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Yaghoobi A, Rezaee M, Hedayati N, Keshavarzmotamed A, Khalilzad MA, Russel R, Asemi Z, Rajabi Moghadam H, Mafi A. Insight into the cardioprotective effects of melatonin: shining a spotlight on intercellular Sirt signaling communication. Mol Cell Biochem 2025; 480:799-823. [PMID: 38980593 DOI: 10.1007/s11010-024-05002-3] [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: 11/30/2023] [Accepted: 03/25/2024] [Indexed: 07/10/2024]
Abstract
Cardiovascular diseases (CVDs) are the leading causes of death and illness worldwide. While there have been advancements in the treatment of CVDs using medication and medical procedures, these conventional methods have limited effectiveness in halting the progression of heart diseases to complete heart failure. However, in recent years, the hormone melatonin has shown promise as a protective agent for the heart. Melatonin, which is secreted by the pineal gland and regulates our sleep-wake cycle, plays a role in various biological processes including oxidative stress, mitochondrial function, and cell death. The Sirtuin (Sirt) family of proteins has gained attention for their involvement in many cellular functions related to heart health. It has been well established that melatonin activates the Sirt signaling pathways, leading to several beneficial effects on the heart. These include preserving mitochondrial function, reducing oxidative stress, decreasing inflammation, preventing cell death, and regulating autophagy in cardiac cells. Therefore, melatonin could play crucial roles in ameliorating various cardiovascular pathologies, such as sepsis, drug toxicity-induced myocardial injury, myocardial ischemia-reperfusion injury, hypertension, heart failure, and diabetic cardiomyopathy. These effects may be partly attributed to the modulation of different Sirt family members by melatonin. This review summarizes the existing body of literature highlighting the cardioprotective effects of melatonin, specifically the ones including modulation of Sirt signaling pathways. Also, we discuss the potential use of melatonin-Sirt interactions as a forthcoming therapeutic target for managing and preventing CVDs.
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Affiliation(s)
- Alireza Yaghoobi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Malihe Rezaee
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Neda Hedayati
- School of Medicine, Iran University of Medical Science, Tehran, Iran
| | | | | | - Reitel Russel
- Department of Cell Systems and Anatomy, UT Health. Long School of Medicine, San Antonio, TX, USA.
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Hasan Rajabi Moghadam
- Department of Cardiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
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Zhang Z, Bao Y, Wei P, Yan X, Qiu Q, Qiu L. Melatonin attenuates dental pulp stem cells senescence due to vitro expansion via inhibiting MMP3. Oral Dis 2024; 30:2410-2424. [PMID: 37448325 DOI: 10.1111/odi.14649] [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: 11/06/2022] [Revised: 05/07/2023] [Accepted: 06/05/2023] [Indexed: 07/15/2023]
Abstract
OBJECTIVE We aimed to identify the crucial genes involved in dental pulp stem cell (DPSC) senescence and evaluate the impact of melatonin on DPSC senescence. METHODS Western blotting, SA-β-Gal staining and ALP staining were used to evaluate the senescence and differentiation potential of DPSCs. The optimal concentration of melatonin was determined using the CCK-8 assay. Differentially expressed genes (DEGs) involved in DPSC senescence were obtained via bioinformatics analysis, followed by RT-qPCR. Gain- and loss-of-function studies were conducted to explore the role of MMP3 in DPSC in vitro expansion and in response to melatonin. GSEA was employed to analyse MMP3-related pathways in cellular senescence. RESULTS Treatment with 0.1 μM melatonin attenuated cellular senescence and differentiation potential suppression in DPSCs due to long-term in vitro expansion. MMP3 was a crucial gene in senescence, as confirmed by bioinformatics analysis, RT-qPCR and Western blotting. Furthermore, gain- and loss-of-function studies revealed that MMP3 played a regulatory role in cellular senescence. Rescue assays showed that overexpression of MMP3 reversed the effect of melatonin on senescence. GSEA revealed that the MMP3-dependent anti-senescence effect of melatonin was associated with the IL6-JAK-STAT3, TNF-α-Signalling-VIA-NF-κB, COMPLEMENT, NOTCH Signalling and PI3K-AKT-mTOR pathways. CONCLUSION Melatonin attenuated DPSC senescence caused by long-term expansion by inhibiting MMP3.
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Affiliation(s)
- Zeying Zhang
- Department of Endodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Yandong Bao
- Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Penggong Wei
- Department of Endodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Xiaoyuan Yan
- Department of Endodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Qiujing Qiu
- Department of Endodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Lihong Qiu
- Department of Endodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China
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Zhong Y, Yang Y, Xu Y, Qian B, Huang S, Long Q, Qi Z, He X, Zhang Y, Li L, Hai W, Wang X, Zhao Q, Ye X. Design of a Zn-based nanozyme injectable multifunctional hydrogel with ROS scavenging activity for myocardial infarction therapy. Acta Biomater 2024; 177:62-76. [PMID: 38237713 DOI: 10.1016/j.actbio.2024.01.015] [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: 10/22/2023] [Revised: 12/21/2023] [Accepted: 01/11/2024] [Indexed: 02/03/2024]
Abstract
The existing strategies for myocardial infarction therapy mainly focus on reinstating myocardial blood supply, often disregarding the intrinsic and intricate microenvironment created by elevated levels of reactive oxygen species (ROS) that accompanies myocardial infarction. This microenvironment entails cardiomyocytes apoptosis, substantial vascular cell death, excessive inflammatory infiltration and fibrosis. In such situation, the present study introduces a zinc-based nanozyme injectable multifunctional hydrogel, crafted from ZIF-8, to counteract ROS effects after myocardial infarction. The hydrogel exhibits both superoxide dismutase (SOD)-like and catalase (CAT)-like enzymatic activities, proficiently eliminating surplus ROS in the infarcted region and interrupting ROS-driven inflammatory cascades. Furthermore, the hydrogel's exceptional immunomodulatory ability spurs a notable transformation of macrophages into the M2 phenotype, effectively neutralizing inflammatory factors and indirectly fostering vascularization in the infarcted region. For high ROS and demanding for zinc of the infarcted microenvironment, the gradual release of zinc ions as the hydrogel degrades further enhances the bioactive and catalytic performance of the nanozymes, synergistically promoting cardiac function post myocardial infarction. In conclusion, this system of deploying catalytic nanomaterials within bioactive matrices for ROS-related ailment therapy not only establishes a robust foundation for biomedical material development, but also promises a holistic approach towards addressing myocardial infarction complexities. STATEMENT OF SIGNIFICANCE: Myocardial infarction remains the leading cause of death worldwide. However, the existing strategies for myocardial infarction therapy mainly focus on reinstating myocardial blood supply. These therapies often ignore the intrinsic and intricate microenvironment created by elevated levels of reactive oxygen species (ROS). Hence, we designed an injectable Zn-Based nanozyme hydrogel with ROS scavenging activity for myocardial infarction therapy. ALG-(ZIF-8) can significantly reduce ROS in the infarcted area and alleviate the ensuing pathological process. ALG-(ZIF-8) gradually releases zinc ions to participate in the repair process and improves cardiac function. Overall, this multifunctional hydrogel equipped with ZIF-8 makes full use of the characteristics of clearing ROS and slowly releasing zinc ions, and we are the first to test the therapeutic efficacy of Zinc-MOFs crosslinked-alginate hydrogel for myocardial infarction.
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Affiliation(s)
- Yiming Zhong
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Yi Yang
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Yuze Xu
- College of Chemistry and Materials Science, Shanghai Normal University, Shanghai, 200234, China
| | - Bei Qian
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Shixing Huang
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Qiang Long
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Zhaoxi Qi
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Xiaojun He
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Yecen Zhang
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Lihui Li
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Wangxi Hai
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Xinming Wang
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
| | - Qiang Zhao
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
| | - Xiaofeng Ye
- Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
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Skubis-Sikora A, Sikora B, Małysiak W, Wieczorek P, Czekaj P. Regulation of Adipose-Derived Stem Cell Activity by Melatonin Receptors in Terms of Viability and Osteogenic Differentiation. Pharmaceuticals (Basel) 2023; 16:1236. [PMID: 37765045 PMCID: PMC10535461 DOI: 10.3390/ph16091236] [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: 07/12/2023] [Revised: 08/27/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Melatonin is a hormone secreted mainly by the pineal gland and acts through the Mel1A and Mel1B receptors. Among other actions, melatonin significantly increases osteogenesis during bone regeneration. Human adipose-derived mesenchymal stem cells (ADSCs) are also known to have the potential to differentiate into osteoblast-like cells; however, inefficient culturing due to the loss of properties over time or low cell survival rates on scaffolds is a limitation. Improving the process of ADSC expansion in vitro is crucial for its further successful use in bone regeneration. This study aimed to assess the effect of melatonin on ADSC characteristics, including osteogenicity. We assessed ADSC viability at different melatonin concentrations as well as the effect on its receptor inhibitors (luzindole or 4-P-PDOT). Moreover, we analyzed the ADSC phenotype, apoptosis, cell cycle, and expression of MTNR1A and MTNR1B receptors, and its potential for osteogenic differentiation. We found that ADSCs treated with melatonin at a concentration of 100 µM had a higher viability compared to those treated at higher melatonin concentrations. Melatonin did not change the phenotype of ADSCs or induce apoptosis and it promoted the activity of some osteogenesis-related genes. We concluded that melatonin is safe, non-toxic to normal ADSCs in vitro, and can be used in regenerative medicine at low doses (100 μM) to improve cell viability without negatively affecting the osteogenic potential of these cells.
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Affiliation(s)
- Aleksandra Skubis-Sikora
- Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland
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Zhang K, Du X, Gao Y, Liu S, Xu Y. Mesenchymal Stem Cells for Treating Alzheimer's Disease: Cell Therapy and Chemical Reagent Pretreatment. J Alzheimers Dis 2023:JAD221253. [PMID: 37125553 DOI: 10.3233/jad-221253] [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: 05/02/2023]
Abstract
As the size of the population aged 65 and older continues to grow, the incidence and mortality rates of Alzheimer's disease (AD) are increasing annually. Unfortunately, current treatments only treat symptoms temporarily and do not alter the patients' life expectancy or course of AD. Mesenchymal stem cells (MSCs) have shown a certain therapeutic potential in neurodegenerative diseases including AD due to their neuroinflammatory regulation and neuroprotective effects. However, the low survival and homing rates of MSCs after transplantation seriously affect their therapeutic effectiveness. Therefore, appropriate in vitro preconditioning is necessary to increase the survival and homing rates of MSCs to improve their effectiveness in treating AD. Here we summarize the therapeutic mechanisms of MSCs in AD and the chemical reagents used for the pretreatment of MSCs.
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Affiliation(s)
- Kexin Zhang
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Xinzhe Du
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yao Gao
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Sha Liu
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yong Xu
- Department of Psychiatry, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China
- Department of Mental Health, Shanxi Medical University, Taiyuan, China
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Fernández-Mateos P, Cano-Barquilla P, Jiménez-Ortega V, Virto L, Pérez-Miguelsanz J, Esquifino AI. Effect of Melatonin on Redox Enzymes Daily Gene Expression in Perirenal and Subcutaneous Adipose Tissue of a Diet Induced Obesity Model. Int J Mol Sci 2023; 24:ijms24020960. [PMID: 36674472 PMCID: PMC9863119 DOI: 10.3390/ijms24020960] [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: 11/11/2022] [Revised: 12/26/2022] [Accepted: 12/28/2022] [Indexed: 01/06/2023] Open
Abstract
Increased adiposity is related to oxidative stress, inflammation and metabolic disorders. Our group has shown that melatonin totally or partially prevents the alterations that obesity causes in some neuroendocrine and inflammatory parameters indicative of oxidative stress. This study analyzes the effects of HFD on the relative gene expression of several redox balance enzymes on adult male Wistar rats subcutaneous (SAT) and perirenal adipose tissue (PRAT) and the possible preventive role of melatonin. Three experimental groups were established: control, high fat diet (HFD) and HFD plus 25 μg/mL melatonin in tap water. After 11 weeks, animals were sacrificed at 09:00 a.m. and 01:00 a.m. and PRAT and SAT were collected for selected redox enzymes qRT-PCR. Differential expression of redox enzyme genes, except for SODMn, GPx and catalase, was observed in the control group as a function of fat depot. HFD causes the disappearance of the temporal changes in the expression of the genes studied in the two fat depots analyzed. PRAT seems to be more sensitive than SAT to increased oxidative stress induced by obesity. Melatonin combined with a HFD intake, partially prevents the effects of the HFD on the gene expression of the redox enzymes. According to our results, melatonin selectively prevents changes in the relative gene expression of redox enzymes in PRAT and SAT of animals fed an HFD.
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Affiliation(s)
- Pilar Fernández-Mateos
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28003 Madrid, Spain
- Department of Cellular Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain
- Correspondence: (P.F.-M.); (A.I.E.); Tel.: +34-913947256 (P.F.-M.); +34-913947189 (A.I.E.)
| | - Pilar Cano-Barquilla
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28003 Madrid, Spain
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain
| | - Vanesa Jiménez-Ortega
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28003 Madrid, Spain
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain
| | - Leire Virto
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28003 Madrid, Spain
- Department of Anatomy and Embryology, Faculty of Optics, Complutense University, 28037 Madrid, Spain
| | - Juliana Pérez-Miguelsanz
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28003 Madrid, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain
| | - Ana I. Esquifino
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28003 Madrid, Spain
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain
- Correspondence: (P.F.-M.); (A.I.E.); Tel.: +34-913947256 (P.F.-M.); +34-913947189 (A.I.E.)
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Wan JT, Qiu XS, Fu ZH, Huang YC, Min SX. Tumor necrosis factor-α inhibition restores matrix formation by human adipose-derived stem cells in the late stage of chondrogenic differentiation. World J Stem Cells 2022; 14:798-814. [PMID: 36483847 PMCID: PMC9724386 DOI: 10.4252/wjsc.v14.i11.798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 10/05/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Cartilage tissue engineering is a promising strategy for treating cartilage damage. Matrix formation by adipose-derived stem cells (ADSCs), which are one type of seed cell used for cartilage tissue engineering, decreases in the late stage of induced chondrogenic differentiation in vitro, which seriously limits research on ADSCs and their application. AIM To improve the chondrogenic differentiation efficiency of ADSCs in vitro, and optimize the existing chondrogenic induction protocol. METHODS Tumor necrosis factor-alpha (TNF-α) inhibitor was added to chondrogenic culture medium, and then Western blotting, enzyme linked immunosorbent assay, immunofluorescence and toluidine blue staining were used to detect the cartilage matrix secretion and the expression of key proteins of nuclear factor kappa-B (NF-κB) signaling pathway. RESULTS In this study, we found that the levels of TNF-α and matrix metalloproteinase 3 were increased during the chondrogenic differentiation of ADSCs. TNF-α then bound to its receptor and activated the NF-κB pathway, leading to a decrease in cartilage matrix synthesis and secretion. Blocking TNF-α with its inhibitors etanercept (1 μg/mL) or infliximab (10 μg/mL) significantly restored matrix formation. CONCLUSION Therefore, this study developed a combination of ADSC therapy and targeted anti-inflammatory drugs to optimize the chondrogenesis of ADSCs, and this approach could be very beneficial for translating ADSC-based approaches to treat cartilage damage.
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Affiliation(s)
- Jiang-Tao Wan
- Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
- Institute of Orthopedics, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, Guangdong Province, China
| | - Xian-Shuai Qiu
- Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Zhuo-Hang Fu
- Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
- Institute of Orthopedics, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, Guangdong Province, China
| | - Yong-Can Huang
- Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
- Institute of Orthopedics, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, Guangdong Province, China
| | - Shao-Xiong Min
- Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
- Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China.
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Naeimi A, Zaminy A, Amini N, Balabandi R, Golipoor Z. Effects of melatonin-pretreated adipose-derived mesenchymal stem cells (MSC) in an animal model of spinal cord injury. BMC Neurosci 2022; 23:65. [PMCID: PMC9667651 DOI: 10.1186/s12868-022-00752-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 11/04/2022] [Indexed: 11/18/2022] Open
Abstract
Background One of the most serious nervous system diseases is spinal cord injury(SCI), which is increasing for various reasons. Although no definitive treatment has yet been identified for SCI, one possible treatment is adipose-derived stem cells(ADSCs). However, a key issue in transplantation is improving cells’ survival and function in the target tissue. Melatonin(MT) hormone with antioxidant properties can prolong cell survival and improve cell function. This study investigates the pre-conditioning of ADSCs with melatonin for enhancing the engraftment and neurological function of rats undergoing SCI. Methods 42 male Sprague–Dawley rats were divided into six groups, including Control, Sham, Model, Vehicle, and Lesion treatments A and B. After acquiring white adipose tissue, stem cells were evaluated by flow cytometry. SCI was then applied in Model, Vehicle, A, and B groups. Group A and B received ADSCs and ADSCs + melatonin, respectively, 1 week after SCI, but the vehicle received only an intravenous injection for simulation; The other groups were recruited for the behavioral test. Immunohistochemistry(IHC) was used to assess the engraftment and differentiation of ADSCs in the SCI site. Basso, Beattie, and Bresnahan's score was used to evaluate motor function between the six groups. Results Histological studies and cell count confirmed ADSCs implantation at the injury site, which was higher in the MT-ADSCs (P < 0.001). IHC revealed the differentiation of ADSCs and MT-ADSCs into neurons, astrocytes, and oligodendrocyte lineage cells, which were higher in MT-ADSCs. Functional improvement was observed in SCI + ADSCs and SCI + MT-ADSCs groups. Conclusion The pre-conditioning of ADSCs with melatonin positively affects engraftment and neuronal differentiation in SCI but does not impact performance improvement compared to the ADSCs.
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Affiliation(s)
- Arvin Naeimi
- grid.411874.f0000 0004 0571 1549Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Arash Zaminy
- grid.411874.f0000 0004 0571 1549Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Naser Amini
- grid.411746.10000 0004 4911 7066Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Raziye Balabandi
- grid.411874.f0000 0004 0571 1549Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Zoleikha Golipoor
- grid.411874.f0000 0004 0571 1549Cellular and Molecular Research Center, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran
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Zhang T, Ouyang H, Liu S, Xiong L, Zhong Z, Wang Q, Qiu Z, Ding Y, Zhou W, Wang X. pH/Thermosensitive dual-responsive hydrogel based sequential delivery for site-specific acute limb ischemia treatment. J Mater Chem B 2022; 10:7836-7846. [PMID: 36070240 DOI: 10.1039/d2tb00474g] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Acute limb ischemia (ALI) is the most severe manifestation of peripheral artery disease, accompanied by pH/temperature-microenvironment changes in two different phases. In the acute phase, temperature and pH are significantly decreased, and reactive oxygen species (ROS) are excessively generated owing to the sharp reduction of blood perfusion. Afterwards, in the chronic phase, although the temperature gradually recovers, angiogenesis is delayed due to chronic vascular injury, skeletal muscle cell apoptosis and endothelial cell dysfunction. Current therapeutic strategies mainly focus on recanalization; however, their effects on scavenging ROS in the acute phase and promoting angiogenesis in the chronic phase are quite limited. Herein, an injectable pH and temperature dual-responsive poloxamer 407 (PF127)/hydroxymethyl cellulose (HPMC)/sodium alginate (SA)-derived hydrogel (FHSgel), encapsulating melatonin and diallyl trisulfide-loaded biodegradable hollow mesoporous silica nanoparticles (DATS@dHMSNs), is developed, which can intelligently respond to the different phases of ALI. In the acute phase of ischemia, the decreased pH results in the rapid release of melatonin to scavenge excessive ischemia-induced ROS. On the other hand, in the chronic repair phase, the recovered temperature triggers the sustained release of DATS@dHMSNs from the FHSgel, thus generating hydrogen sulfide (H2S) to enhance the angiogenesis and microcirculation reconstruction of ischemic limbs.
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Affiliation(s)
- Teng Zhang
- Department of Vascular Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, P. R. China. .,The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, P. R. China.
| | - Huan Ouyang
- Department of Vascular and Thyroid Surgery, Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, 230022, P. R. China
| | - Shichen Liu
- Department of Vascular Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, P. R. China. .,The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, P. R. China.
| | - Lei Xiong
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, P. R. China.
| | - Zhiwei Zhong
- Department of Vascular Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, P. R. China.
| | - Qingqing Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, P. R. China.
| | - Zhuang Qiu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, P. R. China. .,School of Public Health & Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang, Jiangxi, 330088, P. R. China
| | - Yajia Ding
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, P. R. China.
| | - Weimin Zhou
- Department of Vascular Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, P. R. China.
| | - Xiaolei Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, P. R. China. .,College of Chemistry, Nanchang University, Nanchang, Jiangxi, 330088, P. R. China
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Huang QY, Chen SR, Zhao YX, Chen JM, Chen WH, Lin S, Shi QY. Melatonin enhances autologous adipose-derived stem cells to improve mouse ovarian function in relation to the SIRT6/NF-κB pathway. Stem Cell Res Ther 2022; 13:399. [PMID: 35927704 PMCID: PMC9351187 DOI: 10.1186/s13287-022-03060-2] [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: 04/27/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Background Premature ovarian insufficiency (POI) is the main cause of female infertility. Adipose-derived stem cells (ADSCs) are ideal candidates for the treatment of POI. However, some deficient biological characteristics of ADSCs limit their utility. This study investigated whether melatonin (MLT)-pretreated autologous ADSCs were superior to ADSCs alone in the treatment of the POI mouse model. Methods Autologous ADSCs were isolated and cultured in MLT-containing medium. Surface markers of ADSCs were detected by flow cytometry. To determine the effect of MLT on ADSCs, CCK-8 assay was used to detect ADSCs proliferation and enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion of cytokines. The POI model was established by intraperitoneal injection of cyclophosphamide and busulfan. Then, MLT-pretreated autologous ADSCs were transplanted into mice by intraovarian injection. After 7 days of treatment, ovarian morphology, follicle counts, and sex hormones levels were evaluated by hematoxylin and eosin (H&E) staining and ELISA, and the recovery of fertility was also observed. The expressions of SIRT6 and NF-κB were detected by immunohistochemical (IHC) staining and quantitative real-time polymerase chain reaction (qRT-PCR). Results Flow cytometry showed that autologous ADSCs expressed CD90 (99.7%) and CD29 (97.5%). MLT can not only promote the proliferation of ADSCs but also boost their secretory function, especially when ADSCs were pretreated with 5 µM MLT for 3 days, improving the interference effect. After transplantation of autologous ADSCs pretreated with 5 µM MLT, the serum hormone levels and reproductive function were significantly recovered, and the mean counts of primordial follicle increased. At the same time, the expression of SIRT6 was remarkably increased and the expression of NF-κB was significantly decreased in this group. Conclusions MLT enhances several effects of ADSCs in restoring hormone levels, mean primordial follicle counts, and reproductive capacity in POI mice. Meanwhile, our results suggest that the SIRT6/NF-κB signal pathway may be the potential therapeutic mechanism for ADSCs to treat POI.
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Affiliation(s)
- Qiao-Yi Huang
- Department of Gynaecology and Obstetrics, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Shao-Rong Chen
- Department of Gynaecology and Obstetrics, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Yun-Xia Zhao
- Department of Gynaecology and Obstetrics, University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Jia-Ming Chen
- Department of Gynaecology and Obstetrics, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Wei-Hong Chen
- Department of Gynaecology and Obstetrics, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China. .,Group of Neuroendocrinology, Garvan Institute of Medical Research, 384 Victoria St, Sydney, Australia.
| | - Qi-Yang Shi
- Department of Gynaecology and Obstetrics, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China.
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11
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Tobeiha M, Jafari A, Fadaei S, Mirazimi SMA, Dashti F, Amiri A, Khan H, Asemi Z, Reiter RJ, Hamblin MR, Mirzaei H. Evidence for the Benefits of Melatonin in Cardiovascular Disease. Front Cardiovasc Med 2022; 9:888319. [PMID: 35795371 PMCID: PMC9251346 DOI: 10.3389/fcvm.2022.888319] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/10/2022] [Indexed: 12/13/2022] Open
Abstract
The pineal gland is a neuroendocrine gland which produces melatonin, a neuroendocrine hormone with critical physiological roles in the circadian rhythm and sleep-wake cycle. Melatonin has been shown to possess anti-oxidant activity and neuroprotective properties. Numerous studies have shown that melatonin has significant functions in cardiovascular disease, and may have anti-aging properties. The ability of melatonin to decrease primary hypertension needs to be more extensively evaluated. Melatonin has shown significant benefits in reducing cardiac pathology, and preventing the death of cardiac muscle in response to ischemia-reperfusion in rodent species. Moreover, melatonin may also prevent the hypertrophy of the heart muscle under some circumstances, which in turn would lessen the development of heart failure. Several currently used conventional drugs show cardiotoxicity as an adverse effect. Recent rodent studies have shown that melatonin acts as an anti-oxidant and is effective in suppressing heart damage mediated by pharmacologic drugs. Therefore, melatonin has been shown to have cardioprotective activity in multiple animal and human studies. Herein, we summarize the most established benefits of melatonin in the cardiovascular system with a focus on the molecular mechanisms of action.
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Affiliation(s)
- Mohammad Tobeiha
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ameneh Jafari
- Advanced Therapy Medicinal Product (ATMP) Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Fadaei
- Department of Internal Medicine and Endocrinology, Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Atefeh Amiri
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Russel J. Reiter
- Department of Cell Systems and Anatomy, UT Health. Long School of Medicine, San Antonio, TX, United States
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Johannesburg, South Africa
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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12
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Diaz Villamil E, De Roeck L, Vanorlé M, Communi D. UTP Regulates the Cardioprotective Action of Transplanted Stem Cells Derived From Mouse Cardiac Adipose Tissue. Front Pharmacol 2022; 13:906173. [PMID: 35784739 PMCID: PMC9240194 DOI: 10.3389/fphar.2022.906173] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/20/2022] [Indexed: 11/26/2022] Open
Abstract
Adipose tissue is a source of stem cells with a high potential of differentiation for cell-based regenerative therapies. We previously identified mouse P2Y2, an ATP and UTP nucleotide receptor, as a regulator of adipogenic and endothelial differentiation of cardiac adipose-derived stem cells (cADSC). We investigated here the potential involvement of P2Y2 receptor in the cardioprotective action of undifferentiated cADSC transplantation in mouse ischemic heart. Transplantation of cADSC was realized in the periphery of the infarcted zone of ischemic heart, 3 days after left anterior descending artery ligation. A strong reduction of collagen stained area was observed 14 days after cADSC injection, compared to PBS injection. Interestingly, loss of P2Y2 expression totally inhibits the ability of transplanted cADSC to reduce cardiac fibrosis. A detailed gene ontology enrichment analysis was realized by comparing RNA-sequencing data obtained for UTP-treated wild type cASDC and UTP-treated P2Y2-null cASDC. We identified UTP target genes linked to extracellular matrix organization such as matrix metalloproteinases and various collagen types, UTP target genes related to macrophage chemotaxis and differentiation into pro-fibrotic foam cells, and a significant number of UTP target genes linked to angiogenesis regulation. More particularly, we showed that UTP regulated the secretion of CCL5, CXCL5, and CCL12 chemokines and serum amyloid apolipoprotein 3, in the supernatants of UTP-treated cADSC. Interestingly, CCL5 is reported as a key factor in post-infarction heart failure and in the reparative and angiogenic action of transplanted ADSC on ischemic tissue. We investigated then if a UTP-pretreatment of cADSC amplifies their effect on cardiac revascularization in mouse ischemic heart. Transplantation of cADSC was able to increase peri-infarct capillary density, 14 days after their injection. This beneficial effect on cardiac revascularization was enhanced by a UTP-pretreatment of cADSC before their transplantation, and not observed using P2Y2-null cADSC. Our data support that the efficacy of transplanted cADSC can be regulated by the release of inflammatory mediators such as extracellular nucleotides in the ischemic site. The present study highlights the P2Y2 receptor as a regulator of cADSC cardioprotective action, and as a potential target for the therapeutic use of undifferentiated cADSC in post-ischemic cardiac ischemia.
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Affiliation(s)
| | | | | | - Didier Communi
- *Correspondence: Didier Communi, , orcid.org/0000-0003-1050-1493
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13
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Melatonin and the Programming of Stem Cells. Int J Mol Sci 2022; 23:ijms23041971. [PMID: 35216086 PMCID: PMC8879213 DOI: 10.3390/ijms23041971] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/03/2022] [Accepted: 02/08/2022] [Indexed: 02/06/2023] Open
Abstract
Melatonin interacts with various types of stem cells, in multiple ways that comprise stimulation of proliferation, maintenance of stemness and self-renewal, protection of survival, and programming toward functionally different cell lineages. These various properties are frequently intertwined but may not be always jointly present. Melatonin typically stimulates proliferation and transition to the mature cell type. For all sufficiently studied stem or progenitor cells, melatonin’s signaling pathways leading to expression of respective morphogenetic factors are discussed. The focus of this article will be laid on the aspect of programming, particularly in pluripotent cells. This is especially but not exclusively the case in neural stem cells (NSCs) and mesenchymal stem cells (MSCs). Concerning developmental bifurcations, decisions are not exclusively made by melatonin alone. In MSCs, melatonin promotes adipogenesis in a Wnt (Wingless-Integration-1)-independent mode, but chondrogenesis and osteogenesis Wnt-dependently. Melatonin upregulates Wnt, but not in the adipogenic lineage. This decision seems to depend on microenvironment and epigenetic memory. The decision for chondrogenesis instead of osteogenesis, both being Wnt-dependent, seems to involve fibroblast growth factor receptor 3. Stem cell-specific differences in melatonin and Wnt receptors, and contributions of transcription factors and noncoding RNAs are outlined, as well as possibilities and the medical importance of re-programming for transdifferentiation.
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14
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Al-Otaibi AM, Al-Gebaly AS, Almeer R, Albasher G, Al-Qahtani WS, Abdel Moneim AE. Melatonin pre-treated bone marrow derived-mesenchymal stem cells prompt wound healing in rat models. Biomed Pharmacother 2022; 145:112473. [PMID: 34861635 DOI: 10.1016/j.biopha.2021.112473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/16/2021] [Accepted: 11/23/2021] [Indexed: 01/16/2023] Open
Abstract
Bone marrow derived-mesenchymal stem cells (BMSCs)-based therapy is an outstanding candidate for cutaneous wound healing. Melatonin (MEL) has been reported for its anti-inflammatory as well as tissue regenerative properties. Existing work aimed to explore the potential healing power of BMSCs pre-treated with MEL in a skin wound model. Adult rats were allocated into control, PIO, BMSCs (1 × 105 cells), and MEL/BMSCs groups. On the 21 days post-wounding, tissues were sampled for analysis. The results demonstrated that compared to the control group, MEL/BMSCs therapy induced noticeable decline in wound area and elevated rate of wound retraction. Furthermore, marked increases in tissue hydroxyproline, as well as tissue content and gene expression level of vascular endothelial growth factor in MEL/BMSCs treated-wounded animals. Compared to the untreated control group, marked increases were found in antioxidant enzymatic activities together with elevated GSH levels in wounded tissues after MEL/BMSCs treatment. Moreover, therapeutically handled wounds with MEL/BMSCs revealed low levels of MDA, NO and protein carbonyls. Combined therapy with MEL/BMSCs relieved the inflammation witnessed by decreasing IL-1β, TNF-α and NF-κB levels in wounded tissues. Furthermore, noteworthy rises in levels of TGF-β and gene expression of α-SMA were noticed after MEL/BMSCs application that reveals their anti-scarring properties. Histologically, noticeable improvement in histopathological skin lesions in wound area and elevated the collagen synthesis and deposition. Collectively, the obtained data depict that the pre-treatment of BMSCs with MEL could potentially be a successful strategy for scaling-up the wound healing outcomes more than using BMSCs monotherapy in rat models.
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Affiliation(s)
- Aljohara M Al-Otaibi
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Asma S Al-Gebaly
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Rafa Almeer
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Gadah Albasher
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Wedad S Al-Qahtani
- Department of Forensic Sciences, College of Forensic Justice, Naif Arab University for Security Sciences, Riyadh, Saudi Arabia
| | - Ahmed E Abdel Moneim
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt.
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15
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Yea JH, Yoon YM, Lee JH, Yun CW, Lee SH. Exosomes isolated from melatonin-stimulated mesenchymal stem cells improve kidney function by regulating inflammation and fibrosis in a chronic kidney disease mouse model. J Tissue Eng 2021; 12:20417314211059624. [PMID: 34868540 PMCID: PMC8638070 DOI: 10.1177/20417314211059624] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic kidney disease (CKD) is defined as structural and functional abnormalities of the kidney due to inflammation and fibrosis. We investigated the therapeutic effects of exosomes secreted by melatonin-stimulated mesenchymal stem cells (Exocue) on the functional recovery of the kidney in a CKD mouse model. Exocue upregulated gene expression of micro RNAs (miRNAs) associated with anti-inflammatory and anti-fibrotic effects. Exocue-treated groups exhibited low tumor necrosis factor-α and transforming growth factor-β levels in serum and fibrosis inhibition in kidney tissues mediated through regulation of cell apoptosis and proliferation of fibrosis-related cells. Exocue treatment decreased the gene expression of CKD progression-related miRNAs. Moreover, the CKD severity was alleviated in the Exocue group via upregulation of aquaporin 2 and 5 levels and reduction of blood urea nitrogen and creatinine, resulting in functional recovery of the kidney. In conclusion, Exocue could be a novel therapeutic agent for treating CKD by regulating inflammation and fibrosis.
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Affiliation(s)
- Ji-Hye Yea
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Yeo Min Yoon
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Jun Hee Lee
- Institute of Tissue Regeneration Engineering, Dankook University, Cheonan, Republic of Korea.,Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Republic of Korea.,Department of Oral Anatomy, College of Dentistry, Dankook University, Cheonan, Republic of Korea.,Cell and Matter Institute, Dankook University, Cheonan, Republic of Korea
| | - Chul Won Yun
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Sang Hun Lee
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.,Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea.,Department of Biochemistry, BK21FOUR Project2, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea.,Stembio Ltd., Asan, Republic of Korea
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16
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Veiga ECDA, Simões RDS, Caviola LL, Abreu LC, Cavalli RC, Cipolla-Neto J, Baracat EC, Soares JM. Melatonin and the cardiovascular system in animals: systematic review and meta-analysis. Clinics (Sao Paulo) 2021; 76:e2863. [PMID: 34644731 PMCID: PMC8478132 DOI: 10.6061/clinics/2021/e2863] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 08/16/2021] [Indexed: 12/09/2022] Open
Abstract
Melatonin, a hormone released by the pineal gland, demonstrates several effects on the cardiovascular system. Herein, we performed a systematic review and meta-analysis to verify the effects of melatonin in an experimental model of myocardial infarction. We performed a systematic review according to PRISMA recommendations and reviewed MEDLINE, Embase, and Cochrane databases. Only articles in English were considered. A systematic review of the literature published between November 2008 and June 2019 was performed. The meta-analysis was conducted using the RevMan 5.3 program provided by the Cochrane Collaboration. In total, 858 articles were identified, of which 13 were included in this review. The main results of this study revealed that melatonin benefits the cardiovascular system by reducing infarct size, improving cardiac function according to echocardiographic and hemodynamic analyses, affords antioxidant effects, improves the rate of apoptosis, decreases lactate dehydrogenase activity, enhances biometric analyses, and improves protein levels, as analyzed by western blotting and quantitative PCR. In the meta-analysis, we observed a statistically significant decrease in infarct size (mean difference [MD], -20.37 [-23.56, -17.18]), no statistical difference in systolic pressure (MD, -1.75 [-5.47, 1.97]), a statistically significant decrease in lactate dehydrogenase in animals in the melatonin group (MD, -4.61 [-6.83, -2.40]), and a statistically significant improvement in the cardiac ejection fraction (MD, -8.12 [-9.56, -6.69]). On analyzing potential bias, we observed that most studies presented a low risk of bias; two parameters were not included in the analysis, and one parameter had a high risk of bias. Melatonin exerts several effects on the cardiovascular system and could be a useful therapeutic target to combat various cardiovascular diseases.
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Affiliation(s)
- Eduardo Carvalho de Arruda Veiga
- Departamento de Obstetricia e Ginecologia, Hospital das Clinicas HCFMRP-USP, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, BR
| | - Ricardo dos Santos Simões
- Departamento de Obstetricia e Ginecologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Leonardo L. Caviola
- Departamento de Obstetricia e Ginecologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Luiz Carlos Abreu
- Disciplina de escrita cientifica, Faculdade de Medicina do ABC, Santo Andre, SP, BR
| | - Ricardo Carvalho Cavalli
- Departamento de Obstetricia e Ginecologia, Hospital das Clinicas HCFMRP-USP, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, BR
| | - José Cipolla-Neto
- Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biomedicas (ICB-USP), Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Edmund Chada Baracat
- Departamento de Obstetricia e Ginecologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - José Maria Soares
- Departamento de Obstetricia e Ginecologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
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17
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Buscail E, Le Cosquer G, Gross F, Lebrin M, Bugarel L, Deraison C, Vergnolle N, Bournet B, Gilletta C, Buscail L. Adipose-Derived Stem Cells in the Treatment of Perianal Fistulas in Crohn's Disease: Rationale, Clinical Results and Perspectives. Int J Mol Sci 2021; 22:ijms22189967. [PMID: 34576129 PMCID: PMC8470328 DOI: 10.3390/ijms22189967] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/07/2021] [Accepted: 09/12/2021] [Indexed: 12/16/2022] Open
Abstract
Between 20 to 25% of Crohn’s disease (CD) patients suffer from perianal fistulas, a marker of disease severity. Seton drainage combined with anti-TNFα can result in closure of the fistula in 70 to 75% of patients. For the remaining 25% of patients there is room for in situ injection of autologous or allogenic mesenchymal stem cells such as adipose-derived stem/stromal cells (ADSCs). ADSCs exert their effects on tissues and effector cells through paracrine phenomena, including the secretome and extracellular vesicles. They display anti-inflammatory, anti-apoptotic, pro-angiogenic, proliferative, and immunomodulatory properties, and a homing within the damaged tissue. They also have immuno-evasive properties allowing a clinical allogeneic approach. Numerous clinical trials have been conducted that demonstrate a complete cure rate of anoperineal fistulas in CD ranging from 46 to 90% of cases after in situ injection of autologous or allogenic ADSCs. A pivotal phase III-controlled trial using allogenic ADSCs (Alofisel®) demonstrated that prolonged clinical and radiological remission can be obtained in nearly 60% of cases with a good safety profile. Future studies should be conducted for a better knowledge of the local effect of ADSCs as well as for a standardization in terms of the number of injections and associated procedures.
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Affiliation(s)
- Etienne Buscail
- Department of Surgery, CHU Toulouse-Rangueil and Toulouse University, UPS, 31059 Toulouse, France;
- IRSD, University of Toulouse, INSERM 1022, INRAe, ENVT, UPS, 31300 Toulouse, France; (C.D.); (N.V.)
| | - Guillaume Le Cosquer
- Department of Gastroenterology and Pancreatology, CHU Toulouse-Rangueil and Toulouse University, UPS, 31059 Toulouse, France; (G.L.C.); (B.B.); (C.G.)
| | - Fabian Gross
- Centre for Clinical Investigation in Biotherapy, CHU Toulouse-Rangueil and INSERM U1436, 31059 Toulouse, France; (F.G.); (M.L.); (L.B.)
| | - Marine Lebrin
- Centre for Clinical Investigation in Biotherapy, CHU Toulouse-Rangueil and INSERM U1436, 31059 Toulouse, France; (F.G.); (M.L.); (L.B.)
| | - Laetitia Bugarel
- Centre for Clinical Investigation in Biotherapy, CHU Toulouse-Rangueil and INSERM U1436, 31059 Toulouse, France; (F.G.); (M.L.); (L.B.)
| | - Céline Deraison
- IRSD, University of Toulouse, INSERM 1022, INRAe, ENVT, UPS, 31300 Toulouse, France; (C.D.); (N.V.)
| | - Nathalie Vergnolle
- IRSD, University of Toulouse, INSERM 1022, INRAe, ENVT, UPS, 31300 Toulouse, France; (C.D.); (N.V.)
| | - Barbara Bournet
- Department of Gastroenterology and Pancreatology, CHU Toulouse-Rangueil and Toulouse University, UPS, 31059 Toulouse, France; (G.L.C.); (B.B.); (C.G.)
| | - Cyrielle Gilletta
- Department of Gastroenterology and Pancreatology, CHU Toulouse-Rangueil and Toulouse University, UPS, 31059 Toulouse, France; (G.L.C.); (B.B.); (C.G.)
| | - Louis Buscail
- Department of Gastroenterology and Pancreatology, CHU Toulouse-Rangueil and Toulouse University, UPS, 31059 Toulouse, France; (G.L.C.); (B.B.); (C.G.)
- Centre for Clinical Investigation in Biotherapy, CHU Toulouse-Rangueil and INSERM U1436, 31059 Toulouse, France; (F.G.); (M.L.); (L.B.)
- Correspondence: ; Tel.: +33-561323055
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18
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Zhang J, Jia G, Xue P, Li Z. Melatonin restores osteoporosis-impaired osteogenic potential of bone marrow mesenchymal stem cells and alleviates bone loss through the HGF/ PTEN/ Wnt/β-catenin axis. Ther Adv Chronic Dis 2021; 12:2040622321995685. [PMID: 34457228 PMCID: PMC8392808 DOI: 10.1177/2040622321995685] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 01/26/2021] [Indexed: 01/04/2023] Open
Abstract
Background: Previous studies reported that melatonin exerts its effect on mesenchymal stem cell (MSC) survival and differentiation into osteogenic and adipogenic lineage. In the current study we aimed to explore the effect of melatonin on osteoporosis and relevant mechanisms. Methods: Real-time qualitative polymerase chain reaction (RT-qPCR) and Western blot analysis were conducted to determine expression of HGF, PTEN, and osteoblast differentiation-related genes in ovariectomy (OVX)-induced osteoporosis mice and the isolated bone marrow MSCs (BMSCs). Pre-conditioning with melatonin (1 μmol/l, 10 μmol/l and 100 μmol/l) was carried out in OVX mice BMSCs. Bone microstructure was analyzed using micro-computed tomography and the contents of alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase 5b (TRAP5b) were detected by enzyme-linked immunosorbent assay in serum. BMSC proliferation was measured by cell-counting kit (CCK)-8 assay. Alizarin red S (ARS) staining and ALP activity assay were performed to assess BMSC mineralization and calcification. The activity of the Wnt/β-catenin pathway was evaluated by dual-luciferase reporter assay. Results: Melatonin prevented bone loss in OVX mice. Melatonin increased ALP expression and reduced TRAP5b expression. HGF and β-catenin were downregulated, while PTEN was upregulated in the femur of OVX mice. Melatonin elevated HGF expression and then stimulated BMSC proliferation and osteogenic differentiation. Additionally, HGF diminished the expression of PTEN, resulting in activated Wnt/β-catenin pathway both in vitro and in vivo. Furthermore, melatonin was shown to ameliorate osteoporosis in OVX mice via the HGF/PTEN/Wnt/β-catenin axis. Conclusion: Melatonin could potentially enhance osteogenic differentiation of BMSCs and retard bone loss through the HGF/PTEN/Wnt/β-catenin axis.
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Affiliation(s)
- Jun Zhang
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, P.R. China
| | - Guoliang Jia
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, P.R. China
| | - Pan Xue
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, P.R. China
| | - Zhengwei Li
- Department of Orthopedics, The Second Hospital of Jilin University, No. 218, Ziqiang Road, Changchun, Jilin Province 130041, P.R. China
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Osikov MV, Ageeva AA, Fedosov AA, Ushakova VA. Role of mast cells in skin regeneration after thermal burn treated with melatonin-enriched dermal film. BULLETIN OF RUSSIAN STATE MEDICAL UNIVERSITY 2021. [DOI: 10.24075/brsmu.2021.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The development of novel local therapies for thermal burns (TB) and their pathogenetic rationale are a pressing challenge. Melatonin (MT) is an endogenous factor of hemostasis regulation with pleiotropic potential. The aim of this study was to assess some parameters of tissue regeneration, the functional state of mast cells and the levels of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in the experimentally induced TB treated with the original MT-enriched dermal film (DF). A second-degree burn (3.5% of the total body surface area) was modelled by exposing a patch of skin to hot water. Applications of 12 cm2 DF enriched with 5 mg/g MT were performed every day for 5 days. The following parameters were calculated: the wound area, the rate of wound epithelization, the number of MC in the wound, the intensity of degranulation, and the levels of MMP-9 and VEGF expression. Over the course of treatment, the absolute wound area shrank by 35%, its epithelization rate increased, the number of MC rose, their functional state changed, and the expression of ММР-9 and VEGF increased. A negative correlation was established between the wound area and the expression of ММР-9 and VEGF, as well as between the wound area and the degranulation coefficient. Applications of MT-enriched DF resulted in the reduction of the wound area, higher epithelization rate, an increase in the total MC count and degranulation intensity on days 5 and 10; it also led to a reduction in the total MC count and a loss in degranulation intensity on day 20 (166.87 (154.95; 178.78) un/mm2 vs. 464.84 (452.92; 476.76) un/mm2) in the group of intact animals), an increase in MMP-9 expression on day 5 (14.20 (11.30; 18.10) vs. 3.30 (2.20; 4.40) in the intact group), an increase in VEGF expression on days 5 and 10 (33.00 (30.20; 34.90) vs 25.40 (22.20; 29.30) in the intact group), and a reduction in MMP-9 expression on days 10 and 20 after thermal injury.
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Vanorlé M, Lemaire A, di Pietrantonio L, Horckmans M, Communi D. UTP is a regulator of in vitro and in vivo angiogenic properties of cardiac adipose-derived stem cells. Purinergic Signal 2021; 17:681-691. [PMID: 34351588 DOI: 10.1007/s11302-021-09812-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 07/11/2021] [Indexed: 10/20/2022] Open
Abstract
The ability of cardiac adipose-derived stem cells (cADSC) to differentiate into multiple cell types has opened new perspectives in cardiac cell-based regenerative therapies. P2Y nucleotide receptors have already been described as regulators of adipogenic differentiation of cADSC and bone marrow-derived stem cells. In this study, we defined UTP as a regulator of cADSC endothelial differentiation. A daily UTP stimulation of cADSC during endothelial predifferentiation increased their capacity to form an endothelial network in matrigel. Additionally, pro-angiogenic UTP target genes such as epiregulin and hyaluronan synthase-1 were identified in predifferentiated cADSC by RNA sequencing experiments. Their regulation by UTP was confirmed by qPCR and ELISA experiments. We then evaluated the capacity of UTP-treated predifferentiated cADSC to increase post-ischemic revascularization in mice subjected to left anterior descending artery ligation. Predifferentiated cADSC treated or not with UTP were injected in the periphery of the infarcted zone, 3 days after ligation. We observed a significant increase of capillary density 14 and 30 days after UTP-treated predifferentiated cADSC injection, correlated with a reduction of cardiac fibrosis. This revascularization increase was not observed after injection of UTP-treated cADSC deficient for UTP and ATP nucleotide receptor P2Y2. The present study highlights the P2Y2 receptor as a regulator of cADSC endothelial differentiation and as a potential target for the therapeutic use of cADSC in post-ischemic heart revascularization.
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Affiliation(s)
- Marion Vanorlé
- Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, ULB, Building C (5th floor), Campus Erasme, 808 Route de Lennik, 1070, Brussels, Belgium
| | - Anne Lemaire
- Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, ULB, Building C (5th floor), Campus Erasme, 808 Route de Lennik, 1070, Brussels, Belgium
| | - Larissa di Pietrantonio
- Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, ULB, Building C (5th floor), Campus Erasme, 808 Route de Lennik, 1070, Brussels, Belgium
| | - Michael Horckmans
- Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, ULB, Building C (5th floor), Campus Erasme, 808 Route de Lennik, 1070, Brussels, Belgium
| | - Didier Communi
- Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, ULB, Building C (5th floor), Campus Erasme, 808 Route de Lennik, 1070, Brussels, Belgium.
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21
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Çil N, Yaka M, Neşet NG, Seçme M, Mete GA. Effects of different doses of melatonin on rat adipose derived mesenchymal stem cells. Horm Mol Biol Clin Investig 2021; 42:395-401. [PMID: 34344063 DOI: 10.1515/hmbci-2021-0013] [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: 02/15/2021] [Accepted: 07/06/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Stem cell treatment is based on Melatonin which is crucial for lots of pathological and physiological pathways. Our aim is determining the most appropriate dose of melatonin affecting the rat adipose tissue mesenchymal stem cells. METHODS Stem cells were isolated from male rat adipose tissue. Differentiation and characterization experiments were performed. Cell viability analyses in stem cells were used the XTT [2,3-Bis-(2-methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide] assay. After 24 h incubation, different concentrations (0.5, 1, 5, 10, 50 µM) of extract were treated to the stem cells for 24 h, 48 and 72 h considering time and dose dependent manner. Total antioxidant status (TAS) and the total oxidant status (TOS) in control cells and melatonin treated cells (5, 10 µM) were determined Rel Assay commercial kits. RESULTS In 24 h, melatonin increased cell viability in all groups. When we evaluate the effect of melatonin in 48 h, the most proliferation increase was seen at 5, 10 µM doses. When the total oxidant activity melatonin was found to be significantly lower in 5 and 10 µM dose groups of melatonin. CONCLUSIONS Melatonin increases the survivor of stem cells and the most effective dose is 5 and 10 µM. The reduction of the oxidative stress index as a result of treating melatonin to mesenchymal stem cells showed that melatonin is a powerful antioxidant for stem cells.
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Affiliation(s)
- Nazlı Çil
- Department of Histology and Embryology, Pamukkale University, School of Medicine, Denizli, Turkey
| | - Mutlu Yaka
- Department of Histology and Embryology, Pamukkale University, School of Medicine, Denizli, Turkey
| | - Nazire Gül Neşet
- Department of Histology and Embryology, Pamukkale University, School of Medicine, Denizli, Turkey
| | - Mücahit Seçme
- Department of Medical Biology, Pamukkale University, School of Medicine, Denizli, Turkey
| | - Gülçin Abban Mete
- Department of Histology and Embryology, Pamukkale University, School of Medicine, Denizli, Turkey
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Wang Q, Wang Y, Du L, Xu C, Liu Y, Liu Q, Fan S. Quantitative proteomic analysis of the effects of melatonin treatment for mice suffered from small intestinal damage induced by γ-ray radiation. Int J Radiat Biol 2021; 97:1206-1216. [PMID: 34264173 DOI: 10.1080/09553002.2021.1956006] [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: 12/21/2020] [Revised: 06/17/2021] [Accepted: 06/23/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Intestinal damage induced by radiation exposure is a major clinic concern of radiotherapy for patients with abdominal or pelvic tumor. Melatonin (N-acetyl-5-methoxytryptamine) is likely be an ideal radioprotector to protect individuals from radiation exposure. The study aimed to define the role of melatonin in small intestinal damage caused by abdominal irradiation (ABI). MATERIALS AND METHODS 30-day survival rate and pathological histology of the intestines from melatonin-treated mice after 13 Gy ABI exposure was first detected. Next, quantitative proteomics analysis of the small intestines tissue was examined and GO term and KEGG pathways analysis were performed. RESULTS Melatonin treatment before ABI exposure significantly increased 30-day survival rate to 83% and ameliorated damage to the intestinal epithelial cells. Melatonin significantly altered the proteins profile of the small intestines following irradiation. For the irradiated mice treated with melatonin in comparison with the irradiated mice, the enriched GO terms were mainly involved in defense response to other organism (BP, GO: 0098542), response to other organism (BP, GO: 0051707), anion transmembrane transporter activity (MF, GO: 0008509), and secondary active transmembrane transporter activity (MF, GO: 0015291). In the process of antioxidant activity (MF, GO: 0016209), melatonin treatment prior to radiation exhibited high protein levels of Sod3 and Gpx3. The markedly KEGG pathways for melatonin treatment prior to radiation mainly included protein digestion and absorption (ko 04974) and mineral absorption (ko 04978). p53 signaling pathway and DNA repair pathways were enriched in melatonin treated mice. The amount of radiation-induced DNA damage and the cell apoptosis of the small intestines was decreased in the melatonin-treated mice. CONCLUSIONS Melatonin may protect small intestines from radiation damage through increasing DNA repair and decreasing cell apoptosis of the small intestines. Our data provided perspective for the study of melatonin in mitigating ABI-caused intestinal damage.
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Affiliation(s)
- Qin Wang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Yan Wang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Liqing Du
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Chang Xu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Yang Liu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Qiang Liu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Saijun Fan
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
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23
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Martín Giménez VM, Bergam I, Reiter RJ, Manucha W. Metal ion homeostasis with emphasis on zinc and copper: Potential crucial link to explain the non-classical antioxidative properties of vitamin D and melatonin. Life Sci 2021; 281:119770. [PMID: 34197883 DOI: 10.1016/j.lfs.2021.119770] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/11/2021] [Accepted: 06/21/2021] [Indexed: 12/21/2022]
Abstract
Metal ion homeostasis is an essential physiological mechanism necessary for achieving an adequate balance of these ions' concentrations in the different cellular compartments. This fact is of great importance because both an excess and a deficiency of cellular metal ion levels are usually equally harmful due to the exacerbated increase in oxidative stress that may occur in both cases. Metal ion homeostasis ensures an equilibrium among multiple functions associated with the body's antioxidative defense network controlled by metallic micronutrients such as zinc and copper, some of the central regulators of redox processes. These micronutrients significantly modulate the activity of some isoforms of superoxide dismutase (SOD) and other enzymes such as metallothioneins (MTs) and ceruloplasmin (CP), which are directly or indirectly involved in the regulation of redox homeostasis. Although it is well known that both melatonin (MEL) and vitamin D have important roles as natural antioxidants, often some of these effects are related to their actions on antioxidative processes dependent on metal ions. Thus, in addition to their classical antioxidative properties usually associated with mitochondrial effects, it is known that MEL and vitamin D modulate the expression and activity of Cu/Zn-dependent SOD isoforms, MTs and CP; function as copper chelators and regulate genomic and non-genomic mechanisms related to the zinc transport. This review summarizes the main findings related to the crucial participation of zinc and copper in physiological antioxidative status and their relationship with the non-classical antioxidant effects of MEL and vitamin D, suggesting a potential synergism among these four micronutrients.
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Affiliation(s)
- Virna M Martín Giménez
- Instituto de Investigaciones en Ciencias Químicas, Facultad de Ciencias Químicas y Tecnológicas, Universidad Católica de Cuyo, Sede San Juan, Argentina
| | - Ivana Bergam
- CROATIA Osiguranje Pension Company for Voluntary Pension Fund Management D.O.O., Zagreb, Croatia
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, Long School of Medicine, San Antonio, TX, USA
| | - Walter Manucha
- Laboratorio de Farmacología Experimental Básica y Traslacional, Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina; Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigación Científica y Tecnológica (IMBECU-CONICET), Argentina.
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Rahbarghazi A, Siahkouhian M, Rahbarghazi R, Ahmadi M, Bolboli L, Keyhanmanesh R, Mahdipour M, Rajabi H. Role of melatonin in the angiogenesis potential; highlights on the cardiovascular disease. J Inflamm (Lond) 2021; 18:4. [PMID: 33531055 PMCID: PMC7852194 DOI: 10.1186/s12950-021-00269-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 01/21/2021] [Indexed: 01/18/2023] Open
Abstract
Melatonin possesses multi-organ and pleiotropic effects with potency to control angiogenesis at both molecular and cellular levels. To date, many efforts have been made to control and regulate the dynamic of angiogenesis modulators in a different milieu. The term angiogenesis or neovascularization refers to the development of de novo vascular buds from the pre-existing blood vessels. This phenomenon is tightly dependent on the balance between the pro- and anti-angiogenesis factors which alters the functional behavior of vascular cells. The promotion of angiogenesis is thought to be an effective strategy to accelerate the healing process of ischemic changes such as infarcted myocardium. Of note, most of the previous studies have focused on the anti-angiogenesis capacity of melatonin in the tumor niche. To the best of our knowledge, few experiments highlighted the melatonin angiogenesis potential and specific regulatory mechanisms in the cardiovascular system. Here, we aimed to summarize some previous experiments related to the application of melatonin in cardiovascular diseases such as ischemic injury and hypertension by focusing on the regulatory mechanisms.
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Affiliation(s)
- Afshin Rahbarghazi
- Department of Physical Education and Sports Sciences, Faculty of Educational Science & Psychology, University of Mohaghegh Ardabili, Daneshgah Street, Ardabil, Iran
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marefat Siahkouhian
- Department of Physical Education and Sports Sciences, Faculty of Educational Science & Psychology, University of Mohaghegh Ardabili, Daneshgah Street, Ardabil, Iran.
| | - Reza Rahbarghazi
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mahdi Ahmadi
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Lotfali Bolboli
- Department of Physical Education and Sports Sciences, Faculty of Educational Science & Psychology, University of Mohaghegh Ardabili, Daneshgah Street, Ardabil, Iran
| | - Rana Keyhanmanesh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Rajabi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Ozkalayci F, Kocabas U, Altun BU, Pandi-Perumal S, Altun A. Relationship Between Melatonin and Cardiovascular Disease. Cureus 2021; 13:e12935. [PMID: 33654615 PMCID: PMC7914336 DOI: 10.7759/cureus.12935] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality worldwide. The coronary atherosclerotic process involves different pathological mechanisms; inflammation is one of the major triggers for the development of atherosclerotic plaque. Although several studies showed the favorable effects of melatonin on the cardiovascular system (CVS), melatonin seems not to take its rightful place in today's clinical practice. This review aims to point out the role of melatonin on cardiovascular disease (CVD) and its' risk factors. All data were obtained via PubMed, Wikipedia, and Google.
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Affiliation(s)
| | - Umut Kocabas
- Cardiology, Baskent University Izmir Hospital, Izmir, TUR
| | | | | | - Armagan Altun
- Cardiology, Baskent University İstanbul Hospital, Istanbul, TUR
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Adipose-Derived Stem Cells: Current Applications and Future Directions in the Regeneration of Multiple Tissues. Stem Cells Int 2020; 2020:8810813. [PMID: 33488736 PMCID: PMC7787857 DOI: 10.1155/2020/8810813] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/04/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022] Open
Abstract
Adipose-derived stem cells (ADSCs) can maintain self-renewal and enhanced multidifferentiation potential through the release of a variety of paracrine factors and extracellular vesicles, allowing them to repair damaged organs and tissues. Consequently, considerable attention has increasingly been paid to their application in tissue engineering and organ regeneration. Here, we provide a comprehensive overview of the current status of ADSC preparation, including harvesting, isolation, and identification. The advances in preclinical and clinical evidence-based ADSC therapy for bone, cartilage, myocardium, liver, and nervous system regeneration as well as skin wound healing are also summarized. Notably, the perspectives, potential challenges, and future directions for ADSC-related researches are discussed. We hope that this review can provide comprehensive and standardized guidelines for the safe and effective application of ADSCs to achieve predictable and desired therapeutic effects.
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Li Z, Chinnathambi A, Ali Alharbi S, Yin F. Plumbagin protects the myocardial damage by modulating the cardiac biomarkers, antioxidants, and apoptosis signaling in the doxorubicin-induced cardiotoxicity in rats. ENVIRONMENTAL TOXICOLOGY 2020; 35:1374-1385. [PMID: 32691977 DOI: 10.1002/tox.23002] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/18/2020] [Accepted: 06/28/2020] [Indexed: 06/11/2023]
Abstract
Cardiovascular disease created enormous health and economic burdens worldwide, which is responsible for the highest mobility and mortality that results in nearly 6.2% of in-hospital deaths every year. Plumbagin is a major bioactive compound that occurs in the Plumbago indica and P. zeylanica with numerous therapeutic benefits. The current research exploration was planned to investigate the therapeutic role of plumbagin against doxorubicin stimulated cardiotoxicity in rats. The cardiotoxicity was stimulated to the rats by administering the 2.5 mg/kg of doxorubicin for 14 days with concurrent supplementation with plumbagin. The hemodynamic parameters were studied by using the tail-cuff plethysmography. The lipid peroxidation and antioxidant status was examined by the standard procedures. The myocardial function and damage markers were assessed with the help of commercial kits. The expression status of inflammatory markers and PI3K/Akt signaling markers were investigated by reverse transcription polymerase chain reaction (RT-PCR) and western blotting analysis, respectively. The plumbagin supplementation appreciably regained the body weight and heart weight of the investigational animals. Hemodynamic parameters and antioxidants statuses were escalated by the plumbagin treatment. The severe elevation in the cardiac damage markers and inflammatory markers were noticeably ameliorated by the plumbagin treatment. The plumbagin treatment also assuaged the overexpression of inflammatory and apoptotic proteins in the heart tissues of doxorubicin-challenged rats. The histopathological analysis revealed that the plumbagin appreciably protected the heart tissues from the doxorubicin-induced damages. The findings of this exploration evidenced that plumbagin treatment attenuated the doxorubicin-stimulated cardiotoxicity in rats.
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Affiliation(s)
- Zhe Li
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi Province, China
| | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Sulaiman Ali Alharbi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Fuyu Yin
- Department of Cardiology, Xidian Group Hospital, Xi'an, Shaanxi Province, China
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Qiu F, Han Y, Shao X, Paulo P, Li W, Zhu M, Tang N, Guo S, Chen Y, Wu H, Zhao D, Liu Y, Chu W. Knockdown of endogenous RNF4 exacerbates ischaemia-induced cardiomyocyte apoptosis in mice. J Cell Mol Med 2020; 24:9545-9559. [PMID: 32722882 PMCID: PMC7520334 DOI: 10.1111/jcmm.15363] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 01/13/2020] [Accepted: 03/28/2020] [Indexed: 12/15/2022] Open
Abstract
RNF4, a poly‐SUMO‐specific E3 ubiquitin ligase, is associated with protein degradation, DNA damage repair and tumour progression. However, the effect of RNF4 in cardiomyocytes remains to be explored. Here, we identified the alteration of RNF4 from ischaemic hearts and oxidative stress‐induced apoptotic cardiomyocytes. Upon myocardial infarction (MI) or H2O2/ATO treatment, RNF4 increased rapidly and then decreased gradually. PML SUMOylation and PML nuclear body (PML‐NB) formation first enhanced and then degraded upon oxidative stress. Reactive oxygen species (ROS) inhibitor was able to attenuate the elevation of RNF4 expression and PML SUMOylation. PML overexpression and RNF4 knockdown by small interfering RNA (siRNA) enhanced PML SUMOylation, promoted p53 recruitment and activation and exacerbated H2O2/ATO‐induced cardiomyocyte apoptosis which could be partially reversed by knockdown of p53. In vivo, knockdown of endogenous RNF4 via in vivo adeno‐associated virus infection deteriorated post‐MI structure remodelling including more extensive interstitial fibrosis and severely fractured and disordered structure. Furthermore, knockdown of RNF4 worsened ischaemia‐induced cardiac dysfunction of MI models. Our results reveal a novel myocardial apoptosis regulation model that is composed of RNF4, PML and p53. The modulation of these proteins may provide a new approach to tackling cardiac ischaemia.
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Affiliation(s)
- Fang Qiu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China
| | - Yanna Han
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China
| | - Xiaoqi Shao
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China.,Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, P. R. China
| | - Petro Paulo
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China
| | - Wenyue Li
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China
| | - Mengying Zhu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China
| | - Nannan Tang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China
| | - Shuaili Guo
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China
| | - Yibing Chen
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China
| | - Han Wu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China
| | - Dan Zhao
- Departments of Clinical Pharmacy and Cardiology, the 2nd Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, P.R. China
| | - Yu Liu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China
| | - Wenfeng Chu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China
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Liao N, Shi Y, Wang Y, Liao F, Zhao B, Zheng Y, Zeng Y, Liu X, Liu J. Antioxidant preconditioning improves therapeutic outcomes of adipose tissue-derived mesenchymal stem cells through enhancing intrahepatic engraftment efficiency in a mouse liver fibrosis model. Stem Cell Res Ther 2020; 11:237. [PMID: 32546282 PMCID: PMC7298967 DOI: 10.1186/s13287-020-01763-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/25/2020] [Accepted: 06/08/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Although it has been preclinically suggested that adipose tissue-derived mesenchymal stem cell (ADSC)-based therapy could effectively treat chronic liver diseases, the hepatic engraftment of ADSCs is still extremely low, which severely limits their long-term efficacy for chronic liver diseases. This study was designed to investigate the impact of antioxidant preconditioning on hepatic engraftment efficiency and therapeutic outcomes of ADSC transplantation in liver fibrotic mice. METHODS Liver fibrosis model was established by using intraperitoneal injection of carbon tetrachloride (CCl4) in the male C57BL/6 mice. Subsequently, the ADSCs with or without antioxidant pretreatment (including melatonin and reduced glutathione (GSH)) were administrated into fibrotic mice via tail vein injection. Afterwards, the ADSC transplantation efficiency was analyzed by ex vivo imaging, and the liver functions were assessed by biochemical analysis and histopathological examination, respectively. Additionally, a typical hydrogen peroxide (H2O2)-induced cell injury model was applied to mimic the cell oxidative injury to further investigate the protective effects of antioxidant preconditioning on cell migration, proliferation, and apoptosis of ADSCs. RESULTS Our data showed that antioxidant preconditioning could enhance the therapeutic effects of ADSCs on liver function recovery by reducing the level of AST, ALT, and TBIL, as well as the content of hepatic hydroxyproline and fibrotic area in liver tissues. Particularly, we also found that antioxidant preconditioning could enhance hepatic engraftment efficiency of ADSCs in liver fibrosis model through inhibiting oxidative injury. CONCLUSIONS Antioxidant preconditioning could effectively improve therapeutic effects of ADSC transplantation for liver fibrosis through enhancing intrahepatic engraftment efficiency by reducing oxidative injuries. These findings might provide a practical strategy for enhancing ADSC transplantation and therapeutic efficiency.
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Affiliation(s)
- Naishun Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Yingjun Shi
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Yingchao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Fangyu Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Bixing Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Youshi Zheng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Yongyi Zeng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025 People’s Republic of China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Jingfeng Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025 People’s Republic of China
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Analyzing Impetus of Regenerative Cellular Therapeutics in Myocardial Infarction. J Clin Med 2020; 9:jcm9051277. [PMID: 32354170 PMCID: PMC7287592 DOI: 10.3390/jcm9051277] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/20/2020] [Accepted: 04/26/2020] [Indexed: 02/06/2023] Open
Abstract
Both vasculature and myocardium in the heart are excessively damaged following myocardial infarction (MI), hence therapeutic strategies for treating MI hearts should concurrently aim for true cardiac repair by introducing new cardiomyocytes to replace lost or injured ones. Of them, mesenchymal stem cells (MSCs) have long been considered a promising candidate for cell-based therapy due to their unspecialized, proliferative differentiation potential to specific cell lineage and, most importantly, their capacity of secreting beneficial paracrine factors which further promote neovascularization, angiogenesis, and cell survival. As a consequence, the differentiated MSCs could multiply and replace the damaged tissues to and turn into tissue- or organ-specific cells with specialized functions. These cells are also known to release potent anti-fibrotic factors including matrix metalloproteinases, which inhibit the proliferation of cardiac fibroblasts, thereby attenuating fibrosis. To achieve the highest possible therapeutic efficacy of stem cells, the other interventions, including hydrogels, electrical stimulations, or platelet-derived biomaterials, have been supplemented, which have resulted in a narrow to broad range of outcomes. Therefore, this article comprehensively analyzed the progress made in stem cells and combinatorial therapies to rescue infarcted myocardium.
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Mirza-Aghazadeh-Attari M, Reiter RJ, Rikhtegar R, Jalili J, Hajalioghli P, Mihanfar A, Majidinia M, Yousefi B. Melatonin: An atypical hormone with major functions in the regulation of angiogenesis. IUBMB Life 2020; 72:1560-1584. [PMID: 32329956 DOI: 10.1002/iub.2287] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 03/10/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023]
Abstract
Melatonin (N-acetyl-5-methoxytryptamine), a pleotropic molecule with a wide distribution, has received considerable attention in recent years, mostly because of its various major effects on tissues or cells since it has both receptor-dependent and receptor-independent actions over a wide range of concentrations. These biological and physiological functions of melatonin include regulation of circadian rhythms by modulating the expression of core oscillator genes, scavenging the reactive oxygen species and reactive nitrogen species, modulating the immune system and inflammatory response, and exerting cytoprotective and antiapoptotic effects. Given the multiple critical roles of melatonin, dysregulation of its production or any disruption in signaling through its receptors may have contributed in the development of a wide range of disorders including type 2 diabetes, aging, immune-mediated diseases, hypertension, and cancer. Herein, we focus on the modulatory effects of melatonin on angiogenesis and its implications as a therapeutic strategy in cancer and related diseases.
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Affiliation(s)
- Mohammad Mirza-Aghazadeh-Attari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas, USA
| | - Reza Rikhtegar
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Jalili
- Radiology Department, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parisa Hajalioghli
- Radiology Department, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ainaz Mihanfar
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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32
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Xu J, Liu X, Zhao F, Zhang Y, Wang Z. HIF1α overexpression enhances diabetic wound closure in high glucose and low oxygen conditions by promoting adipose-derived stem cell paracrine function and survival. Stem Cell Res Ther 2020; 11:148. [PMID: 32248837 PMCID: PMC7132964 DOI: 10.1186/s13287-020-01654-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 03/11/2020] [Accepted: 03/17/2020] [Indexed: 12/31/2022] Open
Abstract
Background Adipose-derived stem cell (ADSC) transplantation is a promising strategy to promote wound healing because of the paracrine function of stem cells. However, glucose-associated effects on stem cell paracrine function and survival contribute to impaired wound closure in patients with diabetes, limiting the efficacy of ADSC transplantation. Hypoxia-inducible factor (HIF)1α plays important roles in wound healing, and in this study, we investigated the effects of HIF1α overexpression on ADSCs in high glucose and low oxygen conditions. Methods Adipose samples were obtained from BALB/C mice, and ADSCs were cultured in vitro by digestion. Control and HIF1α-overexpressing ADSCs were induced by transduction. The mRNA and protein levels of angiogenic growth factors in control and HIF1α-overexpressing ADSCs under high glucose and low oxygen conditions were analyzed by quantitative reverse transcription-polymerase chain reaction and western blotting. The effects of ADSC HIF1α overexpression on the proliferation and migration of mouse aortic endothelial cells (MAECs) under high glucose were evaluated using an in vitro coculture model. Intracellular reactive oxygen species (ROS) and 8-hydroxydeoxyguanosine (8-OHdG) levels in ADSCs were observed using 2,7-dichlorodihydrofluorescein diacetate staining and enzyme-linked immunosorbent assays, respectively. Apoptosis and cell cycle analysis assays were performed by flow cytometry. An in vivo full-thickness skin defect mouse model was used to evaluate the effects of transplanted ADSCs on diabetic wound closure. Results In vitro, HIF1α overexpression in ADSCs significantly increased the expression of vascular endothelial growth factor A, fibroblast growth factor 2, and C-X-C motif chemokine ligand 12, which were inhibited by high glucose. HIF1α overexpression in ADSCs alleviated high glucose-induced defects in MAEC proliferation and migration and significantly suppressed ADSC ROS and 8-OHdG levels, thereby decreasing apoptosis and enhancing survival. In vivo, HIF1α overexpression in ADSCs prior to transplantation significantly enhanced angiogenic growth factor expression, promoting wound closure in diabetic mice. Conclusions HIF1α overexpression in ADSCs efficiently alleviates high glucose-induced paracrine dysfunction, decreases oxidative stress and subsequent DNA damage, improves viability, and enhances the therapeutic effects of ADSCs on diabetic wound healing.
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Affiliation(s)
- Jin Xu
- Department of Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, China
| | - Xiaoyu Liu
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, China
| | - Feng Zhao
- Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory for Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, No. 77 Puhe Street, Shenbei New District, Shenyang, 110122, China
| | - Ying Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, China
| | - Zhe Wang
- Department of Pathology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, China.
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Hu ZP, Fang XL, Sheng B, Guo Y, Yu YQ. Melatonin inhibits macrophage infiltration and promotes plaque stabilization by upregulating anti-inflammatory HGF/c-Met system in the atherosclerotic rabbit: USPIO-enhanced MRI assessment. Vascul Pharmacol 2020; 127:106659. [DOI: 10.1016/j.vph.2020.106659] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 02/06/2020] [Accepted: 02/14/2020] [Indexed: 01/08/2023]
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Xu Z, You W, Liu J, Wang Y, Shan T. Elucidating the Regulatory Role of Melatonin in Brown, White, and Beige Adipocytes. Adv Nutr 2020; 11:447-460. [PMID: 31355852 PMCID: PMC7442421 DOI: 10.1093/advances/nmz070] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/28/2019] [Accepted: 06/13/2019] [Indexed: 12/15/2022] Open
Abstract
The high prevalence of obesity and its associated metabolic diseases has heightened the importance of understanding control of adipose tissue development and energy metabolism. In mammals, 3 types of adipocytes with different characteristics and origins have been identified: white, brown, and beige. Beige and brown adipocytes contain numerous mitochondria and have the capability to burn energy and counteract obesity, while white adipocytes store energy and are closely associated with metabolic disorders and obesity. Thus, regulation of the development and function of different adipocytes is important for controlling energy balance and combating obesity and related metabolic disorders. Melatonin is a neurohormone, which plays multiple roles in regulating inflammation, blood pressure, insulin actions, and energy metabolism. This article summarizes and discusses the role of melatonin in white, beige, and brown adipocytes, especially in affecting adipogenesis, inducing beige formation or white adipose tissue browning, enhancing brown adipose tissue mass and activities, improving anti-inflammatory and antioxidative effects, regulating adipokine secretion, and preventing body weight gain. Based on the current findings, melatonin is a potential therapeutic agent to control energy metabolism, adipogenesis, fat deposition, adiposity, and related metabolic diseases.
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Affiliation(s)
- Ziye Xu
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Wenjing You
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Jiaqi Liu
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Yizhen Wang
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Tizhong Shan
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China,Address correspondence to TS (E-mail: )
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Li HR, Wang C, Sun P, Liu DD, Du GQ, Tian JW. Melatonin attenuates doxorubicin-induced cardiotoxicity through preservation of YAP expression. J Cell Mol Med 2020; 24:3634-3646. [PMID: 32068341 PMCID: PMC7131936 DOI: 10.1111/jcmm.15057] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 01/10/2020] [Accepted: 01/22/2020] [Indexed: 12/21/2022] Open
Abstract
There are increasing concerns related to the cardiotoxicity of doxorubicin in the clinical setting. Recently, melatonin has been shown to exert a cardioprotective effect in various cardiovascular diseases, including cardiotoxic conditions. In this study, we examined the possible protective effects of melatonin on doxorubicin‐induced cardiotoxicity and explored the underlying mechanisms related to this process. We found that in vitro doxorubicin treatment significantly decreased H9c2 cell viability and induced apoptosis as manifested by increased TUNEL‐positive cells, down‐regulation of anti‐apoptotic protein Bcl‐2, as well as up‐regulation of pro‐apoptotic protein Bax. This was associated with increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potentials (MMP). In vivo, five weeks of doxorubicin treatment significantly decreased cardiac function, as evaluated by echocardiography. TUNEL staining results confirmed the increased apoptosis caused by doxorubicin. On the other hand, combinational treatment of doxorubicin with melatonin decreased cardiomyocyte ROS and apoptosis levels, along with increasing MMP. Such doxorubicin‐melatonin co‐treatment alleviated in vivo doxorubicin‐induced cardiac injury. Western Blots, along with in vitro immunofluorescence and in vivo immunohistochemical staining confirmed that doxorubicin treatment significantly down‐regulated Yes‐associated protein (YAP) expression, while YAP levels were maintained under co‐treatment of doxorubicin and melatonin. YAP inhibition by siRNA abolished the protective effects of melatonin on doxorubicin‐treated cardiomyocytes, with reversed ROS level and apoptosis. Our findings suggested that melatonin treatment attenuated doxorubicin‐induced cardiotoxicity through preserving YAP levels, which in turn decreases oxidative stress and apoptosis.
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Affiliation(s)
- Hai-Ru Li
- Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, China
| | - Chao Wang
- Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, China
| | - Ping Sun
- Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, China
| | - Dan-Dan Liu
- Key Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, China.,Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guo-Qing Du
- Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, China
| | - Jia-Wei Tian
- Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, China
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Effects of melatonin on cardiovascular risk factors and metabolic syndrome: a comprehensive review. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:521-536. [DOI: 10.1007/s00210-020-01822-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 01/10/2020] [Indexed: 12/13/2022]
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Mohamed Y, Basyony MA, El-Desouki NI, Abdo WS, El-Magd MA. The potential therapeutic effect for melatonin and mesenchymal stem cells on hepatocellular carcinoma. Biomedicine (Taipei) 2019; 9:24. [PMID: 31724939 PMCID: PMC6855194 DOI: 10.1051/bmdcn/2019090424] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 06/25/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/AIM Herein, we investigated the potential therapeutic effect of Melatonin (Mel) and/or mesenchymal stem cells (MSCs) on rat model of HCC. MATERIALS AND METHODS Female mature rats were divided into 5 groups (n = 10/group): normal (Nor), HCC group intraperitoneally injected with 200 mg/kg DEN, and 3 treated groups; HCC + Mel (Mel) group given Mel intraperitoneally 20 mg/kg, twice a week, HCC + MSCs (MSCs) group intravenously injected by 1 × 106 cells, and HCC + MSCs (Mel +MSCs) group. RESULTS Rats in HCC group showed most deteriorated effect in form of increased mortality and relative liver weight, elevated serum levels of ALT, AST, ALP, AFP and GGT in addition to increased pre-neoplastic nodules in liver tissues. Liver tissues of HCC group also exhibited lower level of apoptosis as indicated by decreased DNA fragmentation and expression of p53 caspase 9 and caspase 3 genes and increased PCNA immunoreactivity. Moreover, in this group the expression of IL6 and TGFβ1 genes was significantly upregulated. All these deleterious effects induced by DEN were reversed after administration of Mel and/ or MSCs with best improvement for the combined group (MSCs + Mel). CONCLUSIONS These findings reveal a better therapeutic effect for MSCs when given with Mel and we attribute this beneficial effect, at least in part, to triggering apoptosis and targeting inflammation in HCC. Therefore, combined treatment with Mel and MSCs is recommended to enhance the therapeutic potential against HCC.
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Affiliation(s)
- Yasser Mohamed
- Department of Zoology, Faculty of Science, Tanta University, Tanta 31527, Egypt
| | - Mohamed A Basyony
- Department of Zoology, Faculty of Science, Tanta University, Tanta 31527, Egypt
| | - Nabila I El-Desouki
- Department of Zoology, Faculty of Science, Tanta University, Tanta 31527, Egypt
| | - Walied S Abdo
- Department of Pathology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Mohammed A El-Magd
- Department of Anatomy, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
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Melatonin Rescued Reactive Oxygen Species-Impaired Osteogenesis of Human Bone Marrow Mesenchymal Stem Cells in the Presence of Tumor Necrosis Factor-Alpha. Stem Cells Int 2019; 2019:6403967. [PMID: 31582985 PMCID: PMC6754961 DOI: 10.1155/2019/6403967] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 08/09/2019] [Indexed: 12/22/2022] Open
Abstract
Accumulation of reactive oxygen species (ROS), which can be induced by inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), can significantly inhibit the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). This process can contribute to the imbalance of bone remodeling, which ultimately leads to osteoporosis. Therefore, reducing the ROS generation during osteogenesis of BMSCs may be an effective way to reverse the impairment of osteogenesis. Melatonin (MLT) has been reported to act as an antioxidant during cell proliferation and differentiation, but its antioxidant effect and mechanism of action during osteogenesis of MSCs in the inflammatory microenvironment, especially in the presence of TNF-α, remain unknown and need further study. In our study, we demonstrate that melatonin can counteract the generation of ROS and the inhibitory osteogenesis of BMSCs induced by TNF-α, by upregulating the expression of antioxidases and downregulating the expression of oxidases. Meanwhile, MLT can inhibit the phosphorylation of p65 protein and block the degradation of IκBα protein, thus decreasing the activity of the NF-κB pathway. This study confirmed that melatonin can inhibit the generation of ROS during osteogenic differentiation of BMSCs and reverse the inhibition of osteogenic differentiation of BMSCs in vitro, suggesting that melatonin can antagonize TNF-α-induced ROS generation and promote the great effect of osteogenic differentiation of BMSCs. Accordingly, these findings provide more evidence that melatonin can be used as a candidate drug for the treatment of osteoporosis.
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Abstract
The effects of cell therapy on heart regeneration in patients with chronic cardiomyopathy have been assessed in several clinical trials. These trials can be categorized as those using noncardiac stem cells, including mesenchymal stem cells, and those using cardiac-committed cells, including KIT+ cardiac stem cells, cardiosphere-derived cells, and cardiovascular progenitor cells derived from embryonic stem cells. Although the safety of cell therapies has been consistently reported, their efficacy remains more elusive. Nevertheless, several lessons have been learned that provide useful clues for future studies. This Review summarizes the main outcomes of these studies and draws some perspectives for future cell-based regenerative trials, which are largely based on the primary therapeutic target: remuscularization of chronic myocardial scars by exogenous cells or predominant use of these cells to activate host-associated repair pathways though paracrine signalling. In the first case, the study design should entail delivery of large numbers of cardiac-committed cells, supply of supportive noncardiac cells, and promotion of cell survival and appropriate coupling with endogenous cardiomyocytes. If the primary objective is to harness endogenous repair pathways, then the flexibility of cell type is greater. As the premise is that the transplanted cells need to engraft only transiently, the priority is to optimize their early retention and possibly to switch towards the sole administration of their secretome.
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40
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He YT, Wang W, Shen W, Sun QY, Yin S. Melatonin protects against Fenoxaprop-ethyl exposure-induced meiotic defects in mouse oocytes. Toxicology 2019; 425:152241. [DOI: 10.1016/j.tox.2019.152241] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 06/11/2019] [Accepted: 06/28/2019] [Indexed: 12/14/2022]
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Li X, Ma T, Sun J, Shen M, Xue X, Chen Y, Zhang Z. Harnessing the secretome of adipose-derived stem cells in the treatment of ischemic heart diseases. Stem Cell Res Ther 2019; 10:196. [PMID: 31248452 PMCID: PMC6598280 DOI: 10.1186/s13287-019-1289-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Adipose-derived stem cells (ASCs) are promising therapeutic cells for ischemic heart diseases, due to the ease and efficiency of acquisition, the potential of myocardial lineage differentiation, and the paracrine effects. Recently, many researchers have claimed that the ASC-based myocardial repair is mainly attributed to its paracrine effects, including the anti-apoptosis, pro-angiogenesis, anti-inflammation effects, and the inhibition of fibrosis, rather than the direct differentiation into cardiovascular lineage cells. However, the usage of ASCs comes with the problems of low cardiac retention and survival after transplantation, like other stem cells, which compromises the effectiveness of the therapy. To overcome these drawbacks, researchers have proposed various strategies for improving survival rate and ensuring sustained paracrine secretion. They also investigated the safety and efficacy of phase I and II clinical trials of ASC-based therapy for cardiovascular diseases. In this review, we will discuss the characterization and paracrine effects of ASCs on myocardial repair, followed by the strategies for stimulating the paracrine secretion of ASCs, and finally their clinical usage.
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Affiliation(s)
- Xiaoting Li
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China
| | - Teng Ma
- Department of Cardiovascular Surgery, The First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, No.899, Pinghai Road, Suzhou, 215006, China
| | - Jiacheng Sun
- Department of Cardiovascular Surgery, The First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, No.899, Pinghai Road, Suzhou, 215006, China
| | - Mingjing Shen
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China
| | - Xiang Xue
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China
| | - Yongbing Chen
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China.
| | - Zhiwei Zhang
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China.
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Asprosin improves the survival of mesenchymal stromal cells in myocardial infarction by inhibiting apoptosis via the activated ERK1/2-SOD2 pathway. Life Sci 2019; 231:116554. [PMID: 31194992 DOI: 10.1016/j.lfs.2019.116554] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/29/2019] [Accepted: 06/07/2019] [Indexed: 12/20/2022]
Abstract
AIMS Several adipokines have been proven to improve the therapeutic efficacy of mesenchymal stromal cells (MSCs) when used to treat ischemic heart disease. Asprosin (ASP) is a newly-discovered adipokine. ASP might also predict the severity of coronary pathology. We investigated the role of ASP on MSCs and the effects of ASP-pretreated MSCs on myocardial infarction (MI). MAIN METHODS MSCs were labelled with a lentivirus carrying green fluorescent protein (GFP). For in vivo study, after pretreatment with vehicle or ASP, MSCs were injected into infarcted hearts. Cardiac function and fibrosis were then evaluated 4 weeks after the induction of MI and survival of MSCs evaluated after 1 week. MSCs proliferation and migration were investigated after ASP treatment in vitro. MSCs apoptosis induced by hydrogen peroxide (H2O2) was assessed using flow cytometry. KEY FINDINGS Compared to vehicle-pretreated MSCs, ASP-pretreated MSCs significantly improved the left ventricular ejection fraction (LVEF), and inhibited myocardial fibrosis 4 weeks after MI. ASP pretreatment may have promoted homing of transplanted MSCs. In vitro results showed that ASP had no significant effect on MSC proliferation and migration, but protected these cells from H2O2-induced apoptosis. Among 21 molecules associated with antioxidation and cell death, the antioxidant enzyme SOD2 was significantly upregulated by ASP. Furthermore, ASP treatment inhibited H2O2-induced ROS generation and apoptosis via the activated ERK1/2-SOD2 pathway. SIGNIFICANCE This is the first evidence that ASP can regulate MSCs function and enhance MSCs therapy for ischemic heart disease. Furthermore, we demonstrate that ASP protects MSCs from oxidative stress-induced apoptosis via the ERK1/2-SOD2 pathway.
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Yang F, Li L, Chen K, Li C, Wang Y, Wang G. Melatonin alleviates β-zearalenol and HT-2 toxin-induced apoptosis and oxidative stress in bovine ovarian granulosa cells. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2019; 68:52-60. [PMID: 30870695 DOI: 10.1016/j.etap.2019.03.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 02/28/2019] [Accepted: 03/05/2019] [Indexed: 06/09/2023]
Abstract
β-zearalenol (β-zol) and HT-2 are mycotoxins which cause apoptosis and oxidative stress in mammalian reproductive cells. Melatonin is an endogenous antioxidant involved in apoptosis and oxidative stress-related activities. This study investigated the effects of β-zol and HT-2 on bovine ovarian granulosa cells (BGCs), and how melatonin may counteract these effects. β-zol and HT-2 inhibited cell proliferation in a dose-dependent manner, and induced apoptosis of BGCs. They also yielded upregulation of the apoptosis-related genes Bax/Bcl-2 and Caspase3 and phosphorylation of p38MAPK. Increases in intracellular ROS were observed along with higher levels of mRNA anti-oxidation markers SOD1, SOD2, and CAT. SOD1, SOD2, malonaldehyde (MDA), and glutathione peroxidase (GSH-px) activities increased, as did the levels of SOD1 and SOD2 proteins. All of these effects were reduced or entirely attenuated in BGCs pre-treated with melatonin. Our results demonstrate that melatonin has protective effects against mycotoxin-induced apoptosis and oxidative stress in BGCs.
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Affiliation(s)
- Fangxiao Yang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Lian Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Kunlin Chen
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Chengmin Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Yiru Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Genlin Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China.
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El-Magd MA, Mohamed Y, El-Shetry ES, Elsayed SA, Abo Gazia M, Abdel-Aleem GA, Shafik NM, Abdo WS, El-Desouki NI, Basyony MA. Melatonin maximizes the therapeutic potential of non-preconditioned MSCs in a DEN-induced rat model of HCC. Biomed Pharmacother 2019; 114:108732. [PMID: 30925457 DOI: 10.1016/j.biopha.2019.108732] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 02/22/2019] [Accepted: 02/22/2019] [Indexed: 12/21/2022] Open
Abstract
Pretreatment of mesenchymal stem cells (MSCs) with melatonin (Mel) improves their potential therapeutic effect on chronic diseases and cancers. However, this preconditioning strategy may direct the effect of Mel toward MSCs alone and deprive cancer cells of the oncostatic effect of Mel. Herein, we hypothesized that Mel given before transplantation of non-preconditioned MSCs may maximize the therapeutic outcome via the oncostatic effect of Mel by preparing a suitable tumor microenvironment for MSCs. Female rats (n = 60) were equally divided into 6 groups; normal control, diethylnitrosamine (DEN), DEN + Mel, DEN + MSCs, DEN + MSCs preconditioned with Mel, and DEN + MSCs + Mel. The obtained data revealed that administration of Mel before MSCs treatment without preconditioning yielded a better ameliorative effect against DEN-induced hepatocellular carcinoma (HCC) as evidenced by: 1) reduced serum levels of alpha fetoprotein and gamma-glutamyl transferase; 2) decreased number and area of glutathione S-transferase placental positive foci; 3) induced apoptosis (as indicated by increased cleaved caspase-3 activity, upregulated expression of proapoptotic genes Bax and caspase 3 and downregulated expression of anti-apoptotic genes Bcl2, survivin); 4) decreased malondialdehyde level and increased activities of superoxide dismutase, catalase, and glutathione peroxidase enzymes; and 5) reduced inflammation, angiogenesis and metastasis as indicated by downregulated expression of interleukin 1 beta, nuclear factor kappa B, vascular endothelial growth factor, and matrix metallopeptidase 9 genes and upregulated expression of metalloproteinase inhibitor 1 gene. Thus, administration of Mel before MSCs (without preconditioning) fostered the survival and therapeutic potential of MSCs in HCC, possibly through induction of apoptosis and inhibition of inflammation and oxidative stress. This new strategy showed better therapeutic outcomes and may improve MSC-based therapies for HCC.
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Affiliation(s)
- Mohammed A El-Magd
- Department of Anatomy, Faculty of Veterinary Medicine, Kafrelsheikh University, Egypt.
| | - Yasser Mohamed
- Department of Zoology, Faculty of Science, Tanta University, Egypt
| | - Eman S El-Shetry
- Department of Anatomy, Faculty of Medicine, Zagazig University, Egypt
| | - Shafika A Elsayed
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Egypt
| | - Maha Abo Gazia
- Department of Histology, Faculty of Medicine, Kafrelsheikh University, Egypt
| | - Ghada A Abdel-Aleem
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Egypt
| | - Noha M Shafik
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Egypt
| | - Walied S Abdo
- Department of Pathology, Faculty of Veterinary Medicine, Kafrelsheikh University, Egypt
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Nabavi SM, Nabavi SF, Sureda A, Xiao J, Dehpour AR, Shirooie S, Silva AS, Baldi A, Khan H, Daglia M. Anti-inflammatory effects of Melatonin: A mechanistic review. Crit Rev Food Sci Nutr 2019; 59:S4-S16. [DOI: 10.1080/10408398.2018.1487927] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Affiliation(s)
- Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Seyed Fazel Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Antoni Sureda
- Grup de Nutrici_o Comunit_aria i Estr_es Oxidatiu and CIBEROBN (Physiopathology of Obesity and Nutrition), Universitat de les Illes Balears, Palma de E-07122 Mallorca, Spain
| | - Janbo Xiao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Control in Chinese Medicine, University of Macau, Macau SAR, China
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Shirooie
- School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ana Sanches Silva
- National Institute for Agricultural and Veterinary Research (INIAV), I.P., Vairão, Vila do Conde, Portugal; Center for Study in Animal Science (CECA), ICETA, University of Oporto, Oporto, Portugal
| | - Alessandra Baldi
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Pavia, Italy
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
| | - Maria Daglia
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Pavia, Italy
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Han YS, Kim SM, Lee JH, Jung SK, Noh H, Lee SH. Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrP C -dependent enhancement of the mitochondrial function. J Pineal Res 2019; 66:e12535. [PMID: 30372554 DOI: 10.1111/jpi.12535] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 10/17/2018] [Accepted: 10/19/2018] [Indexed: 12/15/2022]
Abstract
Although mesenchymal stem cell (MSC)-based therapy is a treatment strategy for ischemic diseases associated with chronic kidney disease (CKD), MSCs of CKD patients undergo accelerated senescence, with decreased viability and proliferation upon uremic toxin exposure, inhibiting their utility as a potent stem cell source for transplantation therapy. We investigated the effects of melatonin administration in protecting against cell senescence and decreased viability induced by pathophysiological conditions near the engraftment site. MSCs harvested from CKD mouse models were treated with H2 O2 to induce oxidative stress. CKD-derived MSCs exhibited greater oxidative stress-induced senescence than normal-mMSCs, while melatonin protected CKD-mMSCs from H2 O2 and associated excessive senescence. The latter was mediated by PrPC -dependent mitochondrial functional enhancement; melatonin upregulated PrPC , which bound PINK1, thus promoting mitochondrial dynamics and metabolism. In vivo, melatonin-treated CKD-mMSCs survived longer, with increased secretion of angiogenic cytokines in ischemic disease engraftment sites. CKD-mMSCs are more susceptible to H2 O2 -induced senescence than normal-mMSCs, and melatonin administration protects CKD-mMSCs from excessive senescence by upregulating PrPC and enhancing mitochondrial function. Melatonin showed favorable therapeutic effects by successfully protecting CKD-mMSCs from related ischemic conditions, thereby enhancing angiogenesis and survival. These results elucidate the mechanism underlying senescence inhibition by melatonin in stem cell-based therapies using mouse-derived CKD-mMSCs.
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Affiliation(s)
- Yong-Seok Han
- Soonchunhyang Medical Science Research Institute, Soonchunhyang University, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Sang Min Kim
- Soonchunhyang Medical Science Research Institute, Soonchunhyang University, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Jun Hee Lee
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
| | - Seo Kyung Jung
- Soonchunhyang Medical Science Research Institute, Soonchunhyang University, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Hyunjin Noh
- Department of Internal Medicine, Soonchunhyang University, Seoul, Korea
- Hyonam Kidney Laboratory, Soonchunhyang University, Seoul, Korea
| | - Sang Hun Lee
- Soonchunhyang Medical Science Research Institute, Soonchunhyang University, Soonchunhyang University Seoul Hospital, Seoul, Korea
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, Korea
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Ansari MA, Iqubal A, Ekbbal R, Haque SE. Effects of nimodipine, vinpocetine and their combination on isoproterenol-induced myocardial infarction in rats. Biomed Pharmacother 2018; 109:1372-1380. [PMID: 30551388 DOI: 10.1016/j.biopha.2018.10.199] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 10/22/2018] [Accepted: 10/31/2018] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Myocardial infarction (MI) remains a major cause of morbidity and mortality worldwide. Nimodipine is a calcium (Ca2+) channel blocker as well as a PDE1 inhibitor and primarily used in subarachnoid haemorrhage (SAH) due to its blood-brain barrier crossing property. Nimodipine and vinpocetine inhibit the degradation of phosphodiester bond which increases cGMP and cAMP levels causing vasodilation. MATERIAL AND METHODS We have divided rats randomly into Group I - Vehicle control; Group II - Toxic control (ISO 85 mg/kg, i.p.); Group III, IV and V - Nimodipine (5, 10 and 15 mg/kg, i.p. respectively) with ISO; Group VI- Nimodipine (15 mg/kg) alone; Group VII - Nimodipine + Vinpocetine (10 mg/kg + 10 mg/kg) with ISO; Group VIII - Nimodipine + Vinpocetine (10 mg/kg + 10 mg/kg) alone; Group IX- Diltiazem (25 mg/kg, p.o) with ISO; Group X- Diltiazem (25 mg/kg) alone and Group XI- Vinpocetine (10 mg/kg, p.o.) with ISO for 7 days. After 24 h of the last dose, haemodynamics were assessed then animals were sacrificed and biochemical, histopathological and ultrastructural changes were measured. RESULTS Treatment with ISO significantly deviated the haemodynamic parameters (HR, SAP, DAP and MAP), biochemical parameters (CK-MB, LDH, SGOT, cGMP and Troponin-T) and antioxidant markers (TBARS, SOD, CAT, GSH, GPx, GST and GR). Haemotoxylin and eosin staining of the cardiac tissue and ultrastructural study also indicated significant myocardial damage. Pretreatment with nimodipine (10 and 15 mg/kg, i.p), vinpocetine (10 mg/kg, p.o) and their combination significantly restored the antioxidant status, haemodynamic profile, cellular architecture and ultrastructural changes in the heart. CONCLUSION Nimodipine and vinpocetine both showed cardioprotection when given alone. However, their combination showed better restoration in terms of oxidative stress, cardiac membrane damage, haemodynamics, histopathology and ultrastructural changes.
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Affiliation(s)
- Mohd Asif Ansari
- Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi, 110062, India
| | - Ashif Iqubal
- Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi, 110062, India
| | - Rustam Ekbbal
- Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi, 110062, India
| | - Syed Ehtaishamul Haque
- Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi, 110062, India.
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Shi K, Sun H, Zhang H, Xie D, Yu B. miR-34a-5p
aggravates hypoxia-induced apoptosis by targeting ZEB1 in cardiomyocytes. Biol Chem 2018; 400:227-236. [PMID: 30312158 DOI: 10.1515/hsz-2018-0195] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 09/05/2018] [Indexed: 12/16/2022]
Abstract
Abstract
Myocardial infarction (MI) is an unsolved health problem which seriously affects human health around the world. miR-34a-5p acting as a tumor-suppressor is associated with left ventricular remodeling. We aimed to explore the functional roles of miR-34a-5p in cardiomyocytes. Hypoxia-induced cell injury in H9c2, HL-1 and human cardiac myocytes was analyzed according to the decrease of cell viability and increase of apoptosis. Expression of miR-34a-5p was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) when the concentration of O2 was decreased. Then, the effects of aberrantly expressed miR-34a-5p on proliferation and apoptosis of cardiomyocytes incubated under hypoxia were assessed. Finally, the downstream protein and signaling pathways of miR-34a-5p were explored. The hypoxic model was successfully constructed after incubation under hypoxia for 48 h. When the concentration of O2 decreased, the miR-34a-5p level was increased significantly. Then, we found miR-34a-5p aggravated hypoxia-induced alterations of proliferation and apoptosis in cardiomyocytes. Zinc finger E-box binding homeobox 1 (ZEB1) was identified as a target of miR-34a-5p, and miR-34a-5p conferred its function via targeting ZEB1. Finally, miR-34a-5p inhibition reversed hypoxia-induced decreases of phosphorylated kinases in the JAK/STAT and PI3K/AKT pathways through up-regulating ZEB1. Our study revealed that miR-34a-5p inhibition protected cardiomyocytes against hypoxia-induced cell injury through activating the JAK/STAT and PI3K/AKT pathways by targeting ZEB1.
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Affiliation(s)
- Kaiyao Shi
- Department of Cardiology , China-Japan Union Hospital of Jilin University , Jilin Key Laboratory for Gene Diagnosis of Cardiovascular Disease , Jilin Engineering Laboratory for Endothelial Function and Genetic Diagnosis , No. 126, Xiantai Street , Changchun, Jilin 130033 , China
| | - Huan Sun
- Department of Cardiology , China-Japan Union Hospital of Jilin University , Jilin Key Laboratory for Gene Diagnosis of Cardiovascular Disease , Jilin Engineering Laboratory for Endothelial Function and Genetic Diagnosis , No. 126, Xiantai Street , Changchun, Jilin 130033 , China
| | - Hongli Zhang
- Department of Cardiology , China-Japan Union Hospital of Jilin University , Jilin Key Laboratory for Gene Diagnosis of Cardiovascular Disease , Jilin Engineering Laboratory for Endothelial Function and Genetic Diagnosis , No. 126, Xiantai Street , Changchun, Jilin 130033 , China
| | - Di Xie
- Department of Cardiology , China-Japan Union Hospital of Jilin University , Jilin Key Laboratory for Gene Diagnosis of Cardiovascular Disease , Jilin Engineering Laboratory for Endothelial Function and Genetic Diagnosis , No. 126, Xiantai Street , Changchun, Jilin 130033 , China
| | - Bo Yu
- Department of Cardiology , China-Japan Union Hospital of Jilin University , Jilin Key Laboratory for Gene Diagnosis of Cardiovascular Disease , Jilin Engineering Laboratory for Endothelial Function and Genetic Diagnosis , No. 126, Xiantai Street , Changchun, Jilin 130033 , China
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Hu C, Zhao L, Peng C, Li L. Regulation of the mitochondrial reactive oxygen species: Strategies to control mesenchymal stem cell fates ex vivo and in vivo. J Cell Mol Med 2018; 22:5196-5207. [PMID: 30160351 PMCID: PMC6201215 DOI: 10.1111/jcmm.13835] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 07/11/2018] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are broadly used in cell‐based regenerative medicine because of their self‐renewal and multilineage potencies in vitro and in vivo. To ensure sufficient amounts of MSCs for therapeutic purposes, cells are generally cultured in vitro for long‐term expansion or specific terminal differentiation until cell transplantation. Although physiologically up‐regulated reactive oxygen species (ROS) production is essential for maintenance of stem cell activities, abnormally high levels of ROS can harm MSCs both in vitro and in vivo. Overall, additional elucidation of the mechanisms by which physiological and pathological ROS are generated is necessary to better direct MSC fates and improve their therapeutic effects by controlling external ROS levels. In this review, we focus on the currently revealed ROS generation mechanisms and the regulatory routes for controlling their rates of proliferation, survival, senescence, apoptosis, and differentiation. A promising strategy in future regenerative medicine involves regulating ROS generation via various means to augment the therapeutic efficacy of MSCs, thus improving the prognosis of patients with terminal diseases.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lingfei Zhao
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Conggao Peng
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
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50
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Rafat A, Mohammadi Roushandeh A, Alizadeh A, Hashemi-Firouzi N, Golipoor Z. Comparison of The Melatonin Preconditioning Efficacy between Bone Marrow and Adipose-Derived Mesenchymal Stem Cells. CELL JOURNAL 2018; 20:450-458. [PMID: 30123990 PMCID: PMC6099139 DOI: 10.22074/cellj.2019.5507] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 12/10/2017] [Indexed: 02/02/2023]
Abstract
Objective Mesenchymal stem cells (MSC) from various sources have the potentials to positively affect regenerative medicine. Furthermore, pre-conditioning strategies with different agents could improve the efficacy of cell therapy. This study compares the effects of an anti-inflammatory and antioxidant agent, melatonin, on protection of bone marrow-derived MSCs (BMSCs) and adipose tissue-derived MSCs (ADSCs). Materials and Methods In this experimental study, rat BMSCs and ADSCs were isolated and expanded. Pre-conditioning was performed with 5 μM melatonin for 24 hours. Cell proliferation and viability were detected by MTT assay. Expression of BAX, BCL2, melatonin receptors and osteocalcin genes were evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). Also, apoptosis was detected with tunnel assay. Osteogenic differentiation was analyzed using alizarin red staining. Results No significant increase was found in cell viability between BMSCs and ADSCs after melatonin preconditioning. Following melatonin preconditioning, BAX expression was significantly down-regulated in both ADSCs and BMSCs (P<0.05), with the difference being more significant in ADSCs compared to BMSCs. BCL2 expression was increased significantly in both cell types after preconditioning. Metalothionine 1 and Metalothionine 2 were both upregulated significantly in the two cell types (P<0.05). Melatonin increased osteogenesis capability through increasing osteocalcin expression. However, expression of osteocalcin in BMSCs before and after preconditioning was higher than that in ADSCs. On the other hand, melatonin expression in ADSCs was in higher levels than in BMSCs. Melatonin also improved alizarin red concentration significantly in both BMSCs and ADSCs (P<0.05). Alizarin red staining severity increased significantly in ADSCs after preconditioning compared to BMSCs (P<0.05). Conclusion Here we have shown that the effects of preconditioning on melatonin expression in ADSCs are higher than those in BMSCs. These findings could be used in adoption of a proper preconditioning protocol based on the sources of MSCs in specific clinical applications, especially in bone regeneration.
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Affiliation(s)
- Ali Rafat
- Department of Anatomical Sciences, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Amaneh Mohammadi Roushandeh
- Medical Biotechnology Research Center, Paramedicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
| | - Akram Alizadeh
- Department of Tissue Engineering, School of Advanced Technologies, Shahrekord University of Medichal Sciences, Shahrekord, Iran
| | | | - Zoleikha Golipoor
- Cellular and Molecular Research Center, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran Electronic Address:
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