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Tang JS, Yu HX, Ruan RX, Chen R, Zhu ZQ. LncRNA SNHG14 Delivered by Bone Marrow Mesenchymal Stem Cells-Secreted Exosomes Regulates Osteogenesis and Adipogenesis in Osteoporosis by Mediating the miR-27a-3p/LMNB1 Axis. Kaohsiung J Med Sci 2025; 41:e70004. [PMID: 40052307 DOI: 10.1002/kjm2.70004] [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: 09/19/2024] [Revised: 01/25/2025] [Accepted: 02/06/2025] [Indexed: 05/16/2025] Open
Abstract
The purpose of this study was to investigate the role of LncRNA SNHG14 delivered by bone marrow mesenchymal stem cells-secreted exosomes (BMSC-Exos) in osteoporosis (OP). BMSCs and BMSCs-Exos were isolated and identified. BMSCs were transfected, from which BMSCs-Exos were collected. The treated BMSCs-Exos were co-cultured with BMSCs. After osteogenic induction of BMSCs, the calcification was analyzed by alizarin red S staining. After adipogenic induction of BMSCs, lipid droplets were detected by oil red O staining. Glycerol-3-phosphate dehydrogenase activity was measured in BMSCs. OVX mouse models were established and treated with BMSC-EXOs. HE staining and IHC staining were performed on the femurs of mice. The interaction between SNHG14, miR-27a-3p, and LMNB1 was evaluated by luciferase reporter gene assay and RIP assay. Gene levels were assessed using RT-qPCR and Western blot, respectively. BMSC-Exos promoted osteogenic-adipogenic balance of BMSCs. SNHG14 enhanced the promoting effect of BMSCs-Exos on the balance of osteogenesis and adipogenesis of BMSCs. SNHG14 directly bound miR-27a-3p. SNHG1 mediated osteogenic-adipogenic balance in BMSCs via miR-27a-3p. LMNB1 was a target gene of miR-27a-3p. LMNB1 was involved in the process of SNHG14 regulating osteogenic-adipogenic balance in BMSCs. SNHG14 overexpression promoted bone formation and alleviated OP in vivo. SNHG14 delivered by BMSCs-Exos regulates osteogenesis and adipogenesis in OP by mediating the miR-27a-3p/LMNB1 axis.
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Affiliation(s)
- Jin-Shan Tang
- Department of Joint Surgery, Huai'an Second People's Hospital (The Affiliated Huaian Hospital of Xuzhou Medical University), Huai'an City, Jiangsu Province, China
| | - Huai-Xi Yu
- Department of Joint Surgery, Huai'an Second People's Hospital (The Affiliated Huaian Hospital of Xuzhou Medical University), Huai'an City, Jiangsu Province, China
| | - Ru-Xin Ruan
- Department of Joint Surgery, Huai'an Second People's Hospital (The Affiliated Huaian Hospital of Xuzhou Medical University), Huai'an City, Jiangsu Province, China
| | - Rui Chen
- Department of Joint Surgery, Huai'an Second People's Hospital (The Affiliated Huaian Hospital of Xuzhou Medical University), Huai'an City, Jiangsu Province, China
| | - Zi-Qiang Zhu
- Department of Orthopaedics, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
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Zhang D, Jiang H, Yang X, Zheng S, Li Y, Liu S, Xu X. Traditional Chinese Medicine and renal regeneration: experimental evidence and future perspectives. Chin Med 2024; 19:77. [PMID: 38831435 PMCID: PMC11149241 DOI: 10.1186/s13020-024-00935-9] [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: 02/08/2024] [Accepted: 04/22/2024] [Indexed: 06/05/2024] Open
Abstract
Repair of acute kidney injury (AKI) is a typical example of renal regeneration. AKI is characterized by tubular cell death, peritubular capillary (PTC) thinning, and immune system activation. After renal tubule injury, resident renal progenitor cells, or renal tubule dedifferentiation, give rise to renal progenitor cells and repair the damaged renal tubule through proliferation and differentiation. Mesenchymal stem cells (MSCs) also play an important role in renal tubular repair. AKI leads to sparse PTC, affecting the supply of nutrients and oxygen and indirectly aggravating AKI. Therefore, repairing PTC is important for the prognosis of AKI. The activation of the immune system is conducive for the body to clear the necrotic cells and debris generated by AKI; however, if the immune activation is too strong or lengthy, it will cause damage to renal tubule cells or inhibit their repair. Macrophages have been shown to play an important role in the repair of kidney injury. Traditional Chinese medicine (TCM) has unique advantages in the treatment of AKI and a series of studies have been conducted on the topic in recent years. Herein, the role of TCM in promoting the repair of renal injury and its molecular mechanism is discussed from three perspectives: repair of renal tubular epithelial cells, repair of PTC, and regulation of macrophages to provide a reference for the treatment and mechanistic research of AKI.
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Affiliation(s)
- Denglu Zhang
- Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong Key Laboratory of Dominant Diseases of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Huihui Jiang
- Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xianzhen Yang
- Urinary Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Sanxia Zheng
- Pediatric Department, The Second Affiliated Hospital of Shandong University of Chinese Medicine, Jinan, China
| | - Yi Li
- Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
- Engineering Laboratory of Urinary Organ and Functional Reconstruction of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
| | - Shuai Liu
- Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
- Shandong Key Laboratory of Dominant Diseases of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Xiangdong Xu
- Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
- Shandong Key Laboratory of Dominant Diseases of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
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Rajput S, Malviya R, Uniyal P. Advances in the Treatment of Kidney Disorders using Mesenchymal Stem Cells. Curr Pharm Des 2024; 30:825-840. [PMID: 38482624 DOI: 10.2174/0113816128296105240305110312] [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: 12/01/2023] [Accepted: 02/20/2024] [Indexed: 06/04/2024]
Abstract
Renal disease is a medical condition that poses a potential threat to the life of an individual and is related to substantial morbidity and mortality rates in clinical environments. The aetiology of this condition is influenced by multiple factors, and its incidence tends to increase with progressive aging. Although supportive therapy and kidney transplantation have potential advantages, they also have limitations in terms of mitigating the progression of KD. Despite significant advancements in the domain of supportive therapy, mortality rates in patients continue to increase. Due to their ability to self-renew and multidirectionally differentiate, stem cell therapy has been shown to have tremendous potential in the repair of the diseased kidney. MSCs (Mesenchymal stem cells) are a cell population that is extensively distributed and can be located in various niches throughout an individual's lifespan. The cells in question are characterised by their potential for indefinite replication and their aptitude for undergoing differentiation into fully developed cells of mesodermal origin under laboratory conditions. It is essential to emphasize that MSCs have demonstrated a favorable safety profile and efficacy as a therapeutic intervention for renal diseases in both preclinical as well as clinical investigations. MSCs have been found to slow the advancement of kidney disease, and this impact is thought to be due to their control over a number of physiological processes, including immunological response, tubular epithelial- mesenchymal transition, oxidative stress, renal tubular cell death, and angiogenesis. In addition, MSCs demonstrate recognised effectiveness in managing both acute and chronic kidney diseases via paracrine pathways. The proposal to utilise a therapy that is based on stem-cells as an effective treatment has been put forward in search of discovering novel therapies to promote renal regeneration. Preclinical researchers have demonstrated that various types of stem cells can provide advantages in acute and chronic kidney disease. Moreover, preliminary results from clinical trials have suggested that these interventions are both safe and well-tolerated. This manuscript provides a brief overview of the potential renoprotective effects of stem cell-based treatments in acute as well as chronic renal dysfunction. Furthermore, the mechanisms that govern the process of kidney regeneration induced by stem cells are investigated. This article will examine the therapeutic approaches that make use of stem cells for the treatment of kidney disorders. The analysis will cover various cellular sources that have been utilised, potential mechanisms involved, and the outcomes that have been achieved so far.
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Affiliation(s)
- Shivam Rajput
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Prerna Uniyal
- School of Pharmacy, Graphic Era Hill University, Dehradun, India
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Yu C, Gui F, Huang Q, Luo Y, Zeng Z, Li R, Guo L. Protective effects of muscone on traumatic spinal cord injury in rats. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:685. [PMID: 35845509 PMCID: PMC9279775 DOI: 10.21037/atm-22-2672] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/20/2022] [Indexed: 01/05/2023]
Abstract
Background Traumatic spinal cord injury (SCI) is a major clinical concern, and it is a life-changing neurological condition with substantial socioeconomic implications. Muscone has been widely used in traditional Chinese medicinal formulations for its anti-inflammatory activity. However, its protective effects on traumatic SCI have not been explored. This study investigated whether muscone plays a protective role in SCI and compared its effects with those of methylprednisolone sodium succinate (MPSS). Methods Rats were divided into five groups: normal saline (NS; n=24), methylprednisolone (MP; w=24), and muscone 1 (MO1), muscone 2 (MO2), and muscone 3 (MO3) (n=24 in each group, collectively called the MOx groups). The SCI rat model was established by the modified Allen's method. The rats were administered muscone (MO1: 2.5 mg/kg, MO2: 5 mg/kg, and MO3: 10 mg/kg) or MP (30 mg/kg), or an equivalent volume of saline. The rats were kept under observation for 4 weeks. Malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) levels were detected using enzyme-linked immunosorbent assay (ELISA). The expression of glial fibrillary acidic protein (GFAP), B-cell lymphoma-2 (BCL-2), and caspase3 was detected by western blot analysis. Hematoxylin-eosin (HE), Nissl, and immunocytochemistry (ICC) staining was performed for pathological observation. Basso-Beattie-Bresnahan motor function scores were evaluated for assessment of neural functions after acute SCI. Results Muscone inhibited immune-inflammatory reactions, neuronal necrosis, and apoptosis. The lower limb function recovery was better in the MOx groups compared with NS and MP groups according to Basso-Beattie-Bresnahan scores. The changes were remarkable in the MO2 group compared with the other groups. Conclusions Muscone alleviates secondary injury after SCI by reducing immune-inflammatory reactions, neuronal necrosis, and apoptosis.
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Affiliation(s)
- Chao Yu
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Fei Gui
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Qian Huang
- Department of Orthopedics, The 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuanmeng Luo
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Zili Zeng
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Ruifu Li
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Liang Guo
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
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Lv S, Lei Z, Yan G, Shah SA, Ahmed S, Sun T. Chemical compositions and pharmacological activities of natural musk (Moschus) and artificial musk: A review. JOURNAL OF ETHNOPHARMACOLOGY 2022; 284:114799. [PMID: 34748869 DOI: 10.1016/j.jep.2021.114799] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/22/2021] [Accepted: 11/01/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Natural musk (Moschus), derived naturally from male musk deer (Moschus berezovskii Flerov, Moschus sifanicus Przewalski, or Moschus moschiferus Linnaeus), has long been an important component of traditional Chinese medicine (TCM), and was used as resuscitation, blood circulation, and collateral drainage. detumescence and pain relief. Artificial musk was researched and applied into TCM as natural musk being as unsustainable resources. AIM OF THE STUDY We mainly summarized chemical compositions, pharmacological activities and mechanism of action of natural and artificial musk, and designed to serve as a foundation for further research into musk chemical compositions and pharmacological effect. MATERIALS AND METHODS Those mainstream scientific databases including Google Scholar, ScienceDirect, SpringerLink, CNKI, Wiley Online Library, web of science, were used for searching with below "Keywords", as well as literature-tracking. Literatures spanned 1962 to 2021, and involved into Chinese, English, Janpanese, Korean. RESULTS Natural musk contains some very desirable but scarce compounds, as well as their biological features, which led to the development of artificial musk. The chemical ingredients, pharmacological activities, and mechanisms of action of natural and artificial musk are summarized and compared in this paper. Polypeptide and protein, muscone, musclide, steroids, muscopyridine, and other chemical constituents of musk demonstrated important therapeutic properties against inflammation, immune system disorders, neurological disorders, cardiovascular system disorders, and so on. The mechanism of action contributed to effect on mediators, acceptors and relative signal pathways. CONCLUSIONS Natural and artificial musk were revealed having some activated compounds, and showed excellent pharmacological effect. Meantime, above two sides of natural and artificial musk ought to get further research.
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Affiliation(s)
- Shuquan Lv
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, PR China; School of Environmental and Biological Engineering, Wuhan Technology and Business University, NO. 3 Huangjiahu West Road, Wuhan 430065, PR China; School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, PR China
| | - Zhixin Lei
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, PR China; School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, PR China.
| | - Ge Yan
- School of Environmental and Biological Engineering, Wuhan Technology and Business University, NO. 3 Huangjiahu West Road, Wuhan 430065, PR China
| | - Sayed Afzal Shah
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, 46000, Pakistan
| | - Saeed Ahmed
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, 46000, Pakistan
| | - Taolei Sun
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, PR China; School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, PR China.
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Liu K, Xie L, Deng M, Zhang X, Luo J, Li X. Zoology, chemical composition, pharmacology, quality control and future perspective of Musk (Moschus): a review. Chin Med 2021; 16:46. [PMID: 34147113 PMCID: PMC8214773 DOI: 10.1186/s13020-021-00457-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/10/2021] [Indexed: 12/13/2022] Open
Abstract
Musk, the dried secretion from the musk sac gland which is located between the navel and genitals of mature male musk deer, is utilized as oriental medicine in east Asia. It has been utilized to treat conditions such as stroke, coma, neurasthenia, convulsions, and heart diseases in China since ancient times. This paper aims to provide a comprehensive overview of musk in zoology, chemical composition, pharmacology, clinical applications, and quality control according to the up-to-date literature. Studies found that musk mainly contains macrocyclic ketones, pyridine, steroids, fatty acids, amino acids, peptides, and proteins, whilst the main active ingredient is muscone. Modern pharmacological studies have proven that musk possesses potent anti-inflammatory effects, neuroprotective effects, anti-cancer effects, antioxidant effects, etc. Moreover, muscone, the main active ingredient, possesses anti-inflammatory, neuroprotective, antioxidant, and other pharmacological effects. In the quality control of musk, muscone is usually the main detection indicator, and the common analytical method is GC, and researchers have established novel and convenient methods such as HPLC-RI, RP-UPLC-ELSD, and Single-Sweep Polarography. In addition, quality evaluation methods based on steroids and the bioactivity of musk have been established. As for the identification of musk, due to various objective factors such as the availability of synthetic Muscone, it is not sufficient to rely on muscone alone as an identification index. To date, some novel technologies have also been introduced into the identification of musk, such as the electronic nose and DNA barcoding technology. In future research, more in vivo experiments and clinical studies are encouraged to fully explain the pharmacological effects and toxicity of musk, and more comprehensive methods are needed to evaluate and control the quality of musk.
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Affiliation(s)
- Kai Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People's Republic of China
| | - Long Xie
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People's Republic of China
| | - Mao Deng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People's Republic of China
| | - Xumin Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People's Republic of China
| | - Jia Luo
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People's Republic of China.
| | - Xiaofang Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People's Republic of China.
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Localization and Maintenance of Engrafted Mesenchymal Stem Cells Administered via Renal Artery in Kidneys with Ischemia-Reperfusion Injury. Int J Mol Sci 2021; 22:ijms22084178. [PMID: 33920714 PMCID: PMC8072868 DOI: 10.3390/ijms22084178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 01/13/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a potential therapeutic tool for preventing the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). Herein, we investigated the localization and maintenance of engrafted human bone marrow-derived MSCs in rats subjected to a renal ischemia-reperfusion injury (IRI) and compared the effectiveness of two intravascular injection routes via the renal artery or inferior vena cava. Renal artery injection of MSCs was more effective than intravenous injection at reducing IRI-induced renal fibrosis. Additionally, MSCs injected through the renal artery persisted in injured kidneys for over 21 days, whereas MSCs injected through the inferior vena cava survived for less than 7 days. This difference may be attributed to the antifibrotic effects of MSCs. Interestingly, MSCs injected through the renal artery were localized primarily in glomeruli until day 3 post-IRI, and they decreased in number thereafter. In contrast, the number of MSCs localized in tubular walls, and the interstitium increased gradually until day 21 post-IRI. This localization change may be related to areas of damage caused by IRI because ischemia-induced AKI leads to tubular cell damage. Taken together, these findings suggest renal artery injection of MSCs may be useful for preventing the progression of AKI to CKD.
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Guo J, Wang R, Liu D. Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Sepsis-Induced Acute Kidney Injury by Promoting Mitophagy of Renal Tubular Epithelial Cells via the SIRT1/Parkin Axis. Front Endocrinol (Lausanne) 2021; 12:639165. [PMID: 34248837 PMCID: PMC8267935 DOI: 10.3389/fendo.2021.639165] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 05/03/2021] [Indexed: 12/29/2022] Open
Abstract
Sepsis is a common risk factor for acute kidney injury (AKI). Bone marrow-derived mesenchymal stem cells (BMSCs) bear multi-directional differentiation potential. This study explored the role of BMSCs in sepsis-induced AKI (SI-AKI). A rat model of SI-AKI was established through cecal ligation and perforation. The SI-AKI rats were injected with CM-DiL-labeled BMSCs, followed by evaluation of pathological injury of kidney tissues and kidney injury-related indicators and inflammatory factors. HK-2 cells were treated with lipopolysaccharide (LPS) to establish SI-SKI model in vitro. Levels of mitochondrial proteins, autophagy-related proteins, NLRP3 inflammasome-related protein, and expressions of Parkin and SIRT1 in renal tubular epithelial cells (RTECs) of kidney tissues and HK-2 cells were detected. The results showed that BMSCs could reach rat kidney tissues and alleviate pathological injury of SI-SKI rats. BMSCs inhibited inflammation and promoted mitophagy of RTECs and HK-2 cells in rats with SI-AKI. BMSCs upregulated expressions of Parkin and SIRT1 in HK-2 cells. Parkin silencing or SIRT1 inhibitor reversed the promoting effect of BMSCs on mitophagy. BMSCs inhibited apoptosis and pyroptosis of RTECs in kidney tissues by upregulating SIRT1/Parkin. In conclusion, BMSCs promoted mitophagy and inhibited apoptosis and pyroptosis of RTECs in kidney tissues by upregulating SIRT1/Parkin, thereby ameliorating SI-AKI.
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Wang J, Xing H, Qin X, Ren Q, Yang J, Li L. Pharmacological effects and mechanisms of muscone. JOURNAL OF ETHNOPHARMACOLOGY 2020; 262:113120. [PMID: 32668321 DOI: 10.1016/j.jep.2020.113120] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 05/27/2020] [Accepted: 06/17/2020] [Indexed: 06/11/2023]
Abstract
Musk, the dried secretion from the preputial follicles of the male musk deer (genus Moschus), possesses various pharmacological activities and has been used extensively in traditional Chinese medicine for thousands of years. Muscone is the main active ingredient of musk and exerts pharmacological effects similar to those of musk. Although muscone was notably used to treat various disorders and diseases, such as neurological disorders, chronic inflammation and ischemia-reperfusion injury, most of the mechanisms of the pharmacological action of muscone remain unclear because of slow progress in research before the 21st century. In recent years, the pharmacological activities and mechanisms of muscone have been clarified. The present article summarizes the pharmacological and biological studies on cerebrovascular disease, cardiovascular disease, neurological effects, cancer and others and the associated mechanisms of the action of muscone to date.
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Affiliation(s)
- Jun Wang
- Health Management Center, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China
| | - Hui Xing
- Department of Obstetrics and Gynaecology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China
| | - Xiaomin Qin
- Department of Obstetrics and Gynaecology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China
| | - Qun Ren
- Health Management Center, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China
| | - Jiang Yang
- Department of Obstetrics and Gynaecology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China; Department of Obstetrics and Gynaecology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
| | - Lin Li
- Department of Obstetrics and Gynaecology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China.
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Che M, Gong W, Zhao Y, Liu M. Long noncoding RNA HCG18 inhibits the differentiation of human bone marrow-derived mesenchymal stem cells in osteoporosis by targeting miR-30a-5p/NOTCH1 axis. Mol Med 2020; 26:106. [PMID: 33176682 PMCID: PMC7656763 DOI: 10.1186/s10020-020-00219-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 09/14/2020] [Indexed: 12/15/2022] Open
Abstract
Background Recent studies have demonstrated that long non-coding RNAs (LncRNAs) can influence bone cell differentiation and formation. However, it is unclear whether lncRNA HCG18 is involved in osteoporosis (OP). This study was conducted to investigate the regulation of HCG18 in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Methods BMSCs were isolated and cultured from mouse pathological models and osteoporosis patients. RT-qPCR was performed to detect the expression of HCG18 and miR-30a-5p in BMSCs. The interaction between HCG18 and miR-30a-5p was analyzed by dual luciferase assay and RNA pulldown assay. The interaction between miR-30a-5p and NOTCH1 3′-UTR was analyzed by dual luciferase assay. RT-qPCR and Western blotting were used to detect the expression of osteogenic genes Runx2, OCN and OPN. Hindlimb-unloaded (HU) mice model was established, and HCG18 was knocked down on bone-formation surfaces by using lentivirus mediated shRNA transfection. Results The expression of HCG18 was increased in BMSCs of OP patients, while the expression of miR-30a-5p was decreased. The expression of HCG18 and miR-30a-5p was negatively correlated in BMSCs. During the differentiation from BMSCs to osteoblasts, the expression of HCG18 was significantly downregulated, and the expression of miR-30a-5p was significantly upregulated. Overexpression of HCG18 was able to reverse the osteogenic-induced upregulation of miR-30a-5p expression, and knockdown of HCG18 further promoted the expression of miR-30a-5p. In addition, miR-30a-5p partially abolished the effect of HCG18 on osteogenic differentiation of BMSCs. NOTCH1 was a target protein of miR-30a-5p, and upregulation of NOTCH1 reversed the effect of miR-30a-5p on osteogenic differentiation of BMSCs. Furthermore, this study found that lentivirus mediated HCG18 knockdown on the bone-formation surfaces of hindlimb-unloaded (HU) mice partially alleviated unloading-induced bone loss Conclusions HCG18 inhibited osteogenic differentiation of BMSCs induced by OP via the miR-30a-5p/NOTCH1 axis. HCG18 can be identified as a regulator of osteogenic differentiation of BMSCs.
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Affiliation(s)
- Mingxue Che
- Department of Spine Surgery, The First Hospital of Jilin University, No.1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Weiquan Gong
- Department of Spine Surgery, The First Hospital of Jilin University, No.1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Yao Zhao
- Department of Joint Surgery, The First Hospital of Jilin University, No.1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Mingxi Liu
- Department of Orthopedic Traumatology, The First Hospital of Jilin University, No.1 Xinmin Street, Changchun, 130021, Jilin Province, China.
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Burdeyron P, Giraud S, Hauet T, Steichen C. Urine-derived stem/progenitor cells: A focus on their characterization and potential. World J Stem Cells 2020; 12:1080-1096. [PMID: 33178393 PMCID: PMC7596444 DOI: 10.4252/wjsc.v12.i10.1080] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/26/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023] Open
Abstract
Cell therapy, i.e., the use of cells to repair an affected tissue or organ, is at the forefront of regenerative and personalized medicine. Among the multiple cell types that have been used for this purpose [including adult stem cells such as mesenchymal stem cells or pluripotent stem cells], urine-derived stem cells (USCs) have aroused interest in the past years. USCs display classical features of mesenchymal stem cells such as differentiation capacity and immunomodulation. Importantly, they have the main advantage of being isolable from one sample of voided urine with a cheap and unpainful procedure, which is broadly applicable, whereas most adult stem cell types require invasive procedure. Moreover, USCs can be differentiated into renal cell types. This is of high interest for renal cell therapy-based regenerative approaches. This review will firstly describe the isolation and characterization of USCs. We will specifically present USC phenotype, which is not an object of consensus in the literature, as well as detail their differentiation capacity. In the second part of this review, we will present and discuss the main applications of USCs. These include use as a substrate to generate human induced pluripotent stem cells, but we will deeply focus on the use of USCs for cell therapy approaches with a detailed analysis depending on the targeted organ or system. Importantly, we will also focus on the applications that rely on the use of USC-derived products such as microvesicles including exosomes, which is a strategy being increasingly employed. In the last section, we will discuss the remaining barriers and challenges in the field of USC-based regenerative medicine.
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Affiliation(s)
- Perrine Burdeyron
- INSERM U1082 IRTOMIT, CHU de Poitiers, Poitiers 86021, France
- Faculté de Médecine et Pharmacie, Université de Poitiers, Poitiers 86021, France
| | - Sébastien Giraud
- INSERM U1082 IRTOMIT, CHU de Poitiers, Poitiers 86021, France
- Service de Biochimie, CHU de Poitiers, Poitiers 86021, France
| | - Thierry Hauet
- INSERM U1082 IRTOMIT, CHU de Poitiers, Poitiers 86021, France
- Faculté de Médecine et Pharmacie, Université de Poitiers, Poitiers 86021, France
- Service de Biochimie, CHU de Poitiers, Poitiers 86021, France
| | - Clara Steichen
- INSERM U1082 IRTOMIT, CHU de Poitiers, Poitiers 86021, France
- Faculté de Médecine et Pharmacie, Université de Poitiers, Poitiers 86021, France.
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12
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Phung HM, Lee S, Hwang JH, Kang KS. Preventive Effect of Muscone against Cisplatin Nephrotoxicity in LLC-PK1 Cells. Biomolecules 2020; 10:E1444. [PMID: 33076219 PMCID: PMC7602442 DOI: 10.3390/biom10101444] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/06/2020] [Accepted: 10/12/2020] [Indexed: 02/07/2023] Open
Abstract
Cisplatin, one of the most common antitumor agents, is widely applied to treat various cancerous diseases and is included in the World Health Organization Model List of Essential Medicines. Cisplatin therapy is used to treat 10-20% of all cancerous cases, and its cure rate is especially high in testicular cancer (over 90%). However, a major side effect of this anticancer drug is nephrotoxicity, limiting treatment effect and reducing the quality of life in cancer patients. Muscone, an odoriferous constituent of musk, was confirmed to inhibit cisplatin-induced LLC-PK1 kidney proximal tubule cell death in a dose-dependent manner. In term of renal protective mechanism, muscone inhibited cisplatin oxidative toxicity by decreasing reactive oxygen species (ROS) level and stimulating HO-1 expression. Muscone also exerted anti-inflammation effect through inhibition of p38 phosphorylation. Furthermore, muscone mitigated cisplatin-induced apoptosis in LLC-PK1 cells via both intrinsic and extrinsic pathways by inhibiting pro-apoptotic protein Bax expression, and cleaved caspase-3, 7, and 8; and increase of anti-apoptotic protein Bcl-2 level. In addition, the anti-apoptotic effect of muscone also was enhanced by preventing p53 expression and its phosphorylation. Our study showed that muscone may be a potential protective agent against cisplatin-induced nephrotoxicity.
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Affiliation(s)
- Hung Manh Phung
- College of Korean Medicine, Gachon University, Seongnam 13120, Korea;
| | - Sullim Lee
- Department of Life Science, College of Bio-Nano Technology, Gachon University, Seongnam 13120, Korea;
| | - Ji Hye Hwang
- Department of Acupuncture and Moxibustion Medicine, College of Korean Medicine, Gachon University, Seongnam 13120, Korea
| | - Ki Sung Kang
- College of Korean Medicine, Gachon University, Seongnam 13120, Korea;
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13
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Liu D, Cheng F, Pan S, Liu Z. Stem cells: a potential treatment option for kidney diseases. Stem Cell Res Ther 2020; 11:249. [PMID: 32586408 PMCID: PMC7318741 DOI: 10.1186/s13287-020-01751-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 05/26/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
The prevalence of kidney diseases is emerging as a public health problem. Stem cells (SCs), currently considered as a promising tool for therapeutic application, have aroused considerable interest and expectations. With self-renewal capabilities and great potential for proliferation and differentiation, stem cell therapy opens new avenues for the development of renal function and structural repair in kidney diseases. Mounting evidence suggests that stem cells exert a therapeutic effect mainly by replacing damaged tissues and paracrine pathways. The benefits of various types of SCs in acute kidney disease and chronic kidney disease have been demonstrated in preclinical studies, and preliminary results of clinical trials present its safety and tolerability. This review will focus on the stem cell-based therapy approaches for the treatment of kidney diseases, including various cell sources used, possible mechanisms involved, and outcomes that are generated so far, along with prospects and challenges in clinical application.
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Affiliation(s)
- Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Fei Cheng
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Shaokang Pan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China.
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China.
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He MC, Shi Z, Qin M, Sha NN, Li Y, Liao DF, Lin FH, Shu B, Sun YL, Yuan TF, Wang YJ, Zhang Y. Muscone Ameliorates LPS-Induced Depressive-Like Behaviors and Inhibits Neuroinflammation in Prefrontal Cortex of Mice. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2020; 48:559-577. [PMID: 32345030 DOI: 10.1142/s0192415x20500287] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Depression is partially caused by inflammation in the central nervous system. Early study demonstrated that musk, glandular secretion from male musk deer, exerted an antidepressant-like effect. The aim of this study was to investigate if muscone, a bioactive ingredient in musk, could ameliorate neuroinflammation and depressive-like behaviors as well as explore the potential action mechanism. Mice were intraperitoneally (i.p.) injected with muscone for 2 weeks prior to administration of lipopolysaccharides (LPS, 1mg/kg, i.p.). Pre-treatment with muscone reversed the LPS-induced decrease in body weight within 24h and ameliorated depressive-like behaviors shown by sucrose preference, tail suspension test, and forced swimming test. LPS-induced activation of microglial cells and elevation in expression of inflammatory cytokines including IL-1β, RANTES, and MCP-1 in the prefrontal cortex of mice were effectively abrogated by muscone, which significantly down-regulated expression of TLR4, MyD88, Caspase-1, NLRP3, renin, and Ang II. In addition, treatment of BV2 microglia cells with muscone markedly attenuated the LPS-induced rise in protein expression of TLR4, Ang II, and IL-1β. This study revealed that muscone could ameliorate LPS-induced depressive-like behaviors by repressing neuroinflammation in the prefrontal cortex of mice caused by its suppression on microglia activation and production of inflammatory cytokines via acting on TLR4 pathway and RAS cascade.
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Affiliation(s)
- Ming-Chao He
- Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China.,Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai 200032, P. R. China
| | - Zhe Shi
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, P. R. China.,Division of Stem Cell Regulation and Application, Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha 410208, P. R. China
| | - Meng Qin
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, P. R. China
| | - Nan-Nan Sha
- Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China
| | - Yue Li
- Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China.,Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai 200032, P. R. China
| | - Duan-Fang Liao
- Division of Stem Cell Regulation and Application, Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha 410208, P. R. China
| | - Fu-Hui Lin
- Department of Orthopaedic, Shenzhen Pingle Orthopaedic Hospital, Shenzhen 518000, P. R. China
| | - Bing Shu
- Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China.,Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai 200032, P. R. China
| | - Yue-Li Sun
- Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China.,Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai 200032, P. R. China
| | - Ti-Fei Yuan
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, P. R. China.,Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, P. R. China
| | - Yong-Jun Wang
- Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China.,Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai 200032, P. R. China
| | - Yan Zhang
- Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China.,Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai 200032, P. R. China
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15
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Zhai X, Yan Z, Zhao J, Chen K, Yang Y, Cai M, He C, Huang C, Li B, Yang M, Zhou X, Zhao Y, Wei X, Bai Y, Li M. Muscone Ameliorates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-κb Ligand-Induced Osteoclastogenesis by Suppressing TNF Receptor-Associated Factor 6-Mediated Signaling Pathways. Front Pharmacol 2020; 11:348. [PMID: 32265718 PMCID: PMC7099619 DOI: 10.3389/fphar.2020.00348] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 03/09/2020] [Indexed: 12/18/2022] Open
Abstract
Postmenopausal osteoporosis is caused by the deficiency of estrogen, which breaks bone homeostasis and induces levels of pro-inflammatory cytokines. Muscone is a potent anti-inflammatory agent and is used to treat bone fracture in traditional Chinese medicine. However, its anti-osteoclastogenic effects remain unclear. For in vitro study, morphology tests of osteoclastogenesis were firstly performed. And then, factors in RANK-induced NF-κB and MAPK pathways were examined by RT-PCR and Western blot, and the binding of TNF receptor–associated factor (TRAF)6 to RANK was inspected by coimmunoprecipitation and immunofluorescence staining. For in vivo experiments, C57BL/6 ovariectomized (OVX) mice were used for detection, including H&E staining, TRAP staining, and micro CT. As a result, muscone reduced OVX-induced bone loss in mice and osteoclast differentiation in vitro, by inhibiting TRAF6 binding to RANK, and then suppressed NF-κB and MAPK signaling pathways. The expression of the downstream biomarkers was finally inhibited, including NFATc1, CTR, TRAP, cathepsin K, and MMP-9. The inflammatory factors, TNF-a and IL-6, were also reduced by muscone. Taken together, muscone inhibited the binding of TRAF6 to RANK induced by RANKL, thus blocking NF-kB and MAPK pathways, and down-regulating related gene expression. Finally, muscone inhibited osteoclastogenesis and osteoclast function by blocking RANK-TRAF6 binding, as well as downstream signaling pathways in vitro. Muscone also reduced ovariectomy-induced bone loss in vivo.
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Affiliation(s)
- Xiao Zhai
- Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Zijun Yan
- Graduate Management Unit, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Jian Zhao
- Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Kai Chen
- Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Yilin Yang
- Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Mengxi Cai
- Graduate Management Unit, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Chen He
- Graduate Management Unit, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Chunyou Huang
- Graduate Management Unit, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Bo Li
- Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Mingyuan Yang
- Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Xiaoyi Zhou
- Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Yingchuan Zhao
- Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Xiaozhao Wei
- Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Yushu Bai
- Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
| | - Ming Li
- Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China
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16
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Lu L, Wu C, Lu BJ, Xie D, Wang Z, Bahaji Azami NL, An YT, Wang HJ, Ye G, Sun MY. BabaoDan cures hepatic encephalopathy by decreasing ammonia levels and alleviating inflammation in rats. JOURNAL OF ETHNOPHARMACOLOGY 2020; 249:112301. [PMID: 31622746 DOI: 10.1016/j.jep.2019.112301] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 10/09/2019] [Accepted: 10/11/2019] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE BabaoDan (BBD) is a famous traditional Chinese formula frequently used in TCM clinics to eliminate jaundice and treat infectious viral hepatitis. This paper assesses BBD's preventive and therapeutic effects on hepatic encephalopathy after liver cirrhosis (CHE) and acute liver failure (AHE) in rats and explains its possible mechanism of action. METHODS CHE rat model was established by injection of carbon tetrachloride (CCl4) twice a week for a total of 9 weeks and then by injection of thioacetamide (TAA) to induce hepatic encephalopathy. AHE rat model was established by injection of TAA once a day for a total of 3 days. In CHE rat model, BBD was gavaged once a day at the end of the 6th week until the experiment ended. In AHE rat model,BBD was gavaged once a day 3 days before TAA injection until the experiment ended. The preventive and therapeutic effects of BBD on brain dysfunction, as well as liver injury, pathology and fibrosis were evaluated in vivo. The role of BBD in the regulation of inflammatory factors and myeloid differentiation factor 88/Toll-like receptor 4/nuclear factor kappa-B (TLR4/MyD88/NK-κ B) pathway was detected in both liver and brain in vivo. The rat bone marrow derived macrophages (BMDMs) were activated by Lipopolysaccharide (LPS), and the role of BBD in the regulation of inflammatory factors and NK-κ B pathway were detected in vitro. RESULTS In CHE rat model: BBD significantly improved the total distance as well as the activity rate of rats. BBD also improved the learning and memory abilities of rats compared with the control group. In addition, BBD effectively decreased ammonia levels and significantly decreased the levels of alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBil) and total bile acid (TBA), as well as improved the levels of total protein (TP) and albumin (Alb). In the liver, BBD not only inhibited the gene expressions of tumor necrosis factor alpha (TNF-α), interleukini-6 (IL-6), TLR4, MyD88, and NF-κ B but also inhibited the protein expressions of TLR4, MyD88, NK-κ B and TNF-α. In the brain, BBD inhibited the gene expressions of iNOS, IL-6, TNF-α, TLR-4, MyD88, and NF-κ B, as well as inhibited the protein expressions of TLR4, MyD88, P65 TNF-α and ionized calcium binding adapter molecule 1 (Iba-1). BBD also decreased NO and TNF-α in the blood. IN AHE RAT MODEL BBD improved neurological scores, blood ammonia levels and the brain inflammatory gene expressions of iNOS, TNF-α and IL-1β. BBD also improved liver function biomarkers such as ALT, TBil, TBA, TP, ALB and inflammatory and apoptotic gene expressions of TNF-α, IL-1β, IL-6, Bax, Bcl-2, caspase-9, caspase-3 and NF-κ B. In LPS-activated rat BMDMs, BBD decreased NO and TNF-α production in BMDM culture supernatant. In addition, BBD inhibited the gene expressions of TNF-α, IL-1 β and IL-6 as well as the phosphorylation of P65. CONCLUSION BBD can prevent and cure hepatic encephalopathy (HE) derived from both chronic and acute liver diseases. BBD can reduce hyperammonemia as well as the systematic and neurological inflammation. Inflammation is likely an important target of BBD to treat HE. The anti-inflammatory role of BBD may lie in its regulation of the TLR4/MyD88/NF-κ B pathways.
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Affiliation(s)
- Lu Lu
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Chao Wu
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Bing-Jie Lu
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Dong Xie
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Zheng Wang
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Nisma Lena Bahaji Azami
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yong-Tong An
- Central Research Institute of Shanghai Pharmaceutical Group Co, Ltd, Shanghai, 201203, China.
| | - Hui-Jun Wang
- Central Research Institute of Shanghai Pharmaceutical Group Co, Ltd, Shanghai, 201203, China.
| | - Guan Ye
- Central Research Institute of Shanghai Pharmaceutical Group Co, Ltd, Shanghai, 201203, China.
| | - Ming-Yu Sun
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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17
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Yuan WX, Wang XX, Zheng DH, Ma D, Cui Q, Yang F, Zhang J. Muscone Promotes The Adipogenic Differentiation Of Human Gingival Mesenchymal Stem Cells By Inhibiting The Wnt/β-Catenin Signaling Pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:3291-3306. [PMID: 31571831 PMCID: PMC6756161 DOI: 10.2147/dddt.s220970] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 09/06/2019] [Indexed: 12/22/2022]
Abstract
Objectives This study was performed to evaluate the effects of muscone on the proliferation, migration and differentiation of human gingival mesenchymal stem cells (GMSCs) and to explore the relevant mechanisms. Materials and methods We performed studies to determine the effects and mechanisms of muscone on GMSC proliferation, migration and differentiation. We conducted CCK-8, colony formation, transwell chamber, scratch wound, alkaline phosphatase (ALP) staining and activity, and alizarin red and oil red O staining assays, as well as real-time quantitative polymerase chain reaction (qRT-PCR), to ascertain the effects of muscone on GMSC proliferation, migration and differentiation in vitro. The mechanism by which muscone influences the osteogenic and adipogenic differentiation of GMSCs was elucidated by qRT-PCR and Western blotting. Results We found that muscone significantly promoted GMSC proliferation, chemotaxis, wound healing and fat droplet formation and inhibited ALP activity and mineral deposition. Notably, we observed that the Wnt/β-catenin pathway was closely related to the ability of muscone to inhibit the osteogenic differentiation and promote the adipogenic differentiation of GMSCs. The effect of muscone on the multidirectional differentiation capacity of GMSCs was significantly reversed by the agonist lithium chloride through the Wnt/β-catenin signaling pathway. Conclusion Muscone effectively increased the proliferation and migration, promoted the adipogenic differentiation and inhibited the osteogenic differentiation of GMSCs by inhibiting the Wnt/β-catenin signaling pathway. These results may provide a theoretical basis for the application of GMSCs and muscone in tissue engineering and regenerative medicine.
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Affiliation(s)
- Wen-Xiu Yuan
- Department of Orthodontics, School and Hospital of Stomatology, Shandong University and Shandong Provincial Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong Province, People's Republic of China
| | - Xu-Xia Wang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Shandong University and Shandong Provincial Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong Province, People's Republic of China
| | - De-Hua Zheng
- Department of Orthodontics, School and Hospital of Stomatology, Shandong University and Shandong Provincial Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong Province, People's Republic of China
| | - Dan Ma
- Department of Orthodontics, School and Hospital of Stomatology, Shandong University and Shandong Provincial Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong Province, People's Republic of China
| | - Qun Cui
- Department of Orthodontics, School and Hospital of Stomatology, Shandong University and Shandong Provincial Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong Province, People's Republic of China
| | - Fan Yang
- Department of Orthodontics, School and Hospital of Stomatology, Shandong University and Shandong Provincial Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong Province, People's Republic of China
| | - Jun Zhang
- Department of Orthodontics, School and Hospital of Stomatology, Shandong University and Shandong Provincial Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong Province, People's Republic of China
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Dong J, Li H, Bai Y, Wu C. Muscone ameliorates diabetic peripheral neuropathy through activating AKT/mTOR signalling pathway. ACTA ACUST UNITED AC 2019; 71:1706-1713. [PMID: 31468549 DOI: 10.1111/jphp.13157] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 07/28/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Emerging evidence showed that muscone could improve chronic inflammation after myocardial infarction and protect alcohol-induced osteonecrosis of the femoral head. However, the function of muscone on diabetic peripheral neuropathy (DPN) is obscure. METHODS The neuronal Schwann cell RSC 96 cells were treated with 125 mmol/l glucose to simulate the cells in DPN. The RSC 96 cell viability was detected by cell counting kit-8. The RSC 96 cell cycle and apoptosis were determined by flow cytometry. The expression of marker proteins of apoptosis, autophagy and AKT/mTOR signalling pathway was assessed by Western blot. KEY FINDINGS We observed that after high glucose (HG) treatment, the number of cell apoptosis was increased, cell proliferation was decreased, as well as the expression of apoptosis-related proteins and autophagy-related proteins were changed. However, this phenomenon can be reversed by muscone. Meanwhile, the expression of phosphorylated AKT and mammalian target of rapamycin (mTOR) was down-regulated with HG treatment, while the expression quantity was up-regulated after disposed with muscone. CONCLUSIONS Our outcomes demonstrated that autophagy and apoptosis of RSC 96 cells induced by HG can be alleviated by muscone through modulating AKT/mTOR signalling pathway, suggesting that muscone might be a potential molecule with influence in connection to DPN.
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Affiliation(s)
- Jie Dong
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hua Li
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yang Bai
- Department of Endocrinology, Zhengzhou Seventh People's Hospital, Zhengzhou, China
| | - Cong Wu
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Pei Y, Yao Q, Li Y, Zhang X, Xie B. microRNA-211 regulates cell proliferation, apoptosis and migration/invasion in human osteosarcoma via targeting EZRIN. Cell Mol Biol Lett 2019; 24:48. [PMID: 31333725 PMCID: PMC6617937 DOI: 10.1186/s11658-019-0173-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 06/27/2019] [Indexed: 02/06/2023] Open
Abstract
Background In recent years, microRNA-211 (miR211) has been considered as a tumor suppressor in multiple malignancies. However, the function of miR211 in human osteosarcoma has not been explored intensively so far. In this study, the relationship between miR211 and EZRIN was analyzed in human osteosarcoma. Methods The expression levels of miR211 and EZRIN were measured in both human osteosarcoma cells and tissues. The direct regulatory relationship between miR211 and EZRIN was evaluated using dual-luciferase assay. The effect of miR211 and EZRIN overexpression on cell proliferation, migration/invasion, and apoptosis was detected. Results The expression of miR211 was obviously lower in osteosarcoma tissues than paracancerous tissues. EZRIN was identified as the direct target of miR211, and up-regulation of miR211 increased the percentage of cell apoptosis, and suppressed cell proliferation as well as cell migration/invasion via directly regulating EZRIN. Conclusions Our study indicated that miR211 has an important role in the development and progress of osteosarcoma, and it might become a novel target in the diagnosis and treatment of human osteosarcoma. Electronic supplementary material The online version of this article (10.1186/s11658-019-0173-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yihua Pei
- 1Central laboratory, ZhongShan Hospital XiaMen University, Xiamen, 361004 China.,2Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated ZhongShan Hospital), Xiamen, 361004 China
| | - Qin Yao
- 1Central laboratory, ZhongShan Hospital XiaMen University, Xiamen, 361004 China.,2Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated ZhongShan Hospital), Xiamen, 361004 China
| | - Yingchao Li
- 3Department of Spine Surgery, ZhongShan Hospital XiaMen University, No. 201 Hubin South Road, Xiamen, 361004 China
| | - Xin Zhang
- 4Department of Rehabilitation, ZhongShan Hospital XiaMen University, Xiamen, 361004 China
| | - Bozhen Xie
- 3Department of Spine Surgery, ZhongShan Hospital XiaMen University, No. 201 Hubin South Road, Xiamen, 361004 China
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20
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MicroRNA‑30a regulates cell proliferation, migration, invasion and apoptosis in human nasopharyngeal carcinoma via targeted regulation of ZEB2. Mol Med Rep 2019; 20:1672-1682. [PMID: 31257481 PMCID: PMC6625429 DOI: 10.3892/mmr.2019.10387] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 02/20/2019] [Indexed: 12/12/2022] Open
Abstract
MicroRNA-30a (miR-30a) was previously reported to serve as a tumor suppressor able to inhibit the development and progression of certain types of cancer. A number of previous studies demonstrated that zinc finger E-box binding homeobox 2 (ZEB2) may be regulated by miR-30a in clear cell renal cell carcinoma and breast cancer. However, the function of miR-30a in human nasopharyngeal carcinoma (NPC) remains unclear. The present study aimed to investigate the association between miR-30a and ZEB2 in NPC. Therefore, the expression levels of miR-30a and ZEB2 were measured in human NPC cells and tissues from patients with NPC, and the present results suggested that the expression level of miR-30a was significantly decreased in NPC tissues compared with paracancerous tissues. The direct interaction between miR-30a and the untranslated region of ZEB2 was examined using the dual-luciferase reporter assay, and ZEB2 was identified as a direct target of miR-30a. Additionally, the effects of miR-30a and ZEB2 overexpression on cell proliferation, migration, invasion and apoptosis were additionally investigated. Functional experiments identified that overexpression of miR-30a increased apoptosis and suppressed cell proliferation, cell migration and cell invasion by directly targeting ZEB2. Collectively, the present study suggested that miR-30a may serve an important role in the progression of NPC and may represent a novel target for the treatment of patients with NPC.
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21
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Paracrine action of human placental trophoblast cells attenuates cisplatin-induced acute kidney injury. Life Sci 2019; 230:45-54. [PMID: 31125561 DOI: 10.1016/j.lfs.2019.05.054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/20/2019] [Accepted: 05/20/2019] [Indexed: 02/07/2023]
Abstract
AIMS The action of cell-based therapy against acute kidney injury (AKI) has been demonstrated by different groups for years. However, which kind of cells hold best therapeutic effect remains unclear. In this study, we mainly explored whether human placental trophoblast cells hold the potential to be applied in AKI therapy. MAIN METHODS To study the renoprotective effect, the trophoblast cells were isolated from human placenta and characterized by flow cytometry first. The AKI model was induced using cisplatin in NOD-SCID mice. The therapeutic effect of human placental trophoblast cells on renal function, apoptosis and inflammation were analyzed respectively. KEY FINDINGS The administration of trophoblast cells isolated from human placenta improved the pathological changes of kidney tissues and renal dysfunction induced by cisplatin. In addition, the placental trophoblast cell-based treatment also showed anti-apoptotic effect and decreased the level of apoptotic genes (Bax and Caspase 3) expression in damaged kidney tissues obviously. All of the inflammatory components (MCP-1, IL-10 and RANTES) in kidney tissues were down-regulated with the therapy of placental trophoblast cells. Further analysis indicated that the paracrine effects of human placental trophoblast cells may hold a key position in the AKI therapy process. SIGNIFICANCE In this study, we mainly developed a novel therapeutic strategy to treat cisplatin-induced AKI with human placental trophoblast cells. Even though the detailed mechanism and the optimizations of this cell-based therapy still need further investigation, the application of placental trophoblast cell holds special potential in the treatment of patients with AKI.
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22
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Feng X, Zhang W, Yin W, Kang YJ. The involvement of mitochondrial fission in maintenance of the stemness of bone marrow mesenchymal stem cells. Exp Biol Med (Maywood) 2019; 244:64-72. [PMID: 30614257 DOI: 10.1177/1535370218821063] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
IMPACT STATEMENT How to maintain the stemness of bone marrow mesenchymal stem cells (BMSCs) in cultures is a long-standing question. The present study found that mitochondrial dynamics affects the stemness of BMSCs in cultures and the retaining of mitochondrial fission enhances the stemness of BMSCs. This work thus provides a novel insight into strategic approaches to maintain the stemness of BMSCs in cultures in relation to the clinical application of bone-marrow stem cells.
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Affiliation(s)
- Xiaorong Feng
- 1 Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu 610041, China
| | - Wenjing Zhang
- 1 Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu 610041, China.,2 Memphis Institute of Regenerative Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Wen Yin
- 1 Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu 610041, China
| | - Y James Kang
- 1 Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu 610041, China.,2 Memphis Institute of Regenerative Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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23
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Zhao L, Hu C, Zhang P, Jiang H, Chen J. Preconditioning strategies for improving the survival rate and paracrine ability of mesenchymal stem cells in acute kidney injury. J Cell Mol Med 2018; 23:720-730. [PMID: 30484934 PMCID: PMC6349184 DOI: 10.1111/jcmm.14035] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 10/20/2018] [Accepted: 10/27/2018] [Indexed: 02/06/2023] Open
Abstract
Acute kidney injury (AKI) is a common, severe emergency case in clinics, with high incidence, significant mortality and increased costs. Despite development in the understanding of its pathophysiology, the therapeutic choices are still confined to dialysis and renal transplantation. Considering their antiapoptotic, immunomodulatory, antioxidative and pro‐angiogenic effects, mesenchymal stem cells (MSCs) may be a promising candidate for AKI management. Based on these findings, some clinical trials have been performed, but the results are contradictory (NCT00733876, NCT01602328). The low engraftment, poor survival rate, impaired paracrine ability and delayed administration of MSCs are the four main reasons for the limited clinical efficacy. Investigators have developed a series of preconditioning strategies to improve MSC survival rates and paracrine ability. In this review, by summarizing these encouraging studies, we intend to provide a comprehensive understanding of various preconditioning strategies on AKI therapy and improve the prognosis of AKI patients by regenerative medicine.
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Affiliation(s)
- Lingfei Zhao
- Key Laboratory of Kidney Disease Prevention and Control Technology, Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Ping Zhang
- Key Laboratory of Kidney Disease Prevention and Control Technology, Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Hua Jiang
- Key Laboratory of Kidney Disease Prevention and Control Technology, Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Jianghua Chen
- Key Laboratory of Kidney Disease Prevention and Control Technology, Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, PR China
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24
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Zhao L, Hu C, Zhang P, Jiang H, Chen J. Novel preconditioning strategies for enhancing the migratory ability of mesenchymal stem cells in acute kidney injury. Stem Cell Res Ther 2018; 9:225. [PMID: 30139368 PMCID: PMC6108125 DOI: 10.1186/s13287-018-0973-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Acute kidney injury (AKI) remains a worldwide public health issue due to its increasing incidence, significant mortality, and lack of specific target-orientated therapy. Developments in mesenchymal stem cell (MSC) research make MSCs a promising candidate for AKI management but relevant clinical trials show confusing results (NCT00733876, NCT01602328). One primary cause of the limited therapeutic effect may result from poor engraftment of transplanted cells. To solve this problem, investigators have developed a series of preconditioning strategies to improve MSC engraftment in animal AKI models. In this review, we summarize these previous studies, providing an integrated and updated view of different preconditioning strategies aimed at promoting the therapeutic effect of MSCs in AKI patients.
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Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Ping Zhang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Hua Jiang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China. .,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China. .,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
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25
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Chen G, Zhao X, Tan Z, Wang D, Luo D, Zhang P, Cao J, Wang F, Liu Q, Li L. Investigation of the role of cullin 4A overexpression in human liver cancer. Mol Med Rep 2018; 18:2531-2540. [PMID: 30015884 PMCID: PMC6102737 DOI: 10.3892/mmr.2018.9233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 01/09/2018] [Indexed: 01/15/2023] Open
Abstract
Cullin 4A (CUL4A) is the major component of cullin‑RING‑based E3 ubiquitin‑protein ligase complexes, which regulate the ubiquitination of target proteins. The overexpression of CUL4A has been associated with the development and progression of various cancer types. However, a detailed understanding of the role of CUL4A in human liver cancer has not been determined by previous studies. In the present study, the association between human liver cancer and CUL4A expression was investigated. The expression of CUL4A in liver cancer tissues and paracancerous tissues of patients was investigated by reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemical staining. Overexpression and knockdown of CUL4A were induced with an overexpression vector and small interfering RNA transfection, respectively, in human liver cancer cell lines, and the effects on cell proliferation were analyzed by a Cell Counting Kit‑8 assay to investigate the role of CUL4A in human liver cancer. Cell migration, invasion, apoptosis and the cell cycle were also analyzed following transfection. The results of the present study revealed that the mRNA and protein expression of CUL4A was increased in the liver cancer tissues compared with the paracancerous tissues of 3 patients. Additionally, the results demonstrated that downregulation of CUL4A expression inhibited cell proliferation, migration and invasion, and increased the percentage of cell apoptosis, in HEPG2 and MHCC97‑H cells, while CUL4A overexpression led to the opposite effects. Therefore, the results of the current study indicated that CUL4A may serve an important role in the development and progression of human liver cancer, and highlights the potential of CUL4A as a novel target in the diagnosis and treatment of human liver cancer and potentially other cancer types.
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Affiliation(s)
- Gang Chen
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China
| | - Xiongqi Zhao
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China
| | - Zedan Tan
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China
| | - Dongdong Wang
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China
| | - Ding Luo
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China
| | - Peiyao Zhang
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China
| | - Jun Cao
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China
| | - Fan Wang
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China
| | - Qiyu Liu
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China
| | - Li Li
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China
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26
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Ohtake T, Kobayashi S, Slavin S, Mochida Y, Ishioka K, Moriya H, Hidaka S, Matsuura R, Sumida M, Katagiri D, Noiri E, Okada K, Mizuno H, Tanaka R. Human Peripheral Blood Mononuclear Cells Incubated in Vasculogenic Conditioning Medium Dramatically Improve Ischemia/Reperfusion Acute Kidney Injury in Mice. Cell Transplant 2018; 27:520-530. [PMID: 29737200 PMCID: PMC6038042 DOI: 10.1177/0963689717753186] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Acute kidney injury (AKI) is a major clinical problem that still has no established treatment. We investigated the efficacy of cultured human peripheral blood mononuclear cells (PBMNCs) for AKI. Ischemia/reperfusion injury (IRI) was used to induce AKI in male nonobese diabetic (NOD/severe combined immunodeficiency) mice aged 7 to 8 wk. PBMNCs were isolated from healthy volunteers and were subjected to quality and quantity controlled (QQc) culture for 7 d in medium containing stem cell factor, thrombopoietin, Flt-3 ligand, vascular endothelial growth factor, and interleukin 6. IRI-induced mice were divided into 3 groups and administered (1) 1 × 106 PBMNCs after QQc culture (QQc PBMNCs group), (2) 1 × 106 PBMNCs without QQc culture (non-QQc PBMNCs group), or (3) vehicle without PBMNCs (IRI control group). PBMNCs were injected via the tail vein 24 h after induction of IRI, followed by assessment of renal function, histological changes, and homing of injected cells. Blood urea nitrogen and serum creatinine (Cr) 72 h after induction of IRI in the QQc PBMNCs group dramatically improved compared with those in the IRI control and the non-QQc PBMNCs groups, accompanied by the improvement of tubular damages. Interstitial fibrosis 14 d after induction of IRI was also significantly improved in the QQc PBMNCs group compared with the other groups. The renoprotective effect noted in the QQc PBMNCs group was accompanied by reduction of peritubular capillary loss. The change of PBMNCs’ population (increase of CD34+ cells, CD133+ cells, and CD206+ cells) and increased endothelial progenitor cell colony-forming potential by QQc culture might be one of the beneficial mechanisms for restoring AKI. In conclusion, an injection of human QQc PBMNCs 24 h after induction of IRI dramatically improved AKI in mice.
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Affiliation(s)
- Takayasu Ohtake
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.,2 Division of Regenerative Medicine, Department of Center for Clinical and Translational Science, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Shuzo Kobayashi
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.,2 Division of Regenerative Medicine, Department of Center for Clinical and Translational Science, Shonan Kamakura General Hospital, Kamakura, Japan
| | | | - Yasuhiro Mochida
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Kunihiro Ishioka
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Hidekazu Moriya
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Sumi Hidaka
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Ryo Matsuura
- 4 Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Maki Sumida
- 4 Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Daisuke Katagiri
- 4 Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Eisei Noiri
- 4 Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Kayoko Okada
- 5 Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Ochanomizu, Japan
| | - Hiroshi Mizuno
- 5 Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Ochanomizu, Japan
| | - Rica Tanaka
- 5 Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Ochanomizu, Japan
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27
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The positive effect of chick embryo and nutrient mixture on bone marrow- derived mesenchymal stem cells from aging rats. Sci Rep 2018; 8:7051. [PMID: 29728592 PMCID: PMC5935737 DOI: 10.1038/s41598-018-25563-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 04/24/2018] [Indexed: 12/18/2022] Open
Abstract
The aging of many mammalian tissues is associated with loss of functional adult stem cells, especially bone marrow-derived mesenchymal stem cells (BMSCs). This study was aimed to analyze the biological effect of chick embryo (CE) and nutrient mixture (NM) on the BMSCs of aging rats. The aging rat model was established to be induced by D-galactose (500 mg/kg/d) for 90 days. Meanwhile, aging rats were fed with CE and NM in different dose manner by intragastric administration. At the end of the experimental period, serum was collected from rats and used for BMSCs culture. Flow cytometric analysis was used to investigate the BMSCs surface markers. Alizarin Red and oil red O staining were performed to evaluate the multi-lineage differentiation of BMSCs. The results showed that CE plus NM increased the telomere length of BMSCs and promoted BMSCs proliferation. Moreover, CE plus NM administration promoted BMSCs differentiation into osteoblasts and suppressed differentiation into adipocytes. High-throughput sequencing analysis revealed that there were 326 genes were up-regulated and 59 genes were down-regulated in BMSCs of aging rats treated with CE plus NM. In conclusion, CE plus NM supplement had potential to delay aging through the recovery of BMSCs senescence and could be used as a safe effective approach for nutritional therapy of anti-aging.
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28
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Guo YJ, Luo SH, Tang MJ, Zhou ZB, Yin JH, Gao YS, Dang XQ. Muscone exerts protective roles on alcohol-induced osteonecrosis of the femoral head. Biomed Pharmacother 2017; 97:825-832. [PMID: 29136757 DOI: 10.1016/j.biopha.2017.11.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 10/29/2017] [Accepted: 11/03/2017] [Indexed: 01/24/2023] Open
Abstract
Long-term alcohol abuse causes musculoskeletal disorders, among of which, alcohol-induced osteonecrosis of the femoral head (ONFH) is of concern due to its significant and severe complications. A variety of methods have been attempted to prevent alcohol-induced ONFH, and monomers extracted from Chinese herbs might benefit the disease profoundly. In the current study, muscone, the main ingredient of musk, was used to prevent alcohol-induced ONFH. In vitro, ethanol was used to affect the potential of osteogenesis and proliferation of human bone mesenchymal stem cells (hBMSCs), and beneficial role of muscone was investigated on hBMSCs. In vivo, following the establishment of alcohol-induced ONFH, muscone was employed to treat the diseased rats, which were analyzed by micro-CT scanning and a series of histologic staining. As a result, we found ethanol could significantly suppress osteogenic differentiation of hBMSCs, while muscone held the potential to promote ALP activity and mRNA expressions of COL1 and OCN under ethanol treatment. Meanwhile, imaging analysis revealed muscone could restore BV/TV ratio and bone mineral density of the necrotic femoral head, and the protective role of muscone on alcohol-induced ONFH was further confirmed by histologic examinations. Our study confirmed the protective effect of muscone against alcohol-induced ONFH both in vitro and in vivo. Therefore, muscone may be considered as a valuable therapeutic natural drug for alcohol-induced ONFH in humans.
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Affiliation(s)
- Yan-Jie Guo
- Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an 710004, Shaanxi Province, China; Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Shi-Hua Luo
- Department of Traumatology, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Ming-Jie Tang
- Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an 710004, Shaanxi Province, China; Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Zu-Bin Zhou
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Jun-Hui Yin
- Shanghai Institute of Microsurgery on Extremities, Shanghai 200233, China
| | - You-Shui Gao
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Xiao-Qian Dang
- Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an 710004, Shaanxi Province, China.
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Wang X, Gao J, Wang Y, Zhao B, Zhang Y, Han F, Zheng Z, Hu D. Curcumin pretreatment prevents hydrogen peroxide-induced oxidative stress through enhanced mitochondrial function and deactivation of Akt/Erk signaling pathways in rat bone marrow mesenchymal stem cells. Mol Cell Biochem 2017; 443:37-45. [DOI: 10.1007/s11010-017-3208-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 10/14/2017] [Indexed: 12/13/2022]
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30
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Chen Q, Cui Y, Ding G, Jia Z, Zhang Y, Zhang A, Huang S. PEA3 protects against gentamicin nephrotoxicity: role of mitochondrial dysfunction. Am J Transl Res 2017; 9:2153-2162. [PMID: 28559968 PMCID: PMC5446500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 04/10/2017] [Indexed: 06/07/2023]
Abstract
Toxin-induced nephrotoxicity is one of the major causes leading to the acute kidney injury (AKI). Among these nephrotoxic toxins, gentamicin can induce AKI with elusive mechanisms. Emerging evidence demonstrated that PEA3 (polyomavirus enhancer activator 3) contributed to the nephrogenesis, while its role in AKI remains unknown. Thus, this study was to investigate the role of PEA3 in gentamicin nephrotoxicity, as well as the underlying mechanisms. In rats, gentamicin treatment (200 mg/kg twice per day) for two days induced remarkable kidney injury with a peak damage on day 5 evaluated by the tubular injury score, proteinuria, and tubular injury markers of NGAL and KIM-1. In parallel with the tubular injury, PEA3 protein and mRNA expressions were significantly upregulated by gentamicin and peaked on day 5. To define the role of PEA3 in gentamicin nephrotoxicity, proximal tubule cells were transfected with PEA3 plasmid with or without gentamicin treatment (1 mg/ml). Notably, overexpression of PEA3 attenuated gentamicin-induced cell injury shown by the ameliorated cell apoptosis and NGAL and KIM-1 upregulation. Meantime, gentamicin caused severe mitochondrial dysfunction, which was largely normalized by PEA3 overexpression. In contrast, silencing PEA3 by a siRNA strategy further deteriorated gentamicin-induced cell apoptosis and mitochondrial dysfunction. In sum, PEA3 protected against gentamicin nephrotoxicity possibly via a mitochondrial mechanism.
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Affiliation(s)
- Qiuxia Chen
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, Jiangsu Province, P. R. China
- Jiangsu Key Laboratory of PediatricsNanjing 210029, Jiangsu Province, P. R. China
| | - Yiyun Cui
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, Jiangsu Province, P. R. China
- Jiangsu Key Laboratory of PediatricsNanjing 210029, Jiangsu Province, P. R. China
| | - Guixia Ding
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, Jiangsu Province, P. R. China
- Jiangsu Key Laboratory of PediatricsNanjing 210029, Jiangsu Province, P. R. China
| | - Zhanjun Jia
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, Jiangsu Province, P. R. China
- Jiangsu Key Laboratory of PediatricsNanjing 210029, Jiangsu Province, P. R. China
| | - Yue Zhang
- Jiangsu Key Laboratory of PediatricsNanjing 210029, Jiangsu Province, P. R. China
| | - Aihua Zhang
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, Jiangsu Province, P. R. China
- Jiangsu Key Laboratory of PediatricsNanjing 210029, Jiangsu Province, P. R. China
| | - Songming Huang
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, Jiangsu Province, P. R. China
- Jiangsu Key Laboratory of PediatricsNanjing 210029, Jiangsu Province, P. R. China
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Qin J, Mai Y, Li Y, Jiang Z, Gao Y. Effect of mild hypothermia preconditioning against low temperature (4°C) induced rat liver cell injury in vitro. PLoS One 2017; 12:e0176652. [PMID: 28453529 PMCID: PMC5409157 DOI: 10.1371/journal.pone.0176652] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Accepted: 04/13/2017] [Indexed: 02/07/2023] Open
Abstract
Bioartificial liver holds special position in the field of regenerative medicine, and cold environment at 4℃ is widely used for the short storage of both organ and liver cell for later application. However, the disadvantages of such cold storage could influence cell viability and lead to cell apoptosis in different degrees. In this study, we mainly explore the pre-protective effect of mild hypothermia against low temperature (4℃)-induced rat liver cell injury in vitro. Our results indicated that the precondition with mild hypothermia could increase cell viability, such as cell proliferation, LDH regulation and glycogen synthesis ability of liver cell. The precondition also decreased the ROS production and relieved cell apoptosis in liver cells. Compared with the model group, the mitochondrial membrane potential was restored in the mild hypothermia group, as well as the mitochondrial membrane permeability transition pore opening, indicating that the therapeutic mechanism was related to mitochondrial protection. Further analysis showed that PI3K-Akt-GSK3β signal pathway might be associated with the pre-protective effect of mild hypothermia. Thus, our study suggested that the precondition with mild hypothermia hold the protective effect for liver cell in cold environment, and further developed a novel strategy for the storage of liver seed cells, even bioartificial liver.
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Affiliation(s)
- Jiasheng Qin
- Second Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
- Institute of Regenerative Medicine, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Yanxing Mai
- Department of Geriatrics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Yang Li
- Second Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
- Institute of Regenerative Medicine, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Zesheng Jiang
- Second Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
- Institute of Regenerative Medicine, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Yi Gao
- Second Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
- Institute of Regenerative Medicine, Southern Medical University, Guangzhou, Guangdong, P.R. China
- * E-mail:
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Zhao L, Feng Y, Chen X, Yuan J, Liu X, Chen Y, Zhao Y, Liu P, Li Y. Effects of IGF-1 on neural differentiation of human umbilical cord derived mesenchymal stem cells. Life Sci 2016; 151:93-101. [DOI: 10.1016/j.lfs.2016.03.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 02/28/2016] [Accepted: 03/01/2016] [Indexed: 12/12/2022]
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Skeletal Muscle-Derived Stem/Progenitor Cells: A Potential Strategy for the Treatment of Acute Kidney Injury. Stem Cells Int 2016; 2016:9618480. [PMID: 27069485 PMCID: PMC4812499 DOI: 10.1155/2016/9618480] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 01/21/2016] [Accepted: 02/08/2016] [Indexed: 12/17/2022] Open
Abstract
Skeletal muscle-derived stem/progenitor cells (MDSPCs) have been thoroughly investigated and already used in preclinical studies. However, therapeutic potential of MDSPCs isolated using preplate isolation technique for acute kidney injury (AKI) has not been evaluated. We aimed to characterize rat MDSPCs, compare them with bone marrow mesenchymal stem cells (BM-MSCs), and evaluate the feasibility of MDSPCs therapy for gentamicin-induced AKI in rats. We have isolated and characterized rat MDSPCs and BM-MSCs. Characteristics of rat BM-MSCs and MDSPCs were assessed by population doubling time, flow cytometry, immunofluorescence staining, RT-PCR, and multipotent differentiation capacity. Gentamicin-induced AKI model in rat was used to examine MDSPCs therapeutic effect. Physiological and histological kidney parameters were determined. MDSPCs exhibited similar immunophenotype, stem cell gene expression, and multilineage differentiation capacities as BM-MSCs, but they demonstrated higher proliferation rate. Single intravenous MDSPCs injection accelerated functional and morphological kidney recovery, as reflected by significantly lower serum creatinine levels, renal injury score, higher urinary creatinine, and GFR levels. PKH-26-labeled MDSPCs were identified within renal cortex 1 and 2 weeks after cell administration, indicating MDSPCs capacity to migrate and populate renal tissue. In conclusion, MDSPCs are capable of mediating functional and histological kidney recovery and can be considered as potential strategy for AKI treatment.
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Liu P, Feng Y, Dong D, Liu X, Chen Y, Wang Y, Zhou Y. Enhanced renoprotective effect of IGF-1 modified human umbilical cord-derived mesenchymal stem cells on gentamicin-induced acute kidney injury. Sci Rep 2016; 6:20287. [PMID: 26830766 PMCID: PMC4735814 DOI: 10.1038/srep20287] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 12/30/2015] [Indexed: 02/07/2023] Open
Abstract
The therapeutic action of umbilical cord-derived mesenchymal stem cells (UC-MSCs) against acute kidney injury (AKI) has been demonstrated by several groups. However, how to further enhance the renoprotective effect of UC-MSCs and improve the therapy effect, are still unclear. In this study, we mainly investigated whether insulin-like growth factor-1 (IGF-1)-modified UC-MSCs hold an enhanced protective effect on gentamicin-induced AKI in vivo. Our results indicated that the IGF-1 overexpression could enhance the therapeutic action of human UC-MSCs, and the AKI rats treated with IGF-1-overexpressed UC-MSCs (UC-MSCs-IGF-1) showed better recovery of biochemical variables in serum or urine associated with renal function, histological injury and renal apoptosis, compared with AKI rats treated with normal UC-MSCs. RNA microarray analysis indicated that some key genes in the signal pathways associated with anti-oxidation, anti-inflammatory, and cell migratory capacity were up-regulated in UC-MSCs-IGF-1, and the results were further confirmed with qPCR. Furthermore, a series of detection in vitro and in vivo indicated that the UC-MSCs-IGF-1 hold better anti-oxidation, anti-inflammatory, and cell migratory capacity for IGF-1 overexpression. Thus, our study indicated that enhancement of UC-MSCs bioactivities with IGF-1 overexpression could increase the UC-MSCs therapeutic potential and further developed a new therapeutic strategy for the treatment of AKI.
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Affiliation(s)
- Pengfei Liu
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
- Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Yetong Feng
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, P.R. China
| | - Delu Dong
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
| | - Xiaobo Liu
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
- Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Yaoyu Chen
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
- Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Yi Wang
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
| | - Yulai Zhou
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
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Wang G, Zhang Q, Zhuo Z, Wu S, Xu Y, Zou L, Gan L, Tan K, Xia H, Liu Z, Gao Y. Enhanced Homing of CXCR-4 Modified Bone Marrow-Derived Mesenchymal Stem Cells to Acute Kidney Injury Tissues by Micro-Bubble-Mediated Ultrasound Exposure. ULTRASOUND IN MEDICINE & BIOLOGY 2016; 42:539-548. [PMID: 26610714 DOI: 10.1016/j.ultrasmedbio.2015.10.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 10/04/2015] [Accepted: 10/10/2015] [Indexed: 06/05/2023]
Abstract
Although the curative effects of bone marrow stromal cells (BMSCs) for acute kidney injury (AKI) have been recognized, their in vivo reparative capability is limited by the low levels of targeted homing and retention of intravenous injected cells. Stromal cell-derived factor-1 (SDF-1) plays an important role in stem cell homing and retention through interaction with its specific functional receptor, CXCR4, which is presumably related to the poor homing in AKI therapy. However, most of the functional CXCR4 chemokine receptors are lost upon in vitro culturing. Ultrasound-targeted micro-bubble destruction (UTMD) has become one of the most promising strategies for the targeted delivery of drugs and genes. To improve BMSC homing to AKI kidneys, we isolated and cultured rat BMSCs to third passage and enhanced CXCR-4 transfection efficiency in vitro by applying UTMD and polyethylenimine. Transwell migration assay showed that the migration ability of CXCR4-modified BMSCs was nine-fold higher than controls. Then, mercuric chloride-induced AKI rats were injected with transfected BMSCs through their tail veins. We showed that enhanced homing and retention of BMSCs were observed in the CXCR-4 modified group compared with other groups at 1, 2 and 3 d post-treatment. Collectively, our data indicated that UTMD was an effective method to increase BMSCs' engraftment to AKI kidney tissues by increasing CXCR-4 expression.
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Affiliation(s)
- Gong Wang
- Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Qian Zhang
- Department of Nephropathy, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Zhongxiong Zhuo
- Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Shengzheng Wu
- Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Yali Xu
- Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Linru Zou
- Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Ling Gan
- Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Kaibin Tan
- Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Hongmei Xia
- Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Zheng Liu
- Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Yunhua Gao
- Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
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Liu P, Cai J, Dong D, Chen Y, Liu X, Wang Y, Zhou Y. Effects of SOX2 on Proliferation, Migration and Adhesion of Human Dental Pulp Stem Cells. PLoS One 2015; 10:e0141346. [PMID: 26496354 PMCID: PMC4619695 DOI: 10.1371/journal.pone.0141346] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 10/07/2015] [Indexed: 01/09/2023] Open
Abstract
As a key factor for cell pluripotent and self-renewing phenotypes, SOX2 has attracted scientists’ attention gradually in recent years. However, its exact effects in dental pulp stem cells (DPSCs) are still unclear. In this study, we mainly investigated whether SOX2 could affect some biological functions of DPSCs. DPSCs were isolated from the dental pulp of human impacted third molar. SOX2 overexpressing DPSCs (DPSCs-SOX2) were established through retroviral infection. The effect of SOX2 on cell proliferation, migration and adhesion ability was evaluated with CCK-8, trans-well system and fibronectin-induced cell attachment experiment respectively. Whole genome expression of DPSCs-SOX2 was analyzed with RNA microarray. Furthermore, a rescue experiment was performed with SOX2-siRNA in DPSC-SOX2 to confirm the effect of SOX2 overexpression in DPSCs. We found that SOX2 overexpression could result in the enhancement of cell proliferation, migration, and adhesion in DPSCs obviously. RNA microarray analysis indicated that some key genes in the signal pathways associated with cell cycle, migration and adhesion were upregulated in different degree, and the results were further confirmed with qPCR and western-blot. Finally, DPSC-SOX2 transfected with SOX2-siRNA showed a decrease of cell proliferation, migration and adhesion ability, which further confirmed the biological effect of SOX2 in human DPSCs. This study indicated that SOX2 could improve the cell proliferation, migration and adhesion ability of DPSCs through regulating gene expression about cell cycle, migration and adhesion, and provided a novel strategy to develop seed cells with strong proliferation, migration and adhesion ability for tissue engineering.
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Affiliation(s)
- Pengfei Liu
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
- Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Jinglei Cai
- Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Delu Dong
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
| | - Yaoyu Chen
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
- Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Xiaobo Liu
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
- Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Yi Wang
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
| | - Yulai Zhou
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
- * E-mail:
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Sherif IO, Al-Mutabagani LA, Alnakhli AM, Sobh MA, Mohammed HE. Renoprotective effects of angiotensin receptor blocker and stem cells in acute kidney injury: Involvement of inflammatory and apoptotic markers. Exp Biol Med (Maywood) 2015; 240:1572-9. [PMID: 25825359 DOI: 10.1177/1535370215577582] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 01/20/2015] [Indexed: 12/11/2022] Open
Abstract
Cisplatin, Cis-diamminedichloroplatinum (CDDP), is a platinum-based chemotherapy drug, and its chemotherapeutic use is restricted by nephrotoxicity. Inflammatory and apoptotic mechanisms play a central role in the pathogenesis of CDDP-induced acute kidney injury (AKI). The aim of this study was to compare the therapeutic potential of candesartan, angiotensin II receptor blocker, versus bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of CDDP-induced nephrotoxicity. Adult male Wistar rats (n = 40) were divided into four groups; Normal control: received saline injection, CDPP group: received CDDP injection (6 mg/kg single dose), Candesartan group: received candesartan (10 mg/kg/day) for 10 days + CDDP at day 3, and Stem cells group: received CDDP + BM-MSCs intravenously one day after CDDP injection. The rats were sacrificed seven days after CDDP injection. Significant elevation in serum creatinine and urea, renal levels of tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1, renal expressions of nuclear factor kappa B (NF-κB), p38-mitogen-activated protein kinase (MAPK), caspase-3 and Bcl-2-associated x protein (Bax) were found in CDDP-injected rats when compared to normal rats. Both candesartan and BM-MSCs ameliorated renal function and reduced significantly the inflammatory markers (TNF-α , NF-κB, p38-MAPK and MCP-1) and apoptotic markers (caspase-3 and Bax) in renal tissue after CDDP injection. Candesartan as well as BM-MSCs have anti-inflammatory and anti-apoptotic actions and they can be used as nephroprotective agents against CDDP-induced nephrotoxicity. BM-MSCs is more effective than candesartan in amelioration of AKI induced by CDDP.
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Affiliation(s)
- Iman O Sherif
- Pharmaceutical Sciences Department, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh 11671, Kingdom of Saudi Arabia
| | - Laila A Al-Mutabagani
- Chemistry Department, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Kingdom of Saudi Arabia
| | - Anwar M Alnakhli
- Pharmaceutical Sciences Department, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh 11671, Kingdom of Saudi Arabia
| | - Mohamed A Sobh
- Zoology Department, College of Science, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Hoda E Mohammed
- Biochemistry Department, College of Pharmacy, Zagazig University, Zagazig 44519, Egypt
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Bianchi F, Sala E, Donadei C, Capelli I, La Manna G. Potential advantages of acute kidney injury management by mesenchymal stem cells. World J Stem Cells 2014; 6:644-650. [PMID: 25426262 PMCID: PMC4178265 DOI: 10.4252/wjsc.v6.i5.644] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 09/08/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells are currently considered as a promising tool for therapeutic application in acute kidney injury (AKI) management. AKI is characterized by acute tubular injury with rapid loss of renal function. After AKI, inflammation, oxidative stress and excessive deposition of extracellular matrix are the molecular events that ultimately cause the end-stage renal disease. Despite numerous improvement of supportive therapy, the mortality and morbidity among patients remain high. Therefore, exploring novel therapeutic options to treat AKI is mandatory. Numerous evidence in animal models has demonstrated the capability of mesenchymal stem cells (MSCs) to restore kidney function after induced kidney injury. After infusion, MSCs engraft in the injured tissue and release soluble factors and microvesicles that promote cell survival and tissue repairing. Indeed, the main mechanism of action of MSCs in tissue regeneration is the paracrine/endocrine secretion of bioactive molecules. MSCs can be isolated from several tissues, including bone marrow, adipose tissue, and blood cord; pre-treatment procedures to improve MSCs homing and their paracrine function have been also described. This review will focus on the application of cell therapy in AKI and it will summarize preclinical studies in animal models and clinical trials currently ongoing about the use of mesenchymal stem cells after AKI.
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Liu P, Feng Y, Wang Y, Zhou Y. Therapeutic action of bone marrow-derived stem cells against acute kidney injury. Life Sci 2014; 115:1-7. [PMID: 25219881 DOI: 10.1016/j.lfs.2014.08.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 09/02/2014] [Accepted: 08/20/2014] [Indexed: 12/20/2022]
Abstract
Acute kidney injury (AKI) is a frequent clinical disease with a high morbidity rate and mortality rate, while the treatment options for this intractable disease are limited currently. In recent years, bone marrow-derived mesenchymal stem cells (BMSCs) have been demonstrated to hold an effect therapeutic action against AKI by scientists gradually, and the cells are capable to localize to renal compartments and contribute to kidney regeneration though differentiation or paracrine action. Especially, the advantages of BMSCs, such as low toxicity and side effect as well as autologous transplantation, endue the cell with a promising potential in clinical therapy against AKI. In this review, we mainly provide a concise overview of the application of BMSCs in the treatment of AKI, and summarize a series of published data regarding the mechanisms and optimizations of the BMSC-based therapy in renal repair after AKI. Even though some critical points about the BMSC-based therapy model still need clarification, we hope to develop more reliable pharmacological or biotechnical strategies utilizing the stem cell for the eventual treatment of humans with AKI, based on these studies and the understanding of mechanism of renal protection by BMSCs.
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Affiliation(s)
- Pengfei Liu
- Department of Regeneration Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China; Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Yetong Feng
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, P.R. China
| | - Yi Wang
- Department of Regeneration Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China.
| | - Yulai Zhou
- Department of Regeneration Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China.
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