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Park JH, Brown NE, Tucker SJ, Temenoff JS, El-Deiry M, Park HJ, Tkaczuk AT, Hollister SJ. Feasibility Assessment of 3D Printing-Based Tubular Tissue Flap in a Porcine Model for Long Segmental Tracheal Reconstruction. Tissue Eng Regen Med 2025:10.1007/s13770-025-00718-9. [PMID: 40397370 DOI: 10.1007/s13770-025-00718-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 02/26/2025] [Accepted: 03/11/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Despite advances in tissue engineering, current clinical reconstructive options for long segment tracheal defects are limited. In this study, a 3D printing based tubular tissue flap strategy was developed for long segment tracheal reconstruction. METHOD A stent-patterned airway scaffold with sufficient radial rigidity and longitudinal bending flexibility was designed and its mechanical behavior was analyzed using finite element analysis (FEA). The stent-patterned airway scaffolds with a removable central core to preserve an internal lumen were created by selective laser sintering (SLS) based 3D printing. The stent-patterned airway scaffold with the central core, filled with poly (ethylene glycol) diacrylate-dithiothreitol (PEGDA-DTT) hydrogel containing erythropoietin (EPO) to enhance vascularization, was then implanted into the latissimus dorsi muscle of a Yucatan minipig. RESULTS A tubular tissue flap, with controlled luminal layer thickness was successfully created by removing the central core from the retrieved tissue flap containing the airway scaffold after 45 days of implantation in the Yucatan minipig model. CONCLUSION The current work validated the potential of the tubular tissue flap based on the 3D printing as a clinically viable tissue engineering strategy for long segment tracheal reconstruction.
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Affiliation(s)
- Jeong Hun Park
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA
- Center for 3D Medical Fabrication, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA
| | - Nettie E Brown
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA
- Center for 3D Medical Fabrication, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA
| | - Sarah Jo Tucker
- Global Center for Medical Innovation, 575 14th Street, Atlanta, GA, 30318, USA
| | - Johnna S Temenoff
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA, 30332, USA
| | - Mark El-Deiry
- Department of Otolaryngology Head and Neck Surgery, Emory University School of Medicine, 550 Peachtree Street NE, Atlanta, GA, 30308, USA
| | - Hyun-Ji Park
- Department of Molecular Science and Technology, Ajou University, 206 Worldcup-Ro, Suwon, 16499, Republic of Korea
- Advanced College of Bio-Convergence Engineering, Ajou University, 206 Worldcup-Ro, Suwon, 16499, Republic of Korea
| | - Andrew T Tkaczuk
- Department of Otolaryngology Head and Neck Surgery, Emory University School of Medicine, 550 Peachtree Street NE, Atlanta, GA, 30308, USA.
| | - Scott J Hollister
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA.
- Center for 3D Medical Fabrication, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA.
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Deng T, Liang Y, Xu C, Hao L, Fu J, Chen J. Factors associated with high hidden blood loss in patients undergoing primary total knee arthroplasty for osteoarthritis: a cross-sectional retrospective study of 1444 patients. BMC Musculoskelet Disord 2025; 26:439. [PMID: 40319268 PMCID: PMC12048921 DOI: 10.1186/s12891-025-08698-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 04/24/2025] [Indexed: 05/07/2025] Open
Abstract
PURPOSE Total knee arthroplasty (TKA) can cause significant hidden blood loss after surgery, and transfusion or erythropoietin (EPO) treatment may be required. This study aimed to identify the factors associated with blood loss in patients undergoing TKA for osteoarthritis (OA). METHODS We retrospectively enrolled 1444 OA patients undergoing primary TKA from January 2022 to June 2024. The patients were divided into two groups according to the grade of hidden blood loss. To identify the key influencing factors, we conducted a logistic regression analysis. RESULTS This study analyzed 1,444 primary arthroplasty cases, identifying 236 patients with high hidden blood loss (HHBL). Coronary artery disease (CAD) was significantly more prevalent in the HHBL group (15.3% vs. 9.4%, p = 0.006). Preoperative EPO use was higher in the low hidden blood loss (LHBL) group (21.9% vs. 9.3%, p < 0.001). Significant preoperative lab differences included hemoglobin, hematocrit, and platelet count. Surgical factors associated with HHBL included left knee TKA, conventional mechanical TKA (CMTKA), longer operation times, and intraoperative blood loss (IBL) > 20%. Postoperatively, the HHBL group had significantly more transfusions and longer hospital stays. Logistic regression identified CAD, platelet count, left knee surgery, CMTKA, operation time, and preoperative EPO use as significant factors influencing HHBL. These findings highlight the need for targeted strategies to manage blood loss in knee arthroplasty patients. CONCLUSIONS This study identifies several factors associated with high hidden blood loss in patients undergoing TKA for osteoarthritis. CAD, CMTKA, prolonged operation time, left-sided surgery, lower preoperative platelet count, and lack of preoperative erythropoietin (EPO) use were significantly linked to HHBL. While these associations highlight potential targets for intervention, further prospective studies are needed to confirm causality.
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Affiliation(s)
- Tao Deng
- Medical School of Chinese PLA, Beijing, People's Republic of China
- Department of Orthopedic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China
- Department of Orthopedic Surgery, The First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, People's Republic of China
| | - Yongjian Liang
- Medical School of Chinese PLA, Beijing, People's Republic of China
| | - Chi Xu
- Department of Orthopedic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China
- Department of Orthopedic Surgery, The First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, People's Republic of China
| | - Libo Hao
- Department of Orthopedic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China
- Department of Orthopedic Surgery, The First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, People's Republic of China
| | - Jun Fu
- Department of Orthopedic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China.
- Department of Orthopedic Surgery, The First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, People's Republic of China.
| | - Jiying Chen
- Department of Orthopedic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China.
- Department of Orthopedic Surgery, The First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, People's Republic of China.
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Zhang R, Nie Y, Chen X, Jiang T, Wang J, Peng Y, Zhou G, Li Y, Zhao L, Chen B, Ni Y, Cheng Y, Xu Y, Zhu Z, Gao X, Wu Z, Li T, Zhao J, Liu C, Zhao G, Chen J, Zhao J, Ji G, Han X, He J, Li Y. A multicenter prospective clinical trial reveals cell-free DNA methylation markers for early esophageal cancer. J Clin Invest 2025; 135:e186816. [PMID: 39998886 PMCID: PMC11996849 DOI: 10.1172/jci186816] [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: 09/18/2024] [Accepted: 02/19/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUNDCurrent methods for detecting esophageal cancer (EC) are generally invasive or exhibit limited sensitivity and specificity, especially for the identification of early-stage tumors.METHODSWe identified potential methylated DNA markers (MDMs) from multiple genomic regions in a discovery cohort, and a diagnostic model was developed and verified in a model-verification cohort of 297 participants. The accuracy of the MDM panel was validated in a multicenter, prospective cohort (n = 1,429). The clinical performance of identified MDMs were compared with current tumor-associated protein markers.RESULTSFrom 31 significant differentially methylated EC-associated regions identified in the marker discovery, we trained and validated a 3-MDM diagnostic model that could discriminate among patients with EC and volunteers without EC in a multicenter clinical prospective cohort with a sensitivity of 85.5% and a specificity of 95.3%. This panel showed higher sensitivity in diagnosing early-stage tumors, with sensitivities of 56% for stage 0 and 77% for stage I, compared with the performance of current biochemical markers. In population with high risk for EC, the sensitivity and specificity were 85.68% and 93.61%, respectively.CONCLUSIONThe assessment of tumor-associated methylation status in blood samples can facilitate noninvasive and reliable diagnosis of early-stage EC, which warrants further development to expand screening and reduce mortality rates.TRIAL REGISTRATIONChiCTR2400083525.FUNDINGScience and technology funds of Beijing Municipal Science & Technology Commission, Administrative Commission of Zhongguancun Science Park. Project number: Z201100005420007.
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Affiliation(s)
- Ruixiang Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Xiaobing Chen
- Department of Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Tao Jiang
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, Shaanxi, China
| | - Jinhai Wang
- Department of Gastroenterology, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Yuhui Peng
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Guangpeng Zhou
- BioChain (Beijing) Science & Technology Inc., Beijing, China
| | - Yong Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lina Zhao
- Department of Radiation Oncology and
| | - Beibei Chen
- Department of Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Yunfeng Ni
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, Shaanxi, China
| | - Yan Cheng
- Department of Gastroenterology, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Yiwei Xu
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zhenyu Zhu
- BioChain (Beijing) Science & Technology Inc., Beijing, China
| | - Xianchun Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Zhen Wu
- BioChain (Beijing) Science & Technology Inc., Beijing, China
| | - Tianbao Li
- BioChain (Beijing) Science & Technology Inc., Beijing, China
| | - Jie Zhao
- BioChain (Beijing) Science & Technology Inc., Beijing, China
| | - Cantong Liu
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Gang Zhao
- Department of Gastroenterology, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Jiakuan Chen
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, Shaanxi, China
| | - Jing Zhao
- Department of Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Gang Ji
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Xiaoliang Han
- BioChain (Beijing) Science & Technology Inc., Beijing, China
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yin Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Tian P, Luo FL, Chen AZ, Yuan YX, Yu L. Examining the lifespan of red blood cells in individuals with systemic lupus erythematosus. Clin Hemorheol Microcirc 2025:13860291241305508. [PMID: 39973432 DOI: 10.1177/13860291241305508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
OBJECTIVE The objective of this study is to examine the lifespan of red blood cells (RBCs) in individuals with systemic lupus erythematosus (SLE), explore the factors influencing this lifespan, and assess its significance in clinical contexts. METHODS The experimental group comprised of 182 patients with SLE, while the control group consisted of 90 healthy participants. By using a non-invasive breath test, we measured the RBC lifespan in both groups. Subsequently, we conducted a comparative analysis of general clinical data and laboratory findings to explore the correlation between RBC lifespan in patients with SLE and various parameters associated with RBC characteristics, inflammatory markers, and immunological indicators. Furthermore, we examined the impact of COVID-19 infection on RBC lifespan among patients with SLE and assessed the diagnostic efficacy of RBC lifespan. RESULTS RBC lifespan was notably reduced in the SLE group in comparison to the healthy control group (P = 0.002). A positive correlation was observed between RBC lifespan and hemoglobin (HB), complement 3, and complement 4, whereas a negative correlation was noted with IgG, erythrocyte sedimentation rate (ESR), C-reactive protein, and anti-dsDNA levels (all P < 0.05). Noteworthy independent contributors to the reduction in RBC lifespan among patients with SLE included disease activity and presence of anemia. While RBC lifespan remained unchanged in the control group before and after COVID-19 infection (P > 0.05), a reduction in RBC lifespan post-COVID-19 infection was observed among patients with SLE (P < 0.05). Also, RBC lifespan was notably shorter during the active disease phase of SLE compared to the stable phase, with post-COVID-19 active patients with SLE exhibiting even shorter RBC lifespan compared to the pre-COVID-19 active group (all P < 0.05). An optimal cutoff for the prediction of anemia in patients with SLE on the day of assessment was determined to be 93.5 days (AUC 0.792, P < 0.05). CONCLUSION Patients with SLE exhibited shorter RBC lifespan in contrast to the healthy population, which is notably linked with levels of inflammatory and immune markers, as well as the incidence of COVID-19 infection. This discovery holds crucial significance for both the diagnosis of anemia and the comprehension of its underlying pathogenic mechanisms within the context of SLE.
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Affiliation(s)
- Pan Tian
- Department of Rheumatology, Longyan First Affiliated Hospital of Fujian Medical University, Fujian, People's Republic of China
| | - Feng-Lan Luo
- Department of Infectious, The Second Hospital of Longyan, Fujian, People's Republic of China
| | - Ai-Zhen Chen
- Department of Rheumatology, Longyan First Affiliated Hospital of Fujian Medical University, Fujian, People's Republic of China
| | - Yue-Xing Yuan
- Department of Rheumatology, Longyan First Affiliated Hospital of Fujian Medical University, Fujian, People's Republic of China
| | - Lian Yu
- Department of Rheumatology, Longyan First Affiliated Hospital of Fujian Medical University, Fujian, People's Republic of China
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Sabry NC, Michel HE, Menze ET. Repurposing of erythropoietin as a neuroprotective agent against methotrexate-induced neurotoxicity in rats. J Psychopharmacol 2025; 39:147-163. [PMID: 39535118 DOI: 10.1177/02698811241295379] [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] [Indexed: 11/16/2024]
Abstract
BACKGROUND Methotrexate (MTX) is a cytotoxic drug that can trigger neurotoxicity via enhancing oxidative stress, apoptosis, and inflammation. On the other hand, erythropoietin (EPO) functions as an antioxidant, anti-apoptotic, and anti-inflammatory agent, in addition to its hematopoietic effects. AIM The present study was developed to examine the neuroprotective impact of EPO against MTX-provoked neurotoxicity in rats. METHODS Chemo fog was elicited in Wistar rats via injection of one dosage of MTX (20 mg/kg, i.p) on the sixth day of the study. EPO was injected at 500 IU/kg/day, i.p for 10 successive days. RESULTS MTX triggered memory and learning impairment as evidenced by Morris water maze, passive avoidance, and Y-maze cognitive tests. In addition, MTX induced oxidative stress as evident from the decline in hippocampal Nrf2 and HO-1 levels. MTX brought about apoptosis, as demonstrated by the elevation in p53, caspase-3, and Bax levels, as well as the decrease in Bcl2 levels. MTX also decreased Beclin-1, an autophagy-related marker, and increased P62 expression. In addition, MTX downregulated Sirt-1/AKT/FoxO3a pathway and increased miRNA-34a gene expression. Moreover, MTX increased acetylcholinesterase activity and reduced neurogenesis. EPO administration remarkably counteracted MTX-induced molecular and behavioral disorders in rat hippocampi. CONCLUSION Our findings impart preclinical indication for repurposing of EPO as a promising neuroprotective agent through modulating miRNA-34a, autophagy, and the Sirt-1/FoxO3a signaling pathway.
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Affiliation(s)
- Nadine C Sabry
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Ain Shams University, Cairo, Egypt
| | - Haidy E Michel
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Ain Shams University, Cairo, Egypt
| | - Esther T Menze
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Ain Shams University, Cairo, Egypt
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Hong JM, Shin HS. Reinforcement of Transdural Angiogenesis: A Novel Approach to Treating Ischemic Stroke With Cerebral Perfusion Impairment. J Stroke 2025; 27:30-40. [PMID: 39916452 PMCID: PMC11834342 DOI: 10.5853/jos.2024.02810] [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: 07/16/2024] [Revised: 10/07/2024] [Accepted: 10/21/2024] [Indexed: 02/20/2025] Open
Abstract
Cerebral hypoperfusion plays a critical role in early neurological deterioration and long-term outcomes in patients with acute ischemic stroke, which remains a major global health challenge. This review explored transdural angiogenesis as a promising therapeutic strategy to restore cerebral perfusion in patients with ischemic stroke. The multiple burr hole procedure has been preliminarily used as an indirect revascularization method to induce transdural arteriogenesis. Theoretically, its efficacy could be enhanced by combining it with angiogenic boosters, such as erythropoietin. Recent clinical and preclinical studies have revealed that this combination therapy promotes angiogenesis and arteriogenesis, leading to successful revascularization across the dura mater and improved cerebral blood flow. This strategy may be particularly beneficial for high-risk patients with recurrent ischemic events, such as those with moyamoya disease or intracranial arterial occlusion, representing an effective strategy when conventional medical treatments are insufficient. This review highlights the potential of transdural angiogenesis enhancement as a novel intervention for ischemic stroke, offering an alternative to thrombolysis or endovascular treatment, particularly in acute stroke patients with impaired cerebral perfusion. This approach has the potential to bridge the treatment gap for patients outside the therapeutic window for acute stroke interventions. Although further research is required to refine this technique and validate its efficacy in broader clinical settings, early results have revealed promising outcomes at reducing stroke-related complications and improving patient prognosis. This review indicates that this novel strategy may offer hope for managing ischemic stroke and related conditions associated with significant cerebral hypoperfusion.
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Affiliation(s)
- Ji Man Hong
- Department of Neurology, Ajou University Medical Center, Ajou University School of Medicine, Suwon, Korea
- Department of Biomedical Science, Ajou University Medical Center, Ajou University School of Medicine, Suwon, Korea
| | - Hee Sun Shin
- Department of Biomedical Science, Ajou University Medical Center, Ajou University School of Medicine, Suwon, Korea
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Sinha A, Gupta M, Bhaskar SMM. Evolucollateral dynamics in stroke: Evolutionary pathophysiology, remodelling and emerging therapeutic strategies. Eur J Neurosci 2024; 60:6779-6798. [PMID: 39498733 DOI: 10.1111/ejn.16585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 10/13/2024] [Accepted: 10/15/2024] [Indexed: 11/07/2024]
Abstract
Leptomeningeal collaterals (LMCs) are crucial in mitigating the impact of acute ischemic stroke (AIS) by providing alternate blood flow routes when primary arteries are obstructed. This article explores the evolutionary pathophysiology of LMCs, highlighting their critical function in stroke and the genetic and molecular mechanisms governing their development and remodelling. We address the translational challenges of applying animal model findings to human clinical scenarios, emphasizing the need for further research to validate emerging therapies-such as pharmacological agents, gene therapy and mechanical interventions-in clinical settings, aimed at enhancing collateral perfusion. Computational modelling emerges as a promising method for integrating experimental data, which requires precise parameterization and empirical validation. We introduce the 'Evolucollateral Dynamics' hypothesis, proposing a novel framework that incorporates evolutionary biology principles into therapeutic strategies, offering new perspectives on enhancing collateral circulation. This hypothesis emphasizes the role of genetic predispositions and environmental influences on collateral circulation, which may impact therapeutic strategies and optimize treatment outcomes. Future research must incorporate human clinical data to create robust treatment protocols, thereby maximizing the therapeutic potential of LMCs and improving outcomes for stroke patients.
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Affiliation(s)
- Akansha Sinha
- Global Health Neurology Lab, Sydney, NSW, Australia
- UNSW Medicine and Health, University of New South Wales (UNSW), South West Sydney Clinical Campuses, Sydney, NSW, Australia
| | - Muskaan Gupta
- Global Health Neurology Lab, Sydney, NSW, Australia
- UNSW Medicine and Health, University of New South Wales (UNSW), South West Sydney Clinical Campuses, Sydney, NSW, Australia
| | - Sonu M M Bhaskar
- Global Health Neurology Lab, Sydney, NSW, Australia
- UNSW Medicine and Health, University of New South Wales (UNSW), South West Sydney Clinical Campuses, Sydney, NSW, Australia
- NSW Brain Clot Bank, NSW Health Pathology, Sydney, NSW, Australia
- Department of Neurology & Neurophysiology, Liverpool Hospital and South West Sydney Local Health District, Liverpool, NSW, Australia
- Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
- Department of Neurology, Division of Cerebrovascular Medicine and Neurology, National Cerebral and Cardiovascular Center (NCVC), Suita, Osaka, Japan
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Feizi N, Mohamadzadeh-Nabiei M, Vahedi H, Farabi Maleki S, Jafarizadeh A. Therapeutic role of erythropoietin in methanol induced optic neuropathy: a systematic review. Daru 2024; 33:2. [PMID: 39613913 PMCID: PMC11607285 DOI: 10.1007/s40199-024-00551-w] [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: 01/07/2024] [Accepted: 11/06/2024] [Indexed: 12/01/2024] Open
Abstract
PURPOSE Despite various therapeutic attempts, an approved treatment for Methanol-induced optic neuropathy (MION), a sight-threatening disorder, is still lacking. Erythropoietin known as an erythropoietic cytokine, possesses various non-hematopoietic properties that make it a candidate for MION treatment. This systematic review aims to assess the potential therapeutic role of erythropoietin in MION. METHOD We systematically searched English and Persian databases including PubMed, Scopus, Embase, Web of Science, and Scientific Information Database (SID) as of July 2024. Two independent authors screened the articles based on their titles, abstracts, and full texts to finalize the included articles in this study. The selected articles underwent quality assessments via the Joanna Briggs Institute (JBI) checklists. RESULTS Out of 139 studies identified in the databases, 11 were finally included in the analysis. These studies encompassed 212 participants, with 192 receiving erythropoietin treatment. Visual acuity (VA) improved in 184 patients, with improvements ranging from no light perception to full vision recovery, or minor enhancements such as an improvement from 1.75 ± 0.72 to 1.32 ± 0.79 LogMAR. Only 8 patients showed no change or experienced deterioration. Additionally, 21 cases exhibited a reduction in retinal nerve fiber layer thickness, with one showing a reduction towards the normal range. CONCLUSION This review highlights erythropoietin's positive impact on VA in patients with MION. However, simultaneous use of erythropoietin and corticosteroids in studies without control groups complicates evaluating erythropoietin's independent efficacy. Future research should involve large, controlled trials to clarify erythropoietin's role and establish it as a standard treatment. PROSPERO REGISTRATION NUMBER CRD42023485772.
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Affiliation(s)
- Neda Feizi
- Research Center for Evidence-Based Medicine, Iranian EBM Centre: A Joanna Briggs Institute Affiliated Group, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahsa Mohamadzadeh-Nabiei
- Research Center for Evidence-Based Medicine, Iranian EBM Centre: A Joanna Briggs Institute Affiliated Group, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Vahedi
- Nikookari Eye Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Shadi Farabi Maleki
- Nikookari Eye Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Ali Jafarizadeh
- Nikookari Eye Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran.
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Arias Fernández DA, Romero Diaz HA, Figueroa Garnica AD, Iturri-Soliz P, Arias-Reyes C, Schneider Gasser EM, Soliz J. Low and sustained doses of erythropoietin prevent preterm infants from intraventricular hemorrhage. Respir Physiol Neurobiol 2024; 331:104363. [PMID: 39510295 DOI: 10.1016/j.resp.2024.104363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 10/21/2024] [Accepted: 10/28/2024] [Indexed: 11/15/2024]
Abstract
In addition to its hematopoietic function, erythropoietin (EPO) has demonstrated neuroprotective properties in preclinical studies, particularly in cases of reduced oxygenation or ischemia in the neonatal brain. While these findings have sparked optimism for its potential clinical application, the efficacy of EPO remains contentious in translational assays. Notably, while repeated administration of low doses of EPO has correlated with a decrease in adverse outcomes, the use of high EPO doses has shown either negligible or potentially detrimental effects on the incidence of brain injury. In this pilot study, we explored the effects of low and sustained doses of EPO (400 IU/kg) on the incidence of intraventricular hemorrhage (IVH) in premature infants. EPO was administered intravenously three times a week until the infants reached 32 weeks corrected gestational age. Our results indicate a significant decrease in the incidence of IVH with EPO treatment. Although, this study does not provide conclusive evidence on EPO's ability to reverse established IVH, these results strongly support the need for larger-scale clinical trials to further assess EPO's therapeutic potential.
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Affiliation(s)
| | | | | | - Pablo Iturri-Soliz
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Universite Laval, Quebec City, Quebec, Canada; Brain Research Center, High Altitude Research Foundation, La Paz, Bolivia
| | - Christian Arias-Reyes
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, USA; Brain Research Center, High Altitude Research Foundation, La Paz, Bolivia
| | - Edith Mariane Schneider Gasser
- Institute of Veterinary Physiology, Vetsuisse-Faculty, University of Zurich, Switzerland, and Center for Neuroscience Zurich (ZNZ), Zurich, Switzerland; Brain Research Center, High Altitude Research Foundation, La Paz, Bolivia
| | - Jorge Soliz
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Universite Laval, Quebec City, Quebec, Canada; Brain Research Center, High Altitude Research Foundation, La Paz, Bolivia.
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Silva IMG, Rodrigues AQ, Ribeiro RB, Aguiar BA, Marinho AESP, Souza EAM, Ferreira YB, Azevedo VCO, Oliveira DM, Báo SN, Goulart JT, Lucci CM, Paulini F. Erythropoietin effects on cryopreserved/transplanted cat ovarian tissue: A comparison of two incubation methods. Cryobiology 2024; 115:104861. [PMID: 38423494 DOI: 10.1016/j.cryobiol.2024.104861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 01/31/2024] [Accepted: 02/12/2024] [Indexed: 03/02/2024]
Abstract
Many feline species are currently threatened with extinction. Therefore, germplasm bank establishment has become imperative. However, cryoinjury and ischemia-reperfusion injury pose significant obstacles to both cryopreservation and xenotransplantation. In this regard, erythropoietin (Epo) represents a potential alternative strategy due to its properties. This study aimed to assess the incubation of domestic cat ovarian tissue in Epo, both before and after cryopreservation, and investigate its effectiveness in promoting revascularization following xenotransplantation. Sixteen ovaries from 8 healthy cats were sliced following elective bilateral ovariohysterectomy (OHE). Subsequently, 8 fragments measuring 3 mm³ each were obtained from the cortical region of each ovary. The fragments were allocated into 3 treatment groups: Cryo group, fragments were cryopreserved, thawed and immediately transplanted; Cryo + Epo group, fragments were first cryopreserved in nitrogen, thawed, incubated in Epo (100 IU) for 2h and transplanted; and the Epo + Cryo group, in which fragments were first incubated in Epo (100 IU) for 2h, cryopreserved, thawed and immediately transplanted. The fragments were then xenotransplanted into the dorsal subcutaneous region of ovariectomized female nude mice and retrieved at 7, 14, 21, and 28 days post-transplantation. The results indicated that Epo effectively enhanced follicular survival, preservation of viability, and tissue revascularization. The Epo + Cryo group displayed better revascularization rates on D14 and D21 post-transplantation and an increase in primordial and growing follicles on D28, the Cryo + Epo group exhibited significantly more follicles on D14 and D21, with fewer degenerated follicles.
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Affiliation(s)
- Isabella M G Silva
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Aline Q Rodrigues
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Rayane B Ribeiro
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Beatriz A Aguiar
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Anne E S P Marinho
- University of Brasilia, Health Sciences Faculty, Department of Pharmacy, Brasilia-DF, 70910-900, Brazil
| | - Elisa A M Souza
- University of Brasilia, Health Sciences Faculty, Department of Pharmacy, Brasilia-DF, 70910-900, Brazil
| | - Yasmin B Ferreira
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Victoria C O Azevedo
- University of Brasilia, Health Sciences Faculty, Department of Pharmacy, Brasilia-DF, 70910-900, Brazil
| | - Daniela M Oliveira
- University of Brasilia, Institute of Biological Sciences, Department of Genetics and Morphology, Brasiilia 70910-900, Brazil
| | - Sônia N Báo
- University of Brasilia, Institute of Biological Sciences, Department of Cellular Biology, Brasilia-DF, 70910-900, Brazil
| | - Jair T Goulart
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Carolina M Lucci
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Fernanda Paulini
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil.
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11
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Onoda H, Imamura T, Ueno H, Oshima A, Ueno Y, Ushijima R, Sobajima M, Kinugawa K. Prognostic impact of elevated erythropoietin levels in patients with severe aortic stenosis receiving trans-catheter aortic valve implantation. J Cardiol 2024; 83:149-154. [PMID: 37479082 DOI: 10.1016/j.jjcc.2023.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 07/12/2023] [Accepted: 07/14/2023] [Indexed: 07/23/2023]
Abstract
BACKGROUND Elevated endogenous erythropoietin (EPO) levels are associated with worse clinical outcomes in patients with heart failure (HF). The clinical implication of endogenous EPO levels in patients undergoing trans-catheter aortic valve implantation (TAVI) beyond other conventional risk factors remains unknown. METHODS Consecutive patients with EPO measurements who underwent TAVI for the treatment of their severe aortic stenosis at our institute between May 2015 and December 2020 were included. The association between the endogenous EPO levels and the primary outcome consisting of all-cause mortality and HF hospitalization was evaluated. RESULTS A total of 263 patients (85.1 ± 5.1 years old, 74 men) were included and tertiled according to the baseline EPO levels. The high EPO group had more advanced anemia, renal impairment, and hypoalbuminemia than the other two tertiled groups (p < 0.05 for both). Patients with high EPO had a significantly higher cumulative incidence of the primary outcomes compared to the other two groups (p = 0.002) with an adjusted hazard ratio of 6.0 (95 % confidence interval 1.9-18.1) in its logarithmic value (p < 0.001). CONCLUSIONS Elevated baseline EPO levels were independently associated with mortality and morbidity following TAVI. The clinical implication of aggressive intervention on the elevated EPO levels in this cohort remains the next concern.
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Affiliation(s)
- Hiroshi Onoda
- The Second Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Teruhiko Imamura
- The Second Department of Internal Medicine, University of Toyama, Toyama, Japan.
| | - Hiroshi Ueno
- The Second Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Akira Oshima
- The Second Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Yohei Ueno
- The Second Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Ryuichi Ushijima
- The Second Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Mitsuo Sobajima
- The Second Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Koichiro Kinugawa
- The Second Department of Internal Medicine, University of Toyama, Toyama, Japan
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12
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Zhu L, Yuan Q, Jing C, Sun L, Jiang L. Angiogenic responses are enhanced by recombinant human erythropoietin in a model of periventricular white matter damage of neonatal rats through EPOR-ERK1 signaling. J Neuropathol Exp Neurol 2024; 83:161-167. [PMID: 38263262 PMCID: PMC10880070 DOI: 10.1093/jnen/nlae001] [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] [Indexed: 01/25/2024] Open
Abstract
Recombinant human erythropoietin (rh-EPO) has been shown to stimulate neurogenesis and angiogenesis, both of which play crucial roles in the repair of brain injuries. Previously, we observed that rh-EPO treatment effectively reduced brain damage and enhanced angiogenesis in a neonatal rat model of periventricular white matter damage (PWMD). The objective of this research is to investigate the specific mechanism through which rh-EPO regulates angiogenesis following PWMD in premature neonates. We conducted experiments utilizing a neonatal PWMD model. Following rh-EPO treatment, the levels of erythropoietin receptor (EPOR) were found to be increased in the damaged brain of rats. Although the total amount of extracellular signal-regulated kinase (ERK), a downstream protein in the EPO signaling pathway, remained unchanged, there was clear upregulation of phosphorylated ERK1 (p-ERK1) levels. The increase in levels of p-ERK1 was inhibited by an ERK kinase inhibitor, while the total amount of ERK remained unchanged. Conversely, the levels of EPOR were not affected by the inhibitor. Notably, the introduction of rh-EPO led to a significant increase in the frequency of angiogenesis-related cells and the expression levels of angiogenic factors. However, these effects were nullified when the ERK pathway was blocked. These findings indicate that rh-EPO enhances angiogenic responses through the EPOR-ERK1 pathway in a neonatal PWMD model.
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Affiliation(s)
- Lihua Zhu
- Department of Clinical Medicine, Jiangsu Health Vocational College, Nanjing 211800, China
| | - Qichao Yuan
- Department of Pediatrics, Danyang People’s Hospital Affiliate of Nantong University, Danyang 212300, China
| | - Chunping Jing
- Department of Pediatrics, Danyang People’s Hospital Affiliate of Nantong University, Danyang 212300, China
| | - Lingxian Sun
- Department of Clinical Medicine, Jiangsu Health Vocational College, Nanjing 211800, China
| | - Li Jiang
- Department of Pediatrics, Zhongda Hospital, Southeast University, Nanjing 210009, China
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Liu ZB, Fan XY, Wang CW, Ye X, Wu CJ. Potentially active compounds that improve PAD through angiogenesis: A review. Biomed Pharmacother 2023; 168:115634. [PMID: 37879211 DOI: 10.1016/j.biopha.2023.115634] [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: 08/08/2023] [Revised: 09/25/2023] [Accepted: 10/03/2023] [Indexed: 10/27/2023] Open
Abstract
Peripheral arterial disease (PAD) has been historically neglected, which has resulted in a lack of effective drugs in clinical practice. However, with the increasing prevalence of diseases like atherosclerosis and diabetes, the incidence of PAD is rising and cannot be ignored. Researchers are exploring the potential of promoting angiogenesis through exogenous compounds to improve PAD. This paper focuses on the therapeutic effect of natural products (Salidroside, Astragaloside IV, etc.) and synthetic compounds (Cilostazol, Dapagliflozin, etc.). Specifically, it examines how they can promote autocrine secretion of vascular endothelial cells, enhance cell paracrine interactions, and regulate endothelial progenitor cell function. The activation of these effects may be closely related to PI3K, AMPK, and other pathways. Overall, these exogenous compounds have promising therapeutic potential for PAD. This study aims to summarize the potential active compounds, provide a variety of options for the search for drugs for the treatment of PAD, and bring light to the treatment of patients.
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Affiliation(s)
- Zi-Bo Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xin-Yun Fan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Chen-Wei Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xun Ye
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Chun-Jie Wu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy/Academy for Interdiscipline, Chengdu Univesity of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Karimzadeh I, Rasekh H, Karimian A, Shabani-Borujeni M, Vazin A. Drug Utilization Evaluation of Erythropoietin at a Referral Teaching Hospital in Iran. Adv Pharmacol Pharm Sci 2023; 2023:6685602. [PMID: 38029231 PMCID: PMC10645503 DOI: 10.1155/2023/6685602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 10/07/2023] [Accepted: 10/09/2023] [Indexed: 12/01/2023] Open
Abstract
Objectives Drug utilization evaluation (DUE) studies aim to survey the appropriateness of drug use. DUE is an executive approach used to improve the use of medications as well as reduce the cost of treatment, ensure drug adequacy, and improve patient safety. The aim of this study was to evaluate the pattern of erythropoietin use, according to standard guidelines, in patients admitted to Namazi Hospital in Shiraz, Iran. Methods In this descriptive, retrospective study, 230 patients were assessed. All patients who were hospitalized in different wards of Namazi Hospital, affiliated to Shiraz University of Medical Sciences, and received at least three doses of erythropoietin from September 2019 to March 2020 participated in this study. The following standard indicators of erythropoietin use were evaluated through reviewing medical charts of the cohort: drug dose, dosing intervals, route of administration, indication, monitoring of laboratory parameters, drug dose adjustment based on the response rate as well as target hemoglobin ≥12 g/dl, attention to major drug interactions, and administration of injectable or oral iron supplementation during treatment. Results Most (65.2%) of the participants were male. The mean ± SD age of the patients was 47.55 ± 22.71 years. More than half (51.3%) of the included subjects were hospitalized in the nephrology ward. PDpoetin® and Cinnapoietin® were given to 52.6% and 47.4% of the study participants, respectively. Treatment of anemia due to chronic kidney disease was the most frequent indication of erythropoietin. The time interval of erythropoietin administration was three times a week for 68.3% of the patients. The most frequently administered weekly dose of erythropoietin was 12,000 units. The weekly dose, dose interval, and route of administration of erythropoietin were appropriate in 52.6%, 77.4%, and 100% of the patients, respectively. Dose adjustment based on the response rate, attention to major drug interactions as well as absolute-relative contraindications, and attention to the target hemoglobin ≥12 g/dl to decide whether or not to continue treatment were based on standard guideline in 98.1%, 98.7%, and 93% of the patients, respectively. The sum indexes of erythropoietin use were in line with standard guidelines in 75.84% of the cases. Conclusion According to our results, in the setting of erythropoietin use in hospitals, physicians need more attention and education in areas such as selecting the proper dose of medication, correct indication of the drug, temporal arrangement of monitoring laboratory items, and the patient's need for iron supplements.
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Affiliation(s)
- Iman Karimzadeh
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hanieh Rasekh
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ava Karimian
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mojtaba Shabani-Borujeni
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Afsaneh Vazin
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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15
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Rodrigues AQ, Silva IM, Goulart JT, Araújo LO, Ribeiro RB, Aguiar BA, Ferreira YB, Silva JKO, Bezerra JLS, Lucci CM, Paulini F. Effects of erythropoietin on ischaemia-reperfusion when administered before and after ovarian tissue transplantation in mice. Reprod Biomed Online 2023; 47:103234. [PMID: 37524029 DOI: 10.1016/j.rbmo.2023.05.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 05/04/2023] [Accepted: 05/10/2023] [Indexed: 08/02/2023]
Abstract
RESEARCH QUESTION Is the optimal timing for administering erythropoietin to minimize ischaemic injury in ovarian tissue transplantation before ovary removal for cryopreservation and subsequent transplantation or after transplantation? DESIGN Thirty Swiss mice (nu/nu) were divided into three groups: treatment control group (n = 10); erythropoietin before harvesting group (EPO-BH) (n = 10) and erythropoietin after transplantation group (EPO-AT) (n = 10). Animals underwent bilateral ovariohysterectomy and their hemiovaries were cryopreserved by slow freezing. At the same time, previously cryopreserved hemiovaries were transplanted subcutaneously in the dorsal region. Erythropoietin (250 IU/kg) and sterile 0.9% saline solution were administered every 12/12 h over 5 consecutive days in the EPO-AT and EPO-BH groups, respectively. RESULTS Administration of erythropoietin in the EPO-AT group improved the viability of ovarian follicles, reducing degeneration and increasing the number of morphologically normal growing follicles at 14 days after transplantation compared with the EPO-BH group (P = 0.002). This group also showed higher percentages of proliferative follicles at 7 days after transplantation (P ≤ 0.03), increased blood vessel count (P ≤ 0.03) and greater tissue area occupied by blood vessels at days 7 and 14 after transplantation (P ≤ 0.03), compared with hormone administration before cryopreservation (EPO-BH group) and the treatment control group. Additionally, treatment with erythropoietin before or after transplantation reduced fibrotic areas at 7 days after transplantation (P = 0.004). CONCLUSION Erythropoietin treatment after transplantation reduced ischaemic damage in transplanted ovarian tissue, increased angiogenesis, maintenance of ovarian follicle proliferation and reduced fibrosis areas in the grafted tissue.
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Affiliation(s)
- Aline Q Rodrigues
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Isabella Mg Silva
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Jair T Goulart
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Luane O Araújo
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Rayane B Ribeiro
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Beatriz A Aguiar
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Yasmin B Ferreira
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Jessyca Karoline O Silva
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Julliene Larissa S Bezerra
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Carolina M Lucci
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil
| | - Fernanda Paulini
- University of Brasilia, Institute of Biological Sciences, Department of Physiological Sciences, Brasilia-DF, 70910-900, Brazil.
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Saberi A, Kouhjani M, Mohammadi M, Hosta-Rigau L. Novel scaffold platforms for simultaneous induction osteogenesis and angiogenesis in bone tissue engineering: a cutting-edge approach. J Nanobiotechnology 2023; 21:351. [PMID: 37770928 PMCID: PMC10536787 DOI: 10.1186/s12951-023-02115-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 09/15/2023] [Indexed: 09/30/2023] Open
Abstract
Despite the recent advances in the development of bone graft substitutes, treatment of critical size bone defects continues to be a significant challenge, especially in the elderly population. A current approach to overcome this challenge involves the creation of bone-mimicking scaffolds that can simultaneously promote osteogenesis and angiogenesis. In this context, incorporating multiple bioactive agents like growth factors, genes, and small molecules into these scaffolds has emerged as a promising strategy. To incorporate such agents, researchers have developed scaffolds incorporating nanoparticles, including nanoparticulate carriers, inorganic nanoparticles, and exosomes. Current paper provides a summary of the latest advancements in using various bioactive agents, drugs, and cells to synergistically promote osteogenesis and angiogenesis in bone-mimetic scaffolds. It also discusses scaffold design properties aimed at maximizing the synergistic effects of osteogenesis and angiogenesis, various innovative fabrication strategies, and ongoing clinical studies.
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Affiliation(s)
- Arezoo Saberi
- Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Kouhjani
- Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Marzieh Mohammadi
- Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Leticia Hosta-Rigau
- DTU Health Tech, Centre for Nanomedicine and Theranostics, Technical University of Denmark, Produktionstorvet, Building 423, 2800, Kgs. Lyngby, Denmark.
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17
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Rejdak K, Sienkiewicz-Jarosz H, Bienkowski P, Alvarez A. Modulation of neurotrophic factors in the treatment of dementia, stroke and TBI: Effects of Cerebrolysin. Med Res Rev 2023; 43:1668-1700. [PMID: 37052231 DOI: 10.1002/med.21960] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/21/2023] [Accepted: 03/27/2023] [Indexed: 04/14/2023]
Abstract
Neurotrophic factors (NTFs) are involved in the pathophysiology of neurological disorders such as dementia, stroke and traumatic brain injury (TBI), and constitute molecular targets of high interest for the therapy of these pathologies. In this review we provide an overview of current knowledge of the definition, discovery and mode of action of five NTFs, nerve growth factor, insulin-like growth factor 1, brain derived NTF, vascular endothelial growth factor and tumor necrosis factor alpha; as well as on their contribution to brain pathology and potential therapeutic use in dementia, stroke and TBI. Within the concept of NTFs in the treatment of these pathologies, we also review the neuropeptide preparation Cerebrolysin, which has been shown to resemble the activities of NTFs and to modulate the expression level of endogenous NTFs. Cerebrolysin has demonstrated beneficial treatment capabilities in vitro and in clinical studies, which are discussed within the context of the biochemistry of NTFs. The review focuses on the interactions of different NTFs, rather than addressing a single NTF, by outlining their signaling network and by reviewing their effect on clinical outcome in prevalent brain pathologies. The effects of the interactions of these NTFs and Cerebrolysin on neuroplasticity, neurogenesis, angiogenesis and inflammation, and their relevance for the treatment of dementia, stroke and TBI are summarized.
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Affiliation(s)
- Konrad Rejdak
- Department of Neurology, Medical University of Lublin, Lublin, Poland
| | | | | | - Anton Alvarez
- Medinova Institute of Neurosciences, Clinica RehaSalud, Coruña, Spain
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18
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Najafi A, Asadi E, Benson JD. Ovarian tissue cryopreservation and transplantation: a review on reactive oxygen species generation and antioxidant therapy. Cell Tissue Res 2023; 393:401-423. [PMID: 37328708 DOI: 10.1007/s00441-023-03794-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 05/31/2023] [Indexed: 06/18/2023]
Abstract
Cancer is the leading cause of death worldwide. Fortunately, the survival rate of cancer continues to rise, owing to advances in cancer treatments. However, these treatments are gonadotoxic and cause infertility. Ovarian tissue cryopreservation and transplantation (OTCT) is the most flexible option to preserve fertility in women and children with cancer. However, OTCT is associated with significant follicle loss and an accompanying short lifespan of the grafts. There has been a decade of research in cryopreservation-induced oxidative stress in single cells with significant successes in mitigating this major source of loss of viability. However, despite its success elsewhere and beyond a few promising experiments, little attention has been paid to this key aspect of OTCT-induced damage. As more and more clinical practices adopt OTCT for fertility preservation, it is a critical time to review oxidative stress as a cause of damage and to outline potential ameliorative interventions. Here we give an overview of the application of OTCT for female fertility preservation and existing challenges; clarify the potential contribution of oxidative stress in ovarian follicle loss; and highlight potential ability of antioxidant treatments to mitigate the OTCT-induced injuries that might be of interest to cryobiologists and reproductive clinicians.
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Affiliation(s)
- Atefeh Najafi
- Department of Biology, University of Saskatchewan, S7N 5E2, Saskatoon, SK, Canada
| | - Ebrahim Asadi
- Department of Biology, University of Saskatchewan, S7N 5E2, Saskatoon, SK, Canada
| | - James D Benson
- Department of Biology, University of Saskatchewan, S7N 5E2, Saskatoon, SK, Canada.
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19
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Aboouf MA, Thiersch M, Soliz J, Gassmann M, Schneider Gasser EM. The Brain at High Altitude: From Molecular Signaling to Cognitive Performance. Int J Mol Sci 2023; 24:10179. [PMID: 37373327 DOI: 10.3390/ijms241210179] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/13/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
The brain requires over one-fifth of the total body oxygen demand for normal functioning. At high altitude (HA), the lower atmospheric oxygen pressure inevitably challenges the brain, affecting voluntary spatial attention, cognitive processing, and attention speed after short-term, long-term, or lifespan exposure. Molecular responses to HA are controlled mainly by hypoxia-inducible factors. This review aims to summarize the cellular, metabolic, and functional alterations in the brain at HA with a focus on the role of hypoxia-inducible factors in controlling the hypoxic ventilatory response, neuronal survival, metabolism, neurogenesis, synaptogenesis, and plasticity.
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Affiliation(s)
- Mostafa A Aboouf
- Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zürich, 8057 Zurich, Switzerland
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland
| | - Markus Thiersch
- Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zürich, 8057 Zurich, Switzerland
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland
| | - Jorge Soliz
- Institute Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Faculty of Medicine, Université Laval, Québec, QC G1V 4G5, Canada
| | - Max Gassmann
- Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zürich, 8057 Zurich, Switzerland
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland
| | - Edith M Schneider Gasser
- Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zürich, 8057 Zurich, Switzerland
- Institute Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Faculty of Medicine, Université Laval, Québec, QC G1V 4G5, Canada
- Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland
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20
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Poffé C, Robberechts R, Van Thienen R, Hespel P. Exogenous ketosis elevates circulating erythropoietin and stimulates muscular angiogenesis during endurance training overload. J Physiol 2023; 601:2345-2358. [PMID: 37062892 DOI: 10.1113/jp284346] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 04/12/2023] [Indexed: 04/18/2023] Open
Abstract
De novo capillarization is a primary muscular adaptation to endurance exercise training and is crucial to improving performance. Excess training load, however, impedes such beneficial adaptations, yet we recently demonstrated that such downregulation may be counteracted by ketone ester ingestion (KE) post-exercise. Therefore, we investigated whether KE could increase pro-angiogenic factors and thereby stimulate muscular angiogenesis during a 3-week endurance training-overload period involving 10 training sessions/week in healthy, male volunteers. Subjects received either 25 g of a ketone ester (KE, n = 9) or a control drink (CON, n = 9) immediately after each training session and before sleep. In KE, but not in CON, the training intervention increased the number of capillary contacts and the capillary-to-fibre perimeter exchange index by 44% and 42%, respectively. Furthermore, KE also substantially increased vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression both at the protein and at the mRNA level. Serum erythropoietin concentration was concomitantly increased by 26%. Conversely, in CON the training intervention increased only the protein content of eNOS. These data indicate that intermittent exogenous ketosis during endurance overload training stimulates muscular angiogenesis. This likely resulted from a direct stimulation of muscle angiogenesis, which may be at least partly due to stimulation of erythropoietin secretion and elevated VEGF activity, and/or an inhibition of the suppressive effect of overload training on the normal angiogenic response to training. This study provides novel evidence to support the potential of exogenous ketosis to benefit endurance training-induced muscular adaptation. KEY POINTS: Increased capillarization is a primary muscular adaptation to endurance exercise training. However, excess training load may impede such response. We previously observed that intermittent exogenous ketosis by post-exercise and pre-sleep ketone ester ingestion (KE) counteracted physiological dysregulations induced by endurance overload training. Therefore, we investigated whether KE could increase pro-angiogenic factors thereby stimulating muscular angiogenesis during a 3-week endurance training overload period. We show that the overload training period in the presence, but not in the absence, of KE markedly increased muscle capillarization (+40%). This increase was accompanied by higher circulating erythropoietin concentration and stimulation of the pro-angiogenic factors vascular endothelial growth factor and endothelial nitric oxide synthase in skeletal muscle. Collectively, our data indicate that intermittent exogenous ketosis may evolve as a potent nutritional strategy to facilitate recovery from strenuous endurance exercise, thereby stimulating beneficial muscular adaptations.
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Affiliation(s)
- Chiel Poffé
- Exercise Physiology Research Group, Department of Movement Sciences, KU Leuven, Leuven, Belgium
| | - Ruben Robberechts
- Exercise Physiology Research Group, Department of Movement Sciences, KU Leuven, Leuven, Belgium
| | - Ruud Van Thienen
- Exercise Physiology Research Group, Department of Movement Sciences, KU Leuven, Leuven, Belgium
| | - Peter Hespel
- Department of Movement Sciences, KU Leuven, Leuven, Belgium
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21
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Duygu G, Yalcin-Ülker GM, Günbatan M, Soluk-Tekkesin M, Özcakir-Tomruk C. Evaluation of Preventive Role of Systemically Applied Erythropoietin after Tooth Extraction in a Bisphosphonate-Induced MRONJ Model. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1059. [PMID: 37374263 DOI: 10.3390/medicina59061059] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/23/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023]
Abstract
Background and Objectives: In this experimental study, the prophylactic effect of systemically administered erythropoietin (EPO) in medication-related osteonecrosis of the jaw (MRONJ) was evaluated. Materials and Methods: The osteonecrosis model was established using 36 Sprague Dawley rats. EPO was systemically applied before and/or after tooth extraction. Groups were formed based on the application time. All samples were evaluated histologically, histomorphometrically, and immunohistochemically. A statistically significant difference in new bone formation was observed between the groups (p < 0.001). Results: When new bone-formation rates were compared, no significant differences were observed between the control group and the EPO, ZA+PostEPO, and ZA+Pre-PostEPO groups (p = 1, 0.402, and 1, respectively); however, this rate was significantly lower in the ZA+PreEPO group (p = 0.021). No significant differences in new bone formation were observed between the ZA+PostEPO and ZA+PreEPO groups (p = 1); however, this rate was significantly higher in the ZA+Pre-PostEPO group (p = 0.009). The ZA+Pre-PostEPO group demonstrated significantly higher intensity level in VEGF protein expression than the other groups (p < 0.001). Conclusions: Administering EPO two weeks pre-extraction and continuing EPO treatment for three weeks post-extraction in ZA-treated rats optimized the inflammatory reaction, increased angiogenesis by inducing VEGF, and positively affected bone healing. Further studies are needed to determine the exact durations and doses.
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Affiliation(s)
- Gonca Duygu
- Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Tekirdag Namık Kemal University, Tekirdag 59030, Türkiye
| | - Gül Merve Yalcin-Ülker
- Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Istanbul Okan University, Istanbul 34947, Türkiye
| | - Murat Günbatan
- Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Istanbul Okan University, Istanbul 34947, Türkiye
| | - Merva Soluk-Tekkesin
- Department of Tumour Pathology, Institute of Oncology, Istanbul University, Istanbul 34093, Türkiye
| | - Ceyda Özcakir-Tomruk
- Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Yeditepe University, Istanbul 34728, Türkiye
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22
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Basile G, Bellone F, Catalano A, Maltese G, Corica F, Squadrito G, Scicali R, Mandraffino G. Is the relationship between erythropoiesis and renal function one of the secrets of extreme longevity? Nutr Metab Cardiovasc Dis 2023; 33:868-872. [PMID: 36775710 DOI: 10.1016/j.numecd.2023.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 11/22/2022] [Accepted: 01/20/2023] [Indexed: 01/31/2023]
Abstract
BACKGROUND AND AIMS Renal function and erythropoiesis could be impaired with advancing age. Neutrophil gelatinase-associated lipocalin (NGAL) as well as erythropoietin (EPO) levels are two useful biomarkers of the renal status. In advanced age, the relationships between NGAL, EPO and hemoglobin (Hb) levels remains unknown. The aim of the present study is to evaluate the relationship between renal function and erythropoiesis in a small cohort of centenarians. METHODS AND RESULTS We observed thirty-one healthy centenarians with normal hemoglobin levels, a mild reduction in eGFR and no need of erythropoiesis support. We found a significant inverse association between NGAL and GFR, hemoglobin levels and EPO, confirming the key role of the renal function on erythropoiesis also in extreme longevity. A gender difference emerged, showing female participants with lower eGFR and Hb values more than males. CONCLUSIONS Our findings suggested a new link between renal function, erythropoiesis and longevity in centenarians and these could have relevant implications in clinical practice. These findings could explain why very old subjects presenting a slight GFR reduction seemed not to be exposed to a significant risk of mortality.
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Affiliation(s)
- Giorgio Basile
- Unit and School of Geriatrics, Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Federica Bellone
- Unit and School of Geriatrics, Department of Clinical and Experimental Medicine, University of Messina, Italy; Unit of Internal Medicine, Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Antonino Catalano
- Unit and School of Geriatrics, Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Giuseppe Maltese
- Cardiovascular Division, Faculty of Life Science & Medicine, King's College London, London, UK
| | - Francesco Corica
- Unit and School of Geriatrics, Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Giovanni Squadrito
- Unit of Internal Medicine, Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Roberto Scicali
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Giuseppe Mandraffino
- Unit of Internal Medicine, Department of Clinical and Experimental Medicine, University of Messina, Italy.
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23
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Iso Y, Usui S, Suzuki H. Mesenchymal Stem/Stromal Cells in Skeletal Muscle Are Pro-Angiogenic, and the Effect Is Potentiated by Erythropoietin. Pharmaceutics 2023; 15:pharmaceutics15041049. [PMID: 37111534 PMCID: PMC10142054 DOI: 10.3390/pharmaceutics15041049] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/11/2023] [Accepted: 03/23/2023] [Indexed: 04/29/2023] Open
Abstract
The aim of this study was to investigate the angiogenic potential of skeletal muscle mesenchymal stem/stromal cells (mMSCs). Platelet-derived growth factor receptor (PDGFR)-α positive mMSCs secreted vascular endothelial growth factor (VEGF) and hepatocyte growth factor when cultured in an ELISA assay. The mMSC-medium significantly induced endothelial tube formation in an in vitro angiogenesis assay. The mMSC implantation promoted capillary growth in rat limb ischemia models. Upon identifying the erythropoietin receptor (Epo-R) in the mMSCs, we examined how Epo affected the cells. Epo stimulation enhanced the phosphorylation of Akt and STAT3 in the mMSCs and significantly promoted cellular proliferation. Next, Epo was directly administered into the rats' ischemic hindlimb muscles. PDGFR-α positive mMSCs in the interstitial area of muscles expressed VEGF and proliferating cell markers. The proliferating cell index was significantly higher in the ischemic limbs of Epo-treated rats than in untreated controls. Investigations by laser Doppler perfusion imaging and immunohistochemistry demonstrated significantly improved perfusion recovery and capillary growth in the Epo-treated groups versus the control groups. Taken together, the results of this study demonstrated that mMSCs possessed a pro-angiogenic property, were activated by Epo, and potentially contributed to capillary growth in skeletal muscle after ischemic injury.
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Affiliation(s)
- Yoshitaka Iso
- Division of Cardiology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Yokohama City 227-8501, Kanagawa, Japan
| | - Sayaka Usui
- Division of Cardiology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Yokohama City 227-8501, Kanagawa, Japan
| | - Hiroshi Suzuki
- Division of Cardiology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Yokohama City 227-8501, Kanagawa, Japan
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24
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Fetisov TI, Borunova AA, Antipova AS, Antoshina EE, Trukhanova LS, Gorkova TG, Zuevskaya SN, Maslov A, Gurova K, Gudkov A, Lesovaya EA, Belitsky GA, Yakubovskaya MG, Kirsanov KI. Targeting Features of Curaxin CBL0137 on Hematological Malignancies In Vitro and In Vivo. Biomedicines 2023; 11:biomedicines11010230. [PMID: 36672738 PMCID: PMC9856019 DOI: 10.3390/biomedicines11010230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/31/2022] [Accepted: 01/12/2023] [Indexed: 01/19/2023] Open
Abstract
The anticancer activity of Curaxin CBL0137, a DNA-binding small molecule with chromatin remodulating effect, has been demonstrated in different cancers. Herein, a comparative evaluation of CBL0137 activity was performed in respect to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia and multiple myeloma (MM) cultured in vitro. MTT assay showed AML and MM higher sensitivity to CBL0137's cytostatic effect comparatively to other hematological malignancy cells. Flow cytometry cell cycle analysis revealed an increase in subG1 and G2/M populations after CBL0137 cell treatment, but the prevalent type of arrest varied. Apoptosis activation by CBL0137 measured by Annexin-V/PI dual staining was more active in AML and MM cells. RT2 PCR array showed that changes caused by CBL0137 in signaling pathways involved in cancer pathogenesis were more intensive in AML and MM cells. On the murine model of AML WEHI-3, CBL0137 showed significant anticancer effects in vivo, which were evaluated by corresponding changes in spleen and liver. Thus, more pronounced anticancer effects of CBL0137 in vitro were observed in respect to AML and MM. Experiments in vivo also indicated the perspective of CBL0137 use for AML treatment. This in accordance with the frontline treatment approach in AML using epigenetic drugs.
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Affiliation(s)
- Timur I. Fetisov
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Anna A. Borunova
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Alina S. Antipova
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Elena E. Antoshina
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Lubov S. Trukhanova
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Tatyana G. Gorkova
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | | | - Alexei Maslov
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Katerina Gurova
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Andrei Gudkov
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Ekaterina A. Lesovaya
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
- Department of Oncology, I.P. Pavlov Ryazan State Medical University, 390026 Ryazan, Russia
| | - Gennady A. Belitsky
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | | | - Kirill I. Kirsanov
- N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
- Correspondence:
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25
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Manto KM, Govindappa PK, Martinazzi B, Han A, Hegarty JP, Koroneos Z, Talukder MAH, Elfar JC. Erythropoietin-PLGA-PEG as a local treatment to promote functional recovery and neurovascular regeneration after peripheral nerve injury. J Nanobiotechnology 2022; 20:461. [PMID: 36307805 PMCID: PMC9617443 DOI: 10.1186/s12951-022-01666-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 10/07/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Traumatic peripheral nerve injury (TPNI) is a major medical problem with no universally accepted pharmacologic treatment. We hypothesized that encapsulation of pro-angiogenic erythropoietin (EPO) in amphiphilic PLGA-PEG block copolymers could serve as a local controlled-release drug delivery system to enhance neurovascular regeneration after nerve injury. METHODS In this study, we synthesized an EPO-PLGA-PEG block copolymer formulation. We characterized its physiochemical and release properties and examined its effects on functional recovery, neural regeneration, and blood vessel formation after sciatic nerve crush injury in mice. RESULTS EPO-PLGA-PEG underwent solution-to-gel transition within the physiologically relevant temperature window and released stable EPO for up to 18 days. EPO-PLGA-PEG significantly enhanced sciatic function index (SFI), grip strength, and withdrawal reflex post-sciatic nerve crush injury. Furthermore, EPO-PLGA-PEG significantly increased blood vessel density, number of junctions, and myelinated nerve fibers after injury. CONCLUSION This study provides promising preclinical evidence for using EPO-PLGA-PEG as a local controlled-release treatment to enhance functional outcomes and neurovascular regeneration in TPNI.
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Affiliation(s)
- Kristen M Manto
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Prem Kumar Govindappa
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
- Department of Orthopaedics and Sports Medicine, University of Arizona College of Medicine, Tucson, AZ, 85724, USA
| | - Brandon Martinazzi
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Aijie Han
- Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA, 16802, USA
| | - John P Hegarty
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Zachary Koroneos
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - M A Hassan Talukder
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - John C Elfar
- Department of Orthopaedics and Sports Medicine, University of Arizona College of Medicine, Tucson, AZ, 85724, USA.
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26
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Diagnostic Imaging Studies on Local and Systemic Erythropoietin Application for Promoting Bone Regeneration in Rat Calvarial Defects. Vet Sci 2022; 9:vetsci9100578. [PMID: 36288191 PMCID: PMC9607163 DOI: 10.3390/vetsci9100578] [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: 09/14/2022] [Revised: 10/06/2022] [Accepted: 10/15/2022] [Indexed: 11/07/2022] Open
Abstract
The purpose of this study was to compare the effects of local and systemic application of recombinant human erythropoietin (rhEPO) on the healing of rat calvarial defects. Twenty-four male skeletally-mature Wistar rats were used. Two bone 5 mm critical size defects were created in calvarial bones of each rat. In rats from experimental group I (n = 12), EPO was applied locally on a collagen cone in left defects, whereas a collagen cone soaked with physiological saline was placed in right defects. The rats from experimental group II were injected once intraperitoneally with 4900 IU/kg EPO; a collagen cone was only placed in left defects, whereas the right defects were left empty. The systemic effect of EPO treatment was monitored by haematological analyses on days 0, 30 and 90. Bone healing was monitored via radiography and computed tomography on the same time intervals. The results demonstrated that local EPO application had no significant effect on haemopoiesis, unlike the systemic application. At the same time, it resulted in new bone formation and therefore, could be successfully used as a means of promoting bone regeneration.
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27
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Wang L, Sheng G, Cui J, Yao Y, Bai X, Chen F, Yu W. Electroacupuncture attenuates ischemic injury after stroke and promotes angiogenesis via activation of EPO mediated Src and VEGF signaling pathways. PLoS One 2022; 17:e0274620. [PMID: 36108080 PMCID: PMC9477374 DOI: 10.1371/journal.pone.0274620] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 08/29/2022] [Indexed: 11/19/2022] Open
Abstract
Although electroacupuncture (EA) has been shown to be effective in the treatment of stroke, its mechanisms of action remain undefined. This study explored the therapeutic effects of EA in rats with cerebral ischemia-reperfusion injury (CIRI) and evaluated its possible mechanisms in promoting angiogenesis. To evaluate the effect of EA, we used 2, 3, 5-Triphenyl-2H-Tetrazolium Chloride (TTC) staining and behavior score to calculate the cerebral infarct volume and neurological deficit score after CIRI. Western blot (WB) analysis was employed to evaluate the expression of cluster of differentiation 34 (CD34), erythropoietin (EPO), vascular endothelial growth factor (VEGF) and phospho-Src (p-Src) in the brain of the rats with CIRI. On the other hand, we established an oxygen-glucose deprivation/reoxygenation (OGD/R) injury model using brain microvascular endothelial cells (BMECs), and analyzed cell viability and expression of VEGF or p-Src using cell counting kit-8 (CCK-8) and WB, respectively. Our data showed that EA at the GV26 acupoint could significantly promote the expression of CD34, EPO, VEGF and p-Src in CIRI rats. Our CCK-8 results demonstrated that intervention with recombinant EPO and VEGF proteins remarkably improved the viability of BMECs after OGD/R, while a Src inhibitor, PP1, reversed this phenotype. The WB results showed that the recombinant EPO protein increased the expression of VEGF and p-Src, which was significantly inhibited by PP1. Taken together, our findings showed that EA at the GV26 acupoint can significantly attenuate ischemic injury after stroke and promote angiogenesis via activation of EPO-mediated Src and VEGF signaling pathways. Besides, the upregulation of VEGF may also be associated with the activation of Src by EPO.
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Affiliation(s)
- Lifen Wang
- Shaanxi Academy of Traditional Chinese Medicine, Shaanxi Provincial Hospital of Chinese Medicine, Xi’an, China
| | - Gang Sheng
- Shaanxi Academy of Traditional Chinese Medicine, Shaanxi Provincial Hospital of Chinese Medicine, Xi’an, China
| | - Jinjun Cui
- Department of Neurology, Hebei Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Cangzhou, China
| | - Yanling Yao
- Shaanxi Academy of Traditional Chinese Medicine, Shaanxi Provincial Hospital of Chinese Medicine, Xi’an, China
| | - Xue Bai
- College of Acupuncture-Moxibustion and Massage, Shaanxi University of Chinese Medicine, Xian yang, China
| | - Fan Chen
- College of Acupuncture-Moxibustion and Massage, Shaanxi University of Chinese Medicine, Xian yang, China
| | - Wei Yu
- Department of Physiology, Xi’an Medical University, Xi’an, China
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28
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Papic M, Zivanovic S, Vucicevic T, Papic MV, Zdravkovic D, Milivojevic N, Virijevic K, Zivanovic M, Mircic A, Ljujic B, Lukic ML, Popovic M. Pulpal expression of erythropoietin and erythropoietin receptor after direct pulp capping in rat. Eur J Oral Sci 2022; 130:e12888. [PMID: 35917324 DOI: 10.1111/eos.12888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 07/17/2022] [Indexed: 11/27/2022]
Abstract
This study aimed to evaluate the effect of direct pulp capping on the expression of erythropoietin (Epo) and Epo-receptor (Epor) genes in relation to the expression of inflammatory and osteogenic genes in rat pulp. Dental pulps of the first maxillary molars of Wistar Albino rats were exposed and capped with either calcium hydroxide or mineral trioxide aggregate, or were left untreated. After 4 wk, animals were euthanized, and maxillae were prepared for histological and real-time polymerase chain reaction analysis. Histological scores of pulp inflammation and mineralization, and relative expressions of Epo, Epor, inflammatory cytokines, and pulp osteogenic genes were evaluated. The capped pulps showed higher expressions of Epo, while the untreated pulps had the highest expression of Epor. Both calcium hydroxide and mineral trioxide aggregate downregulated the expression of tumor necrosis factor alpha compared to untreated controls, and upregulated transforming growth factor beta compared to healthy controls. Alkaline phosphatase expression was significantly higher in experimental groups. Relative expression of Epo negatively correlated with pulp inflammation, and positively correlated with pulp mineralization. Pulp exposure promoted expression of Epor and pro-inflammatory cytokines, while pulp capping promoted expression of Epo, alkaline phosphatase, and downregulated Epor and pro-inflammatory cytokines.
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Affiliation(s)
- Milos Papic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Suzana Zivanovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Tamara Vucicevic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Mirjana V Papic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Dejan Zdravkovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Nevena Milivojevic
- Department of Science, Institute for Information Technologies, University of Kragujevac, Kragujevac, Serbia
| | - Katarina Virijevic
- Department of Science, Institute for Information Technologies, University of Kragujevac, Kragujevac, Serbia
| | - Marko Zivanovic
- Department of Science, Institute for Information Technologies, University of Kragujevac, Kragujevac, Serbia
| | - Aleksandar Mircic
- Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Biljana Ljujic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Miodrag L Lukic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Milica Popovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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29
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Lv W, Chen W, Huang S, Xu Y, Liang JJ, Zheng Y, Chen S, Chen SL, Ng TK, Chen H. Reduction of Laser-Induced Choroidal Neovascularization in Mice With Erythropoietin RNA Interference. Transl Vis Sci Technol 2022; 11:1. [PMID: 35913417 PMCID: PMC9351596 DOI: 10.1167/tvst.11.8.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
PURPOSE The purpose of this study was to evaluate the pathological involvement of erythropoietin (EPO) in experimental choroidal neovascularization (CNV) and its association with neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) in the Chinese population. METHODS Treatment effect of recombinant EPO protein were assessed by human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation, and ex vivo choroid-sprouting ability. The effect of intravitreal injection of Epo siRNA against neovascularization was evaluated in the laser-induced CNV mouse model. In addition, the association of EPO variants with neovascular AMD and PCV was determined. RESULTS Exogenous supplementation of EPO significantly enhanced the migration and tube formation of HUVECs and promoted ex vivo choroid sprouting in mouse retinal pigment epithelium (RPE)-choroid-sclera complex culture. In the experimental CNV mouse model, Epo expression was found to be significantly upregulated by 3.5-folds in RPE-choroid-sclera complex at day 10 after laser induction as compared to the baseline. Immunofluorescence analysis showed that Epo was mainly expressed around the vascular endothelial cells in the RPE-choroid-sclera complex. Intravitreal injection of siRNA targeting Epo reduced 40% Epo expression and 40% CNV lesion areas as compared to the scramble control. However, EPO variants were not associated with neovascular AMD nor PCV in the Chinese population. CONCLUSIONS This study revealed the promotion of human endothelial cell tube formation in vitro and choroid sprouting ex vivo by EPO, and the reduction of laser-induced CNV in vivo by Epo RNA interference. TRANSLATIONAL RELEVANCE Targeting EPO could be a potential additional treatment for CNV-related diseases.
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Affiliation(s)
- Wenjuan Lv
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong, China
| | - Wen Chen
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong, China
- Shantou University Medical College, Shantou, Guangdong, China
| | - Shaofen Huang
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong, China
| | - Yanxuan Xu
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong, China
| | - Jia-Jian Liang
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong, China
| | - Yuqian Zheng
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong, China
| | - Shaowan Chen
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong, China
| | - Shao-Lang Chen
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong, China
| | - Tsz Kin Ng
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong, China
- Shantou University Medical College, Shantou, Guangdong, China
- Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong
| | - Haoyu Chen
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong, China
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Ramshekar A, Bretz CA, Kunz E, Cung T, Richards BT, Stoddard GJ, Hageman GS, Chaqour B, Hartnett ME. Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization. Biomedicines 2022; 10:1655. [PMID: 35884958 PMCID: PMC9312702 DOI: 10.3390/biomedicines10071655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 01/07/2023] Open
Abstract
Erythropoietin (EPO) has been proposed to reduce the progression of atrophic age-related macular degeneration (AMD) due to its potential role in neuroprotection. However, overactive EPO receptor (EPOR) signaling increased laser-induced choroidal neovascularization (CNV) and choroidal macrophage number in non-lasered mice, which raised the question of whether EPOR signaling increased CNV through the recruitment of macrophages to the choroid that released pro-angiogenic factors or through direct angiogenic effects on endothelial cells. In this study, we addressed the hypothesis that EPOR signaling increased CNV by direct effects on macrophages or endothelial cells. We used tamoxifen-inducible macrophage-specific or endothelial cell-specific EPOR knockout mice in the laser-induced CNV model, and cultured choroidal endothelial cells isolated from adult human donors. We found that macrophage-specific knockout of EPOR influenced laser-induced CNV in females only, whereas endothelial-specific knockout of EPOR reduced laser-induced CNV in male mice only. In cultured human choroidal endothelial cells, knockdown of EPOR reduced EPO-induced signal transducer and activator of transcription 3 (STAT3) activation. Taken together, our findings suggest that EPOR signaling in macrophages or choroidal endothelial cells regulates the development of CNV in a sex-dependent manner. Further studies regarding the role of EPO-induced signaling are required to assess EPO safety and to select or develop appropriate therapeutic approaches.
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Affiliation(s)
- Aniket Ramshekar
- Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA; (A.R.); (C.A.B.); (E.K.); (T.C.)
| | - Colin A. Bretz
- Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA; (A.R.); (C.A.B.); (E.K.); (T.C.)
| | - Eric Kunz
- Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA; (A.R.); (C.A.B.); (E.K.); (T.C.)
| | - Thaonhi Cung
- Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA; (A.R.); (C.A.B.); (E.K.); (T.C.)
| | - Burt T. Richards
- Sharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA; (B.T.R.); (G.S.H.)
| | - Gregory J. Stoddard
- Department of Internal Medicine, University of Utah, 30 N 1900 E, Salt Lake City, UT 84132, USA;
| | - Gregory S. Hageman
- Sharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA; (B.T.R.); (G.S.H.)
| | - Brahim Chaqour
- Department of Ophthalmology, University of Pennsylvania, 422 Curie Boulevard, Philadelphia, PA 19104, USA;
| | - M. Elizabeth Hartnett
- Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA; (A.R.); (C.A.B.); (E.K.); (T.C.)
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Lai YF, Lin TY, Ho PK, Chen YH, Huang YC, Lu DW. Erythropoietin in Optic Neuropathies: Current Future Strategies for Optic Nerve Protection and Repair. Int J Mol Sci 2022; 23:ijms23137143. [PMID: 35806148 PMCID: PMC9267007 DOI: 10.3390/ijms23137143] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/13/2022] [Accepted: 06/24/2022] [Indexed: 02/05/2023] Open
Abstract
Erythropoietin (EPO) is known as a hormone for erythropoiesis in response to anemia and hypoxia. However, the effect of EPO is not only limited to hematopoietic tissue. Several studies have highlighted the neuroprotective function of EPO in extra-hematopoietic tissues, especially the retina. EPO could interact with its heterodimer receptor (EPOR/βcR) to exert its anti-apoptosis, anti-inflammation and anti-oxidation effects in preventing retinal ganglion cells death through different intracellular signaling pathways. In this review, we summarized the available pre-clinical studies of EPO in treating glaucomatous optic neuropathy, optic neuritis, non-arteritic anterior ischemic optic neuropathy and traumatic optic neuropathy. In addition, we explore the future strategies of EPO for optic nerve protection and repair, including advances in EPO derivates, and EPO deliveries. These strategies will lead to a new chapter in the treatment of optic neuropathy.
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Affiliation(s)
- Yi-Fen Lai
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (Y.-F.L.); (T.-Y.L.); (Y.-H.C.)
| | - Ting-Yi Lin
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (Y.-F.L.); (T.-Y.L.); (Y.-H.C.)
| | - Pin-Kuan Ho
- School of Dentistry, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Yi-Hao Chen
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (Y.-F.L.); (T.-Y.L.); (Y.-H.C.)
| | - Yu-Chuan Huang
- School of Pharmacy, National Defense Medical Center, Taipei 11490, Taiwan
- Department of Research and Development, National Defense Medical Center, Taipei 11490, Taiwan
- Correspondence: (Y.-C.H.); (D.-W.L.); Tel.: +886-2-87923100 (Y.-C.H.); +886-2-87927163 (D.-W.L.)
| | - Da-Wen Lu
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (Y.-F.L.); (T.-Y.L.); (Y.-H.C.)
- Correspondence: (Y.-C.H.); (D.-W.L.); Tel.: +886-2-87923100 (Y.-C.H.); +886-2-87927163 (D.-W.L.)
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32
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Sesti LFC, Sbruzzi RC, Polina ER, dos Santos Soares D, Crispim D, Canani LH, dos Santos KG. Association of polymorphisms in the erythropoietin gene with diabetic retinopathy: a case-control study and systematic review with meta-analysis. BMC Ophthalmol 2022; 22:250. [PMID: 35659624 PMCID: PMC9167513 DOI: 10.1186/s12886-022-02467-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/26/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is characterized by ischemia, hypoxia, and angiogenesis. Erythropoietin (EPO), an angiogenic hormone, is upregulated in DR, and the association of EPO genetic variants with DR is still uncertain, as conflicting results have been reported. Therefore, we performed a case-control study followed by a meta-analysis to investigate whether the rs1617640, rs507392, and rs551238 polymorphisms in EPO gene are associated with DR. METHODS The case-control study included 1042 Southern Brazilians with type 2 diabetes (488 without DR and 554 with DR). Eligible studies for the meta-analysis were searched from electronic databases up to June 1, 2021. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for five genetic inheritance models. RESULTS The minor alleles of the EPO polymorphisms had nearly the same frequency in all groups of patients (35%), and no association was detected with DR in the case-control study. The meta-analysis included 14 independent sets of cases and controls with 9117 subjects for the rs1617640 polymorphism and nine independent sets with more than 5000 subjects for the rs507392 and rs551238 polymorphisms. The G allele of the rs1617640 polymorphism was suggestively associated with DR under the dominant (OR = 0.82, 95% CI: 0.68-0.98), heterozygous additive (OR = 0.82, 95% CI: 0.69-0.97), and overdominant (OR = 0.88, 95% CI: 0.79-0.97) models. In the subgroup analyses, the G allele was also suggestively associated with proliferative DR (PDR), non-proliferative DR (NPDR), and DR (PDR + NPDR) among patients with type 1 diabetes (T1DM) or non-Asian ancestry. After considering the Bonferroni correction for multiple comparisons, the G allele remained associated with NPDR and DR in T1DM. Regarding the rs507392 and rs551238 polymorphisms, no association was found between these variants and DR. CONCLUSION Our findings provide additional support to EPO as a susceptibility gene for DR, with the rs1617640 polymorphism deserving further investigation.
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Affiliation(s)
- Luís Fernando Castagnino Sesti
- Lutheran University Center of Palmas, Universidade Luterana do Brasil (ULBRA), Palmas, TO Brazil
- Laboratory of Human Molecular Genetics, Programa de Pós-Graduação em Biologia Celular e Molecular Aplicada à Saúde (PPGBioSaúde), Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001, Prédio 22, 5° andar, Canoas, RS 92425-900 Brazil
| | - Renan Cesar Sbruzzi
- Laboratory of Human Molecular Genetics, Programa de Pós-Graduação em Biologia Celular e Molecular Aplicada à Saúde (PPGBioSaúde), Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001, Prédio 22, 5° andar, Canoas, RS 92425-900 Brazil
| | - Evelise Regina Polina
- Laboratory of Human Molecular Genetics, Programa de Pós-Graduação em Biologia Celular e Molecular Aplicada à Saúde (PPGBioSaúde), Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001, Prédio 22, 5° andar, Canoas, RS 92425-900 Brazil
| | - Douglas dos Santos Soares
- Cardiovascular Research Laboratory, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS Brazil
| | - Daisy Crispim
- Endocrine Division, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS Brazil
| | - Luís Henrique Canani
- Department of Internal Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS Brazil
| | - Kátia Gonçalves dos Santos
- Laboratory of Human Molecular Genetics, Programa de Pós-Graduação em Biologia Celular e Molecular Aplicada à Saúde (PPGBioSaúde), Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001, Prédio 22, 5° andar, Canoas, RS 92425-900 Brazil
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Jean-Baptiste W, Yusuf Ali A, Inyang B, Koshy FS, George K, Poudel P, Chalasani R, Goonathilake MR, Waqar S, George S, Mohammed L. Are There Any Cardioprotective Effects or Safety Concerns of Erythropoietin in Patients With Myocardial Infarction? A Systematic Review. Cureus 2022; 14:e25671. [PMID: 35812547 PMCID: PMC9255911 DOI: 10.7759/cureus.25671] [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: 05/14/2022] [Accepted: 06/05/2022] [Indexed: 12/04/2022] Open
Abstract
Myocardial infarction (MI) is a global cause of morbidity and mortality. MI is the outcome of a chronic process termed atherosclerosis, a buildup of fatty and other substances called plaques inside the coronary vessels, causing hardening and thickening of the arterial wall. Erythropoietin (EPO) is a pleiotropic cytokine released mainly by the kidneys in adults. Besides its well-known erythropoietic functions, EPO possesses anti-apoptotic, mitogenic, and angiogenic effects. This review aims to analyze the strength of any therapeutic or protective value of EPO on the heart and safety concerns regarding its administration in MI individuals. This systematic review was performed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Four databases (PubMed, PubMed Central, Google Scholar, and Sciences Direct) were employed to search for articles published in the last 10 years. Focused studies were relevant articles in the English language, trials, reviews, meta-analyses, and studies with a control group. Following the quality assessment process, nine studies were eligible and hence were included in the review consisting of six randomized controlled trials and three systematic reviews and meta-analyses. Contrary to preclinical studies, EPO administration did not significantly have notable effects on mortality, major adverse cardiovascular events, or infarction size reduction. Significant left ventricle ejection fraction amelioration was not appreciated either. However, EPO seems to reduce the incidence of post-MI arrhythmias.
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Affiliation(s)
- Wilford Jean-Baptiste
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Amina Yusuf Ali
- Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Bithaiah Inyang
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Feeba Sam Koshy
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Kitty George
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Prakar Poudel
- Internal Medicine, Chitwan Medical College of Medical Science, Chitwan, NPL
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Roopa Chalasani
- Research, California Institute of Behavioral Neurosciences & Psychology, fairfield, USA
| | | | - Sara Waqar
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Sheeba George
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Lubna Mohammed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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Jeton F, Perrin-Terrin AS, Yegen CH, Marchant D, Richalet JP, Pichon A, Boncoeur E, Bodineau L, Voituron N. In Transgenic Erythropoietin Deficient Mice, an Increase in Respiratory Response to Hypercapnia Parallels Abnormal Distribution of CO 2/H +-Activated Cells in the Medulla Oblongata. Front Physiol 2022; 13:850418. [PMID: 35514353 PMCID: PMC9061944 DOI: 10.3389/fphys.2022.850418] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/21/2022] [Indexed: 12/03/2022] Open
Abstract
Erythropoietin (Epo) and its receptor are expressed in central respiratory areas. We hypothesized that chronic Epo deficiency alters functioning of central respiratory areas and thus the respiratory adaptation to hypercapnia. The hypercapnic ventilatory response (HcVR) was evaluated by whole body plethysmography in wild type (WT) and Epo deficient (Epo-TAgh) adult male mice under 4%CO2. Epo-TAgh mice showed a larger HcVR than WT mice because of an increase in both respiratory frequency and tidal volume, whereas WT mice only increased their tidal volume. A functional histological approach revealed changes in CO2/H+-activated cells between Epo-TAgh and WT mice. First, Epo-TAgh mice showed a smaller increase under hypercapnia in c-FOS-positive number of cells in the retrotrapezoid nucleus/parafacial respiratory group than WT, and this, independently of changes in the number of PHOX2B-expressing cells. Second, we did not observe in Epo-TAgh mice the hypercapnic increase in c-FOS-positive number of cells in the nucleus of the solitary tract present in WT mice. Finally, whereas hypercapnia did not induce an increase in the c-FOS-positive number of cells in medullary raphe nuclei in WT mice, chronic Epo deficiency leads to raphe pallidus and magnus nuclei activation by hyperacpnia, with a significant part of c-FOS positive cells displaying an immunoreactivity for serotonin in the raphe pallidus nucleus. All of these results suggest that chronic Epo-deficiency affects both the pattern of ventilatory response to hypercapnia and associated medullary respiratory network at adult stage with an increase in the sensitivity of 5-HT and non-5-HT neurons of the raphe medullary nuclei leading to stimulation of fR for moderate level of CO2.
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Affiliation(s)
- Florine Jeton
- Laboratoire "Hypoxie et Poumons", UMR INSERM U1272, Université Paris 13, UFR SMBH, Bobigny, France.,Laboratory of Excellence (Labex) GR-Ex, PRES Sorbonne Paris Cité, Paris, France
| | - Anne-Sophie Perrin-Terrin
- Laboratoire "Hypoxie et Poumons", UMR INSERM U1272, Université Paris 13, UFR SMBH, Bobigny, France.,Inserm, UMR_S1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Sorbonne Université, Paris, France
| | - Celine-Hivda Yegen
- Laboratoire "Hypoxie et Poumons", UMR INSERM U1272, Université Paris 13, UFR SMBH, Bobigny, France
| | - Dominique Marchant
- Laboratoire "Hypoxie et Poumons", UMR INSERM U1272, Université Paris 13, UFR SMBH, Bobigny, France
| | - Jean-Paul Richalet
- Laboratoire "Hypoxie et Poumons", UMR INSERM U1272, Université Paris 13, UFR SMBH, Bobigny, France.,Laboratory of Excellence (Labex) GR-Ex, PRES Sorbonne Paris Cité, Paris, France
| | - Aurélien Pichon
- Laboratoire "Hypoxie et Poumons", UMR INSERM U1272, Université Paris 13, UFR SMBH, Bobigny, France.,Laboratory of Excellence (Labex) GR-Ex, PRES Sorbonne Paris Cité, Paris, France
| | - Emilie Boncoeur
- Laboratoire "Hypoxie et Poumons", UMR INSERM U1272, Université Paris 13, UFR SMBH, Bobigny, France
| | - Laurence Bodineau
- Inserm, UMR_S1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Sorbonne Université, Paris, France
| | - Nicolas Voituron
- Laboratoire "Hypoxie et Poumons", UMR INSERM U1272, Université Paris 13, UFR SMBH, Bobigny, France.,Laboratory of Excellence (Labex) GR-Ex, PRES Sorbonne Paris Cité, Paris, France
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Shu XY, Chen N, Chen BY, Yang HX, Bi H. Myomatous erythrocytosis syndrome: A case report. World J Clin Cases 2022; 10:3206-3212. [PMID: 35611135 PMCID: PMC9082685 DOI: 10.12998/wjcc.v10.i10.3206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/20/2022] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Uterine myoma is the most common benign tumor among women and is often accompanied by anemia. Here, we report the case of a patient with a very large leiomyoma but with a hemoglobin level as high as 197 g/L. After undergoing hysterectomy, all her hematological parameters returned to normal. Immunohistochemical staining of her myoma for erythropoietin showed strong positivity, which suggested that erythropoietin may be the cause of her erythrocytosis. A multidisciplinary team played a significant role in treating the disease.
CASE SUMMARY A 47-year-old woman visited our department complaining that her abdomen had been continuously growing for the past 2 years. After careful examinations, she was suspected of having a very large leiomyoma. She was also diagnosed with erythrocytosis because her RBC count was 6.49 × 1012/L, hemoglobin was 197 g/L. Following a multidisciplinary team consultation, bilateral ureteral stents were placed, and 800 mL blood was removed by phlebotomy. The patient then underwent hysterectomy and bilateral salpingectomy. She recovered well from the operation, and her hemoglobin level decreased sharply following the surgery. Low-molecular-weight heparin was administered daily to prevent postoperative thrombosis. She was discharged from the hospital on the fourth postoperative day. Two months later, all her hematological parameters returned to normal. Pathological analysis of the myoma revealed that it was a benign leiomyoma, with partial hyalinization, and strong positivity for erythropoietin in immunohistochemical staining suggested that erythropoietin may be responsible for the erythrocytosis.
CONCLUSION Erythropoietin ectopically produced from the myoma was responsible for the erythrocytosis in this patient. A multidisciplinary team is strongly recommended.
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Affiliation(s)
- Xin-Yu Shu
- Department of Obstetrics and Gynaecology, Peking University First Hospital, Beijing 100034, China
| | - Na Chen
- Department of Obstetrics and Gynaecology, The Hospital of Cang Town, Cangzhou 223900, Hebei Province, China
| | - Bi-Yun Chen
- Department of Obstetrics and Gynaecology, Peking University First Hospital, Beijing 100034, China
| | - Hui-Xia Yang
- Department of Obstetrics and Gynaecology, Peking University First Hospital, Beijing 100034, China
| | - Hui Bi
- Department of Obstetrics and Gynaecology, Peking University First Hospital, Beijing 100034, China
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Li J, Zhang J, Hao Q, Chen H, Cheng X. Erythropoietin for preventing bronchopulmonary dysplasia in preterm infants: A systematic review and meta-analysis. Pediatr Pulmonol 2022; 57:1051-1063. [PMID: 35043596 DOI: 10.1002/ppul.25837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 01/15/2022] [Accepted: 01/17/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Recombinant erythropoietin (rEPO) has erythropoiesis and anti-inflammatory properties that might help reduce lung injury in preterm infants. OBJECTIVE To conduct a systematic review and meta-analysis to evaluate the possible role of rEPO in altering the risk of bronchopulmonary dysplasia (BPD). METHODS PubMed, EMBASE, Web of Science, and the Cochrane Library databases were searched to identify randomized controlled trials (RCTs) that evaluated the effects of rEPO for the prevention of BPD in preterm infants. RESULTS Fourteen studies (3199 infants) were included. Our results could not demonstrate a significant effect of rEPO on the incidence of BPD36 (risk ratio [RR]: 0.97, 95% confidence interval [CI]: 0.87-1.09, p = 0.63, I2 = 0, 12 RCTs, high-quality evidence), BPD28 (RR: 1.28, 95% CI: 0.91-1.79, p = 0.15, I2 = 17%, three RCTs, low-quality evidence) and oxygen dependence days. The test for subgroup analysis by administration route of rEPO showed similar outcomes above. Some of the included trials reported a significant effect of intravenous rEPO on reduction of sepsis (RR: 0.82, 95% CI: 0.70-0.96, p = 0.01, I2 = 0, high-quality evidence) and any stage necrotizing enterocolitis (NEC) (RR: 0.75, 95% CI: 0.59-0.94, p = 0.01, I2 = 0, moderate-quality evidence). The incidence of mortality and stage II or higher NEC was comparable in rEPO and control infants. CONCLUSION Our results suggest that rEPO does not affect the risk of developing BPD in preterm infants. Adequately powered RCTs are required to further confirm these findings.
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Affiliation(s)
- Jing Li
- Department of Neonatology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou, China
| | - Jing Zhang
- Department of Neonatology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou, China
| | - Qingfei Hao
- Department of Neonatology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou, China
| | - Haoming Chen
- Department of Neonatology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou, China
| | - Xiuyong Cheng
- Department of Neonatology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou, China
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37
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Ma Y, Zhou Z, Yang GY, Ding J, Wang X. The Effect of Erythropoietin and Its Derivatives on Ischemic Stroke Therapy: A Comprehensive Review. Front Pharmacol 2022; 13:743926. [PMID: 35250554 PMCID: PMC8892214 DOI: 10.3389/fphar.2022.743926] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 01/19/2022] [Indexed: 12/17/2022] Open
Abstract
Numerous studies explored the therapeutic effects of erythropoietin (EPO) on neurodegenerative diseases. Few studies provided comprehensive and latest knowledge of EPO treatment for ischemic stroke. In the present review, we introduced the structure, expression, function of EPO, and its receptors in the central nervous system. Furthermore, we comprehensively discussed EPO treatment in pre-clinical studies, clinical trials, and its therapeutic mechanisms including suppressing inflammation. Finally, advanced studies of the therapy of EPO derivatives in ischemic stroke were also discussed. We wish to provide valuable information on EPO and EPO derivatives’ treatment for ischemic stroke for basic researchers and clinicians to accelerate the process of their clinical applications.
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Affiliation(s)
- Yuanyuan Ma
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhiyuan Zhou
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guo-Yuan Yang
- Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Guo-Yuan Yang, ; Jing Ding,
| | - Jing Ding
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
- *Correspondence: Guo-Yuan Yang, ; Jing Ding,
| | - Xin Wang
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China
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A Review of Pleiotropic Potential of Erythropoietin as an Adjunctive Therapy for COVID-19. JOURNAL OF CLINICAL AND BASIC RESEARCH 2022. [DOI: 10.52547/jcbr.6.1.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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39
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Alneami Q. Unexpected finding of endothelial cells in peripheral blood smear. JOURNAL OF APPLIED HEMATOLOGY 2022. [DOI: 10.4103/joah.joah_183_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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40
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Wu XY, Zhu YM, Qi Y, Xu WW, Jing-Zhai. Erythropoietin, as a biological macromolecule in modification of tissue engineered constructs: A review. Int J Biol Macromol 2021; 193:2332-2342. [PMID: 34793816 DOI: 10.1016/j.ijbiomac.2021.11.065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/08/2021] [Accepted: 11/10/2021] [Indexed: 12/14/2022]
Abstract
In recent years, tissue engineering has emerged as a promising approach to address limitations of organ transplantation. The ultimate goal of tissue engineering is to provide scaffolds that closely mimic the physicochemical and biological cues of native tissues' extracellular matrix. In this endeavor, new generation of scaffolds have been designed that utilize the incorporation of signaling molecules in order to improve cell recruitment, enhance angiogenesis, exert healing activities, and increase the engraftment of the scaffolds. Among different signaling molecules, the role of erythropoietin (EPO) in regenerative medicine is increasingly being appreciated. It is a biological macromolecule which can prevent programed cell death, modulate inflammation, induce cell proliferation, and provide tissue protection in different disease models. In this review, we have outlined and critically analyzed different techniques of scaffolds' modification with EPO or EPO-loaded nanoparticles. We have also explored different strategies for the incorporation of EPO into scaffolds. Non-hematopoietic functions of EPO have also been discussed. Finalizing with detailed discussion surrounding the applications, challenges, and future perspectives of EPO-modified scaffolds in regenerative medicine.
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Affiliation(s)
- Xiao-Yu Wu
- Department of Surgical Oncology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Yi-Miao Zhu
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, China
| | - Yang Qi
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, China
| | - Wen-Wen Xu
- Department of Gynaecology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China.
| | - Jing-Zhai
- Department of Surgical Oncology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China.
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Dziembowska I, Wójcik M, Bukowski J, Żekanowska E. Physical Training Increases Erythroferrone Levels in Men. BIOLOGY 2021; 10:1215. [PMID: 34827208 PMCID: PMC8614876 DOI: 10.3390/biology10111215] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 11/14/2021] [Accepted: 11/17/2021] [Indexed: 02/07/2023]
Abstract
Intense physical activity contributes to an increased demand for red blood cells, which transport oxygen to working muscles. The purpose of this study was to assess the concentration of erythroferrone (ERFE), the novel marker of erythroid activity in athletes, during the beginning of their training season. The study group consisted of 39 athletes aged 23.24 ± 3.77 years. The study was carried out during the athletes' preparatory period of the training cycle. The control group consisted of 34 healthy men aged 22.33 ± 2.77 years. The erythropoietic activity was evaluated by determining athletes' concentrations of erythropoietin (EPO) and erythroferrone (ERFE). The level of physical activity was assessed using the International Physical Activity Questionnaire (IPAQ). In the athletes' group, we observed higher concentrations of EPO (Me = 12.65 mIU/mL) and ERFE (40.00 pg/mL) compared to the control group (EPO: Me = 5.74 mIU/ml, p = 0.001; ERFE: Me = 25.50 pg/mL, p = 0.0034). The average intensity of physical exercise significantly differentiated the participants as far as EPO and ERFE concentrations. These results suggest that intense physical activity, at least at the beginning of the training season, may stimulate EPO production, which increases ERFE release. This seems to be an adaptative mechanism that provides adequate iron for enhanced erythropoiesis.
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Affiliation(s)
- Inga Dziembowska
- Department of Pathophysiology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Curie-Skłodowskiej 9, 85-094 Bydgoszcz, Poland; (J.B.); (E.Ż.)
| | - Małgorzata Wójcik
- Institute of Health Sciences, Hipolit Cegielski State University of Applied Sciences in Gniezno, Ks. Kard. Stefana Wyszyńskiego 38, 62-200 Gniezno, Poland;
| | - Jakub Bukowski
- Department of Pathophysiology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Curie-Skłodowskiej 9, 85-094 Bydgoszcz, Poland; (J.B.); (E.Ż.)
| | - Ewa Żekanowska
- Department of Pathophysiology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Curie-Skłodowskiej 9, 85-094 Bydgoszcz, Poland; (J.B.); (E.Ż.)
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The anti-ovarian cancer effect of RPV modified paclitaxel plus schisandra B liposomes in SK-OV-3 cells and tumor-bearing mice. Life Sci 2021; 285:120013. [PMID: 34614418 DOI: 10.1016/j.lfs.2021.120013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/23/2021] [Accepted: 09/29/2021] [Indexed: 02/07/2023]
Abstract
AIMS Due to poor targeting ability of anti-tumor drugs and self-adaptation of tumors, the chemotherapy of ovarian cancer is still poorly effective. In recent years, the treatment of tumor with nano-targeted agents has become a potential research focus. In this study, a new type of short cell-penetrating peptide RPV-modified paclitaxel plus schisandrin B liposomes were constructed to disrupt VM channels, angiogenesis, proliferation and migration for the treatment of ovarian cancer. MATERIALS AND METHODS In this study, clone assay, TUNEL, Transwell, wound-healing, CAM and mimics assay were used to detect the effects of RPV-modified liposomes on ovarian cancer SK-OV-3 cells before and after treatment. HE-staining, immunofluorescence and ELISA were used to further detect the expression of tumor-related proteins. KEY FINDINGS RPV-modified paclitaxel plus schisandrin B liposomes can inhibit angiogenesis, VM channel formation, invasion and proliferation of ovarian SK-OV-3 cells. In vitro and in vivo studies showed that tumor-related protein expression was down-regulated. Modification of RPV can prolong the retention time of liposome in vivo and accumulate in the tumor site, increasing the anti-tumor efficacy. SIGNIFICANCE The RPV-modified paclitaxel plus schisandrin B liposomes have good anti-tumor effect, thus may provide a new avenue for the treatment of ovarian cancer.
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Gong Q, Zeng J, Zhang X, Huang Y, Chen C, Quan J, Ling J. Effect of erythropoietin on angiogenic potential of dental pulp cells. Exp Ther Med 2021; 22:1079. [PMID: 34447472 PMCID: PMC8355638 DOI: 10.3892/etm.2021.10513] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 06/21/2021] [Indexed: 12/26/2022] Open
Abstract
Erythropoietin (EPO) is a 34-kDa glycoprotein that possesses the potential for angiogenesis, as well as anti-inflammatory and anti-apoptotic properties. The present study aimed to examine the effect of EPO on the angiogenesis of dental pulp cells (DPCs) and to explore the underlying mechanisms of these effects. It was demonstrated that EPO not only promoted DPCs proliferation but also induced angiogenesis of DPCs in a paracrine fashion. EPO enhanced the angiogenic capacity by stimulating DPCs to secrete a series of angiogenic cytokines. ELISA confirmed that high concentrations of EPO increased the production of MMP-3 and angiopoietin-1 but decreased the secretion of IL-6. Furthermore, EPO activated the ERK1/2 and p38 signaling pathways in DPCs, while inhibition of these pathways diminished the angiogenesis capacity of DPCs. The present study suggested that EPO may have an important role in the repair and regeneration of dental pulp.
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Affiliation(s)
- Qimei Gong
- Department of Operative Dentistry and Endodontics, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510055, P.R. China
| | - Junyu Zeng
- Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xufang Zhang
- Department of Operative Dentistry and Endodontics, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510055, P.R. China
| | - Yihua Huang
- Department of Operative Dentistry and Endodontics, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510055, P.R. China
| | - Chanchan Chen
- Department of Stomatology, Shenzhen Children's Hospital, Shenzhen, Guangdong 518038, P.R. China
| | - Jingjing Quan
- Department of Operative Dentistry and Endodontics, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510055, P.R. China
| | - Junqi Ling
- Department of Operative Dentistry and Endodontics, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510055, P.R. China
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Tsiftsoglou AS. Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine. Cells 2021; 10:cells10082140. [PMID: 34440909 PMCID: PMC8391952 DOI: 10.3390/cells10082140] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/15/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open
Abstract
Human erythropoietin (EPO) is an N-linked glycoprotein consisting of 166 aa that is produced in the kidney during the adult life and acts both as a peptide hormone and hematopoietic growth factor (HGF), stimulating bone marrow erythropoiesis. EPO production is activated by hypoxia and is regulated via an oxygen-sensitive feedback loop. EPO acts via its homodimeric erythropoietin receptor (EPO-R) that increases cell survival and drives the terminal erythroid maturation of progenitors BFU-Es and CFU-Es to billions of mature RBCs. This pathway involves the activation of multiple erythroid transcription factors, such as GATA1, FOG1, TAL-1, EKLF and BCL11A, and leads to the overexpression of genes encoding enzymes involved in heme biosynthesis and the production of hemoglobin. The detection of a heterodimeric complex of EPO-R (consisting of one EPO-R chain and the CSF2RB β-chain, CD131) in several tissues (brain, heart, skeletal muscle) explains the EPO pleotropic action as a protection factor for several cells, including the multipotent MSCs as well as cells modulating the innate and adaptive immunity arms. EPO induces the osteogenic and endothelial transdifferentiation of the multipotent MSCs via the activation of EPO-R signaling pathways, leading to bone remodeling, induction of angiogenesis and secretion of a large number of trophic factors (secretome). These diversely unique properties of EPO, taken together with its clinical use to treat anemias associated with chronic renal failure and other blood disorders, make it a valuable biologic agent in regenerative medicine for the treatment/cure of tissue de-regeneration disorders.
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Affiliation(s)
- Asterios S Tsiftsoglou
- Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats. PLoS One 2021; 16:e0255022. [PMID: 34339435 PMCID: PMC8328318 DOI: 10.1371/journal.pone.0255022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 07/08/2021] [Indexed: 12/18/2022] Open
Abstract
Prolyl hydroxylase (PH) enzymes control the degradation of hypoxia-inducible factor (HIF), a transcription factor known to regulate erythropoiesis, angiogenesis, glucose metabolism, cell proliferation, and apoptosis. HIF-PH inhibitors (HIF-PHIs) correct anemia in patients with renal disease and in animal models of anemia and kidney disease. However, the effects of HIF-PHIs on comorbidities associated with kidney disease remain largely unknown. We evaluated the effects of the HIF-PHI FG-2216 in obese ZSF1 (Ob-ZSF1) rats, an established model of kidney failure with metabolic syndrome. Following unilateral nephrectomy (Nx) at 8 weeks of age, rats were treated with 40 mg/kg FG-2216 or vehicle by oral gavage three times per week for up to 18 weeks. FG-2216 corrected blood hemoglobin levels and improved kidney function and histopathology in Nx-Ob-ZSF1 rats by increasing the glomerular filtration rate, decreasing proteinuria, and reducing peritubular fibrosis, tubular damage, glomerulosclerosis and mesangial expansion. FG-2216 increased renal glucose excretion and decreased body weight, fat pad weight, and serum cholesterol in Nx-Ob-ZSF1 rats. Additionally, FG-2216 corrected hypertension, improved diastolic and systolic heart function, and reduced cardiac hypertrophy and fibrosis. In conclusion, the HIF-PHI FG-2216 improved renal and cardiovascular outcomes, and reduced obesity in a rat model of kidney disease with metabolic syndrome. Thus, in addition to correcting anemia, HIF-PHIs may provide renal and cardiac protection to patients suffering from kidney disease with metabolic syndrome.
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Chen X, Sun W, Zhong P, Wu D. Colony-Stimulating Factors on Mobilizing CD34 + Cells and Improving Neurological Functions in Patients With Stroke: A Meta-Analysis and a Systematic Review. Front Pharmacol 2021; 12:704509. [PMID: 34366857 PMCID: PMC8339259 DOI: 10.3389/fphar.2021.704509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/07/2021] [Indexed: 11/13/2022] Open
Abstract
Background and Purpose: CSF therapy is considered a promising therapeutic approach for stroke. We performed a meta-analysis to explore the safety and efficacy of CSF in published clinical stroke studies. Methods: We searched articles online and manually. Two reviewers selected studies independently, selecting data based on study quality, characteristics of intervention (administration time, observation time, type, dose, and injection approach of CSF), and the baseline characteristics of patients (age, sex, hypertension, diabetes, smoker, and lipids) were extracted. Main prognosis outcomes were measured as all-cause death in severe adverse events (SAE) and recurrent stroke in SAE. Secondary outcomes were measured as CD34+ cell counts in periphery blood at day 5, National Institutes of Health Stroke Scale (NIHSS), and Barthel index (BI), Side effects of CSF were taken as the indicator of safety. STATA13 software was used to perform the meta-analysis.Keywords: Stroke, Colony-stimulating factor, Meta-analysis, therapy, Neurological Diseases Results: This meta-analysis involved 485 patients from eight studies. Among them, 475 patients from seven studies were gauged SAE (all-cause death), 393 patients from six studies were checked SAE (recurrent stroke); 137 patients from three studies underwent CD34+ measurement, 389 patients from six studies were tested NIHSS and 307 patients from five studies accessed BI. Compared with the control group, both all-causes death (RR= 1.73, 95%CI= (0.61, 4.92), P=0.735, I2=0.0%) and recurrent stroke (RR= 0.43, 95%CI= (0.14, 1.32), P=0.214, I2=33.1%) present no statistical differences, indicating that the application of CSF does not statistically alter the prognosis of patients with stroke. The application of CSF effectively enhanced CD34+ cell counts in periphery blood at day 5 (SMD= 1.23, 95%CI= (0.54, 1.92), P=0.04, I2=69.0%) but did not statistically impact NIHSS (SMD= -0.40, 95%CI= (-0.93, 0.13), P ≤ 0.001, I2=79.7%) or BI (SMD= 0.04, 95%CI= (-0.38, 0.46), P=0.068, I2=54.3%). Conclusion: Our study consolidates the security of CSF administration for its exerting no effect on detrimental outcomes. It has proven to be effective in elevating CD34+ cell counts in periphery blood at day 5, indicating CSF may participate in stroke recovery, but its efficacy in stroke recovery remains detected.
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Affiliation(s)
- Xiuqi Chen
- Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Wenbo Sun
- Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Ping Zhong
- Department of Neurology, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China
| | - Danhong Wu
- Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
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Tarantul VZ, Gavrilenko AV. Gene therapy for critical limb ischemia: Per aspera ad astra. Curr Gene Ther 2021; 22:214-227. [PMID: 34254916 DOI: 10.2174/1566523221666210712185742] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 05/24/2021] [Accepted: 06/02/2021] [Indexed: 11/22/2022]
Abstract
Peripheral artery diseases remain a serious public health problem. Although there are many traditional methods for their treatment using conservative therapeutic techniques and surgery, gene therapy is an alternative and potentially more effective treatment option especially for "no option" patients. This review treats the results of many years of research and application of gene therapy as an example of treatment of patients with critical limb ischemia. Data on successful and unsuccessful attempts to use this technology for treating this disease are presented. Trends in changing the paradigm of approaches to therapeutic angiogenesis are noted: from viral vectors to non-viral vectors, from gene transfer to the whole organism to targeted transfer to cells and tissues, from single gene use to combination of genes; from DNA therapy to RNA therapy, from in vivo therapy to ex vivo therapy.
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Affiliation(s)
- Vyacheslav Z Tarantul
- National Research Center "Kurchatov Institute", Institute of Molecular Genetics, Moscow 123182, Russian Federation
| | - Alexander V Gavrilenko
- A.V.¬ Petrovsky Russian Scientific Center for Surgery, Moscow 119991, Russian Federation
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Cacciottola L, Donnez J, Dolmans MM. Ovarian tissue damage after grafting: systematic review of strategies to improve follicle outcomes. Reprod Biomed Online 2021; 43:351-369. [PMID: 34384692 DOI: 10.1016/j.rbmo.2021.06.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/14/2021] [Accepted: 06/21/2021] [Indexed: 12/17/2022]
Abstract
Frozen-thawed human ovarian tissue endures large-scale follicle loss in the early post-grafting period, characterized by hypoxia lasting around 7 days. Tissue revascularization occurs progressively through new vessel invasion from the host and neoangiogenesis from the graft. Such reoxygenation kinetics lead to further potential damage caused by oxidative stress. The aim of the present manuscript is to provide a systematic review of proangiogenic growth factors, hormones and various antioxidants administered in the event of ovarian tissue transplantation to protect the follicle pool from depletion by boosting revascularization or decreasing oxidative stress. Although almost all investigated studies revealed an advantage in terms of revascularization and reduction in oxidative stress, far fewer demonstrated a positive impact on follicle survival. As the cascade of events driven by ischaemia after transplantation is a complex process involving numerous players, it appears that acting on specific molecular mechanisms, such as concentrations of proangiogenic growth factors, is not enough to significantly mitigate tissue damage. Strategies exploiting the activated tissue response to ischaemia for tissue healing and remodelling purposes, such as the use of antiapoptotic drugs and adult stem cells, are also discussed in the present review, since they yielded promising results in terms of follicle pool protection.
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Affiliation(s)
- Luciana Cacciottola
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Jacques Donnez
- Prof. Emeritus, Université Catholique de Louvain, Brussels, Belgium
| | - Marie-Madeleine Dolmans
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium; Department of Gynecology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
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Cytoprotective effects of erythropoietin: What about the lung? Biomed Pharmacother 2021; 139:111547. [PMID: 33831836 DOI: 10.1016/j.biopha.2021.111547] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/17/2021] [Accepted: 03/23/2021] [Indexed: 02/07/2023] Open
Abstract
Erythropoietin (Epo) is a pleiotropic cytokine, essential for erythropoiesis. Epo and its receptor (Epo-R) are produced by several tissues and it is now admitted that Epo displays other physiological functions than red blood cell synthesis. Indeed, Epo provides cytoprotective effects, which consist in prevention or fight against pathological processes. This perspective article reviews the various protective effects of Epo in several organs and tries to give a proof of concept about its effects in the lung. The tissue-protective effects of Epo could be a promising approach to limit the symptoms of acute and chronic lung diseases.
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Toleubayev M, Dmitriyeva M, Kozhakhmetov S, Igissinov N, Turebayev M, Omarbekov A, Adaibayev K, Shakenov A, Izimbergenov M. Regenerative Properties of Recombinant Human Erythropoietin in the Wound Healing. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.5813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND: Erythropoietin (EPO) is the main stimulator of erythropoiesis, but EPO also has non-hematopoietic effects. The recent data show the positive effects of EPO on tissue regeneration.
AIM: This review aims to know highlights the pathophysiological mechanisms of EPO at different stages of tissue regeneration, and possible clinical applications in wound healing.
METHODS: A review of the literature considering reviews, clinical studies, original papers, and articles from electronic data has been used.
RESULTS: Analysis of animal studies and several clinical trials using EPO in context of wound healing revealed that EPO has a positive effect on all stages of regeneration process and may be a promising therapeutic strategy for the treatment of chronic wounds.
CONCLUSION: An improved understanding of the functions and regulatory mechanisms of EPO in the context of wound healing may lead to new considerations of this growth hormone for its regular clinical application in patients.
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