Low anticoagulant heparin-iron complex targeting inhibition of hepcidin ameliorates anemia of chronic disease in rodents

Liuxiang, Li; Wang, Xiaoxue; Zhang, Hongyu; Chen, Qingqing; Cui, Hui-Fei

doi:10.1016/j.ejphar.2021.173958

Cited by 7 publications

(3 citation statements)

References 33 publications

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“…Modified over-sulfated (SSLMWH-1) or glycol-split heparins (RO-82) as well as the heparinoid pentosan polysulfate (PPS) exert a similar inhibition of hepcidin expression with iron redistribution concomitant to a reduced anticoagulant activity in vitro and in vivo in mice thus depicting a good alternative [312][313][314]. Recently, a low anticoagulant heparin-iron complex was shown to inhibit hepcidin expression and ameliorate AI in mice as well [315], however, it could not inhibit hepcidin formation upon bacterial infection in mice which was also true for dorsomorphin [316]. Interestingly, loss of BMP6 or HJV represses SMAD related HAMP expression in the liver thus causing increased extrahepatic iron loading [317].…”

Section: Modifying Hepcidin Synthetisation By Targeting the Bmp/smad Pathwaymentioning

confidence: 99%

Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis—Mechanistic Insights into Anemia of Inflammation and Its Treatment

et al. 2021

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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.

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Section: Modifying Hepcidin Synthetisation By Targeting the Bmp/smad Pathwaymentioning

confidence: 99%

Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis—Mechanistic Insights into Anemia of Inflammation and Its Treatment

et al. 2021

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“…Oxidative stress was induced by H 2 O 2 treatment for 10 h in ADSCs to test the survival under stress. As STAT3 plays a central role for the regulation of cell growth, differentiation, and survival, and can be activated via tyrosine kinase receptors [ 24 ], we detected p–STAT3 expression through Western blotting. The results demonstrated that the expression of p–STAT3/STAT3 was significantly elevated in AC–ADSCs, regardless of whether they were stimulated with H 2 O 2 .…”

Section: Resultsmentioning

confidence: 99%

dCas9-Based PDGFR–β Activation ADSCs Accelerate Wound Healing in Diabetic Mice through Angiogenesis and ECM Remodeling

You

et al. 2023

IJMS

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The chronic wound represents a serious disease characterized by a failure to heal damaged skin and surrounding soft tissue. Mesenchymal stem cells (MSCs) derived from adipose tissue (ADSCs) are a promising therapeutic strategy, but their heterogeneity may result in varying or insufficient therapeutic capabilities. In this study, we discovered that all ADSCs populations expressed platelet–derived growth factor receptor β (PDGFR–β), while the expression level decreased dynamically with passages. Thus, using a CRISPRa–based system, we endogenously overexpressed PDGFR–β in ADSCs. Moreover, a series of in vivo and in vitro experiments were conducted to determine the functional changes in PDGFR–β activation ADSCs (AC–ADSCs) and to investigate the underlying mechanisms. With the activation of PDGFR–β, AC–ADSCs exhibited enhanced migration, survival, and paracrine capacity relative to control ADSCs (CON–ADSCs). In addition, the secretion components of AC–ADSCs contained more pro–angiogenic factors and extracellular matrix–associated molecules, which promoted the function of endothelial cells (ECs) in vitro. Additionally, in in vivo transplantation experiments, the AC–ADSCs transplantation group demonstrated improved wound healing rates, stronger collagen deposition, and angiogenesis. Consequently, our findings revealed that PDGFR–β overexpression enhanced the migration, survival, and paracrine capacity of ADSCs and improved therapeutic effects after transplantation to diabetic mice.

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“…Another crucial point that makes hepcidin antagonization far from simple is represented by the substantial complexity of molecular regulation of hepcidin production ( 92 , 93 ). Many strategies alternative to direct hepcidin neutralization have been reported, including antagonists of the bone morphogenetic protein 6 (BMP6) pathway with heparin derivatives ( 94 – 97 ), anti-BMP6 antibodies ( 98 ), dorsomorphin ( 99 ), and ferroportin stabilizers ( 100 , 101 ). Further drugs that modulate the hepcidin-ferroportin axis include anti-hemojuvelin (HJV) antibodies (currently under evaluation in two clinical trials NCT05745883 and NCT05320198), and momelotinib.…”

Section: Therapeutic Options For Cancer-chemotherapy-related Anemiamentioning

confidence: 99%

Anemia in patients receiving anticancer treatments: focus on novel therapeutic approaches

Bozzini,

Busti,

Marchi

et al. 2024

Front. Oncol.

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Anemia is common in cancer patients and impacts on quality of life and prognosis. It is typically multifactorial, often involving different pathophysiological mechanisms, making treatment a difficult task. In patients undergoing active anticancer treatments like chemotherapy, decreased red blood cell (RBC) production due to myelosuppression generally predominates, but absolute or functional iron deficiency frequently coexists. Current treatments for chemotherapy-related anemia include blood transfusions, erythropoiesis-stimulating agents, and iron supplementation. Each option has limitations, and there is an urgent need for novel approaches. After decades of relative immobilism, several promising anti-anemic drugs are now entering the clinical scenario. Emerging novel classes of anti-anemic drugs recently introduced or in development for other types of anemia include activin receptor ligand traps, hypoxia-inducible factor-prolyl hydroxylase inhibitors, and hepcidin antagonists. Here, we discuss their possible role in the treatment of anemia observed in patients receiving anticancer therapies.

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Low anticoagulant heparin-iron complex targeting inhibition of hepcidin ameliorates anemia of chronic disease in rodents

Cited by 7 publications

References 33 publications

Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis—Mechanistic Insights into Anemia of Inflammation and Its Treatment

Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis—Mechanistic Insights into Anemia of Inflammation and Its Treatment

dCas9-Based PDGFR–β Activation ADSCs Accelerate Wound Healing in Diabetic Mice through Angiogenesis and ECM Remodeling

Anemia in patients receiving anticancer treatments: focus on novel therapeutic approaches

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