other pathologies such as vitamin deficiencies, true iron deficiency on the basis of bleeding episodes, or renal insufficiency are present. If the underlying disease and/or anemia are not resolved, iron supplementation therapy and/or treatment with erythropoietin stimulating agents may be considered whereas blood transfusions are an emergency treatment for life-threatening anemia. New treatments with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors emerge but their therapeutic efficacy for treatment of AI in ill patients needs to be evaluated in clinical trials.
Collapse
Affiliation(s)
- Lukas Lanser
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (L.L.); (K.K.)
| | - Dietmar Fuchs
- Division of Biological Chemistry, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Katharina Kurz
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (L.L.); (K.K.)
| | - Günter Weiss
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (L.L.); (K.K.)
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, 6020 Innsbruck, Austria
| |
Collapse
|
|
28
|
Enns CA, Jue S, Zhang AS. Hepatocyte neogenin is required for hemojuvelin-mediated hepcidin expression and iron homeostasis in mice. Blood 2021; 138:486-499. [PMID: 33824974 PMCID: PMC8370464 DOI: 10.1182/blood.2020009485] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 03/26/2021] [Indexed: 12/21/2022] Open
Abstract
Neogenin (NEO1) is a ubiquitously expressed multifunctional transmembrane protein. It interacts with hemojuvelin (HJV), a BMP coreceptor that plays a pivotal role in hepatic hepcidin expression. Earlier studies suggest that the function of HJV relies on its interaction with NEO1. However, the role of NEO1 in iron homeostasis remains controversial because of the lack of an appropriate animal model. Here, we generated a hepatocyte-specific Neo1 knockout (Neo1fl/fl;Alb-Cre+) mouse model that circumvented the developmental and lethality issues of the global Neo1 mutant. Results show that ablation of hepatocyte Neo1 decreased hepcidin expression and caused iron overload. This iron overload did not result from altered iron utilization by erythropoiesis. Replacement studies revealed that expression of the Neo1L1046E mutant that does not interact with Hjv, was unable to correct the decreased hepcidin expression and high serum iron in Neo1fl/fl;Alb-Cre+ mice. In Hjv-/- mice, expression of HjvA183R mutant that has reduced interaction with Neo1, also displayed a blunted induction of hepcidin expression. These observations indicate that Neo1-Hjv interaction is essential for hepcidin expression. Further analyses suggest that the Hjv binding triggered the cleavage of the Neo1 cytoplasmic domain by a protease, which resulted in accumulation of truncated Neo1 on the plasma membrane. Additional studies did not support that Neo1 functions by inhibiting Hjv shedding as previously proposed. Together, our data favor a model in which Neo1 interaction with Hjv leads to accumulation of cleaved Neo1 on the plasma membrane, where Neo1 acts as a scaffold to induce the Bmp signaling and hepcidin expression.
Collapse
Affiliation(s)
- Caroline A Enns
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR
| | - Shall Jue
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR
| | - An-Sheng Zhang
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR
| |
Collapse
|
|
29
|
Ledesma-Colunga MG, Weidner H, Vujic Spasic M, Hofbauer LC, Baschant U, Rauner M. Shaping the bone through iron and iron-related proteins. Semin Hematol 2021; 58:188-200. [PMID: 34389111 DOI: 10.1053/j.seminhematol.2021.06.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/18/2021] [Accepted: 06/08/2021] [Indexed: 01/04/2023]
Abstract
Well-controlled iron levels are indispensable for health. Iron deficiency is the most common cause of anemia, whereas iron overload, either hereditary or secondary due to disorders of ineffective erythropoiesis, causes widespread organ failure. Bone is particularly sensitive to fluctuations in systemic iron levels as both iron deficiency and overload are associated with low bone mineral density and fragility. Recent studies have shown that not only iron itself, but also iron-regulatory proteins that are mutated in hereditary hemochromatosis can control bone mass. This review will summarize the current knowledge on the effects of iron on bone homeostasis and bone cell activities, and on the role of proteins that regulate iron homeostasis, i.e. hemochromatosis proteins and proteins of the bone morphogenetic protein pathway, on bone remodeling. As disorders of iron homeostasis are closely linked to bone fragility, deeper insights into common regulatory mechanisms may provide new opportunities to concurrently treat disorders affecting iron homeostasis and bone.
Collapse
Affiliation(s)
- Maria G Ledesma-Colunga
- Divisions of Endocrinology and Molecular Bone Biology, Department of Medicine III & University Center for Healty Aging, Technische Universität Dresden, Dresden, Germany
| | - Heike Weidner
- Divisions of Endocrinology and Molecular Bone Biology, Department of Medicine III & University Center for Healty Aging, Technische Universität Dresden, Dresden, Germany
| | - Maja Vujic Spasic
- Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Germany
| | - Lorenz C Hofbauer
- Divisions of Endocrinology and Molecular Bone Biology, Department of Medicine III & University Center for Healty Aging, Technische Universität Dresden, Dresden, Germany
| | - Ulrike Baschant
- Divisions of Endocrinology and Molecular Bone Biology, Department of Medicine III & University Center for Healty Aging, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Divisions of Endocrinology and Molecular Bone Biology, Department of Medicine III & University Center for Healty Aging, Technische Universität Dresden, Dresden, Germany.
| |
Collapse
|
|
30
|
Colucci S, Marques O, Altamura S. 20 years of Hepcidin: How far we have come. Semin Hematol 2021; 58:132-144. [PMID: 34389105 DOI: 10.1053/j.seminhematol.2021.05.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/12/2021] [Accepted: 05/31/2021] [Indexed: 12/20/2022]
Abstract
Twenty years ago the discovery of hepcidin deeply changed our understanding of the regulation of systemic iron homeostasis. It is now clear that hepcidin orchestrates systemic iron levels by controlling the amount of iron exported into the bloodstream through ferroportin. Hepcidin expression is increased in situations where systemic iron levels should be reduced, such as in iron overload and infection. Conversely, hepcidin is repressed during iron deficiency, hypoxia or expanded erythropoiesis, to increase systemic iron availability and sustain erythropoiesis. In this review, we will focus on molecular mechanisms of hepcidin regulation and on the pathological consequences of their disruption.
Collapse
Affiliation(s)
- Silvia Colucci
- Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, EMBL and University of Heidelberg, Heidelberg, Germany
| | - Oriana Marques
- Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, EMBL and University of Heidelberg, Heidelberg, Germany
| | - Sandro Altamura
- Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, EMBL and University of Heidelberg, Heidelberg, Germany..
| |
Collapse
|
|
31
|
Sanyear C, Chiawtada B, Butthep P, Svasti S, Fucharoen S, Masaratana P. The hypoferremic response to acute inflammation is maintained in thalassemia mice even under parenteral iron loading. PeerJ 2021; 9:e11367. [PMID: 33987030 PMCID: PMC8092106 DOI: 10.7717/peerj.11367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 04/07/2021] [Indexed: 11/20/2022] Open
Abstract
Background Hepcidin controls iron homeostasis by inducing the degradation of the iron efflux protein, ferroportin (FPN1), and subsequently reducing serum iron levels. Hepcidin expression is influenced by multiple factors, including iron stores, ineffective erythropoiesis, and inflammation. However, the interactions between these factors under thalassemic condition remain unclear. This study aimed to determine the hypoferremic and transcriptional responses of iron homeostasis to acute inflammatory induction by lipopolysaccharide (LPS) in thalassemic (Hbbth3/+) mice with/without parenteral iron loading with iron dextran. Methods Wild type and Hbbth3/+ mice were intramuscularly injected with 5 mg of iron dextran once daily for two consecutive days. After a 2-week equilibration, acute inflammation was induced by an intraperitoneal injection of a single dose of 1 µg/g body weight of LPS. Control groups for both iron loading and acute inflammation received equal volume(s) of saline solution. Blood and tissue samples were collected at 6 hours after LPS (or saline) injection. Iron parameters and mRNA expression of hepcidin as well as genes involved in iron transport and metabolism in wild type and Hbbth3/+ mice were analyzed and compared by Kruskal–Wallis test with pairwise Mann–Whitney U test. Results We found the inductive effects of LPS on liver IL-6 mRNA expression to be more pronounced under parenteral iron loading. Upon LPS administration, splenic erythroferrone (ERFE) mRNA levels were reduced only in iron-treated mice, whereas, liver bone morphogenetic protein 6 (BMP6) mRNA levels were decreased under both control and parenteral iron loading conditions. Despite the altered expression of the aforementioned hepcidin regulators, the stimulatory effect of LPS on hepcidin mRNA expression was blunt in iron-treated Hbbth3/+ mice. Contrary to the blunted hepcidin response, LPS treatment suppressed FPN1 mRNA expression in the liver, spleen, and duodenum, as well as reduced serum iron levels of Hbbth3/+ mice with parenteral iron loading. Conclusion Our study suggests that a hypoferremic response to LPS-induced acute inflammation is maintained in thalassemic mice with parenteral iron loading in a hepcidin-independent manner.
Collapse
Affiliation(s)
- Chanita Sanyear
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Buraporn Chiawtada
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Punnee Butthep
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Saovaros Svasti
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Suthat Fucharoen
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Patarabutr Masaratana
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| |
Collapse
|
|
32
|
Li L, Wang X, Zhang H, Chen Q, Cui H. Low anticoagulant heparin-iron complex targeting inhibition of hepcidin ameliorates anemia of chronic disease in rodents. Eur J Pharmacol 2021; 897:173958. [PMID: 33610598 DOI: 10.1016/j.ejphar.2021.173958] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 02/08/2021] [Accepted: 02/15/2021] [Indexed: 11/15/2022]
Abstract
Hepcidin is the only known hormone negatively regulates systemic iron availability, its excess contributes to anemia of chronic disease (ACD).Heparin has been shown to be an efficient hepcidin inhibitor both in vitro and in vivo, but its powerful anticoagulant activity limits this therapeutic application. To this end, heparin-iron complex was prepared by electrostatic interaction and/or coordination between heparin and dihydroxy iron solution ([Fe(OH)2]+) under the condition of ultrasonic assisted. We assessed the anticoagulant activity of heparin-iron in vitro and vivo by sheep plasma, chromogenic substrate method and tail-bleeding in mice, respectively. Anti-hepcidin effect of heparin-iron was detected in HepG2 cell and LPS induced acute inflammation mice by qRT-PCR and ELISA. Turpentine-induced anemia mice were established to evaluate the effect of heparin-iron in ACD. Mice were treated with heparin-iron for 4 weeks. The results indicated that heparin-iron has significantly reduced anticoagulant activity in vitro and in vivo, strongly decreases hepcidin mRNA and IL-6 induced high level of secreted hepcidin in HepG2 cell. Heparin-iron was also found to cause a reduction on hepcidin expression through BMP/SMAD and JAK/STAT3 pathways in LPS induced acute inflammation model in mice. In ACD mice, heparin-iron could lower elevated serum hepcidin and improve anemia. These findings demonstrated low anticoagulant heparin-iron has potential applications for the treatment of ACD with high hepcidin levels.
Collapse
Affiliation(s)
- Liuxiang Li
- Key Laboratory of Chemical Biology, Ministry of Education, Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Xiaoxue Wang
- Key Laboratory of Chemical Biology, Ministry of Education, Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Hongyu Zhang
- Key Laboratory of Chemical Biology, Ministry of Education, Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Qingqing Chen
- National Glycoengineering Research Center, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Huifei Cui
- Key Laboratory of Chemical Biology, Ministry of Education, Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China; National Glycoengineering Research Center, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China; Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
| |
Collapse
|
|
33
|
Varga E, Pap R, Jánosa G, Sipos K, Pandur E. IL-6 Regulates Hepcidin Expression Via the BMP/SMAD Pathway by Altering BMP6, TMPRSS6 and TfR2 Expressions at Normal and Inflammatory Conditions in BV2 Microglia. Neurochem Res 2021; 46:1224-1238. [PMID: 33835366 PMCID: PMC8053173 DOI: 10.1007/s11064-021-03322-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/08/2021] [Accepted: 01/27/2021] [Indexed: 12/19/2022]
Abstract
The hormone hepcidin plays a central role in controlling iron homeostasis. Iron-mediated hepcidin synthesis is triggered via the BMP/SMAD pathway. At inflammation, mainly IL-6 pro-inflammatory cytokine mediates the regulation of hepcidin via the JAK/STAT signalling pathway. Microglial cells of the central nervous system are able to recognize a broad spectrum of pathogens via toll-like receptors and initiate inflammatory response. Although the regulation of hepcidin synthesis is well described in many tissues, little is known about the inflammation mediated hepcidin regulation in microglia. In this study, we investigated the pathways, which are involved in HAMP regulation in BV2 microglia due to inflammatory mediators and the possible relationships between the iron regulatory pathways. Our results showed that IL-6 produced by resting BV2 cells was crucial in maintaining the basal HAMP expression and hepcidin secretion. It was revealed that IL-6 neutralization decreased both STAT3 and SMAD1/5/9 phosphorylation suggesting that IL-6 proinflammatory cytokine is necessary to maintain SMAD1/5/9 activation. We revealed that IL-6 influences BMP6 and TMPRSS6 protein levels, moreover it modified TfR2 expression, as well. In this study, we revealed that BV2 microglia increased their hepcidin secretion upon IL-6 neutralization although the major regulatory pathways were inhibited. Based on our results it seems that both at inflammation and at normal condition the absence of IL-6 triggered HAMP transcription and hepcidin secretion via the NFκB pathway and possibly by the autocrine effect of TNFα cytokine on BV2 microglia.
Collapse
Affiliation(s)
- Edit Varga
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Pécs, Rókus Str. 2, Pécs, 7624, Hungary
| | - Ramóna Pap
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Pécs, Rókus Str. 2, Pécs, 7624, Hungary
| | - Gergely Jánosa
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Pécs, Rókus Str. 2, Pécs, 7624, Hungary
| | - Katalin Sipos
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Pécs, Rókus Str. 2, Pécs, 7624, Hungary
| | - Edina Pandur
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Pécs, Rókus Str. 2, Pécs, 7624, Hungary.
| |
Collapse
|
|
34
|
Weiler S, Nairz M. TAM-ing the CIA-Tumor-Associated Macrophages and Their Potential Role in Unintended Side Effects of Therapeutics for Cancer-Induced Anemia. Front Oncol 2021; 11:627223. [PMID: 33842333 PMCID: PMC8027083 DOI: 10.3389/fonc.2021.627223] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 03/01/2021] [Indexed: 12/21/2022] Open
Abstract
Cancer-induced anemia (CIA) is a common consequence of neoplasia and has a multifactorial pathophysiology. The immune response and tumor treatment, both intended to primarily target malignant cells, also affect erythropoiesis in the bone marrow. In parallel, immune activation inevitably induces the iron-regulatory hormone hepcidin to direct iron fluxes away from erythroid progenitors and into compartments of the mononuclear phagocyte system. Moreover, many inflammatory mediators inhibit the synthesis of erythropoietin, which is essential for stimulation and differentiation of erythroid progenitor cells to mature cells ready for release into the blood stream. These pathophysiological hallmarks of CIA imply that the bone marrow is not only deprived of iron as nutrient but also of erythropoietin as central growth factor for erythropoiesis. Tumor-associated macrophages (TAM) are present in the tumor microenvironment and display altered immune and iron phenotypes. On the one hand, their functions are altered by adjacent tumor cells so that they promote rather than inhibit the growth of malignant cells. As consequences, TAM may deliver iron to tumor cells and produce reduced amounts of cytotoxic mediators. Furthermore, their ability to stimulate adaptive anti-tumor immune responses is severely compromised. On the other hand, TAM are potential off-targets of therapeutic interventions against CIA. Red blood cell transfusions, intravenous iron preparations, erythropoiesis-stimulating agents and novel treatment options for CIA may interfere with TAM function and thus exhibit secondary effects on the underlying malignancy. In this Hypothesis and Theory, we summarize the pathophysiological hallmarks, clinical implications and treatment strategies for CIA. Focusing on TAM, we speculate on the potential intended and unintended effects that therapeutic options for CIA may have on the innate immune response and, consequently, on the course of the underlying malignancy.
Collapse
Affiliation(s)
- Stefan Weiler
- National Poisons Information Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Zurich, Switzerland.,Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Eidgenossische Technische Hochschule Zurich, Zurich, Switzerland
| | - Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| |
Collapse
|
|
35
|
Raichoudhury R, Spinowitz BS. Treatment of anemia in difficult-to-manage patients with chronic kidney disease. Kidney Int Suppl (2011) 2021; 11:26-34. [PMID: 33777493 DOI: 10.1016/j.kisu.2020.12.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/17/2020] [Accepted: 12/29/2020] [Indexed: 12/14/2022] Open
Abstract
The management of anemia of chronic kidney disease (CKD) is often challenging. In particular, for patients with underlying inflammation, comorbid type 2 diabetes or cancer, those hospitalized, and recipients of a kidney transplant, the management of anemia may be suboptimal. Responsiveness to iron and/or erythropoiesis-stimulating agents, the mainstay of current therapy, may be reduced and the risk of adverse reactions to treatment is increased in these difficult-to-manage patients with anemia of CKD. This review discusses the unique patient and disease characteristics leading to complications and suboptimal treatment response. New treatment options in clinical development, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, may be particularly useful for difficult-to-treat patients. In clinical studies, HIF-PH inhibitors provided increased hemoglobin levels and improved iron utilization in anemic patients with non-dialysis-dependent and dialysis-dependent CKD, and preliminary data suggest that HIF-PH inhibitors may be equally effective in patients with or without underlying inflammation. The availability of new treatment options, including HIF-PH inhibitors, may improve treatment outcomes in difficult-to-manage patients with anemia of CKD.
Collapse
Affiliation(s)
- Ritesh Raichoudhury
- Division of Nephrology, Department of Medicine, NewYork-Presbyterian Queens, New York, New York, USA
| | - Bruce S Spinowitz
- Division of Nephrology, Department of Medicine, NewYork-Presbyterian Queens, New York, New York, USA
| |
Collapse
|
|
36
|
Gipson GR, Goebel EJ, Hart KN, Kappes EC, Kattamuri C, McCoy JC, Thompson TB. Structural perspective of BMP ligands and signaling. Bone 2020; 140:115549. [PMID: 32730927 PMCID: PMC7502536 DOI: 10.1016/j.bone.2020.115549] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 06/30/2020] [Accepted: 07/03/2020] [Indexed: 12/13/2022]
Abstract
The Bone Morphogenetic Proteins (BMPs) are the largest class signaling molecules within the greater Transforming Growth Factor Beta (TGFβ) family, and are responsible for a wide array of biological functions, including dorsal-ventral patterning, skeletal development and maintenance, as well as cell homeostasis. As such, dysregulation of BMPs results in a number of diseases, including fibrodysplasia ossificans progressiva (FOP) and pulmonary arterial hypertension (PAH). Therefore, understanding BMP signaling and regulation at the molecular level is essential for targeted therapeutic intervention. This review discusses the recent advances in the structural and biochemical characterization of BMPs, from canonical ligand-receptor interactions to co-receptors and antagonists. This work aims to highlight how BMPs differ from other members of the TGFβ family, and how that information can be used to further advance the field. Lastly, this review discusses several gaps in the current understanding of BMP structures, with the aim that discussion of these gaps will lead to advancements in the field.
Collapse
Affiliation(s)
- Gregory R Gipson
- Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Medical Sciences Building, Cincinnati, OH 45267, USA
| | - Erich J Goebel
- Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Medical Sciences Building, Cincinnati, OH 45267, USA
| | - Kaitlin N Hart
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Medical Sciences Building, Cincinnati, OH 45267, USA
| | - Emily C Kappes
- Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Medical Sciences Building, Cincinnati, OH 45267, USA
| | - Chandramohan Kattamuri
- Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Medical Sciences Building, Cincinnati, OH 45267, USA
| | - Jason C McCoy
- Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Medical Sciences Building, Cincinnati, OH 45267, USA
| | - Thomas B Thompson
- Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Medical Sciences Building, Cincinnati, OH 45267, USA.
| |
Collapse
|
|
37
|
Martinez-Hackert E, Sundan A, Holien T. Receptor binding competition: A paradigm for regulating TGF-β family action. Cytokine Growth Factor Rev 2020; 57:39-54. [PMID: 33087301 DOI: 10.1016/j.cytogfr.2020.09.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023]
Abstract
The transforming growth factor (TGF)-β family is a group of structurally related, multifunctional growth factors, or ligands that are crucially involved in the development, regulation, and maintenance of animal tissues. In humans, the family counts over 33 members. These secreted ligands typically form multimeric complexes with two type I and two type II receptors to activate one of two distinct signal transduction branches. A striking feature of the family is its promiscuity, i.e., many ligands bind the same receptors and compete with each other for binding to these receptors. Although several explanations for this feature have been considered, its functional significance has remained puzzling. However, several recent reports have promoted the idea that ligand-receptor binding promiscuity and competition are critical features of the TGF-β family that provide an essential regulating function. Namely, they allow a cell to read and process multi-ligand inputs. This capability may be necessary for producing subtle, distinctive, or adaptive responses and, possibly, for facilitating developmental plasticity. Here, we review the molecular basis for ligand competition, with emphasis on molecular structures and binding affinities. We give an overview of methods that were used to establish experimentally ligand competition. Finally, we discuss how the concept of ligand competition may be fundamentally tied to human physiology, disease, and therapy.
Collapse
Affiliation(s)
- Erik Martinez-Hackert
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA.
| | - Anders Sundan
- Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, 7491, Trondheim, Norway; Centre of Molecular Inflammation Research (CEMIR), Norwegian University of Science and Technology, 7491, Trondheim, Norway
| | - Toril Holien
- Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, 7491, Trondheim, Norway; Department of Hematology, St. Olav's University Hospital, 7030, Trondheim, Norway.
| |
Collapse
|
|
38
|
Nairz M, Weiss G. Iron in infection and immunity. Mol Aspects Med 2020; 75:100864. [PMID: 32461004 DOI: 10.1016/j.mam.2020.100864] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 04/25/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022]
Abstract
Iron is an essential micronutrient for virtually all living cells. In infectious diseases, both invading pathogens and mammalian cells including those of the immune system require iron to sustain their function, metabolism and proliferation. On the one hand, microbial iron uptake is linked to the virulence of most human pathogens. On the other hand, the sequestration of iron from bacteria and other microorganisms is an efficient strategy of host defense in line with the principles of 'nutritional immunity'. In an acute infection, host-driven iron withdrawal inhibits the growth of pathogens. Chronic immune activation due to persistent infection, autoimmune disease or malignancy however, sequesters iron not only from infectious agents, autoreactive lymphocytes and neoplastic cells but also from erythroid progenitors. This is one of the key mechanisms which collectively result in the anemia of chronic inflammation. In this review, we highlight the most important interconnections between iron metabolism and immunity, focusing on host defense against relevant infections and on the clinical consequences of anemia of inflammation.
Collapse
Affiliation(s)
- Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria; Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Austria.
| |
Collapse
|
|
39
|
Xiao X, Alfaro-Magallanes VM, Babitt JL. Bone morphogenic proteins in iron homeostasis. Bone 2020; 138:115495. [PMID: 32585319 PMCID: PMC7453787 DOI: 10.1016/j.bone.2020.115495] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/12/2020] [Accepted: 06/15/2020] [Indexed: 02/07/2023]
Abstract
The bone morphogenetic protein (BMP)-SMAD signaling pathway plays a central role in regulating hepcidin, which is the master hormone governing systemic iron homeostasis. Hepcidin is produced by the liver and acts on the iron exporter ferroportin to control iron absorption from the diet and iron release from body stores, thereby providing adequate iron for red blood cell production, while limiting the toxic effects of excess iron. BMP6 and BMP2 ligands produced by liver endothelial cells bind to BMP receptors and the coreceptor hemojuvelin (HJV) on hepatocytes to activate SMAD1/5/8 signaling, which directly upregulates hepcidin transcription. Most major signals that influence hepcidin production, including iron, erythropoietic drive, and inflammation, intersect with the BMP-SMAD pathway to regulate hepcidin transcription. Mutation or inactivation of BMP ligands, BMP receptors, HJV, SMADs or other proteins that modulate the BMP-SMAD pathway result in hepcidin dysregulation, leading to iron-related disorders, such as hemochromatosis and iron refractory iron deficiency anemia. Pharmacologic modulators of the BMP-SMAD pathway have shown efficacy in pre-clinical models to regulate hepcidin expression and treat iron-related disorders. This review will discuss recent insights into the role of the BMP-SMAD pathway in regulating hepcidin to control systemic iron homeostasis.
Collapse
Affiliation(s)
- Xia Xiao
- Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Víctor M Alfaro-Magallanes
- Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; LFE Research Group, Department of Health and Human Performance, Faculty of Physical Activity and Sport Sciences, Universidad Politécnica de Madrid (UPM), Madrid, Spain
| | - Jodie L Babitt
- Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
40
|
Rajamanickam K, Leela V, Suganya G, Basha SH, Parthiban M, Pazhanivel N, Mangala Gowri A. Expression of iron regulatory proteins in full-term swine placenta. Reprod Domest Anim 2020; 55:931-942. [PMID: 32449967 DOI: 10.1111/rda.13730] [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: 03/29/2020] [Revised: 05/16/2020] [Accepted: 05/17/2020] [Indexed: 11/29/2022]
Abstract
In swine, even though the pregnant sows were with iron abundance, the inborn iron reserve of piglets was compromised. This indicates the insufficiency of molecular machinery involved in local placental iron flux. Here, we investigated the expression of iron regulatory proteins like hepcidin and ferroportin and also their association with iron reserve, inflammation and oxidative stress in placenta of full-term pregnant sows (n = 6). Amplification and sequencing of placental DNA confirmed the presence of hepcidin (MN579557) and ferroportin (MN565887) sequences and their 100% identity with existing GenBank data. Real-time amplification of placental mRNA revealed significant higher expression of hepcidin (p < .05) than ferroportin. Western blot analysis of placental tissues revealed specific bands for both hepcidin (~8 kDa) and ferroportin (~62 kDa) molecules. Immunohistochemistry revealed the immunoreactivity for both proteins in the cytoplasm and membrane of trophoblastic cells of the placenta. Hepcidin and ferroportin expressions were positively associated with placental non-haem iron reserve (p < .0001; p = .033), lipid peroxidation (p = .0060; p < .0001) and reactive oxygen species level (p = .0092; p = .0292). Hepcidin expression was positively associated with interleukin - 6 (p = .0002) and interferon gamma (p < .0001) expressions but ferroportin expression was negatively associated with interleukin-6 (p = .0005), interleukin-1β (p = .0226) and interferon gamma (p = .0059) expressions. This indicates hepcidin and ferroportin may have a role in controlling the local placental iron flux by acting as a molecular bridge between iron trafficking and inflammation.
Collapse
Affiliation(s)
- Kandasamy Rajamanickam
- Department of Veterinary Physiology, Madras Veterinary College, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India
| | - Venkatasubramanian Leela
- Department of Veterinary Physiology, Madras Veterinary College, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India
| | - Gopalakrishnan Suganya
- Department of Veterinary Physiology, Madras Veterinary College, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India
| | - Sabiha Hayath Basha
- Centre for Stem Cell Research and Regenerative Medicine, Madras Veterinary College, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India
| | - Manoharan Parthiban
- Department of Animal Biotechnology, Madras Veterinary College, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India
| | - Natesan Pazhanivel
- Department of Veterinary Pathology, Madras Veterinary College, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India
| | - Angappan Mangala Gowri
- Centre for Stem Cell Research and Regenerative Medicine, Madras Veterinary College, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India
| |
Collapse
|
|
41
|
Olsen OE, Hella H, Elsaadi S, Jacobi C, Martinez-Hackert E, Holien T. Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors. Biomolecules 2020; 10:biom10040519. [PMID: 32235336 PMCID: PMC7225989 DOI: 10.3390/biom10040519] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/25/2020] [Accepted: 03/27/2020] [Indexed: 12/17/2022] Open
Abstract
Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2, causing activation of the SMAD1/5/8 pathway. In this study, we aimed to dissect how activin A and activin B homodimers, and activin AB and AC heterodimers activate the two main SMAD branches. We compared the activin-induced signaling dynamics of ALK4/7-SMAD2/3 and ALK2-SMAD1/5 in a multiple myeloma cell line. Signaling via the ALK2-SMAD1/5 pathway exhibited greater differences between ligands than signaling via ALK4/ALK7-SMAD2/3. Interestingly, activin B and activin AB very potently activated SMAD1/5, resembling the activation commonly seen with BMPs. As SMAD1/5 was also activated by activins in other cell types, we propose that dual specificity is a general mechanism for activin ligands. In addition, we found that the antagonist follistatin inhibited signaling by all the tested activins, whereas the antagonist cerberus specifically inhibited activin B. Taken together, we propose that activins may be considered dual specificity TGF-β family members, critically affecting how activins may be considered and targeted clinically.
Collapse
Affiliation(s)
- Oddrun Elise Olsen
- Department of Clinical and Molecular Medicine, NTNU – Norwegian University of Science and Technology, 7491 Trondheim, Norway
- Department of Hematology, St. Olav’s University Hospital, 7030 Trondheim, Norway
| | - Hanne Hella
- Department of Clinical and Molecular Medicine, NTNU – Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Samah Elsaadi
- Department of Clinical and Molecular Medicine, NTNU – Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Carsten Jacobi
- Novartis Institutes for BioMedical Research Basel, Musculoskeletal Disease Area, Novartis Pharma AG, CH-4056 Basel, Switzerland
| | - Erik Martinez-Hackert
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
| | - Toril Holien
- Department of Clinical and Molecular Medicine, NTNU – Norwegian University of Science and Technology, 7491 Trondheim, Norway
- Department of Hematology, St. Olav’s University Hospital, 7030 Trondheim, Norway
- Correspondence: ; Tel.: +47-924-21-162
| |
Collapse
|
|
42
|
Wang CY, Xiao X, Bayer A, Xu Y, Dev S, Canali S, Nair AV, Masia R, Babitt JL. Ablation of Hepatocyte Smad1, Smad5, and Smad8 Causes Severe Tissue Iron Loading and Liver Fibrosis in Mice. Hepatology 2019; 70:1986-2002. [PMID: 31127639 PMCID: PMC6874904 DOI: 10.1002/hep.30780] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 05/17/2019] [Indexed: 12/15/2022]
Abstract
A failure of iron to appropriately regulate liver hepcidin production is central to the pathogenesis of hereditary hemochromatosis. SMAD1/5 transcription factors, activated by bone morphogenetic protein (BMP) signaling, are major regulators of hepcidin production in response to iron; however, the role of SMAD8 and the contribution of SMADs to hepcidin production by other systemic cues remain uncertain. Here, we generated hepatocyte Smad8 single (Smad8fl/fl ;Alb-Cre+ ), Smad1/5/8 triple (Smad158;Alb-Cre+ ), and littermate Smad1/5 double (Smad15;Alb-Cre+ ) knockout mice to investigate the role of SMAD8 in hepcidin and iron homeostasis regulation and liver injury. We found that Smad8;Alb-Cre+ mice exhibited no iron phenotype, whereas Smad158;Alb-Cre+ mice had greater iron overload than Smad15;Alb-Cre+ mice. In contrast to the sexual dimorphism reported for wild-type mice and other hemochromatosis models, hepcidin deficiency and extrahepatic iron loading were similarly severe in Smad15;Alb-Cre+ and Smad158;Alb-Cre+ female compared with male mice. Moreover, epidermal growth factor (EGF) failed to suppress hepcidin in Smad15;Alb-Cre+ hepatocytes. Conversely, hepcidin was still increased by lipopolysaccharide in Smad158;Alb-Cre+ mice, although lower basal hepcidin resulted in lower maximal hepcidin. Finally, unlike most mouse hemochromatosis models, Smad158;Alb-Cre+ developed liver injury and fibrosis at 8 weeks. Liver injury and fibrosis were prevented in Smad158;Alb-Cre+ mice by a low-iron diet and were minimal in iron-loaded Cre- mice. Conclusion: Hepatocyte Smad1/5/8 knockout mice are a model of hemochromatosis that encompasses liver injury and fibrosis seen in human disease. These mice reveal the redundant but critical role of SMAD8 in hepcidin and iron homeostasis regulation, establish a requirement for SMAD1/5/8 in hepcidin regulation by testosterone and EGF but not inflammation, and suggest a pathogenic role for both iron loading and SMAD1/5/8 deficiency in liver injury and fibrosis.
Collapse
Affiliation(s)
- Chia-Yu Wang
- Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology,Address correspondence to: Chia-Yu Wang, Massachusetts General Hospital, 185 Cambridge St., CPZN-8150, Boston, MA 02114, Phone: (617)-724-9078, Fax: (617)-643-3182,
| | - Xia Xiao
- Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology
| | - Abraham Bayer
- Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology
| | - Yang Xu
- Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology
| | - Som Dev
- Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology
| | - Susanna Canali
- Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology
| | - Anil V. Nair
- Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology
| | - Ricard Masia
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Jodie L. Babitt
- Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology
| |
Collapse
|
|
43
|
Hawula ZJ, Wallace DF, Subramaniam VN, Rishi G. Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis. Pharmaceuticals (Basel) 2019; 12:ph12040170. [PMID: 31775259 PMCID: PMC6958404 DOI: 10.3390/ph12040170] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/15/2019] [Accepted: 11/19/2019] [Indexed: 12/15/2022] Open
Abstract
The interaction between hepcidin and ferroportin is the key mechanism involved in regulation of systemic iron homeostasis. This axis can be affected by multiple stimuli including plasma iron levels, inflammation and erythropoietic demand. Genetic defects or prolonged inflammatory stimuli results in dysregulation of this axis, which can lead to several disorders including hereditary hemochromatosis and anaemia of chronic disease. An imbalance in iron homeostasis is increasingly being associated with worse disease outcomes in many clinical conditions including multiple cancers and neurological disorders. Currently, there are limited treatment options for regulating iron levels in patients and thus significant efforts are being made to uncover approaches to regulate hepcidin and ferroportin expression. These approaches either target these molecules directly or regulatory steps which mediate hepcidin or ferroportin expression. This review examines the current status of hepcidin and ferroportin agonists and antagonists, as well as inducers and inhibitors of these proteins and their regulatory pathways.
Collapse
Affiliation(s)
- Zachary J. Hawula
- Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia; (Z.J.H.); (D.F.W.)
- School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia
| | - Daniel F. Wallace
- Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia; (Z.J.H.); (D.F.W.)
- School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia
| | - V. Nathan Subramaniam
- Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia; (Z.J.H.); (D.F.W.)
- School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia
- Correspondence: (V.N.S.); (G.R.)
| | - Gautam Rishi
- Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia; (Z.J.H.); (D.F.W.)
- School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland 4059, Australia
- Correspondence: (V.N.S.); (G.R.)
| |
Collapse
|
|
44
|
Moradi-Marjaneh R, Khazaei M, Ferns GA, Aghaee-Bakhtiari SH. The Role of TGF-β Signaling Regulatory MicroRNAs in the Pathogenesis of Colorectal Cancer. Curr Pharm Des 2019; 24:4611-4618. [PMID: 30636580 DOI: 10.2174/1381612825666190110150705] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/24/2018] [Accepted: 12/31/2018] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is one of the most common cancers globally and is associated with a high mortality rate. The transforming growth factor beta (TGF-β) signaling pathway plays an important role in normal intestinal tissue function, but has also been implicated in the development of CRC. MicroRNAs (miRNAs) have also recently emerged as important regulators of cancer development and progression. They act by targeting multiple signaling pathways including the TGF-β signaling pathway. There is growing evidence demonstrating that miRNAs target various components of the TGF-β signaling pathway, including TGF-β1, TGF-β2, regulatory SMADs (SMAD1, 2, 3, 5 and 9), co-mediator SMAD4, inhibitory SMADs (SMAD6 and 7) and the TGF-β receptors, and thereby alter the proliferation and migration of CRC cells. In this review, we summarize the data concerning the interaction between TGF-β signaling pathway and miRNAs with the aim to better understanding the CRC molecular mechanisms and hence better management of this disease.
Collapse
Affiliation(s)
- Reyhaneh Moradi-Marjaneh
- Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran.,Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
| | - Seyed H Aghaee-Bakhtiari
- Bioinformatics Research Group, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
45
|
Abstract
Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element-iron regulatory protein (IRE-IRP) system. In the kidney, iron transport mechanisms independent of the IRE-IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.
Collapse
|
|
46
|
Daher R, Lefebvre T, Puy H, Karim Z. Extrahepatic hepcidin production: The intriguing outcomes of recent years. World J Clin Cases 2019; 7:1926-1936. [PMID: 31423425 PMCID: PMC6695539 DOI: 10.12998/wjcc.v7.i15.1926] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/18/2019] [Accepted: 06/27/2019] [Indexed: 02/05/2023] Open
Abstract
Hepcidin is the hyposideremic hormone regulating iron metabolism. It is a defensin-like disulfide-bonded peptide with antimicrobial activity. The main site of hepcidin production is the liver where its synthesis is modulated by iron, inflammation and erythropoietic signaling. However, hepcidin locally produced in several peripheral organs seems to be an important actor for the maintenance of iron homeostasis in these organs. This review highlights the presence of peripheral hepcidin and its potential functions. Understanding the role of extrahepatic hepcidin could be of great physiological and therapeutic importance for several specific pathologies.
Collapse
Affiliation(s)
- Raêd Daher
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Thibaud Lefebvre
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Hervé Puy
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Zoubida Karim
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| |
Collapse
|
|
47
|
Rethinking ME/CFS Diagnostic Reference Intervals via Machine Learning, and the Utility of Activin B for Defining Symptom Severity. Diagnostics (Basel) 2019; 9:diagnostics9030079. [PMID: 31331036 PMCID: PMC6787626 DOI: 10.3390/diagnostics9030079] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/09/2019] [Accepted: 07/15/2019] [Indexed: 12/17/2022] Open
Abstract
Biomarker discovery applied to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling disease of inconclusive aetiology, has identified several cytokines to potentially fulfil a role as a quantitative blood/serum marker for laboratory diagnosis, with activin B a recent addition. We explored further the potential of serum activin B as a ME/CFS biomarker, alone and in combination with a range of routine test results obtained from pathology laboratories. Previous pilot study results showed that activin B was significantly elevated for the ME/CFS participants compared to healthy (control) participants. All the participants were recruited via CFS Discovery and assessed via the Canadian/International Consensus Criteria. A significant difference for serum activin B was also detected for ME/CFS and control cohorts recruited for this study, but median levels were significantly lower for the ME/CFS cohort. Random Forest (RF) modelling identified five routine pathology blood test markers that collectively predicted ME/CFS at ≥62% when compared via weighted standing time (WST) severity classes. A closer analysis revealed that the inclusion of activin B to the panel of pathology markers improved the prediction of mild to moderate ME/CFS cases. Applying correct WST class prediction from RFA modelling, new reference intervals were calculated for activin B and associated pathology markers, where 24-h urinary creatinine clearance, serum urea and serum activin B showed the best potential as diagnostic markers. While the serum activin B results remained statistically significant for the new participant cohorts, activin B was found to also have utility in enhancing the prediction of symptom severity, as represented by WST class.
Collapse
|
|
48
|
Armitage AE, Moretti D. The Importance of Iron Status for Young Children in Low- and Middle-Income Countries: A Narrative Review. Pharmaceuticals (Basel) 2019; 12:E59. [PMID: 30995720 PMCID: PMC6631790 DOI: 10.3390/ph12020059] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 04/09/2019] [Accepted: 04/12/2019] [Indexed: 12/21/2022] Open
Abstract
Early childhood is characterised by high physiological iron demand to support processes including blood volume expansion, brain development and tissue growth. Iron is also required for other essential functions including the generation of effective immune responses. Adequate iron status is therefore a prerequisite for optimal child development, yet nutritional iron deficiency and inflammation-related iron restriction are widespread amongst young children in low- and middle-income countries (LMICs), meaning iron demands are frequently not met. Consequently, therapeutic iron interventions are commonly recommended. However, iron also influences infection pathogenesis: iron deficiency reduces the risk of malaria, while therapeutic iron may increase susceptibility to malaria, respiratory and gastrointestinal infections, besides reshaping the intestinal microbiome. This means caution should be employed in administering iron interventions to young children in LMIC settings with high infection burdens. In this narrative review, we first examine demand and supply of iron during early childhood, in relation to the molecular understanding of systemic iron control. We then evaluate the importance of iron for distinct aspects of physiology and development, particularly focusing on young LMIC children. We finally discuss the implications and potential for interventions aimed at improving iron status whilst minimising infection-related risks in such settings. Optimal iron intervention strategies will likely need to be individually or setting-specifically adapted according to iron deficiency, inflammation status and infection risk, while maximising iron bioavailability and considering the trade-offs between benefits and risks for different aspects of physiology. The effectiveness of alternative approaches not centred around nutritional iron interventions for children should also be thoroughly evaluated: these include direct targeting of common causes of infection/inflammation, and maternal iron administration during pregnancy.
Collapse
Affiliation(s)
- Andrew E Armitage
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
| | - Diego Moretti
- Laboratory of Human Nutrition, Institute of Food Nutrition and Health, Department of Health Sciences and Technology, ETH Zürich, CH-8092 Zürich, Switzerland.
- Nutrition Group, Health Department, Swiss Distance University of Applied Sciences, CH-8105 Regensdorf, Switzerland.
| |
Collapse
|
|
49
|
van Vuren AJ, Gaillard CAJM, Eisenga MF, van Wijk R, van Beers EJ. The EPO-FGF23 Signaling Pathway in Erythroid Progenitor Cells: Opening a New Area of Research. Front Physiol 2019; 10:304. [PMID: 30971944 PMCID: PMC6443968 DOI: 10.3389/fphys.2019.00304] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 03/07/2019] [Indexed: 12/14/2022] Open
Abstract
We provide an overview of the evidence for an erythropoietin-fibroblast growth factor 23 (FGF23) signaling pathway directly influencing erythroid cells in the bone marrow. We outline its importance for red blood cell production, which might add, among others, to the understanding of bone marrow responses to endogenous erythropoietin in rare hereditary anemias. FGF23 is a hormone that is mainly known as the core regulator of phosphate and vitamin D metabolism and it has been recognized as an important regulator of bone mineralization. Osseous tissue has been regarded as the major source of FGF23. Interestingly, erythroid progenitor cells highly express FGF23 protein and carry the FGF receptor. This implies that erythroid progenitor cells could be a prime target in FGF23 biology. FGF23 is formed as an intact, biologically active protein (iFGF23) and proteolytic cleavage results in the formation of the presumed inactive C-terminal tail of FGF23 (cFGF23). FGF23-knockout or injection of an iFGF23 blocking peptide in mice results in increased erythropoiesis, reduced erythroid cell apoptosis and elevated renal and bone marrow erythropoietin mRNA expression with increased levels of circulating erythropoietin. By competitive inhibition, a relative increase in cFGF23 compared to iFGF23 results in reduced FGF23 receptor signaling and mimics the positive effects of FGF23-knockout or iFGF23 blocking peptide. Injection of recombinant erythropoietin increases FGF23 mRNA expression in the bone marrow with a concomitant increase in circulating FGF23 protein. However, erythropoietin also augments iFGF23 cleavage, thereby decreasing the iFGF23 to cFGF23 ratio. Therefore, the net result of erythropoietin is a reduction of iFGF23 to cFGF23 ratio, which inhibits the effects of iFGF23 on erythropoiesis and erythropoietin production. Elucidation of the EPO-FGF23 signaling pathway and its downstream signaling in hereditary anemias with chronic hemolysis or ineffective erythropoiesis adds to the understanding of the pathophysiology of these diseases and its complications; in addition, it provides promising new targets for treatment downstream of erythropoietin in the signaling cascade.
Collapse
Affiliation(s)
- Annelies J van Vuren
- Van Creveldkliniek, Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Carlo A J M Gaillard
- Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Michele F Eisenga
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Richard van Wijk
- Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Eduard J van Beers
- Van Creveldkliniek, Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| |
Collapse
|
|
50
|
Asperti M, Denardo A, Gryzik M, Arosio P, Poli M. The role of heparin, heparanase and heparan sulfates in hepcidin regulation. VITAMINS AND HORMONES 2019; 110:157-188. [PMID: 30798810 DOI: 10.1016/bs.vh.2019.01.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepcidin is considered the major regulator of systemic iron homeostasis in human and mice, and its expression in the liver is mainly regulated at a transcriptional level. Central to its regulation are the bone morphogenetic proteins, particularly BMP6, that are heparin binding proteins. Heparin was found to inhibit hepcidin expression and BMP6 activity in hepatic cell lines and in mice, suggesting that endogenous heparan sulfates are involved in the pathway of hepcidin expression. This was confirmed by the study of cells and mice overexpressing heparanase, the enzyme that hydrolyzes heparan sulfates, and by cellular models with altered heparan sulfates. The evidences supporting the role of heparan sulfate in hepcidin expression are summarized in this chapter and open the way for new understanding in hepcidin expression and its control in pathological condition.
Collapse
Affiliation(s)
- Michela Asperti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Andrea Denardo
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Magdalena Gryzik
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Paolo Arosio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
| | - Maura Poli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| |
Collapse
|