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Attia GM, Ali LS, Eldesoqui M, Elsaed WM, Mostafa SA, Albadawi EA, Elmansy RA, Elhassan YH, Berika M, Badawy AA, El-Nabalaway M, Dawood AF, Seleem HS. Neuroprotective effects of granulocyte colony-stimulating factor against tramadol-induced cerebellar neurotoxicity. Tissue Cell 2025; 94:102832. [PMID: 40048827 DOI: 10.1016/j.tice.2025.102832] [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: 01/14/2025] [Revised: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND Tramadol (TRM) is a centrally acting synthetic opioid and serotonin/norepinephrine reuptake inhibitor. Despite being a potent painkiller, long-term use can induce permanent neurotoxicity. Granulocyte colony-stimulating factor (G-CSF) is a cytokine that helps to mobilize stem cells and facilitate their integration over injured neurons. AIM This work aims to study the histopathological, biochemical, and molecular alterations in the cerebellar cortex induced by TRM in comparison to the postulated protective effect of G-CSF versus TRM withdrawal. METHODS 32 adult male albino rats were equally divided into four groups: control, TRM, TRM+G-CSF-treated, and TRM withdrawal groups. The TRM group received a daily dose of 80 mg/kg body weight orally via gastric tube for 12 weeks. The TRM+G-CSF-treated group received subcutaneous injections of 100 μg/kg body weight of G-CSF for seven consecutive days, then TRM from the 8th day. The TRM withdrawal group received TRM for 12 weeks; then, the rats were left without TRM administration for a further 12 weeks. The structural, biochemical, and molecular changes of the cerebellum were measured. RESULTS The study revealed that TRM not only induced cerebellar atrophy but also triggered microgliosis, neuroinflammation, and apoptotic indicators, all while suppressing autophagy. However, G-CSF and TRM withdrawal reversed these alterations with superiority to G-CSF. CONCLUSION The current investigation shows that G-CSF may improve behavioral, neurochemical, immunohistochemical, and molecular metrics in the rat cerebellum after tramadol-induced injury. G-CSF exhibits a superior protective effect compared to tramadol withdrawal. This is achieved through its antioxidant, anti-apoptotic, and autophagic enhancement properties, as well as its ability to reduce cerebellar gliosis.
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Affiliation(s)
- Ghalia Mahfouz Attia
- Department of Medical Histology and Cell Biology, Faculty of Medicine Mansoura University, Egypt; Department of Medical Histology and Cell Biology, Faculty of Medicine Horus University, Egypt.
| | - Lashin S Ali
- Department of Basic Medical Science-Faculty of Dentistry, Al-Ahliyya Amman University, Amman, Jordan; Physiology Department-Mansoura Faculty of Medine-Mansoura University, Mansoura, Egypt.
| | - Mamdouh Eldesoqui
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia.
| | - Wael M Elsaed
- Department of Human Anatomy and Embryology, Faculty of Medicine Mansoura University, Egypt; Basic Sciences Department, Riyadh Elm University, Riyadh, Saudi Arabia.
| | - Sally Abdallah Mostafa
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine Mansoura University, Egypt.
| | - Emad A Albadawi
- Department of Basic Medical Sciences, College of Medicine, Taibah University, KSA.
| | - Rasha Ahmed Elmansy
- Anatomy Unit, Department of Basic Medical Sciences, College of Medicine, Qassim University, Buraydah, Saudi Arabia; Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | | | - Mohamed Berika
- Department of Human Anatomy and Embryology, Faculty of Medicine Mansoura University, Egypt; Rehabilitation Science Department, College of Applied Medical Sciences, King Saud University, KSA.
| | - Abdelnaser A Badawy
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia.
| | - Mohammad El-Nabalaway
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia; Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine Mansoura University, Egypt.
| | - Amal Fahmy Dawood
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
| | - Hanan Said Seleem
- Department of Histology & Cell Biology, Faculty of Medicine, Menoufia University, Shebin ElKoum, Menofia, Egypt.
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Ye Y, Rao Z, Xie X, Liu Y, Qiu L, Liu Q, Weng X, Wang C, Bi Y, Zeng T. Naoqing formula alleviates cerebral ischemia/reperfusion injury induced inflammatory injury by regulating Csf3 mediated JAK/STAT pathway and macrophage polarization. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156626. [PMID: 40088744 DOI: 10.1016/j.phymed.2025.156626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 03/03/2025] [Accepted: 03/06/2025] [Indexed: 03/17/2025]
Abstract
BACKGROUND Upon cerebral ischemia/reperfusion injury (CIRI), the brain tissue experiences excessive inflammatory responses, which fuel the activation of immune cells, thereby intensifying cellular damage and inflammatory reactions. Naoqing formula (NQ), a traditional Chinese medicinal compound formulated with musk as the primary component, has been extensively utilized in China for the clinical treatment of ischaemic stroke (IS). PURPOSE The precise pharmacological mechanism underlying NQ's efficacy in managing IS remains elusive. In this study, we investigate the protective effect and molecular mechanism of NQ against CIRI. METHODS C57BL/6 mice were utilized to investigate the protective effects of NQ (130, 260 and 520mg/kg) against middle cerebral artery occlusion (MCAO) induced CIRI and the underlying mechanism. Employing molecular biology techniques, transcriptomics, proteomics, and network pharmacological analyses, the study assessed the role of NQ in the inflammatory response of neuronal cells by establishing a model for neuronal cell and microglia inflammatory injury induced by oxygen-glucose deprivation/reperfusion (OGD/R) and lipopolysaccharide (LPS) stimulation. RESULTS NQ demonstrated significant efficacy in mitigating neuronal damage and cerebral infarction induced by CIRI, achieved through the enhancement of cortical blood flow. Transcriptomic and network pharmacological analyses revealed that NQ mitigated the inflammatory damage caused by CIRI by modulating the Csf3-mediated JAK/STAT pathway. Proteomic analysis further corroborated this finding, indicating that NQ reduced the impact of CIRI by regulating macrophage polarization. Notably, in CIRI mice treated with NQ, there was a notable downregulation of Csf3, JAK2, STAT3, and STAT6, along with a co-localization of Csf3 and CD206. These observations suggested that NQ inhibited the activation of the JAK/STAT pathway and exerted its anti-inflammatory effects by orchestrating the transition of macrophages from the M1 phenotype to the M2 phenotype, triggered by Csf3. Consistent with the in vivo findings, NQ also inhibited the activation of the JAK/STAT pathway in neuronal cells and microglial polarization in vitro, thereby protecting against OGD/R- and LPS-induced inflammatory injury. CONCLUSION This study confirmed that NQ prevented CIRI induced inflammatory injury by inhibiting Csf3-mediated activation of the JAK/STAT pathway and modulating Csf3-mediated macrophage polarization. This study provided a new perspective on the use of NQ in the treatment of IS.
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Affiliation(s)
- Yujun Ye
- Department of Brain Diseases, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangdong, China; School of Combine Traditional Chinese and Western Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China; Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, Guangzhou, Guangdong, China
| | | | - Xuexin Xie
- Department of Brain Diseases, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangdong, China; School of Combine Traditional Chinese and Western Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China; Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yingxin Liu
- School of Combine Traditional Chinese and Western Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China; Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Lingling Qiu
- Department of Brain Diseases, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangdong, China; Sleep Research Institute of Traditional Chinese Medicine, Guangzhou Medical University, Guangdong, China
| | - Qing Liu
- Department of Brain Diseases, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangdong, China; Sleep Research Institute of Traditional Chinese Medicine, Guangzhou Medical University, Guangdong, China
| | - Xuliang Weng
- Department of Brain Diseases, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangdong, China; Sleep Research Institute of Traditional Chinese Medicine, Guangzhou Medical University, Guangdong, China
| | - Chengyin Wang
- Department of Brain Diseases, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangdong, China; Sleep Research Institute of Traditional Chinese Medicine, Guangzhou Medical University, Guangdong, China.
| | - Yiming Bi
- Department of Brain Diseases, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangdong, China; Sleep Research Institute of Traditional Chinese Medicine, Guangzhou Medical University, Guangdong, China.
| | - Ting Zeng
- Department of Brain Diseases, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangdong, China; Sleep Research Institute of Traditional Chinese Medicine, Guangzhou Medical University, Guangdong, China.
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Gomaa S, Nassef M, Tabl G, Gabry SE. Immunoenhancing of the anti-cancer therapy and anti-oxidative stress by co-administration of granulocyte-colony stimulating factor-mobilized stem cells or cells derived from bone marrow and/or spleen plus vaccination with chemotherapeutic cyclophosphamide. Immunol Res 2025; 73:62. [PMID: 40091102 DOI: 10.1007/s12026-025-09610-z] [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: 10/24/2024] [Accepted: 02/19/2025] [Indexed: 03/19/2025]
Abstract
The combination of immunotherapy and chemotherapy, referred to as chemo-immunotherapy, represents a promising regimen for developing new cancer treatments that target the local tumor microenvironment and target tumors in their early stages. However, this approach carries potential risks, including myelo- and immunosuppression, as well as the emergence of chemo-resistant tumor cells. The purpose of this study was to investigate how well mobilizing hematopoietic stem cells (HSCs) work when used alongside chemotherapy and immunotherapy to enhance and modulate the immune response, thereby overcoming immunosuppression and eliminating distant cancer cells. Ehrlich ascetic carcinoma (EAC) tumor-bearing mice were intraperitoneal (i.p.) preconditioned with CTX (4 mg/mouse). EAC-bearing mice that were preconditioned with CTX were intravenous (i.v.) administered with adoptive transferred naive mice-derived bone marrow cells (nBMCs) at 5 × 106 through lateral tail vein (nBMCs group), adoptive transferred tumor-bearing mice-derived bone marrow cells (tBMCs) at 5 × 106 cell/mouse (tBMCs group), a combination of adoptive transferred naïve mice-derived bone marrow cells (nBMCs) and naïve mice-derived splenocytes (nSPs) at 5 × 106 (nBMCs/nSPs group), a combination of adoptive transferred tumor-bearing mice-derived bone marrow cells (tBMCs) and tumor-bearing mice derived-splenocytes (tSPs) at 5 × 106 cell/mouse (tBMCs/tSPs group), or G-CSF administrated subcutaneously (s.c.) at 5 µg/mouse (G-CSF group). Subsequently, all mice groups were vaccinated with tumor lysate at a dosage of 100 µg/mouse. Treating EAC tumor-bearing mice with G-CSF, adoptive transferred nBMCs, adoptive transferred tBMCs, adoptive transferred nBMCs/nSPs, adoptive transferred tBMCs/tSPs, resulted in a significantly enhanced anti-tumor effect that was evidenced by increased anti-proliferative activity and growth inhibition against EAC tumor cells, increased necrosis and apoptosis rates among EAC tumor cells, restricted tumor growth in EAC tumor-bearing mice, and reduced levels of carcinoembryonic antigen (CEA) tumor marker. Furthermore, there was an improvement in serum levels of antioxidant enzyme superoxide dismutase (SOD) and malondialdehyde (MDA) in EAC tumor-bearing mice receiving G-CSF, adoptive transferred tBMCs, adoptive transferred nBMCs/nSPs, and adoptive transferred tBMCs/tSPs. Notably, this treatment regimen ameliorates liver and kidney damage associated with CTX administration in EA tumor-bearing mice. The integration of G-CSF-mobilized HSCs, adoptive transferred nBMCs, adoptive transferred tBMCs, adoptive transferred nBMCs/nSPs combination, and adoptive transferred tBMCs/tSPs combination may yield powerful anti-cancer therapy, thereby facilitating more effective anti-tumor immunotherapy strategies when align with anti-tumor responses. This research may propose a novel therapeutic approach that combines chemotherapy and immunotherapy for addressing early-stage cancer. Further research is necessary to connect the biomedical application and heterogeneity of human tumors and immune systems of this regimen to both diagnostic and therapeutic methodologies.
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Affiliation(s)
- Soha Gomaa
- Department of Zoology, Science Faculty, University of Tanta, 31527, Tanta, Egypt.
| | - Mohamed Nassef
- Department of Zoology, Science Faculty, University of Tanta, 31527, Tanta, Egypt
| | - Ghada Tabl
- Department of Zoology, Science Faculty, University of Tanta, 31527, Tanta, Egypt
| | - Shaimaa El Gabry
- Department of Zoology, Science Faculty, University of Tanta, 31527, Tanta, Egypt
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He Y, Li R, Yu Y, Huang C, Xu Z, Wang T, Chen M, Huang H, Qi Z. Human neural stem cells promote mitochondrial genesis to alleviate neuronal damage in MPTP-induced cynomolgus monkey models. Neurochem Int 2024; 175:105700. [PMID: 38417589 DOI: 10.1016/j.neuint.2024.105700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 02/14/2024] [Accepted: 02/18/2024] [Indexed: 03/01/2024]
Abstract
Currently, there is no effective treatment for Parkinson's disease (PD), and the regenerative treatment of neural stem cells (NSCs) is considered the most promising method. This study aimed to investigate the protective effect and mechanism of NSCs on neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced cynomolgus monkey (Macaca fascicularis) model of PD. We first found that injecting NSCs into the subarachnoid space relieved motor dysfunction in PD cynomolgus monkeys, as well as reduced dopaminergic neuron loss and neuronal damage in the substantia nigra (SN) and striatum. Besides, NSCs decreased 17-estradiol (E2) level, an estrogen, in the cerebrospinal fluid (CSF) of PD cynomolgus monkeys, which shows NSCs may provide neuro-protection by controlling estrogen levels in the CSF. Furthermore, NSCs elevated proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a), mitofusin 2 (MFN2), and optic atrophy 1 (OPA1) expression, three genes mediating mitochondrial biogenesis, in the SN and striatum of PD monkeys. In addition, NSCs suppress reactive oxygen species (ROS) production caused by MPTP, as well as mitochondrial autophagy, therefore preserving dopaminergic neurons. In summary, our findings show that NSCs may preserve dopaminergic and neuronal cells in an MPTP-induced PD cynomolgus monkey model. These protective benefits might be attributed to NSCs' ability of modulating estrogen balance, increasing mitochondrial biogenesis, and limiting oxidative stress and mitochondrial autophagy. These findings add to our understanding of the mechanism of NSC treatment and shed light on further clinical treatment options.
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Affiliation(s)
- Ying He
- Medical College, Guangxi University, Nanning, Guangxi, 530004, China; The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545007, China
| | - Ruicheng Li
- Medical College, Guangxi University, Nanning, Guangxi, 530004, China
| | - Yuxi Yu
- Medical College, Guangxi University, Nanning, Guangxi, 530004, China
| | - Chusheng Huang
- The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530004, China
| | - Zhiran Xu
- Translational Medicine Research Center, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi, 530011, China
| | - Tianbao Wang
- Medical College, Guangxi University, Nanning, Guangxi, 530004, China
| | - Ming Chen
- Jinjiang Municipal Hospital (Shanghai Sixth People's Hospital Fujian Campus), Quanzhou, Fujian, 362200, China
| | - Hongri Huang
- Guangxi Taimei Rensheng Biotechnology Co., Ltd., Nanning, Guangxi, 530011, China
| | - Zhongquan Qi
- Medical College, Guangxi University, Nanning, Guangxi, 530004, China.
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Müller L, Di Benedetto S. Aging brain: exploring the interplay between bone marrow aging, immunosenescence, and neuroinflammation. Front Immunol 2024; 15:1393324. [PMID: 38638424 PMCID: PMC11024322 DOI: 10.3389/fimmu.2024.1393324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 03/25/2024] [Indexed: 04/20/2024] Open
Abstract
Aging is a complex process characterized by a myriad of physiological changes, including alterations in the immune system termed immunosenescence. It exerts profound effects on both the bone marrow and the central nervous system, with significant implications for immunosenescence in neurological contexts. Our mini-review explores the complex relationship between bone marrow aging and its impact on immunosenescence, specifically within the context of neurological diseases. The bone marrow serves as a crucial hub for hematopoiesis and immune cell production, yet with age, it undergoes significant alterations, including alterations in hematopoietic stem cell function, niche composition, and inflammatory signaling. These age-related shifts in the bone marrow microenvironment contribute to dysregulation of immune cell homeostasis and function, impacting neuroinflammatory processes and neuronal health. In our review, we aim to explore the complex cellular and molecular mechanisms that link bone marrow aging to immunosenescence, inflammaging, and neuroinflammation, with a specific focus on their relevance to the pathophysiology of age-related neurological disorders. By exploring this interplay, we strive to provide a comprehensive understanding of how bone marrow aging impacts immune function and contributes to the progression of neurological diseases in aging individuals. Ultimately, this knowledge can hold substantial promise for the development of innovative therapeutic interventions aimed at preserving immune function and mitigating the progression of neurological disorders in the elderly population.
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Affiliation(s)
- Ludmila Müller
- Max Planck Institute for Human Development, Center for Lifespan Psychology, Berlin, Germany
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Alizadeh R, Asghari A, Taghizadeh-Hesary F, Moradi S, Farhadi M, Mehdizadeh M, Simorgh S, Nourazarian A, Shademan B, Susanabadi A, Kamrava K. Intranasal delivery of stem cells labeled by nanoparticles in neurodegenerative disorders: Challenges and opportunities. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2023; 15:e1915. [PMID: 37414546 DOI: 10.1002/wnan.1915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 05/05/2023] [Accepted: 06/11/2023] [Indexed: 07/08/2023]
Abstract
Neurodegenerative disorders occur through progressive loss of function or structure of neurons, with loss of sensation and cognition values. The lack of successful therapeutic approaches to solve neurologic disorders causes physical disability and paralysis and has a significant socioeconomic impact on patients. In recent years, nanocarriers and stem cells have attracted tremendous attention as a reliable approach to treating neurodegenerative disorders. In this regard, nanoparticle-based labeling combined with imaging technologies has enabled researchers to survey transplanted stem cells and fully understand their fate by monitoring their survival, migration, and differentiation. For the practical implementation of stem cell therapies in the clinical setting, it is necessary to accurately label and follow stem cells after administration. Several approaches to labeling and tracking stem cells using nanotechnology have been proposed as potential treatment strategies for neurological diseases. Considering the limitations of intravenous or direct stem cell administration, intranasal delivery of nanoparticle-labeled stem cells in neurological disorders is a new method of delivering stem cells to the central nervous system (CNS). This review describes the challenges and limitations of stem cell-based nanotechnology methods for labeling/tracking, intranasal delivery of cells, and cell fate regulation as theragnostic labeling. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.
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Affiliation(s)
- Rafieh Alizadeh
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alimohamad Asghari
- Skull Base Research Center, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farzad Taghizadeh-Hesary
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Salah Moradi
- Department of Life Science Engineering, Faculty of New Science and Technology, University of Tehran, Tehran, Iran
| | - Mohammad Farhadi
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Mehdizadeh
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Simorgh
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Nourazarian
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
| | - Behrouz Shademan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Susanabadi
- Department of Anesthesia and Pain Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Kamran Kamrava
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Ghasemi M, Roshandel E, Mohammadian M, Farhadihosseinabadi B, Akbarzadehlaleh P, Shamsasenjan K. Mesenchymal stromal cell-derived secretome-based therapy for neurodegenerative diseases: overview of clinical trials. Stem Cell Res Ther 2023; 14:122. [PMID: 37143147 PMCID: PMC10161443 DOI: 10.1186/s13287-023-03264-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 03/06/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Over the past few years, mesenchymal stromal cells (MSCs) have attracted a great deal of scientific attention owing to their promising results in the treatment of incurable diseases. However, there are several concerns about their possible side effects after direct cell transplantation, including host immune response, time-consuming cell culture procedures, and the dependence of cell quality on the donor, which limit the application of MSCs in clinical trials. On the other hand, it is well accepted that the beneficial effects of MSCs are mediated by secretome rather than cell replacement. MSC secretome refers to a variety of bioactive molecules involved in different biological processes, specifically neuro-regeneration. MAIN BODY Due to the limited ability of the central nervous system to compensate for neuronal loss and relieve disease progress, mesenchymal stem cell products may be used as a potential cure for central nervous system disorders. In the present study, the therapeutic effects of MSC secretome were reviewed and discussed the possible mechanisms in the three most prevalent central nervous system disorders, namely Alzheimer's disease, multiple sclerosis, and Parkinson's disease. The current work aimed to help discover new medicine for the mentioned complications. CONCLUSION The use of MSC-derived secretomes in the treatment of the mentioned diseases has encouraging results, so it can be considered as a treatment option for which no treatment has been introduced so far.
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Affiliation(s)
- Maryam Ghasemi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Roshandel
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mozhdeh Mohammadian
- Department of Hematology, School of Medicine, Tarbiat Modares University (TMU), Tehran, Iran
| | | | - Parvin Akbarzadehlaleh
- Pharmaceutical Biotechnology Department, Pharmacy Faculty, Tabriz University of Medical Science, Tabriz, Iran
| | - Karim Shamsasenjan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Mishra A, Singla R, Kumar R, Sharma A, Joshi R, Sarma P, Kaur G, Prajapat M, Bhatia A, Medhi B. Granulocyte Colony-Stimulating Factor Improved Core Symptoms of Autism Spectrum Disorder via Modulating Glutamatergic Receptors in the Prefrontal Cortex and Hippocampus of Rat Brains. ACS Chem Neurosci 2022; 13:2942-2961. [PMID: 36166499 DOI: 10.1021/acschemneuro.2c00270] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Chronic neuroinflammation-induced anomalous glutamate receptor activation has been identified as one of the important factors in the pathogenesis of autism spectrum disorder (ASD). Thus, the current study was designed to elucidate the neuroprotective effect of the granulocyte colony-stimulating factor (G-CSF), a haemopoietic growth factor, an anti-inflammatory, and a neuroprotectant to decipher the underlying mechanism(s) in the valproic acid (VPA)-induced experimental model of ASD. Experimentally, the ASD rat model was induced by a single dose of VPA (600 mg/kg; i.p.) on gestation day 12.5 to the pregnant female rats. After birth, pups were treated with vehicle, normal saline 0.9% i.p., risperidone (2.5 mg/kg; i.p.), and G-CSF (10, 35, and 70 μg/kg; i.p.) from postnatal day (PND) 23 to 43. All the groups were subjected to various developmental and behavior tests from birth. The rats were sacrificed on PND 55, and their brain was excised and processed for biochemical parameters (oxidative stress, inflammatory markers, BDNF), histological examination (H&E, Nissl staining), NMDA, and AMPA receptor expression by immunohistochemistry, western blot, and real-time polymerase chain reaction evaluation. Also, the possible interaction of the G-CSF with NMDA and AMPA receptors was evaluated using the in-silico method. The results of the study showed that in VPA-exposed rats, postnatal treatment of G-CSF rescued all the behavioral abnormalities, oxidative stress, and inflammatory parameters in a dose-dependent manner while risperidone did not show any significant results. The in-silico analysis showed the direct interaction of G-CSF with NMDA and AMPA receptors. The upregulated expression of NMDA and AMPA both in the prefrontal cortex as well as hippocampus was alleviated by G-CSF thereby validating its anti-inflammatory and excitoprotective properties. Thus, G-CSF demonstrated neuroprotection against the core symptoms of autism in the VPA-induced rodent model, making it a potential candidate for the treatment of ASD.
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Affiliation(s)
- Abhishek Mishra
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Rubal Singla
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Rohit Kumar
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - AmitRaj Sharma
- Department of Neurology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Rupa Joshi
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Phulen Sarma
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Gurjeet Kaur
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Manisha Prajapat
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Alka Bhatia
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Bikash Medhi
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
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Cai H, Wang Z, Tang W, Ke X, Zhao E. Recent advances of the mammalian target of rapamycin signaling in mesenchymal stem cells. Front Genet 2022; 13:970699. [PMID: 36110206 PMCID: PMC9468880 DOI: 10.3389/fgene.2022.970699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/11/2022] [Indexed: 11/22/2022] Open
Abstract
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in a variety of cellular functions, such as cell proliferation, metabolism, autophagy, survival and cytoskeletal organization. Furthermore, mTOR is made up of three multisubunit complexes, mTOR complex 1, mTOR complex 2, and putative mTOR complex 3. In recent years, increasing evidence has suggested that mTOR plays important roles in the differentiation and immune responses of mesenchymal stem cells (MSCs). In addition, mTOR is a vital regulator of pivotal cellular and physiological functions, such as cell metabolism, survival and ageing, where it has emerged as a novel therapeutic target for ageing-related diseases. Therefore, the mTOR signaling may develop a large impact on the treatment of ageing-related diseases with MSCs. In this review, we discuss prospects for future research in this field.
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Affiliation(s)
- Huarui Cai
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Zhongze Wang
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Wenhan Tang
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China
| | - Xiaoxue Ke
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
- *Correspondence: Xiaoxue Ke, ; Erhu Zhao,
| | - Erhu Zhao
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
- *Correspondence: Xiaoxue Ke, ; Erhu Zhao,
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Transcriptomic Analysis Reveals That Granulocyte Colony-Stimulating Factor Trigger a Novel Signaling Pathway (TAF9-P53-TRIAP1-CASP3) to Protect Retinal Ganglion Cells after Ischemic Optic Neuropathy. Int J Mol Sci 2022; 23:ijms23158359. [PMID: 35955492 PMCID: PMC9368818 DOI: 10.3390/ijms23158359] [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: 06/13/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 02/01/2023] Open
Abstract
Optic nerve head (ONH) infarct can result in progressive retinal ganglion cell (RGC) death. The granulocyte colony-stimulating factor (GCSF) protects the RGC after ON infarct. However, protective mechanisms of the GCSF after ONH infarct are complex and remain unclear. To investigate the complex mechanisms involved, the transcriptome profiles of the GCSF-treated retinas were examined using microarray technology. The retinal mRNA samples on days 3 and 7 post rat anterior ischemic optic neuropathy (rAION) were analyzed by microarray and bioinformatics analyses. GCSF treatment influenced 3101 genes and 3332 genes on days 3 and 7 post rAION, respectively. ONH infarct led to changes in 702 and 179 genes on days 3 and 7 post rAION, respectively. After cluster analysis, the levels of TATA box-binding protein (TBP)-associated factor were significantly reduced after ONH infarct, but these significantly increased after GCSF treatment. The network analysis revealed that TBP associated factor 9 (TAF9) can bind to P53 to induce TP53-regulated inhibitor of apoptosis 1 (TRIAP1) expression. To evaluate the function of TAF9 in RGC apoptosis, GCSF plus TAF9 siRNA-treated rats were evaluated using retrograde labeling with FluoroGold assay, TUNEL assay, and Western blotting in an rAION model. The RGC densities in the GCSF plus TAF9 siRNA-treated rAION group were 1.95-fold (central retina) and 1.75-fold (midperipheral retina) lower than that in the GCSF-treated rAION group (p < 0.05). The number of apoptotic RGC in the GCSF plus TAF9 siRNA-treated group was threefold higher than that in the GCSF-treated group (p < 0.05). Treatment with TAF9 siRNA significantly reduced GCSF-induced TP53 and TRIAP1 expression by 2.4-fold and 4.7-fold, respectively, in the rAION model. Overexpression of TAF9 significantly reduced apoptotic RGC and CASP3 levels, and induced TP53 and TRIAP1 expression in the rAION model. Therefore, we have demonstrated that GCSF modulated a new pathway, TAF9-P53-TRIAP1-CASP3, to control RGC death and survival after ON infarct.
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11
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Rahbaran M, Zekiy AO, Bahramali M, Jahangir M, Mardasi M, Sakhaei D, Thangavelu L, Shomali N, Zamani M, Mohammadi A, Rahnama N. Therapeutic utility of mesenchymal stromal cell (MSC)-based approaches in chronic neurodegeneration: a glimpse into underlying mechanisms, current status, and prospects. Cell Mol Biol Lett 2022; 27:56. [PMID: 35842587 PMCID: PMC9287902 DOI: 10.1186/s11658-022-00359-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 06/30/2022] [Indexed: 12/11/2022] Open
Abstract
Recently, mesenchymal stromal cell (MSC)-based therapy has become an appreciated therapeutic approach in the context of neurodegenerative disease therapy. Accordingly, a myriad of studies in animal models and also some clinical trials have evinced the safety, feasibility, and efficacy of MSC transplantation in neurodegenerative conditions, most importantly in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). The MSC-mediated desired effect is mainly a result of secretion of immunomodulatory factors in association with release of various neurotrophic factors (NTFs), such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Thanks to the secretion of protein-degrading molecules, MSC therapy mainly brings about the degradation of pathogenic protein aggregates, which is a typical appearance of chronic neurodegenerative disease. Such molecules, in turn, diminish neuroinflammation and simultaneously enable neuroprotection, thereby alleviating disease pathological symptoms and leading to cognitive and functional recovery. Also, MSC differentiation into neural-like cells in vivo has partially been evidenced. Herein, we focus on the therapeutic merits of MSCs and also their derivative exosome as an innovative cell-free approach in AD, HD, PD, and ALS conditions. Also, we give a brief glimpse into novel approaches to potentiate MSC-induced therapeutic merits in such disorders, most importantly, administration of preconditioned MSCs.
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Affiliation(s)
- Mohaddeseh Rahbaran
- Biotechnology Department, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Angelina Olegovna Zekiy
- Department of Prosthetic Dentistry, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Mahta Bahramali
- Biotechnology Department, University of Tehran, Tehran, Iran
| | | | - Mahsa Mardasi
- Biotechnology Department, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Delaram Sakhaei
- School of Medicine, Sari Branch, Islamic Azad University, Sari, Iran
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Ali Mohammadi
- Department of Neurology, Imam Khomeini Hospital, Urmia University of Medical Sciences, Urmia, Iran.
| | - Negin Rahnama
- Department of Internal Medicine and Health Services, Semnan University of Medical Sciences, Semnan, Iran.
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12
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Zhong Y, Cai X, Ding L, Liao J, Liu X, Huang Y, Chen X, Long L. Nrf2 Inhibits the Progression of Parkinson’s Disease by Upregulating AABR07032261.5 to Repress Pyroptosis. J Inflamm Res 2022; 15:669-685. [PMID: 35140498 PMCID: PMC8818975 DOI: 10.2147/jir.s345895] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/16/2022] [Indexed: 12/31/2022] Open
Abstract
Objective Parkinson’s disease (PD) is associated with dysregulated neural cell death, such as pyroptosis, but its regulatory mechanisms are poorly understood. This study investigated roles of nuclear factor E2-related factor 2 (Nrf2) in regulating pyroptosis and PD development. Methods Cellular and rat PD models established by 6-OHDA exposure were subjected to Nrf2 overexpression. Neurobehavioral functions were assessed by the traction test, Morris Water Maze, and open field test. Cell proliferation was analyzed by MTS assay, while flow cytometry was applied to quantify levels of reactive oxygen species (ROS) and apoptosis. Nissl bodies in rat brains were detected by Nissl staining, and cell apoptosis in brain tissues was assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Differential expression of lncRNA and mRNA was characterized by deep sequencing. Results A cellular PD model was successfully established by inducing PC12 cell differentiation with nerve growth factor-β and exposing differentiated cells to 6-OHDA. Cells exhibited significantly increased ROS levels, enhanced pyroptosis, and inhibited Nrf2 phosphorylation. The rat PD model exhibited impaired muscle strength, increased pyroptosis, and repressed Nrf2 phosphorylation. Nrf2 overexpression effectively repressed pyroptosis in both cellular and rat PD models. Marked alterations of lncRNA and mRNA profiles were induced by Nrf2 overexpression in the cellular PD model, which involved multiple signaling pathways. Silencing of the lncRNA AABR07032261.5 significantly promoted pyroptosis in the cellular PD model. Conclusion Nrf2 suppressed PD pathogenesis in cellular and animal models by promoting AABR07032261.5, which repressed pyroptosis.
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Affiliation(s)
- Yunxiao Zhong
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510600, People’s Republic of China
| | - Xiaodong Cai
- Department of Neurology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510655, People’s Republic of China
| | - Li Ding
- Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Jinchi Liao
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510600, People’s Republic of China
| | - Xu Liu
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510600, People’s Republic of China
| | - Yiying Huang
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510600, People’s Republic of China
| | - Xiaohong Chen
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510600, People’s Republic of China
| | - Ling Long
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510600, People’s Republic of China
- Correspondence: Ling Long; Xiaohong Chen, Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510600, People’s Republic of China, Tel +86-20-85253275, Email ;
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13
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Zhao Y, Suo Y, Yang Z, Hao Y, Li W, Su Y, Shi Y, Gao Y, Song L, Yin X, Shi H. Inspiration for the prevention and treatment of neuropsychiatric disorders: New insight from the bone-brain-axis. Brain Res Bull 2021; 177:263-272. [PMID: 34678443 DOI: 10.1016/j.brainresbull.2021.10.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 10/09/2021] [Accepted: 10/15/2021] [Indexed: 11/30/2022]
Abstract
Bone is the main supporting structure of the body and the main organ involved in body movement and calcium and phosphorus metabolism. Recent studies have shown that bone is also a potential new endocrine organ that participates in the physiological and pathophysiological processes of the cardiovascular, digestive, and endocrine systems through various bioactive cytokines secreted by bone cells and bone marrow. Bone-derived active cytokines can also directly act on the central nervous system and regulate brain function and individual behavior. The bidirectional regulation of the bone-brain axis has gradually attracted attention in the field of neuroscience. This paper reviews the regulatory effects of bone-derived active cytokines and bone-derived cells on individual brain function and brain diseases, as well as the occurrence and development of related neuropsychiatric diseases. The central regulatory mechanism function is briefly introduced, which will broaden the scope for mechanistic research and help establish prevention and treatment strategies for neuropsychiatric diseases based on the bone-brain axis.
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Affiliation(s)
- Ye Zhao
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China
| | - Yining Suo
- Child Health Department, Hebei Children's Hospital, Shijiazhuang 050031, China
| | - Zhenbang Yang
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China
| | - Ying Hao
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China
| | - Wenshuya Li
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China
| | - Yujiao Su
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China
| | - Yun Shi
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang 050017, China
| | - Yuan Gao
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang 050017, China
| | - Li Song
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang 050017, China
| | - Xi Yin
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Department of Functional Region of Diagnosis, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.
| | - Haishui Shi
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang 050017, China.
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14
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Dumbuya JS, Chen L, Wu JY, Wang B. The role of G-CSF neuroprotective effects in neonatal hypoxic-ischemic encephalopathy (HIE): current status. J Neuroinflammation 2021; 18:55. [PMID: 33612099 PMCID: PMC7897393 DOI: 10.1186/s12974-021-02084-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/14/2021] [Indexed: 12/23/2022] Open
Abstract
Hypoxic-ischemic encephalopathy (HIE) is an important cause of permanent damage to central nervous system (CNS) that may result in neonatal death or manifest later as mental retardation, epilepsy, cerebral palsy, or developmental delay. The primary cause of this condition is systemic hypoxemia and/or reduced cerebral blood flow with long-lasting neurological disabilities and neurodevelopmental impairment in neonates. About 20 to 25% of infants with HIE die in the neonatal period, and 25-30% of survivors are left with permanent neurodevelopmental abnormalities. The mechanisms of hypoxia-ischemia (HI) include activation and/or stimulation of myriad of cascades such as increased excitotoxicity, oxidative stress, N-methyl-D-aspartic acid (NMDA) receptor hyperexcitability, mitochondrial collapse, inflammation, cell swelling, impaired maturation, and loss of trophic support. Different therapeutic modalities have been implicated in managing neonatal HIE, though translation of most of these regimens into clinical practices is still limited. Therapeutic hypothermia, for instance, is the most widely used standard treatment in neonates with HIE as studies have shown that it can inhibit many steps in the excito-oxidative cascade including secondary energy failure, increases in brain lactic acid, glutamate, and nitric oxide concentration. Granulocyte-colony stimulating factor (G-CSF) is a glycoprotein that has been implicated in stimulation of cell survival, proliferation, and function of neutrophil precursors and mature neutrophils. Extensive studies both in vivo and ex vivo have shown the neuroprotective effect of G-CSF in neurodegenerative diseases and neonatal brain damage via inhibition of apoptosis and inflammation. Yet, there are still few experimentation models of neonatal HIE and G-CSF's effectiveness, and extrapolation of adult stroke models is challenging because of the evolving brain. Here, we review current studies and/or researches of G-CSF's crucial role in regulating these cytokines and apoptotic mediators triggered following neonatal brain injury, as well as driving neurogenesis and angiogenesis post-HI insults.
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Affiliation(s)
- John Sieh Dumbuya
- Department of Pediatrics, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, People's Republic of China
| | - Lu Chen
- Department of Pediatrics, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, People's Republic of China
| | - Jang-Yen Wu
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
| | - Bin Wang
- Department of Pediatrics, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, People's Republic of China.
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15
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Yan Z, Shi X, Wang H, Si C, Liu Q, Du Y. Neurotrophin-3 Promotes the Neuronal Differentiation of BMSCs and Improves Cognitive Function in a Rat Model of Alzheimer's Disease. Front Cell Neurosci 2021; 15:629356. [PMID: 33642999 PMCID: PMC7902862 DOI: 10.3389/fncel.2021.629356] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 01/21/2021] [Indexed: 11/13/2022] Open
Abstract
Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has the potential to be developed into an effective treatment for neurodegenerative diseases such as Alzheimer's disease (AD). However, the therapeutic effects of BMSCs are limited by their low neural differentiation rate. We transfected BMSCs with neurotrophin-3 (NT-3), a neurotrophic factor that promotes neuronal differentiation, and investigated the effects of NT-3 gene overexpression on the differentiation of BMSCs into neurons in vitro and in vivo. We further studied the possible molecular mechanisms. We found that overexpression of NT-3 promoted the differentiation of BMSCs into neurons in vitro and in vivo and improved cognitive function in rats with experimental AD. By contrast, silencing NT-3 inhibited the differentiation of BMSCs and decreased cognitive function in rats with AD. The Wnt/β-catenin signaling pathway was involved in the mechanism by which NT-3 gene modification influenced the neuronal differentiation of BMSCs in vitro and in vivo. Our findings support the prospect of using NT-3-transduced BMSCs for the development of novel therapies for AD.
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Affiliation(s)
- Zhongrui Yan
- Departments of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Neurology, Jining No. 1 People's Hospital, Jining, China
| | - Xianjing Shi
- Department of Neurology, Jining No. 1 People's Hospital, Jining, China
| | - Hui Wang
- Department of Neurology, Jining No. 1 People's Hospital, Jining, China
| | - Cuiping Si
- Department of Neurology, Jining No. 1 People's Hospital, Jining, China
| | - Qian Liu
- Department of Neurology, Jining No. 1 People's Hospital, Jining, China
| | - Yifeng Du
- Departments of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Departments of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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16
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Shi J, Zhao YC, Niu ZF, Fan HJ, Hou SK, Guo XQ, Sang L, Lv Q. Mesenchymal stem cell-derived small extracellular vesicles in the treatment of human diseases: Progress and prospect. World J Stem Cells 2021; 13:49-63. [PMID: 33584979 PMCID: PMC7859991 DOI: 10.4252/wjsc.v13.i1.49] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 11/02/2020] [Accepted: 11/11/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are self-renewing, multipotent cells that could differentiate into multiple tissues. MSC-based therapy has become an attractive and promising strategy for treating human diseases through immune regulation and tissue repair. However, accumulating data have indicated that MSC-based therapeutic effects are mainly attributed to the properties of the MSC-sourced secretome, especially small extracellular vesicles (sEVs). sEVs are signaling vehicles in intercellular communication in normal or pathological conditions. sEVs contain natural contents, such as proteins, mRNA, and microRNAs, and transfer these functional contents to adjacent cells or distant cells through the circulatory system. MSC-sEVs have drawn much attention as attractive agents for treating multiple diseases. The properties of MSC-sEVs include stability in circulation, good biocompatibility, and low toxicity and immunogenicity. Moreover, emerging evidence has shown that MSC-sEVs have equal or even better treatment efficacies than MSCs in many kinds of disease. This review summarizes the current research efforts on the use of MSC-sEVs in the treatment of human diseases and the existing challenges in their application from lab to clinical practice that need to be considered.
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Affiliation(s)
- Jie Shi
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China
- Department of Biomaterials and Regenrative Medicine, Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Yu-Chen Zhao
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China
- Department of Biomaterials and Regenrative Medicine, Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Zhi-Fang Niu
- General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Hao-Jun Fan
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China
- Department of Biomaterials and Regenrative Medicine, Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Shi-Ke Hou
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China
- Department of Biomaterials and Regenrative Medicine, Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Xiao-Qin Guo
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China
- Department of Biomaterials and Regenrative Medicine, Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Lu Sang
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China
- Department of Biomaterials and Regenrative Medicine, Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Qi Lv
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China
- Department of Biomaterials and Regenrative Medicine, Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China.
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17
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Neuroprotection through G-CSF: recent advances and future viewpoints. Pharmacol Rep 2021; 73:372-385. [PMID: 33389706 DOI: 10.1007/s43440-020-00201-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 11/18/2020] [Accepted: 11/21/2020] [Indexed: 12/14/2022]
Abstract
Granulocyte-colony stimulating factor (G-CSF), a member of the cytokine family of hematopoietic growth factors, is 19.6 kDa glycoprotein which is responsible for the proliferation, maturation, differentiation, and survival of neutrophilic granulocyte lineage. Apart from its proven clinical application to treat chemotherapy-associated neutropenia, recent pre-clinical studies have highlighted the neuroprotective roles of G-CSF i.e., mobilization of haemopoietic stem cells, anti-apoptotic, neuronal differentiation, angiogenesis and anti-inflammatory in animal models of neurological disorders. G-CSF is expressed by numerous cell types including neuronal, immune and endothelial cells. G-CSF is released in autocrine manner and binds to its receptor G-CSF-R which further activates numerous signaling transduction pathways including PI3K/AKT, JAK/STAT and MAP kinase, and thereby promote neuronal survival, proliferation, differentiation, mobilization of hematopoietic stem and progenitor cells. The expression of G-CSF receptors (G-CSF-R) in the different brain regions and their upregulation in response to neuronal insult indicates the autocrine protective signaling mechanism of G-CSF by inhibition of apoptosis, inflammation, and stimulation of neurogenesis. These observed neuroprotective effects of G-CSF makes it an attractive target to mitigate neurodegeneration associated with neurological disorders. The objective of the review is to highlight and summarize recent updates on G-CSF as a therapeutically versatile neuroprotective agent along with mechanisms of action as well as possible clinical applications in neurodegenerative disorders including AD, PD and HD.
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