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Article ; Online: Beyond hematopoietic targets: the role of erythropoietin in diabetic wound healing.

Hamed, Saher

2011 Volume 5, Issue 3, Page(s) 365–367

MeSH term(s)	Administration, Topical ; Diabetes Complications/drug therapy ; Erythropoietin/physiology ; Erythropoietin/therapeutic use ; Humans ; Skin/injuries ; Wound Healing/drug effects ; Wounds and Injuries/drug therapy ; Wounds and Injuries/etiology
Chemical Substances	Erythropoietin (11096-26-7)
Language	English
Publishing date	2011-06
Publishing country	England
Document type	Editorial
ZDB-ID	2481014-9
ISSN	1752-0371 ; 1752-0363
ISSN (online)	1752-0371
ISSN	1752-0363
DOI	10.2217/bmm.11.30
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Article: Interim Results of the Remede d'Or Study: A Multicenter, Single-Blind, Randomized, Controlled Trial to Assess the Safety and Efficacy of an Innovative Topical Formulation of Erythropoietin for Treating Diabetic Foot Ulcers.

Hamed, Saher / Belokopytov, Mark / Ullmann, Yehuda / Safadi, Muhammad / Stark, Yafit / Shoufani, Aziz / Akita, Sadanori / Liu, Paul Y / Teot, Luc

Advances in wound care

2019 Volume 8, Issue 10, Page(s) 514–521

Abstract: Objective: ...

Abstract	Objective:
Language	English
Publishing date	2019-08-21
Publishing country	United States
Document type	News
ZDB-ID	2650541-1
ISSN	2162-1934 ; 2162-1918
ISSN (online)	2162-1934
ISSN	2162-1918
DOI	10.1089/wound.2018.0808
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Article ; Online: Topical Erythropoietin Accelerates Wound Closure in Patients with Diabetic Foot Ulcers: A Prospective, Multicenter, Single-Blind, Randomized, Controlled Trial.

Hamed, Saher / Ullmann, Yehuda / Belokopytov, Mark / Shoufani, Aziz / Kabha, Hoda / Masri, Suher / Feldbrin, Zeev / Kogan, Leonid / Kruchevsky, Danny / Najjar, Roger / Liu, Paul Y / Kerihuel, Jean-Charles / Akita, Sadanori / Teot, Luc

Rejuvenation research

2021 Volume 24, Issue 4, Page(s) 251–261

Abstract: The diabetic foot ulcer (DFU) is a major disabling complication of diabetes mellitus. Growing evidence suggests that topical erythropoietin (EPO) can promote wound healing. The aim of this study is to clinically assess the efficacy of a proprietary ... ...

Abstract	The diabetic foot ulcer (DFU) is a major disabling complication of diabetes mellitus. Growing evidence suggests that topical erythropoietin (EPO) can promote wound healing. The aim of this study is to clinically assess the efficacy of a proprietary topical EPO-containing hydrogel for treating DFUs. We conducted a randomized, controlled trial in 20 patients with DFUs. After a 14-day screening period, the DFUs of 20 eligible participants who fulfilled the inclusion criteria were randomly assigned (1:1) to either a 12-week of daily treatment with topical EPO and standard-of-care (SOC) or SOC treatment alone. The DFUs were assessed weekly until week 12. The primary outcome was 75% ulcer closure or higher. After 12 weeks of treatment, 75% ulcer closure was achieved in 6 of the 10 patients whose DFUs were treated with topical EPO and in one of the 8 patients whose DFUs were treated with SOC alone. The mean area of the DFUs that were treated with topical EPO and SOC was significantly smaller than those treated with SOC alone (1.2 ± 1.4 cm
MeSH term(s)	Diabetes Mellitus ; Diabetic Foot/drug therapy ; Erythropoietin/therapeutic use ; Humans ; Prospective Studies ; Single-Blind Method ; Treatment Outcome ; Wound Healing
Chemical Substances	Erythropoietin (11096-26-7)
Language	English
Publishing date	2021-04-01
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Randomized Controlled Trial
ZDB-ID	2150779-X
ISSN	1557-8577 ; 1549-1684
ISSN (online)	1557-8577
ISSN	1549-1684
DOI	10.1089/rej.2020.2397
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Article ; Online: Nitric oxide: a key factor behind the dysfunctionality of endothelial progenitor cells in diabetes mellitus type-2.

Hamed, Saher / Brenner, Benjamin / Roguin, Ariel

Cardiovascular research

2011 Volume 91, Issue 1, Page(s) 9–15

Abstract: Diabetes mellitus type-2 (DM-2) contributes to atherogenesis by inducing endothelial cell injury and dysfunction. Endothelial progenitor cells (EPCs) are essential to blood vessel formation, can differentiate into mature endothelial cells, and promote ... ...

Abstract	Diabetes mellitus type-2 (DM-2) contributes to atherogenesis by inducing endothelial cell injury and dysfunction. Endothelial progenitor cells (EPCs) are essential to blood vessel formation, can differentiate into mature endothelial cells, and promote the repair of damaged endothelium. In DM-2, the circulating EPC count is low and their functionality is impaired. The mechanisms that underlie this reduced count and impaired functionality are poorly understood. Nitric oxide (NO) is a short-lived signalling molecule that is produced by vascular endothelial cells and participates in the maintenance of vascular tone. NO is also known to participate in other physiological processes, such as cell survival, proliferation, and migration. The bioavailability of NO is reduced in EPCs from DM-2 patients. Interestingly, an inverse relationship exists between the reduction in NO bioavailability in EPCs and the patient's plasma glucose and glycated haemoglobin levels. In addition, NO bioavailability in EPCs correlates with plasma oxidized low-density lipoprotein levels in DM-2. Although this reduction in NO bioavailability could be attributed to oxidative stress in DM-2 patients, it also may be due to impairment of one or more members of the protein signalling cascades that are responsible for NO production. The stimulation of NO production or its signalling cascades in EPCs may increase their numbers and improve their function, thus attenuating endothelium damage, independent of the vasodilatory effects of NO. This review summarizes the metabolic alterations that underlie the molecular mechanisms that may be responsible for EPC decrease and dysfunction in DM-2 with emphasis on the involvement of the NO system.
MeSH term(s)	Animals ; Blood Glucose/metabolism ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Diabetic Angiopathies/etiology ; Diabetic Angiopathies/metabolism ; Diabetic Angiopathies/pathology ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Glycated Hemoglobin A/metabolism ; Humans ; Lipoproteins, LDL/blood ; Nitric Oxide/metabolism ; Signal Transduction ; Stem Cells/metabolism ; Stem Cells/pathology
Chemical Substances	Blood Glucose ; Glycated Hemoglobin A ; Lipoproteins, LDL ; hemoglobin A1c protein, human ; oxidized low density lipoprotein ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2011-07-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvq412
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Zs.A 565: Show issues

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Article: [Endothelial progenitor cells and atherosclerosis].

Hamed, Saher / Roguin, Ariel

Harefuah

2006 Volume 145, Issue 5, Page(s) 358–61, 397

Abstract: The integrity and functional activity of the endothelial monolayer play a crucial role in the prevention of atherosclerosis. Extended endothelial cell damage by cardiovascular risk factors can result in endothelial cell apoptosis with loss of the ... ...

Abstract	The integrity and functional activity of the endothelial monolayer play a crucial role in the prevention of atherosclerosis. Extended endothelial cell damage by cardiovascular risk factors can result in endothelial cell apoptosis with loss of the integrity of the endothelium. Endothelial progenitor cells (EPCs) originating from the bone marrow play a significant role in neovascularization of ischemic tissues and in re-endothelialization of injured blood vessels. This may potentially limit atherosclerotic lesion formation. However, risk factors for coronary artery disease such as age and smoking, hypertension, hyperlipidemia and diabetes reduce the number and functional activity of these circulating endothelial progenitor cells, potentially restricting the therapeutic prospective of progenitor cells and limiting the regenerative capacity. The impairment of EPCs by risk factors may contribute to atherogenesis and atherosclerotic disease progression. The article reviews the role of EPCs as markers for atherosclerosis and cardiovascular outcomes and highlights possible novel strategies to interfere with the balance of injury and repair mechanisms.
MeSH term(s)	Atherosclerosis/pathology ; Atherosclerosis/therapy ; Endothelium, Vascular/pathology ; Humans ; Stem Cell Transplantation ; Stem Cells/cytology ; Stem Cells/pathology
Language	Hebrew
Publishing date	2006-05
Publishing country	Israel
Document type	English Abstract ; Journal Article ; Review
ZDB-ID	953872-0
ISSN	0017-7768
ISSN	0017-7768
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Article ; Online: Erythropoietin, a novel repurposed drug: an innovative treatment for wound healing in patients with diabetes mellitus.

Hamed, Saher / Bennett, Charles L / Demiot, Claire / Ullmann, Yehuda / Teot, Luc / Desmoulière, Alexis

Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society

2014 Volume 22, Issue 1, Page(s) 23–33

Abstract: Developing a new drug is expensive: the cost of going from bench to bedside is about $US1 billion. Therefore, the repurposing of an approved drug is potentially rewarding because it expands the drug's existing therapeutic profile and preempts additional ... ...

Abstract	Developing a new drug is expensive: the cost of going from bench to bedside is about $US1 billion. Therefore, the repurposing of an approved drug is potentially rewarding because it expands the drug's existing therapeutic profile and preempts additional development costs. As the safety profile of a repurposed drug is already well known, any new investigations could then focus on its efficacy and other therapeutic benefits. Recombinant erythropoietin (EPO) is a potential candidate for repurposing because the results of numerous studies have shown that systemic and topical EPO is therapeutically beneficial when it is administered to healthy and diabetic animals with acute and chronic skin wounds and burns. Moreover, the molecular mechanisms of EPO's actions have been elucidated: EPO acts on those nonhematopoietic cells which are involved in the innate immune response where it promotes cellular proliferation and differentiation, exerts its cytoprotective actions, and inhibits apoptosis. In this review, the mechanism of EPO's action in skin wound healing is reviewed, and its potential for treating acute and chronic skin wounds and stimulating tissue regeneration in diabetic patients is discussed.
MeSH term(s)	Administration, Topical ; Animals ; Apoptosis/drug effects ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cost-Benefit Analysis ; Diabetes Mellitus, Experimental/complications ; Diabetes Mellitus, Experimental/immunology ; Diabetes Mellitus, Experimental/pathology ; Erythropoietin/pharmacology ; Female ; Humans ; Immunity, Cellular ; Male ; Mice ; Neovascularization, Physiologic/drug effects ; Rats ; Receptors, Erythropoietin/metabolism ; Recombinant Proteins/pharmacology ; Regenerative Medicine ; Skin/injuries ; Skin/metabolism ; Wound Healing/drug effects ; Wounds and Injuries/drug therapy ; Wounds and Injuries/immunology ; Wounds and Injuries/pathology
Chemical Substances	Receptors, Erythropoietin ; Recombinant Proteins ; Erythropoietin (11096-26-7)
Language	English
Publishing date	2014-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1174873-4
ISSN	1524-475X ; 1067-1927
ISSN (online)	1524-475X
ISSN	1067-1927
DOI	10.1111/wrr.12135
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Zs.A 3890: Show issues

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Article ; Online: Red wine consumption improves in vitro migration of endothelial progenitor cells in young, healthy individuals.

Hamed, Saher / Alshiek, Jonia / Aharon, Anat / Brenner, Benjamin / Roguin, Ariel

The American journal of clinical nutrition

2010 Volume 92, Issue 1, Page(s) 161–169

Abstract: Background: Endothelial progenitor cells (EPCs) contribute to the maintenance of vascular endothelial function. The moderate consumption of red wine provides cardiovascular protection.: Objective: We investigated the underlying molecular mechanism of ...

Abstract	Background: Endothelial progenitor cells (EPCs) contribute to the maintenance of vascular endothelial function. The moderate consumption of red wine provides cardiovascular protection. Objective: We investigated the underlying molecular mechanism of EPC migration in young, healthy individuals who drank red wine. Design: Fourteen healthy volunteers consumed 250 mL red wine daily for 21 consecutive days. Vascular endothelial function, plasma stromal cell-derived factor 1alpha (SDF1alpha) concentrations, and the number, migration, and nitric oxide production of EPCs were determined before and after the daily consumption of red wine. EPCs were glucose stressed to study the effect of red wine on EPC migration, proliferation, and senescence and to study the expressions of CXC chemokine receptor 4 (CXCR4) and members of the Pi3K/Akt/eNOS (phosphatidylinositol 3-kinase/protein kinase B/endothelial nitric oxide synthase) signaling pathway by Western blotting. Results: Daily red wine consumption for 21 consecutive days significantly enhanced vascular endothelial function. Although plasma SDF1alpha concentrations were unchanged, EPC count and migration were significantly increased after this 21-d consumption period. Red wine increased the migration, proliferation, CXCR4 expression, and activity of the Pi3K/Akt/eNOS signaling pathway and decreased the extent of apoptosis in glucose-stressed EPCs. Conclusions: The results of the present study indicate that red wine exerts its effect through the up-regulation of CXCR4 expression and activation of the SDF1alpha/CXCR4/Pi3K/Akt/eNOS signaling pathway, which results in increased EPC migration and proliferation and decreased extent of apoptosis. Our findings suggest that these effects could be linked to the mechanism of cardiovascular protection that is associated with the regular consumption of red wine.
MeSH term(s)	Adult ; Antigens, CD/blood ; Blood Flow Velocity ; Blood Glucose/metabolism ; Blood Pressure ; Body Mass Index ; Cell Culture Techniques ; Cell Movement/physiology ; Chemokine CXCL12/blood ; Cholesterol/blood ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; Endothelial Cells/physiology ; Endothelium, Vascular/physiology ; Female ; Humans ; Male ; Nitric Oxide/metabolism ; Proto-Oncogene Proteins c-akt/blood ; Stem Cells/cytology ; Stem Cells/physiology ; Triglycerides/blood ; Wine
Chemical Substances	Antigens, CD ; Blood Glucose ; Chemokine CXCL12 ; Cholesterol, HDL ; Cholesterol, LDL ; Triglycerides ; Nitric Oxide (31C4KY9ESH) ; Cholesterol (97C5T2UQ7J) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2010-04-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	280048-2
ISSN	1938-3207 ; 0002-9165
ISSN (online)	1938-3207
ISSN	0002-9165
DOI	10.3945/ajcn.2009.28408
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Article ; Online: Topical Erythropoietin Treatment Accelerates the Healing of Cutaneous Burn Wounds in Diabetic Pigs Through an Aquaporin-3-Dependent Mechanism.

Hamed, Saher / Ullmann, Yehuda / Egozi, Dana / Keren, Aviad / Daod, Essam / Anis, Omer / Kabha, Hoda / Belokopytov, Mark / Ashkar, Manal / Shofti, Rona / Zaretsky, Asaph / Schlesinger, Michal / Teot, Luc / Liu, Paul Y

Diabetes

2017 Volume 66, Issue 8, Page(s) 2254–2265

Abstract: We have previously reported that the topical application of erythropoietin (EPO) to cutaneous wounds in rats and mice with experimentally induced diabetes accelerates their healing by stimulating angiogenesis, reepithelialization, and collagen deposition, ...

Abstract	We have previously reported that the topical application of erythropoietin (EPO) to cutaneous wounds in rats and mice with experimentally induced diabetes accelerates their healing by stimulating angiogenesis, reepithelialization, and collagen deposition, and by suppressing the inflammatory response and apoptosis. Aquaporins (AQPs) are integral membrane proteins whose function is to regulate intracellular fluid hemostasis by enabling the transport of water and glycerol. AQP3 is the AQP that is expressed in the skin where it facilitates cell migration and proliferation and re-epithelialization during wound healing. In this report, we provide the results of an investigation that examined the contribution of AQP3 to the mechanism of EPO action on the healing of burn wounds in the skin of pigs with experimentally induced type 1 diabetes. We found that topical EPO treatment of the burns accelerated their healing through an AQP3-dependent mechanism that activates angiogenesis, triggers collagen and hyaluronic acid synthesis and the formation of the extracellular matrix (ECM), and stimulates reepithelialization by keratinocytes. We also found that incorporating fibronectin, a crucial constituent of the ECM, into the topical EPO-containing gel, can potentiate the accelerating action of EPO on the healing of the burn injury.
MeSH term(s)	Administration, Topical ; Angiogenesis Inducing Agents/administration & dosage ; Animals ; Aquaporin 3/metabolism ; Burns/drug therapy ; Burns/genetics ; Collagen/genetics ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Type 1/genetics ; Erythropoietin/administration & dosage ; Extracellular Matrix/genetics ; Fibronectins/administration & dosage ; Hyaluronic Acid/biosynthesis ; Keratinocytes/metabolism ; Neovascularization, Physiologic ; Re-Epithelialization/genetics ; Skin/metabolism ; Swine ; Wound Healing/drug effects ; Wound Healing/genetics
Chemical Substances	Angiogenesis Inducing Agents ; Fibronectins ; Erythropoietin (11096-26-7) ; Aquaporin 3 (158801-98-0) ; Hyaluronic Acid (9004-61-9) ; Collagen (9007-34-5)
Language	English
Publishing date	2017-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db16-1205
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Article ; Online: Nitric oxide and superoxide dismutase modulate endothelial progenitor cell function in type 2 diabetes mellitus

Brenner Benjamin / Hamed Saher / Aharon Anat / Daoud Deeb / Roguin Ariel

Cardiovascular Diabetology, Vol 8, Iss 1, p

2009 Volume 56

Abstract: Abstract Background The function of endothelial progenitor cells (EPCs), which are key cells in vascular repair, is impaired in diabetes mellitus. Nitric oxide (NO) and reactive oxygen species can regulate EPC functions. EPCs tolerate oxidative stress by ...

Abstract	Abstract Background The function of endothelial progenitor cells (EPCs), which are key cells in vascular repair, is impaired in diabetes mellitus. Nitric oxide (NO) and reactive oxygen species can regulate EPC functions. EPCs tolerate oxidative stress by upregulating superoxide dismutase (SOD), the enzyme that neutralizes superoxide anion (O 2 - ). Therefore, we investigated the roles of NO and SOD in glucose-stressed EPCs. Methods The functions of circulating EPCs from patients with type 2 diabetes were compared to those from healthy individuals. Healthy EPCs were glucose-stressed, and then treated with insulin and/or SOD. We assessed O 2 - generation, NO production, SOD activity, and their ability to form colonies. Results EPCs from diabetic patients generated more O 2 - , had higher NAD(P)H oxidase and SOD activity, but lower NO bioavailability, and expressed higher mRNA and protein levels of p22-phox, and manganese SOD and copper/zinc SOD than those from the healthy individuals. Plasma glucose and HbA1c levels in the diabetic patients were correlated negatively with the NO production from their EPCs. SOD treatment of glucose-stressed EPCs attenuated O 2 - generation, restored NO production, and partially restored their ability to form colonies. Insulin treatment of glucose-stressed EPCs increased NO production, but did not change O 2 - generation and their ability to form colonies. However, their ability to produce NO and to form colonies was fully restored after combined SOD and insulin treatment. Conclusion Our data provide evidence that SOD may play an essential role in EPCs, and emphasize the important role of antioxidant therapy in type 2 diabetic patients.
Keywords	Diseases of the circulatory (Cardiovascular) system ; RC666-701 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Cardiovascular ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	333
Language	English
Publishing date	2009-10-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Nitric oxide and superoxide dismutase modulate endothelial progenitor cell function in type 2 diabetes mellitus.

Hamed, Saher / Brenner, Benjamin / Aharon, Anat / Daoud, Deeb / Roguin, Ariel

Cardiovascular diabetology

2009 Volume 8, Page(s) 56

Abstract: Background: The function of endothelial progenitor cells (EPCs), which are key cells in vascular repair, is impaired in diabetes mellitus. Nitric oxide (NO) and reactive oxygen species can regulate EPC functions. EPCs tolerate oxidative stress by ... ...

Abstract	Background: The function of endothelial progenitor cells (EPCs), which are key cells in vascular repair, is impaired in diabetes mellitus. Nitric oxide (NO) and reactive oxygen species can regulate EPC functions. EPCs tolerate oxidative stress by upregulating superoxide dismutase (SOD), the enzyme that neutralizes superoxide anion (O2-). Therefore, we investigated the roles of NO and SOD in glucose-stressed EPCs. Methods: The functions of circulating EPCs from patients with type 2 diabetes were compared to those from healthy individuals. Healthy EPCs were glucose-stressed, and then treated with insulin and/or SOD. We assessed O2- generation, NO production, SOD activity, and their ability to form colonies. Results: EPCs from diabetic patients generated more O2-, had higher NAD(P)H oxidase and SOD activity, but lower NO bioavailability, and expressed higher mRNA and protein levels of p22-phox, and manganese SOD and copper/zinc SOD than those from the healthy individuals. Plasma glucose and HbA1c levels in the diabetic patients were correlated negatively with the NO production from their EPCs. SOD treatment of glucose-stressed EPCs attenuated O2- generation, restored NO production, and partially restored their ability to form colonies. Insulin treatment of glucose-stressed EPCs increased NO production, but did not change O2- generation and their ability to form colonies. However, their ability to produce NO and to form colonies was fully restored after combined SOD and insulin treatment. Conclusion: Our data provide evidence that SOD may play an essential role in EPCs, and emphasize the important role of antioxidant therapy in type 2 diabetic patients.
MeSH term(s)	Cells, Cultured ; Diabetes Mellitus, Type 2/enzymology ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Endothelium, Vascular/enzymology ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/pathology ; Female ; Humans ; Male ; Middle Aged ; Nitric Oxide/physiology ; Oxidative Stress/physiology ; Stem Cells/enzymology ; Stem Cells/metabolism ; Stem Cells/pathology ; Superoxide Dismutase/physiology
Chemical Substances	Nitric Oxide (31C4KY9ESH) ; Superoxide Dismutase (EC 1.15.1.1)
Language	English
Publishing date	2009-10-30
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1475-2840
ISSN (online)	1475-2840
DOI	10.1186/1475-2840-8-56
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