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Zhao J, Han M, Nie Q, Wen X, Geng H, Zou Y, Li S, Xie W. Network pharmacology combined with experimental analysis to explore the mechanism of the XinShuaiNing formula on heart failure. 3 Biotech 2025; 15:110. [PMID: 40191450 PMCID: PMC11965065 DOI: 10.1007/s13205-025-04288-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 03/22/2025] [Indexed: 04/09/2025] Open
Abstract
This study was conducted to elucidate the mechanism of action of the Traditional Chinese Medicine XinShuaiNing (XSN) formula in CHF based on network pharmacology. A total of 489 compounds in the XSN formula were screened. These compounds predicted 778 targets. A search of CHF yielded 789 corresponding targets, and 151 intersections between the potential targets of the XSN formula and CHF, involving AKT1, AGT, eNOS, and VEGF. Abdominal aortic coarctation (AAC) was used to establish a CHF rat model, and isoproterenol-induced H9c2 cells to establish a myocardial injury cell model. The results showed that the XSN formula downregulated ET-1, BNP, and Hcy and upregulated the ALB levels and also relieved cardiac histopathological damage. The XSN formula reduced the content of pro-inflammatory factors and inhibited the apoptosis of cardiomyocytes. In addition, the expression of fibronectin, α-SMA, collagen 1, and collagen 3 was downregulated by XSN formula treatment, and the fibrotic areas of myocardial tissue were reduced. The XSN formula promoted phosphorylation of AKT1-induced VEGF and eNOS signaling and inhibited AGT signaling. Besides, the XSN formula can affect the apoptosis of H9c2 cells by affecting AKT1, AGT, eNOS, and VEGF. The XSN formula regulates inflammatory factors by inducing phosphorylation of AKT1, upregulating eNOS and VEGF, and downregulating AGT to protect cardiomyocytes from apoptosis and myocardial fibrosis to alleviate CHF. In conclusion, this study identified the target of XSN prescription through network pharmacology screening and experimental validation and confirmed its anti-inflammatory, antiapoptotic, and antifibrotic effects.
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Affiliation(s)
- Jue Zhao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mingjun Han
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qian Nie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xin Wen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hongyu Geng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu Zou
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Songyun Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wen Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Di X, Li Y, Wei J, Li T, Liao B. Targeting Fibrosis: From Molecular Mechanisms to Advanced Therapies. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410416. [PMID: 39665319 PMCID: PMC11744640 DOI: 10.1002/advs.202410416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/27/2024] [Indexed: 12/13/2024]
Abstract
As the final stage of disease-related tissue injury and repair, fibrosis is characterized by excessive accumulation of the extracellular matrix. Unrestricted accumulation of stromal cells and matrix during fibrosis impairs the structure and function of organs, ultimately leading to organ failure. The major etiology of fibrosis is an injury caused by genetic heterogeneity, trauma, virus infection, alcohol, mechanical stimuli, and drug. Persistent abnormal activation of "quiescent" fibroblasts that interact with or do not interact with the immune system via complicated signaling cascades, in which parenchymal cells are also triggered, is identified as the main mechanism involved in the initiation and progression of fibrosis. Although the mechanisms of fibrosis are still largely unknown, multiple therapeutic strategies targeting identified molecular mechanisms have greatly attenuated fibrotic lesions in clinical trials. In this review, the organ-specific molecular mechanisms of fibrosis is systematically summarized, including cardiac fibrosis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis. Some important signaling pathways associated with fibrosis are also introduced. Finally, the current antifibrotic strategies based on therapeutic targets and clinical trials are discussed. A comprehensive interpretation of the current mechanisms and therapeutic strategies targeting fibrosis will provide the fundamental theoretical basis not only for fibrosis but also for the development of antifibrotic therapies.
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Affiliation(s)
- Xingpeng Di
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Ya Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Jingwen Wei
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Tianyue Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Banghua Liao
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
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Thandar M, Zhang L, Yang X, Chi P, Li Y. Proteomics analysis revealed the therapeutic role of adipose-derived mesenchymal stem cells on radiation-induced colorectal fibrosis in rats. Biomed Pharmacother 2025; 182:117763. [PMID: 39693908 DOI: 10.1016/j.biopha.2024.117763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/07/2024] [Accepted: 12/12/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Radiation-induced colorectal fibrosis (RICF) is a chronic condition that can develop after pelvic radiation therapy for colorectal cancer. Adipose-derived mesenchymal stem cells (ADSCs) have emerged as promising candidate for fibrosis treatment, yet the mode of action of ADSC upon RICF remains obscure. This study aimed to investigate the optimal delivery route, treatment timing, anti-fibrotic effects, and underlying mechanisms of ADSCs upon RICF. METHODS The RICF rat model was constructed by single dose of 20 Gy irradiation, and ADSCs were delivered via diverse ways (e.g., tail vein injection, abdominal aorta injection, peritoneal injection, or perianal tissue injection) at different frequencies (once, twice, or thrice a week) for 10 weeks. TMT-labelled proteomic and phosphoproteomic analysis was conducted for dissecting the underlying mechanisms of ADSCs upon RICF. ADSCs were co-cultured with primary human intestinal fibroblasts to verify the anti-fibrotic effects upon radiation-induced fibroblasts. Additionally, 4D label-free proteomic analysis and 4D-parallel reaction monitoring were carried out to explore their molecular mechanisms. RESULTS RICF rats revealed better outcomes after intraperitoneal injection of ADSCs rather than the relative ways, and in particular, those with thrice-weekly injections showed effective prevention and improvement in RICF. Proteomic and phosphoproteomic analyses, together with multifaceted analyses (e.g., co-culture, 4D-PRM analysis), indicated Cytochrome b-245 alpha chain (Cyba) as a candidate target in mediating the efficacy of ADSCs upon RICF. CONCLUSIONS This comprehensive multilevel proteomic study provides valuable insights into the molecular mechanisms underlying RICF and enhances understanding of the potential of ADSCs-based cytotherapy.
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Affiliation(s)
- Mya Thandar
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Leisheng Zhang
- Shandong Provincial Key Medical and Health Laboratory of Blood Ecology and Biointelligence, Jinan Key Laboratory of Medical Cell Bioengineering, Science and Technology Innovation Center, Cardio-cerebrovascular Disease Hospital of Jinan, The Fourth People's Hospital of Jinan, Shandong Second Medical University, Jinan 250031, China
| | - Xiaojie Yang
- Department of Thoracic Surgery, Third Affiliated Hospital of Chongqing Medical University, Chongqing 401100, China
| | - Pan Chi
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China; Training Center of Minimally Invasive Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province 350001, China.
| | - Yang Li
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
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Babaeenezhad E, Dezfoulian O, Moradi Sarabi M, Ahmadvand H. Monoterpene linalool restrains gentamicin-mediated acute kidney injury in rats by subsiding oxidative stress, apoptosis, and the NF-κB/iNOS/TNF-α/IL-1β pathway and regulating TGF-β. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:5701-5714. [PMID: 38294506 DOI: 10.1007/s00210-024-02978-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 01/23/2024] [Indexed: 02/01/2024]
Abstract
The clinical use of gentamicin (GM) is restricted by its nephrotoxic effects. This study aimed for the first time to elucidate the ameliorative effects of the monoterpene linalool (Lin) against GM-mediated acute kidney injury in rats. A total of thirty-two rats were subdivided into four equal groups: control (saline), Lin (100 mg/kg/day), GM (100 mg/kg/day), and GM + Lin (100 and 100 mg/kg/day). Lin and GM were intraperitoneally administered for 12 days. Our results illustrated that Lin ameliorated GM-mediated renal histopathological abnormalities and reduced serum urea and creatinine levels in rats exposed to GM. Lin treatment mitigated oxidative stress in nephrotoxic animals as manifested by reducing serum and renal levels of malondialdehyde and increasing the activities of serum and renal glutathione peroxidase and renal catalase. Moreover, Lin markedly inhibited GM-triggered inflammation by downregulating NF-κB, iNOS, TNF-α, and IL-1β and reducing renal myeloperoxidase activity and nitric oxide levels. Interestingly, Lin repressed GM-induced apoptosis, as reflected by a marked downregulation of Bax and caspase-3 expression, concurrent with the upregulation of Bcl2 expression. Finally, Lin administration led to a significant downregulation of TGF-β expression in nephrotoxic animals. In summary, Lin ameliorated GM-mediated nephrotoxicity in rats, at least through its antioxidant, anti-inflammatory, and anti-apoptotic activities and by modulating TGF-β.
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Affiliation(s)
- Esmaeel Babaeenezhad
- Nutritional Health Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Omid Dezfoulian
- Department of Pathobiology, School of Veterinary Medicine, Lorestan University, Khorramabad, Iran.
| | - Mostafa Moradi Sarabi
- Razi Herbal Medicines Research Center, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran.
- Department of Clinical Biochemistry, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran.
| | - Hassan Ahmadvand
- Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
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Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
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Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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Chen XM, Wang X, Hou Z. Editorial: MSC-derived exosomes in tissue regeneration. Front Cell Dev Biol 2023; 11:1293109. [PMID: 37854070 PMCID: PMC10581203 DOI: 10.3389/fcell.2023.1293109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 09/19/2023] [Indexed: 10/20/2023] Open
Affiliation(s)
- Xin-Ming Chen
- Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia
- Renal Medicine, The University of Sydney, Darlington, NSW, Australia
| | - Xiaodan Wang
- Central Laboratory of Kunming Yan’an Hospital, Kunming Medical University, Kunming, Yunnan, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, China
| | - Zongliu Hou
- Central Laboratory of Kunming Yan’an Hospital, Kunming Medical University, Kunming, Yunnan, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, China
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Dysregulated balance in Th17/Treg axis of Pristane-induced lupus mouse model, are mesenchymal stem cells therapeutic? Int Immunopharmacol 2023; 117:109699. [PMID: 36867923 DOI: 10.1016/j.intimp.2023.109699] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/20/2022] [Accepted: 01/04/2023] [Indexed: 03/05/2023]
Abstract
BACKGROUND Despite advances in general and targeted immunosuppressive therapies, limiting all mainstay treatment options in refractory systemic lupus erythematosus (SLE) cases has necessitated the development of new therapeutic strategies. Mesenchymal stem cells (MSCs) have recently emerged with unique properties, including a solid propensity to reduce inflammation, exert immunomodulatory effects, and repair injured tissues. METHODS An animal model of acquired SLE mice was induced via intraperitoneal immunization with Pristane and affirmed by measuring specific biomarkers. Bone marrow (BM) MSCs were isolated from healthy BALB/c mice and cultured in vitro, then were identified and confirmed by flow cytometry and cytodifferentiation. Systemic MSCs transplantation was performed and then several parameters were analyzed and compared, including specific cytokines (IL-17, IL-4, IFN-ɣ, TGF-β) at the serum level, the percentage of Th cell subsets (Treg/Th17, Th1/Th2) in splenocytes, and also the relief of lupus nephritis, respectively by enzyme-linked immunosorbent assay (ELISA), flow cytometry analysis and by hematoxylin & eosin staining and also immunofluorescence assessment. Experiments were carried out with different initiation treatment time points (early and late stages of disease). Analysis of variance (ANOVA) followed by post hoc Tukey's test was used for multiple comparisons. RESULTS The rate of proteinuria, anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies, and serum creatinine levels decreased with BM-MSCs transplantation. These results were associated with attenuated lupus renal pathology in terms of reducing IgG and C3 deposition and lymphocyte infiltration. Our findings suggested that TGF-β (associated with lupus microenvironment) can contribute to MSC-based immunotherapy by modulating the population of TCD4+ cell subsets. Obtained results indicated that MSCs-based cytotherapy could negatively affect the progression of induced SLE by recovering the function of Treg cells, suppressing Th1, Th2, and Th17 lymphocyte function, and downregulating their pro-inflammatory cytokines. CONCLUSION MSC-based immunotherapy showed a delayed effect on the progression of acquired SLE in a lupus microenvironment-dependent manner. Allogenic MSCs transplantation revealed the ability to re-establish the balance of Th17/Treg, Th1/Th2 and restore the plasma cytokines network in a pattern dependent on disease conditions. The conflicting results of early versus advanced therapy suggest that MSCs may produce different effects depending on when they are administered and their activation status.
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Ahmed ASF, Sharkawi SS, AbdelHameed SS, Bayoumi AM, Moussa RS, Alhakamy NA, Al Sadoun H, Mansouri RA, El-Moselhy MA, El-Daly M, Anter AF, Truhan TE. Ketogenic diet restores hormonal, apoptotic/proliferative balance and enhances the effect of metformin on a letrozole-induced polycystic ovary model in rats. Life Sci 2023; 313:121285. [PMID: 36526050 DOI: 10.1016/j.lfs.2022.121285] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 12/02/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Polycystic ovaries (PCO) is a hormonal disorder that is a leading cause of infertility. The formation of multiple persistent cysts and hormonal imbalance are hallmarks of PCO. Recent clinical studies reported a beneficial effect of the ketogenic diet (KD; high-fat, low-carbohydrate) on PCO. The aim of this study was to investigate the effect of the KD alone and in combination with metformin on letrozole-induced PCO in female rats. METHODS Female rats were grouped into control and PCO (letrozole; 1 mg/kg for 21 days). The PCO group was subdivided into PCO (non-treated), PCO-metformin (300 mg/kg), PCO rats fed with KD only, and PCO rats treated with metformin and fed with KD. All groups continued to receive letrozole during the 21-day treatment period. At the end of the experiment, serum and ovaries were collected for further analysis. RESULTS The untreated-PCO rats showed increased testosterone, LH/FSH ratio, and ovary weights. Disturbed apoptosis and proliferation balance were evident as a low caspase-3 activation and proliferating cell nuclear antigen expression and increased TGF-β expression. The KD improved the letrozole-induced effects, which was comparable to the effect of metformin. Combining the KD with metformin treatment additively enhanced the metformin effect. CONCLUSION Our results indicate that the KD has a protective role against PCO in rats, especially when combined with metformin. This study reveals a potential therapeutic role of the KD in PCO, which could prompt valuable future clinical applications.
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Affiliation(s)
- Al-Shaimaa F Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt.
| | - Sara S Sharkawi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Sara S AbdelHameed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Asmaa M Bayoumi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Rabab S Moussa
- Department of Pathology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Nabil A Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Hadeel Al Sadoun
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Rasha A Mansouri
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mohamed A El-Moselhy
- Clinical Pharmacy and Pharmacology Department, Ibn Sina National College for Medical Studies, Jeddah 21589, Saudi Arabia
| | - Mahmoud El-Daly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Aliaa F Anter
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt
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Wang H, Jiang Q, Zhang L. Baicalin protects against renal interstitial fibrosis in mice by inhibiting the TGF-β/Smad signalling pathway. PHARMACEUTICAL BIOLOGY 2022; 60:1407-1416. [PMID: 35938471 PMCID: PMC9361769 DOI: 10.1080/13880209.2022.2097700] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
CONTEXT Baicalin, a flavonoid extracted from radix scutellariae, possesses various pharmacological effects, including protective effects on renal interstitial fibrosis (RIF), but its possible role and mechanisms have not been fully elucidated. OBJECTIVE This study explores the protective effects and mechanisms of baicalin on RIF. MATERIALS AND METHODS C57BL/6 male mice were divided into six groups: sham, model, low baicalin, middle baicalin, high baicalin and positive drug groups. The unilateral ureteral obstruction (UUO) model of RIF was constructed and treated with baicalin doses (10, 20 and 40 mg/kg) and a positive control drug (valsartan, 8 mg/kg). H&E staining was used to observe the pathological changes in renal tissues, Masson staining was performed to evaluate collagen deposition in renal tissues, and immunohistochemical examination was adopted to determine α-SMA and extracellular matrix (ECM) expression. Primary mouse fibroblasts were isolated, extracted and treated with baicalin and/or TGF-β. qRT-PCR and enzyme-linked immunosorbent assay (ELISA) were applied to detect the inflammatory responses. Moreover, ECM and TGF-β/Smad expression levels were evaluated by western blot assay. RESULTS Baicalin ameliorated RIF in UUO mice by inhibiting fibrosis and inflammatory responses. The TGF-β/Smad pathway was significantly suppressed in the UUO mouse model. Additionally, baicalin significantly inhibited ECM expression and inflammatory factors in fibroblasts treated with TGF-β. TGF-β/Smad pathway activation was significantly decreased in fibroblasts. DISCUSSION AND CONCLUSIONS These findings support the use of baicalin as a potential therapeutic option for the treatment of RIF by possibly inhibiting the TGF-β/Smad signalling pathway.
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Affiliation(s)
- Hui Wang
- Department of Clinical Medicine, Jiangsu Health Vocational College, Nanjing, China
| | - Qingtao Jiang
- Department of Clinical Medicine, Jiangsu Health Vocational College, Nanjing, China
| | - Lizhu Zhang
- Department of Nanxin Pharm, Nanjing, China
- CONTACT Lizhu Zhang Department of Nanxin Pharm, No. 9 Weidi Road, Nanjing, Jiangsu210000, China
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lncRNA TUG1 regulates hyperuricemia-induced renal fibrosis in a rat model. Acta Biochim Biophys Sin (Shanghai) 2022; 54:1365-1375. [PMID: 36148952 PMCID: PMC9828301 DOI: 10.3724/abbs.2022128] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Renal fibrosis is most common among chronic kidney diseases. Molecular studies have shown that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) participate in renal fibrosis, while the roles of lncRNA taurine upregulated gene 1 (TUG1) and miR-140-3p in hyperuricemia-induced renal fibrosis remain less investigated. In this study, a rat hyperuricemia model is constructed by oral administration of adenine. TUG1, miR-140-3p, and cathepsin D (CtsD) expression levels in rat models are measured. After altering TUG1, miR-140-3p, or CtsD expression in modelled rats, biochemical indices, including uric acid (UA), serum creatine (SCr), blood urea nitrogen (BUN), and 24-h urine protein are detected, pathological changes in the renal tissues, and renal fibrosis are examined. In renal tissues from hyperuricemic rats, TUG1 and CtsD are upregulated, while miR-140-3p is downregulated. Inhibiting TUG1 or CtsD or upregulating miR-140-3p relieves renal fibrosis in hyperuricemic rats. Downregulated miR-140-3p reverses the therapeutic effect of TUG1 reduction, while overexpression of CtsD abolishes the role of miR-140-3p upregulation in renal fibrosis. Collectively, this study highlights that TUG1 inhibition upregulates miR-140-3p to ameliorate renal fibrosis in hyperuricemic rats by inhibiting CtsD.
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Hendawy H, Metwally E, Elfadadny A, Yoshida T, Ma D, Shimada K, Hamabe L, Sasaki K, Tanaka R. Cultured versus freshly isolated adipose-derived stem cells in improvement of the histopathological outcomes in HCL-induced cystitis in a rat model. Biomed Pharmacother 2022; 153:113422. [DOI: 10.1016/j.biopha.2022.113422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 11/02/2022] Open
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Liu L, Sun Q, Davis F, Mao J, Zhao H, Ma D. Epithelial-mesenchymal transition in organ fibrosis development: current understanding and treatment strategies. BURNS & TRAUMA 2022; 10:tkac011. [PMID: 35402628 PMCID: PMC8990740 DOI: 10.1093/burnst/tkac011] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 12/16/2021] [Indexed: 01/10/2023]
Abstract
Organ fibrosis is a process in which cellular homeostasis is disrupted and extracellular matrix is excessively deposited. Fibrosis can lead to vital organ failure and there are no effective treatments yet. Although epithelial–mesenchymal transition (EMT) may be one of the key cellular mechanisms, the underlying mechanisms of fibrosis remain largely unknown. EMT is a cell phenotypic process in which epithelial cells lose their cell-to-cell adhesion and polarization, after which they acquire mesenchymal features such as infiltration and migration ability. Upon injurious stimulation in different organs, EMT can be triggered by multiple signaling pathways and is also regulated by epigenetic mechanisms. This narrative review summarizes the current understanding of the underlying mechanisms of EMT in fibrogenesis and discusses potential strategies for attenuating EMT to prevent and/or inhibit fibrosis. Despite better understanding the role of EMT in fibrosis development, targeting EMT and beyond in developing therapeutics to tackle fibrosis is challenging but likely feasible.
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Affiliation(s)
- Lexin Liu
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK.,Department of Nephrology and Urology, Pediatric Urolith Center, The Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province, 310003, China
| | - Qizhe Sun
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK
| | - Frank Davis
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK
| | - Jianhua Mao
- Department of Nephrology, The Children Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang Province, 310003, China
| | - Hailin Zhao
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK
| | - Daqing Ma
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK
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Hamam G, Bahaa N, Raafat M. Can intranasal administration of adipose-derived stem cells reach and affect the histological structure of distant organs of aged wistar rat? J Microsc Ultrastruct 2022; 11:1-11. [PMID: 37144165 PMCID: PMC10153733 DOI: 10.4103/jmau.jmau_78_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 08/19/2020] [Indexed: 11/16/2022] Open
Abstract
Introduction Stem cell therapy is a highly promising strategy in various degenerative diseases. Intranasal administration of stem cells could be considered as a non-invasive treatment option. However, there is great debate concerning the ability of stem cells to reach distant organs. It is also unclear in such a case if they can alleviate age-related structural changes in these organs. Aim The aim of this study is to evaluate the ability of intranasal administration of adipose-derived stem cells (ADSCs) to reach distant organs of rats at different time intervals and to investigate their effects on age-related structural changes in these organs. Materials and Methods Forty-nine female Wistar rats were used in this study, seven of which were adults (6-month-old) and 42 were aged (2-year-old). Rats were divided into three-groups: Group-I (adult control), Group-II (aged), and Group-III (aged ADSCs treated). Rats of Groups I and II were sacrificed after 15 days from the beginning of the experiment. Rats of Group III were treated with intranasal ADSCs and were sacrificed after 2-h, 1-day, 3-day, 5-day, and 15-day. Heart, liver, kidney, and spleen specimens were collected and processed for H and E, CD105 immunohistochemistry, and immunofluorescent techniques. Morphometric study and statistical analysis were performed. Results ADSCs appeared in all organs examined after 2-h of intranasal administration. Their maximum presence was detected after 3-day of administration, after which their immunofluorescence gradually decreased and nearly disappeared from these organs by the 15th day. Improvement of some age-related deterioration in the structure of the kidney and liver occurred at day 5 after intranasal administration. Conclusions ADSCs effectively reached the heart, liver, kidney, and spleen after intranasal administration. ADSCs ameliorated some age-related changes in these organs.
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Caneparo C, Sorroza-Martinez L, Chabaud S, Fradette J, Bolduc S. Considerations for the clinical use of stem cells in genitourinary regenerative medicine. World J Stem Cells 2021; 13:1480-1512. [PMID: 34786154 PMCID: PMC8567446 DOI: 10.4252/wjsc.v13.i10.1480] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/12/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
The genitourinary tract can be affected by several pathologies which require repair or replacement to recover biological functions. Current therapeutic strategies are challenged by a growing shortage of adequate tissues. Therefore, new options must be considered for the treatment of patients, with the use of stem cells (SCs) being attractive. Two different strategies can be derived from stem cell use: Cell therapy and tissue therapy, mainly through tissue engineering. The recent advances using these approaches are described in this review, with a focus on stromal/mesenchymal cells found in adipose tissue. Indeed, the accessibility, high yield at harvest as well as anti-fibrotic, immunomodulatory and proangiogenic properties make adipose-derived stromal/SCs promising alternatives to the therapies currently offered to patients. Finally, an innovative technique allowing tissue reconstruction without exogenous material, the self-assembly approach, will be presented. Despite advances, more studies are needed to translate such approaches from the bench to clinics in urology. For the 21st century, cell and tissue therapies based on SCs are certainly the future of genitourinary regenerative medicine.
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Affiliation(s)
- Christophe Caneparo
- Centre de Recherche en Organogénèse Expérimentale de l'Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Quebec G1J1Z4, Canada
| | - Luis Sorroza-Martinez
- Centre de Recherche en Organogénèse Expérimentale de l'Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Quebec G1J1Z4, Canada
| | - Stéphane Chabaud
- Centre de Recherche en Organogénèse Expérimentale de l'Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Quebec G1J1Z4, Canada
| | - Julie Fradette
- Centre de Recherche en Organogénèse Expérimentale de l'Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Quebec G1J1Z4, Canada
- Department of Surgery, Faculty of Medicine, Université Laval, Quebec G1V0A6, Canada
| | - Stéphane Bolduc
- Centre de Recherche en Organogénèse Expérimentale de l'Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Quebec G1J1Z4, Canada
- Department of Surgery, Faculty of Medicine, Université Laval, Quebec G1V0A6, Canada
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15
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Liu Y, Su YY, Yang Q, Zhou T. Stem cells in the treatment of renal fibrosis: a review of preclinical and clinical studies of renal fibrosis pathogenesis. Stem Cell Res Ther 2021; 12:333. [PMID: 34112221 PMCID: PMC8194041 DOI: 10.1186/s13287-021-02391-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/14/2021] [Indexed: 02/05/2023] Open
Abstract
Renal fibrosis commonly leads to glomerulosclerosis and renal interstitial fibrosis and the main pathological basis involves tubular atrophy and the abnormal increase and excessive deposition of extracellular matrix (ECM). Renal fibrosis can progress to chronic kidney disease. Stem cells have multilineage differentiation potential under appropriate conditions and are easy to obtain. At present, there have been some studies showing that stem cells can alleviate the accumulation of ECM and renal fibrosis. However, the sources of stem cells and the types of renal fibrosis or renal fibrosis models used in these studies have differed. In this review, we summarize the pathogenesis (including signaling pathways) of renal fibrosis, and the effect of stem cell therapy on renal fibrosis as described in preclinical and clinical studies. We found that stem cells from various sources have certain effects on improving renal function and alleviating renal fibrosis. However, additional clinical studies should be conducted to confirm this conclusion in the future.
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Affiliation(s)
- Yiping Liu
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Yan-Yan Su
- Department of Nephrology, Huadu District People's Hospital of Guangzhou, Southern Medical University, Guangzhou, China
| | - Qian Yang
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China.
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16
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Wei J, Zhao Q, Yang G, Huang R, Li C, Qi Y, Hao C, Yao W. Mesenchymal stem cells ameliorate silica-induced pulmonary fibrosis by inhibition of inflammation and epithelial-mesenchymal transition. J Cell Mol Med 2021; 25:6417-6428. [PMID: 34076355 PMCID: PMC8256359 DOI: 10.1111/jcmm.16621] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/10/2021] [Accepted: 04/28/2021] [Indexed: 12/19/2022] Open
Abstract
Silicosis is a devastating occupational disease caused by long-term inhalation of silica particles, inducing irreversible lung damage and affecting lung function, without effective treatment. Mesenchymal stem cells (MSCs) are a heterogeneous subset of adult stem cells that exhibit excellent self-renewal capacity, multi-lineage differentiation potential and immunomodulatory properties. The aim of this study was to explore the effect of bone marrow-derived mesenchymal stem cells (BMSCs) in a silica-induced rat model of pulmonary fibrosis. The rats were treated with BMSCs on days 14, 28 and 42 after perfusion with silica. Histological examination and hydroxyproline assays showed that BMSCs alleviated silica-induced pulmonary fibrosis in rats. Results from ELISA and qRT-PCR indicated that BMSCs inhibited the expression of inflammatory cytokines TNF-α, IL-1β and IL-6 in lung tissues and bronchoalveolar lavage fluid of rats exposed to silica particles. We also performed qRT-PCR, Western blot and immunohistochemistry to examine epithelial-mesenchymal transition (EMT)-related indicators and demonstrated that BMSCs up-regulate E-cadherin and down-regulate vimentin and extracellular matrix (ECM) components such as fibronectin and collagen Ⅰ. Additionally, BMSCs inhibited the silica-induced increase in TGF-β1, p-Smad2 and p-Smad3 and decrease in Smad7. These results suggested that BMSCs can inhibit inflammation and reverse EMT through the inhibition of the TGF-β/Smad signalling pathway to exhibit an anti-fibrotic effect in the rat silicosis model. Our study provides a new and meaningful perspective for silicosis treatment strategies.
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Affiliation(s)
- Jingjing Wei
- School of Public HealthZhengzhou UniversityZhengzhouChina
| | - Qiuyan Zhao
- School of Public HealthZhengzhou UniversityZhengzhouChina
| | - Guo Yang
- School of Public HealthZhengzhou UniversityZhengzhouChina
| | - Ruoxuan Huang
- School of Public HealthZhengzhou UniversityZhengzhouChina
| | - Chao Li
- School of Public HealthZhengzhou UniversityZhengzhouChina
| | - Yuanmeng Qi
- School of Public HealthZhengzhou UniversityZhengzhouChina
| | - Changfu Hao
- School of Public HealthZhengzhou UniversityZhengzhouChina
| | - Wu Yao
- School of Public HealthZhengzhou UniversityZhengzhouChina
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17
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Junren C, Xiaofang X, Huiqiong Z, Gangmin L, Yanpeng Y, Xiaoyu C, Yuqing G, Yanan L, Yue Z, Fu P, Cheng P. Pharmacological Activities and Mechanisms of Hirudin and Its Derivatives - A Review. Front Pharmacol 2021; 12:660757. [PMID: 33935784 PMCID: PMC8085555 DOI: 10.3389/fphar.2021.660757] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/22/2021] [Indexed: 12/13/2022] Open
Abstract
Hirudin, an acidic polypeptide secreted by the salivary glands of Hirudo medicinalis (also known as "Shuizhi" in traditional Chinese medicine), is the strongest natural specific inhibitor of thrombin found so far. Hirudin has been demonstrated to possess potent anti-thrombotic effect in previous studies. Recently, increasing researches have focused on the anti-thrombotic activity of the derivatives of hirudin, mainly because these derivatives have stronger antithrombotic activity and lower bleeding risk. Additionally, various bioactivities of hirudin have been reported as well, including wound repair effect, anti-fibrosis effect, effect on diabetic complications, anti-tumor effect, anti-hyperuricemia effect, effect on cerebral hemorrhage, and others. Therefore, by collecting and summarizing publications from the recent two decades, the pharmacological activities, pharmacokinetics, novel preparations and derivatives, as well as toxicity of hirudin were systematically reviewed in this paper. In addition, the clinical application, the underlying mechanisms of pharmacological effects, the dose-effect relationship, and the development potential in new drug research of hirudin were discussed on the purpose of providing new ideas for application of hirudin in treating related diseases.
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Affiliation(s)
- Chen Junren
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xie Xiaofang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhang Huiqiong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Gangmin
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yin Yanpeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cao Xiaoyu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Gao Yuqing
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Yanan
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhang Yue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Peng Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China.,West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Peng Cheng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,Chengdu University of Traditional Chinese Medicine, Chengdu, China
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18
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Dong J, Ding L, Wang L, Yang Z, Wang Y, Zang Y, Cao X, Tang L. Effects of bradykinin on proliferation, apoptosis, and cycle of glomerular mesangial cells via the TGF-β1/Smad signaling pathway. Turk J Biol 2021; 45:17-25. [PMID: 33597818 PMCID: PMC7877713 DOI: 10.3906/biy-2007-58] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 10/19/2020] [Indexed: 12/25/2022] Open
Abstract
We aimed to assess the effects of bradykinin (BK) on the proliferation, apoptosis, and cycle of glomerular mesangial cells via the transforming growth factor-β 1 (TGF-β1)/Smad signaling pathway. Rat glomerular mesangial cells, HBZY-1, were divided into normal group (untreated), model group (5 ng/L TGF-β1), BK group (5 ng/L TGF-β1 + 1 ng/L BK), and inhibitor group [5 ng/L TGF-β1 + 1 ng/L LY2109761 (TGF-β1-specific inhibitor)]. The cell proliferation, cycle, apoptosis, expression of type I collagen (Col-1), and protein expressions of Col-1, TGF-β1, and phosphorylated Smad2 (p-Smad2) were detected by EdU labeling, flow cytometry, acridine orange/ethidium bromide (AO/EB) dual staining, immunofluorescence assay, and Western blotting, respectively. Compared with the normal group, the cell proliferation rate (P = 0.02) and protein expression levels of Col-1 (P = 0.02), TGF-β1 (P = 0.01), p-Smad2 (P = 0.02), and p-Smad7 (P = 0.00) in the model group significantly increased, and apoptosis rate (P = 0.01) significantly decreased. Compared with the model group, the BK and inhibitor groups significantly decreased in proliferation rate (P = 0.01) and protein expression levels of Col-1 (P = 0.01), TGF-β1 (P = 0.01), and p-Smad2 (P = 0.00). Also, they were significantly elevated in apoptosis rate (P = 0.02) and p-Smad7 protein expression (P = 0.02). BK regulates the proliferation, apoptosis, and the cycle of glomerular mesangial cells by inhibiting the TGF-β1/Smad signaling pathway.
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Affiliation(s)
- Ji Dong
- Department of Medicine, Henan Medical College, Zhengzhou, Henan Province China
| | - Li Ding
- Henan Institute for Occupational Medicine, Zhengzhou, Henan Province China
| | - Liuwei Wang
- Department of Nephropathy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province China
| | - Zijun Yang
- Department of Nephropathy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province China
| | - Yulin Wang
- Department of Nephropathy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province China
| | - Ying Zang
- Department of Medicine, Henan Medical College, Zhengzhou, Henan Province China
| | - Xuexia Cao
- Department of Medicine, Henan Medical College, Zhengzhou, Henan Province China
| | - Lin Tang
- Department of Nephropathy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province China
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19
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Mattei A, Bertrand B, Jouve E, Blaise T, Philandrianos C, Grimaud F, Giraudo L, Aboudou H, Dumoulin C, Arnaud L, Revis J, Galant C, Velier M, Veran J, Dignat-George F, Dessi P, Sabatier F, Magalon J, Giovanni A. Feasibility of First Injection of Autologous Adipose Tissue-Derived Stromal Vascular Fraction in Human Scarred Vocal Folds: A Nonrandomized Controlled Trial. JAMA Otolaryngol Head Neck Surg 2021; 146:355-363. [PMID: 32053141 DOI: 10.1001/jamaoto.2019.4328] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Importance Patients with scarred vocal folds, whether congenitally or after phonosurgery, often exhibit dysphonia that negatively affects daily life and is difficult to treat. The autologous adipose tissue-derived stromal vascular fraction (ADSVF) is a readily accessible source of cells with angiogenic, anti-inflammatory, immunomodulatory, and regenerative properties. Objective To evaluate the feasibility and tolerability of local injections of autologous ADSVF in patients with scarred vocal folds. Design, Setting, and Participants CELLCORDES (Innovative Treatment for Scarred Vocal Cords by Local Injection of Autologous Stromal Vascular Fraction) is a prospective, open-label, single-arm, single-center, nonrandomized controlled trial with a 12-month follow-up and patient enrollment from April 1, 2016, to June 30, 2017. Eight patients with severe dysphonia attributable to vocal fold scarring associated with a congenital malformation or resulting from microsurgical sequelae (voice handicap index score >60 of 120) completed the study. Data analysis was performed from September 1, 2018, to January 1, 2019. Interventions Injection of ADSVF into 1 or 2 vocal folds. Main Outcomes and Measures The primary outcomes were feasibility and the number and severity of adverse events associated with ADSVF-based therapy. The secondary outcomes were changes in vocal assessment, videolaryngostroboscopy, self-evaluation of dysphonia, and quality of life at 1, 6, and 12 months after cell therapy. Results Seven women and 1 man (mean [SD] age, 44.6 [10.4] years) were enrolled in this study. Adverse events associated with liposuction and ADSVF injection occurred; most of them resolved spontaneously. One patient received minor treatment to drain local bruising, and another experienced a minor contour defect at the liposuction site. At 12 months, the voice handicap index score was improved in all patients, with a mean (SD) improvement from baseline of 40.1 (21.5) points. Seven patients (88%) were considered to be responders, defined as improvement by 18 points or more in the voice handicap index score (the minimum clinically important difference). Conclusions and Relevance The findings suggest that autologous ADSVF injection in scarred vocal folds is feasible and tolerable. The findings require confirmation in a randomized clinical trial with a larger population. Trial Registration ClinicalTrials.gov Identifier: NCT02622464.
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Affiliation(s)
- Alexia Mattei
- Department of Oto-Rhino-Laryngology and Head and Neck Surgery, Assistance Publique-Hôpitaux de Marseille, La Conception University Hospital, Marseille, France.,Laboratoire Parole et Langage, Centre National de la Recherche Scientifique, Aix Marseille University, Aix-en-Provence, France
| | - Baptiste Bertrand
- Department of Plastic and Reconstructive Surgery, Assistance Publique-Hôpitaux de Marseille, La Conception University Hospital, Marseille, France
| | - Elisabeth Jouve
- Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, Institut de Neurosciences des Systèmes, Service de Pharmacologie Clinique et Pharmacovigilance, Centre d'Investigation Clinique Centre de Pharmacologie Clinique et d'Évaluation Thérapeutique, Aix Marseille University, Marseille, France
| | - Théo Blaise
- Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, Institut de Neurosciences des Systèmes, Service de Pharmacologie Clinique et Pharmacovigilance, Centre d'Investigation Clinique Centre de Pharmacologie Clinique et d'Évaluation Thérapeutique, Aix Marseille University, Marseille, France
| | - Cécile Philandrianos
- Department of Plastic and Reconstructive Surgery, Assistance Publique-Hôpitaux de Marseille, La Conception University Hospital, Marseille, France
| | - Fanny Grimaud
- Cell Therapy Department, Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, La Conception University Hospital, Aix Marseille University, Marseille, France
| | - Laurent Giraudo
- Cell Therapy Department, Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, La Conception University Hospital, Aix Marseille University, Marseille, France
| | - Houssein Aboudou
- Cell Therapy Department, Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, La Conception University Hospital, Aix Marseille University, Marseille, France
| | - Chloé Dumoulin
- Cell Therapy Department, Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, La Conception University Hospital, Aix Marseille University, Marseille, France
| | - Laurent Arnaud
- Cell Therapy Department, Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, La Conception University Hospital, Aix Marseille University, Marseille, France
| | - Joana Revis
- Department of Oto-Rhino-Laryngology and Head and Neck Surgery, Assistance Publique-Hôpitaux de Marseille, La Conception University Hospital, Marseille, France.,Laboratoire Parole et Langage, Centre National de la Recherche Scientifique, Aix Marseille University, Aix-en-Provence, France
| | - Camille Galant
- Department of Oto-Rhino-Laryngology and Head and Neck Surgery, Assistance Publique-Hôpitaux de Marseille, La Conception University Hospital, Marseille, France.,Laboratoire Parole et Langage, Centre National de la Recherche Scientifique, Aix Marseille University, Aix-en-Provence, France
| | - Mélanie Velier
- Cell Therapy Department, Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, La Conception University Hospital, Aix Marseille University, Marseille, France.,Institut National de la Sante et de la Recherche Medicale and Institut National de la Recherche Agronomique, Aix Marseille University, Centre Recherche en CardioVasculaire et Nutrition, Marseille, France
| | - Julie Veran
- Cell Therapy Department, Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, La Conception University Hospital, Aix Marseille University, Marseille, France
| | - Françoise Dignat-George
- Cell Therapy Department, Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, La Conception University Hospital, Aix Marseille University, Marseille, France.,Institut National de la Sante et de la Recherche Medicale and Institut National de la Recherche Agronomique, Aix Marseille University, Centre Recherche en CardioVasculaire et Nutrition, Marseille, France
| | - Patrick Dessi
- Department of Oto-Rhino-Laryngology and Head and Neck Surgery, Assistance Publique-Hôpitaux de Marseille, La Conception University Hospital, Marseille, France.,French National Centre for Scientific Research, Centre National de la Recherche Scientifique, Etablissement Français du Sang, Anthropologie bio-culturelle, Droit, Ethique et Santé, Aix Marseille University, Marseille, France
| | - Florence Sabatier
- Cell Therapy Department, Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, La Conception University Hospital, Aix Marseille University, Marseille, France.,Institut National de la Sante et de la Recherche Medicale and Institut National de la Recherche Agronomique, Aix Marseille University, Centre Recherche en CardioVasculaire et Nutrition, Marseille, France
| | - Jérémy Magalon
- Cell Therapy Department, Assistance Publique-Hôpitaux de Marseille, Institut National de la Sante et de la Recherche Medicale, La Conception University Hospital, Aix Marseille University, Marseille, France.,Institut National de la Sante et de la Recherche Medicale and Institut National de la Recherche Agronomique, Aix Marseille University, Centre Recherche en CardioVasculaire et Nutrition, Marseille, France
| | - Antoine Giovanni
- Department of Oto-Rhino-Laryngology and Head and Neck Surgery, Assistance Publique-Hôpitaux de Marseille, La Conception University Hospital, Marseille, France.,Laboratoire Parole et Langage, Centre National de la Recherche Scientifique, Aix Marseille University, Aix-en-Provence, France
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Shentu Y, Jiang H, Liu X, Chen H, Yang D, Zhang J, Cheng C, Zheng Y, Zhang Y, Chen C, Zheng C, Zhou Y. Nestin Promotes Peritoneal Fibrosis by Protecting HIF1-α From Proteasomal Degradation. Front Physiol 2020; 11:517912. [PMID: 33391003 PMCID: PMC7772359 DOI: 10.3389/fphys.2020.517912] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 11/20/2020] [Indexed: 12/30/2022] Open
Abstract
Background Peritoneal dialysis (PD) is a treatment for end stage renal disease patients, but it can also cause peritoneal fibrosis. Nestin is known as a neural stem cell marker and it has many functions. The hypoxia induced factor (HIF) signaling pathway can be activated under hypoxia conditions, leading to the overexpression of some angiogenesis related genes. The aim of our study is to demonstrate Nestin’s role in the development of peritoneal fibrosis (PF), and to provide a new target (Nestin) to treat PF. Methods PD mice models were constructed by an intraperitoneal administration of PDS at 10 ml/100g/d for 4 weeks. Nestin-positive cells were isolated from peritonea of Nestin-GFP mice by flow cytometry. The relationship of Nestin and HIF1-α-VEGFA pathway was detected by Nestin knockdown, Co-immunoprecipitation and immunofluorescence. Also, proteasomal activity was demonstrated by CHX and MG132 application, followed by Western blotting and Co-immunoprecipitation. Results In our experiments, we found that Nestin expression resulted in PF. Also, HIF1-α/VEGFA pathway was activated in PF. Nestin knockdown reduced the level of HIF1-α. Nestin directly bound to HIF1-α and protected HIF1-α from proteasomal degradation. Overexpression of HIF1-α reverts the fibrosis levels in Nestin-knockdown cells. In brief, Nestin inhibited the degradation of HIF1-α by mitigating its ubiquitination level, leading to the activation of HIF1-α signaling pathway, and eventually promoted PF. Conclusion We found a novel mechanism of PF that Nestin promotes by protecting HIF1-α from proteasomal degradation. Taken together, our key findings highlight a novel mechanism by which the silencing of Nestin hinders HIF1- α -induced PF.
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Affiliation(s)
- Yangping Shentu
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huanchang Jiang
- Department of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaoyuan Liu
- Department of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hao Chen
- Department of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Dicheng Yang
- Department of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jinqi Zhang
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Chen Cheng
- Department of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yulin Zheng
- Department of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yang Zhang
- Department of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chaosheng Chen
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chenfei Zheng
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ying Zhou
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Li L, Wang C, Gu Y. Collagen IV, a promising serum biomarker for evaluating the prognosis of revascularization in a 2-kidney, 1-clip hypertensive rat model. Interact Cardiovasc Thorac Surg 2020; 30:483-490. [PMID: 31725159 DOI: 10.1093/icvts/ivz275] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 09/25/2019] [Accepted: 10/10/2019] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVES The goal of this study was to investigate the expression of serum collagen IV and its value for evaluating the prognosis of revascularization in a 2-kidney, 1-clip hypertensive rat model. METHODS A total of 40 Sprague-Dawley rats were randomly and evenly divided into a control group and 3-, 10- and 20-day (D) groups (namely, the ischaemic time for 3, 10 and 20 days, respectively). The systolic blood pressure and laboratory values such as serum creatinine and collagen IV levels were measured before and after clipping the renal artery. Histological Masson staining and immunohistochemical staining of collagen IV were conducted in a kidney specimen from each group to assess the severity of renal fibrosis and the level of collagen IV expression. RESULTS After clipping, systolic blood pressure in the 3D, 10D and 20D groups increased significantly from 108 ± 8 to 126 ± 7 and from 153 ± 8 to 157 ± 6 mmHg, respectively (10D vs 20D group, P = 0.224; between other groups, P < 0.001). The expression of serum creatinine in the 3D, 10D and 20D groups increased significantly from 35.39 ± 5.64 to 57.53 ± 7.05, 101.86 ± 8.94 and 119.76 ± 9.37 mmol/l, respectively (between each group: P < 0.001). Serum collagen IV levels in the 10D and 20D groups increased significantly from 38.5 ± 10.4 to 60.8 ± 15.0 and 87.3 ± 11.5 ng/ml, respectively (control vs 3D group, P = 0.718; between other groups, P < 0.001). The Masson staining indicated that sclerotic changes in the glomeruli of the 10D and 20D groups significantly increased from 2.20 ± 1.03 to 15.20 ± 5.03 and 28.20 ± 7.07%, respectively (control vs 3D group, P = 0.175; between other groups, P < 0.001). The grade of tubulointerstitial damage in the 3D, 10D and 20D groups increased significantly from 0.30 ± 0.48 to 1.90 ± 0.74, 1.80 ± 0.79 and 3.20 ± 0.79, respectively (3D vs 10D group, P = 0.755; between other groups, P < 0.001). The semi-quantification from immunohistochemical staining indicated that the percentage of collagen IV positive areas in the 3D, 10D and 20D groups increased significantly from 3.50 ± 1.58 to 8.60 ± 2.11, 16.60 ± 8.55 and 23.10 ± 6.15, respectively (control vs 3D group, P = 0.043; 3D vs 10D group, P = 0.002; 10D vs 20D group, P = 0.011; between other groups, P < 0.001). The area under the curve of the receiver operating characteristic curve was 0.783 (P = 0.008; 95% confidence interval 0.634-0.932). There were positive associations of serum collagen IV levels with systolic blood pressure, serum creatinine and collagen IV quantification in kidney with correlation coefficients of 0.665, 0.775 and 0.628, respectively (P < 0.001). CONCLUSIONS As the clear ischaemia time-response relationship identified in our study indicates, the increase in serum collagen IV levels may be a satisfactory biomarker to indicate a poor prognosis of renal artery revascularization in a 2-kidney, 1-clip hypertensive rat model. However, it is perhaps not a good early biomarker for the early detection of renovascular hypertension.
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Affiliation(s)
- Liqiang Li
- Department of Vascular Surgery, Xuanwu Hospital and Institute of Vascular Surgery, Capital Medical University, Beijing, China
| | - Cong Wang
- Department of Vascular Surgery, Xuanwu Hospital and Institute of Vascular Surgery, Capital Medical University, Beijing, China
| | - Yongquan Gu
- Department of Vascular Surgery, Xuanwu Hospital and Institute of Vascular Surgery, Capital Medical University, Beijing, China
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22
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Yang Q, Chen W, Han D, Zhang C, Xie Y, Sun X, Liu G, Deng C. Intratunical injection of human urine-derived stem cells derived exosomes prevents fibrosis and improves erectile function in a rat model of Peyronie's disease. Andrologia 2020; 52:e13831. [PMID: 32986908 DOI: 10.1111/and.13831] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/08/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023] Open
Abstract
We aimed to evaluate the effects of intratunical injection of exosomes derived from human urine-derived stem cells (USC-exo) on plaque formation and erectile function in a transforming growth factor-β1 (TGF-β1) induced Peyronie's disease (PD) rat model. Twenty-four SD rats were randomly assigned equally to three groups: (I) Sham group (50 μl phosphate-buffered saline [PBS] injected into the tunica albuginea [TA]), (II) PD group (0.5 μg TGF-β1 in 50 μl PBS injected into the TA) and (III) USC-exo group (0.5 ug TGF-β1 plus 100 μg USC-exo injected into the TA at the same day). The maximum intracavernous pressure (ICPmax ) and mean arterial pressure (MAP) of each group were evaluated 4 weeks after injection. The plaque formation, fibrosis, matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs (TIMPs) in the TA were evaluated. Four weeks after injection, USC-exo group showed more significantly enhanced ICPmax and ICPmax /MAP than PD group (p < .05). USC-exo could significantly ameliorate the TA fibrosis that could be associated with the inhibition of transdifferentiation of fibroblasts into myofibroblasts, decreased expression of TIMPs (TIMP-1, 2, 3) and increased activity of MMPs (MMP-1, 3, 9) in the TA. According to these findings, USC-exo can be a new candidate for the prevention of PD.
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Affiliation(s)
- Qiyun Yang
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wanmei Chen
- Department of Anesthesiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Dayu Han
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chi Zhang
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yun Xie
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiangzhou Sun
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guihua Liu
- Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Chunhua Deng
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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23
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DeBari MK, Abbott RD. Adipose Tissue Fibrosis: Mechanisms, Models, and Importance. Int J Mol Sci 2020; 21:ijms21176030. [PMID: 32825788 PMCID: PMC7503256 DOI: 10.3390/ijms21176030] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/15/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023] Open
Abstract
Increases in adipocyte volume and tissue mass due to obesity can result in inflammation, further dysregulation in adipose tissue function, and eventually adipose tissue fibrosis. Like other fibrotic diseases, adipose tissue fibrosis is the accumulation and increased production of extracellular matrix (ECM) proteins. Adipose tissue fibrosis has been linked to decreased insulin sensitivity, poor bariatric surgery outcomes, and difficulty in weight loss. With the rising rates of obesity, it is important to create accurate models for adipose tissue fibrosis to gain mechanistic insights and develop targeted treatments. This article discusses recent research in modeling adipose tissue fibrosis using in vivo and in vitro (2D and 3D) methods with considerations for biomaterial selections. Additionally, this article outlines the importance of adipose tissue in treating other fibrotic diseases and methods used to detect and characterize adipose tissue fibrosis.
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Affiliation(s)
- Megan K. DeBari
- Department of Materials Science and Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA;
| | - Rosalyn D. Abbott
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Correspondence:
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24
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Hu D, Zhang D, Liu B, Liu Y, Zhou Y, Yu Y, Shen L, Long C, Zhang D, Liu X, Lin T, He D, Xu T, Timashev P, Butnaru D, Zhang Y, Wei G. Human ucMSCs seeded in a decellularized kidney scaffold attenuate renal fibrosis by reducing epithelial-mesenchymal transition via the TGF-β/Smad signaling pathway. Pediatr Res 2020; 88:192-201. [PMID: 31896126 DOI: 10.1038/s41390-019-0736-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 09/28/2019] [Accepted: 10/02/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Renal fibrosis occurs largely through epithelial-mesenchymal transition (EMT). This study explored the beneficial effects of a human umbilical cord mesenchymal stem cell-loaded decellularized kidney scaffold (ucMSC-DKS) on renal fibrosis in a rodent model of post-transplantation renal failure, and the underlying mechanism. METHODS Rat-derived DKSs were examined after preparation, and then recellularized with human ucMSCs to prepare cell-loaded patches. A rat model of renal failure was established after subtotal nephrectomy (STN). The cell patches were transplanted to remnant kidneys. Changes in renal function, histology, EMT, and proteins related to the transforming growth factor-β (TGF-β)/Smad signaling pathway in the remnant kidneys were examined 8 weeks after surgery, compared with non-cell patch controls. RESULTS The DKSs were acellular and porous, with rich cytokine and major extracellular matrix components. The ucMSCs were distributed uniformly in the DKSs. Renal function was improved, renal fibrosis and EMT were reduced, and the TGF-β/Smad signaling pathway was inhibited compared with controls at 8 weeks after ucMSC-DKS patch transplantation. CONCLUSIONS The ucMSC-DKS restores renal function and reduces fibrosis by reducing EMT via the TGF-β/Smad signaling pathway in rats that have undergone STN. It provides an alternative for renal fibrosis treatment.
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Affiliation(s)
- Dong Hu
- Department of Urology, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.,Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.,Department of Pediatric Surgery, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, 611731, Chengdu, China
| | - Deying Zhang
- Department of Urology, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China. .,Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.
| | - Bo Liu
- Department of Urology, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.,Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Yang Liu
- Department of Radiology, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China
| | - Yu Zhou
- Department of Urology, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.,Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Yihang Yu
- Department of Urology, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.,Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Lianju Shen
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Chunlan Long
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Dan Zhang
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Xing Liu
- Department of Urology, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.,Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Tao Lin
- Department of Urology, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.,Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Dawei He
- Department of Urology, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.,Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Tao Xu
- Bio-manufacturing Center, Department of Mechanical Engineering, Tsinghua University, 100084, Beijing, China
| | - Peter Timashev
- Institute for Regenerative Medicine, Sechenov University, 8-2 Trubetskaya Street, 119991, Moscow, Russia
| | - Denis Butnaru
- Research Institute for Uronephrology, Sechenov First Moscow State Medical University, 119991, Moscow, Russia
| | - Yuanyuan Zhang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27101, USA
| | - Guanghui Wei
- Department of Urology, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China. .,Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.
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25
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Hirudin Ameliorates Renal Interstitial Fibrosis via Regulating TGF- β1/Smad and NF- κB Signaling in UUO Rat Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:7291075. [PMID: 32714415 PMCID: PMC7336220 DOI: 10.1155/2020/7291075] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 05/20/2020] [Accepted: 06/05/2020] [Indexed: 12/12/2022]
Abstract
Purpose Hirudin, a polypeptide structure containing 65 amino acids, is a potent natural thrombin inhibitor with anticoagulant property extracted from Hirudo medicinalis. It has been reported to have anti-inflammatory and antifibrotic property. Here we explored the renoprotective effect of hirudin on unilateral ureteral obstruction (UUO) induced renal interstitial fibrosis (RIF). Methods Rats were randomly divided into five groups: sham group, UUO alone group, and three UUO + hirudin-treatment groups (10, 20, or 40 IU/kg/d, for 14 continuous days). At the end of the experiment period, animals were sacrificed. Pathologic changes in renal specimens were observed using hematoxylin and eosin (HE) staining and Masson staining. The expressions of collagen III (Col III), fibronectin (FN), α-smooth muscle actin (α-SMA), protease-activated receptor 1 (PAR-1), and proteins in the TGF-β1/Smad and NF-κB pathways in renal tissues were examined by immunohistochemistry and/or Western blotting. Results HE and Masson staining showed that hirudin-treated UUO rats had lower extent of renal injury and deposition of extracellular matrix (ECM) in renal interstitium than those in the UUO group. The results of immunohistochemistry and WB indicated decreased protein expressions of Col III, FN, α-SMA, PAR-1, and inflammatory markers such as tumor necrosis factor-α and interleukin-6 after hirudin treatment. Furthermore, hirudin reduced the expressions of transforming growth factor β1 (TGF-β1), phosphorylated-Smad2, and phosphorylated-Smad3 in the UUO model. In parallel, we found inhibited nuclear factor-κB (NF-κB) signaling after hirudin treatment, with downregulated protein expressions of P65, phosphorylated-P65, and phosphorylated-iκBα and increased iκBα. Conclusion Hirudin improves kidney injury and suppresses inflammatory response and ECM accumulation in UUO rats; its underlying mechanism may be associated with the inhibition of TGF-β1/Smad and NF-κB signaling.
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26
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Siregar S, Noegroho BS, Karim MI. The effect of intravenous human adipose-derived stem cells (hADSC) on transforming growth factor β1 (TGF-β1), collagen type 1, and kidney histopathological features in the unilateral ureteropelvic junction obstruction model of wistar rats. Turk J Urol 2020; 46:236-242. [PMID: 32401706 DOI: 10.5152/tud.2020.20024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 04/06/2020] [Indexed: 11/22/2022]
Abstract
OBJECTIVE The fibrotic process of kidney resulting in glomerulosclerosis was found in patients with ureteropelvic junction obstruction (UPJO) who underwent renal biopsy during pyeloplasty. Transforming growth factor β1 (TGF-β1) plays a role in collagen accumulation, resulting in fibrosis. Adipose tissue-derived stem cells (ADSCs) have an anti-apoptotic effect on target cells and enhance the kidney function recovery. We will further investigate the use of ADSC in the prevention of kidney fibrosis in the unilateral UPJO model of Wistar rats. MATERIAL AND METHODS A total of twenty-two 12-week-old Wistar rats were divided into three groups. We made the UPJO models using nylon 6-0 inside the left ureter and tied the ureter with nylon 6-0, creating partial ureteral obstruction. The treatment group was then injected with 1.0 × 106 cells of human ADSC via the tail vein of rats. All rats were euthanized after 2 and 4 weeks of treatment. The left kidney used hematoxylin-eosin for histopathological examination. Statistical analysis using one-way analysis of variance (ANOVA) was done with SPSS version 21.0. RESULTS TGF-β1 concentration in the treatment group was significantly lower in the 4th week of observation (p4=0.0001), as well as collagen type 1, which was also significantly lower in the 4th week (p4=0.0001). There was a significant difference in the glomerulus count between the control group and the human ADSC (hADSC) group therapy in week 2 and week 4 (p2=0.0001 and p4=0.026). CONCLUSION Administration of hADSC therapy reduces TGF-β1 and collagen type 1 levels and then improves the histopathological features in the process of renal fibrosis in the UPJO model.
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Affiliation(s)
- Safendra Siregar
- Department of Urology, Faculty of Medicine Universitas Padjadjaran, Dr. Hasan Sadikin General Hospital, Indonesia
| | - Bambang Sasongko Noegroho
- Department of Urology, Faculty of Medicine Universitas Padjadjaran, Dr. Hasan Sadikin General Hospital, Indonesia
| | - Muhammad Ilhamul Karim
- Department of Urology, Faculty of Medicine Universitas Padjadjaran, Dr. Hasan Sadikin General Hospital, Indonesia
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27
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Ali EMT, Abdallah HI, El-Sayed SM. Histomorphological, VEGF and TGF-β immunoexpression changes in the diabetic rats' ovary and the potential amelioration following treatment with metformin and insulin. J Mol Histol 2020; 51:287-305. [PMID: 32399705 DOI: 10.1007/s10735-020-09880-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/05/2020] [Indexed: 12/29/2022]
Abstract
Diabetes mellitus (DM) affects the ovary by reducing the number and diameters of ovarian follicles and increasing atretic follicles. Follicular growth and diameters depend on VEGF production. Hyperglycemia causes ovarian stromal and follicular degeneration then fibrosis by activating TGF-β. Insulin and metformin promote development of ovarian follicles and reduce atretic follicles. Therefore, the present study investigates the ovarian VEGF and TGF-β immune-expression and its variations in diabetic, insulin and metformin-treated rats. Forty adult female albino rats were divided equally into four groups: control, diabetic (STZ-induced diabetes), diabetic metformin-treated group (100 mg/kg/day orally/eight weeks) and diabetic insulin-treated group (5 U insulin /day). Ovarian sections were stained with hematoxylin and eosin, Masson's trichrome, immunohistochemistry for VEGF and TGF-β. The diabetic group showed noticeable atrophic and degenerative changes in cortex and medulla as well as increased density and distribution of the collagenous fibers. The number and diameter of primary, secondary and tertiary follicles were decreased. However, the number of atretic follicles and corpus luteum was increased. Significant decrease in the surface area percentage of VEGF immuno-expression and significant increase in TGF-β immuno-expression surface area percentage were detected. By treating animals with metformin and insulin, there was restoration of the ovarian histological structure more or less as in control. DM negatively affects the histological and morphometric parameters of ovaries. Furthermore, insulin showed more beneficial effects than metformin in hindering these complications by modifying the expression of VEGF and TGF-β.
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Affiliation(s)
- Eyad M T Ali
- Department of Anatomy, Faculty of medicine, Taibah University, Madinah, Kingdom of Saudi Arabia. .,Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
| | - Hesham I Abdallah
- Department of Anatomy, Faculty of medicine, Taibah University, Madinah, Kingdom of Saudi Arabia.,Department of Anatomy, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sayed M El-Sayed
- Department of Anatomy, Faculty of medicine, Taibah University, Madinah, Kingdom of Saudi Arabia.,Department of Anatomy, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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28
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Zhou T, Li HY, Liao C, Lin W, Lin S. Clinical Efficacy and Safety of Mesenchymal Stem Cells for Systemic Lupus Erythematosus. Stem Cells Int 2020; 2020:6518508. [PMID: 32322279 PMCID: PMC7157802 DOI: 10.1155/2020/6518508] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 02/02/2020] [Accepted: 02/29/2020] [Indexed: 02/05/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a polymorphic, multisystemic autoimmune disease that causes multiorgan damage in which cellular communication occurs through the involvement of autoantibodies directed against autoantigen production. Mesenchymal stem cells (MSCs), which have strong protective and immunomodulatory abilities, are obtained not only from bone marrow but also from medical waste such as adipose tissue and umbilical cord tissue and have been recognized as a promising tool for the treatment of various autoimmune diseases and inflammatory disorders. This meta-analysis is aimed at assessing whether MSCs can become a new treatment for SLE with good efficacy and safety. Based on predetermined criteria, a bibliographical search was performed from January 1, 2000, to July 31, 2019, by searching the following databases: ISI Web of Science, Embase, PubMed, the Cochrane Library, and the Chinese Biomedical Literature Database (CBM). Eligible studies and data were identified. Statistical analysis was conducted to assess the efficacy (proteinuria, systemic lupus erythematosus disease activity index (SLEDAI), Scr, BUN, albumin, C3, and C4) and safety (rate of adverse events) of MSCs for SLE using Cochrane Review Manager Version 5.3. Ten studies fulfilled the inclusion criteria and were eligible for this meta-analysis, which comprised 8 prospective or retrospective case series and four randomized controlled trails (RCTs) studies. In the RCT, the results indicated that the MSC group had lower proteinuria than the control group at 3 months and 6 months and the MSC group displayed a lower SLEDAI than the control group at 2 months and 6 months. Furthermore, the MSC group showed a lower rate of adverse events than the control group (OR = 0.26, 95% CI: 0.07, 0.89, P = 0.03). In the case series trials, the results indicated that the MSC group had lower proteinuria at 1 month, 2 months, 3 months, 4 months, 6 months, and 12 months. In conclusion, MSCs might be a promising therapeutic agent for patients with SLE.
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Affiliation(s)
- Tianbiao Zhou
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China
| | - Hong-Yan Li
- Department of Nephrology, Huadu District People's Hospital of Guangzhou, Southern Medical University, 510800 Guangzhou, China
| | - Chunling Liao
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China
| | - Wenshan Lin
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China
| | - Shujun Lin
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China
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Song Y, Lv S, Wang F, Liu X, Cheng J, Liu S, Wang X, Chen W, Guan G, Liu G, Peng C. Overexpression of BMP‑7 reverses TGF‑β1‑induced epithelial‑mesenchymal transition by attenuating the Wnt3/β‑catenin and TGF-β1/Smad2/3 signaling pathways in HK‑2 cells. Mol Med Rep 2019; 21:833-841. [PMID: 31974602 PMCID: PMC6947920 DOI: 10.3892/mmr.2019.10875] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 11/21/2019] [Indexed: 12/15/2022] Open
Abstract
Tubular epithelial cells undergoing epithelial-mesenchymal transition (EMT) is a crucial event in the progression of renal interstitial fibrosis (RIF). Bone morphogenetic protein-7 (BMP-7) has been reported to exhibit anti-fibrotic functions in various renal diseases. However, the function of BMP-7 in regulating EMT and the progression of RIF remains largely unknown. The aim of the present study was to examine the potential effect of BMP-7 on transforming growth factor β1 (TGF-β1)-induced EMT and the underlying mechanisms by which BMP-7 exerted its effects. Human renal proximal tubular epithelial cells (HK-2) were treated with TGF-β1 for various time periods and at various concentrations and lentiviral vectors were used to overexpress BMP-7. Cell Counting Kit-8 and Transwell assays were used to evaluate the viability and migration of HK-2 cells in vitro. EMT was estimated by assessing the changes in cell morphology and the expression of EMT markers. In addition, the activation of the Wnt3/β-catenin and TGF-β1/Smad2/3 signaling pathways were analyzed using western blotting. TGF-β1 induced EMT in a time- and dose-dependent manner in HK-2 cells. Treatment with TGF-β1 induced morphological changes, decreased cell viability and the expression of E-cadherin, increased cell migration and the expression of α-smooth muscle actin, fibroblast-specific protein 1, collagen I and vimentin, and activated the Wnt3/β-catenin and TGF-β1/Smad2/3 signaling pathways in HK-2 cells. However, BMP-7 overexpression notably reversed all these effects. These results suggest that BMP-7 effectively suppresses TGF-β1-induced EMT through the inhibition of the Wnt3/β-catenin and TGF-β1/Smad2/3 signaling pathways, highlighting a potential novel anti-RIF strategy.
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Affiliation(s)
- Yan Song
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Shasha Lv
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Fang Wang
- Institute of Medical Sciences, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Xiaoli Liu
- Department of Hematology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Jing Cheng
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Shanshan Liu
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Xiaoying Wang
- Department of Pathology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Wei Chen
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, P.R. China
| | - Guangju Guan
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Gang Liu
- Department of Nephrology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Changliang Peng
- Department of Orthopedics, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
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Hu X, Huang X. Alleviation of Inflammatory Response of Pulmonary Fibrosis in Acute Respiratory Distress Syndrome by Puerarin via Transforming Growth Factor (TGF-β1). Med Sci Monit 2019; 25:6523-6531. [PMID: 31471534 PMCID: PMC6738016 DOI: 10.12659/msm.915570] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 04/13/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) in infants is acute and progressive hypoxic respiratory failure caused by various extrapulmonary pathogenic factors besides cardiogenic factors. Diffuse alveolar injury and progression to pulmonary fibrosis are pathological features of ARDS. The present study sought to determine how puerarin influences the inflammatory response caused by pulmonary fibrosis in ARDS in infants. MATERIAL AND METHODS The human lung fibroblasts cell line HLF1 was treated with different concentrations of puerarin in different groups for various times. TGF-ß1 was overexpressed by TGF-ß1 (2 ng/mL) in routine experiments, and the treated cells and culture supernatant were collected for analysis in each step. Cell apoptosis was measured by flow cytometry, TUNEL assay, and detection of caspase 3 and Bcl-2. Cell proliferation was assessed by CCK-8 assay. Real-time PCR and Western blot assay were used to assess mRNA and protein levels of TGF-ß1 and Smad3, respectively. The related cytokines were assessed by ELISA. RESULTS Results showed that puerarin promoted the apoptosis and inhibited the proliferation of HLF1 cells. Caspase 3 was upregulated, whereas Bcl-2, TGF-ß1, and Smad3 were downregulated by puerarin. IL-1, IL-2, and IL-4, secreted by HLF1 cells, were reduced, but IL-10 showed the opposite trend. When TGF-ß1 was overexpressed, Smad3 was promoted, and IL-1, IL-2, and IL-4 was increased in HLF1 cells. Finally, overexpression of TGF-ß1 reversed the effect of puerarin in HLF1 cells. CONCLUSIONS Puerarin regulated the proliferation and apoptosis of pulmonary fibrosis cells, and affected the secretion of inflammatory cytokines. Thus, puerarin alleviated the inflammatory response resulting from pulmonary fibrosis by regulating the TGF-ß1/Smad3 pathway in infants with ARDS.
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Affiliation(s)
- Xiaoming Hu
- Department of Neonatology, Children’s Hospital of Capital Institute of Pediatrics, Beijing, P.R. China
| | - Xiaolan Huang
- Experimental Center of the Capital Institute of Pediatrics, Beijing, P.R. China
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Liguori TTA, Liguori GR, Moreira LFP, Harmsen MC. Adipose tissue-derived stromal cells' conditioned medium modulates endothelial-mesenchymal transition induced by IL-1β/TGF-β2 but does not restore endothelial function. Cell Prolif 2019; 52:e12629. [PMID: 31468648 PMCID: PMC6869467 DOI: 10.1111/cpr.12629] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 04/03/2019] [Indexed: 12/12/2022] Open
Abstract
Objectives Endothelial cells undergo TGF‐β–driven endothelial‐mesenchymal transition (EndMT), representing up to 25% of cardiac myofibroblasts in ischaemic hearts. Previous research showed that conditioned medium of adipose tissue–derived stromal cells (ASC‐CMed) blocks the activation of fibroblasts into fibrotic myofibroblasts. We tested the hypothesis that ASC‐CMed abrogates EndMT and prevents the formation of adverse myofibroblasts. Materials and methods Human umbilical vein endothelial cells (HUVEC) were treated with IL‐1β and TGF‐β2 to induce EndMT, and the influence of ASC‐CMed was assessed. As controls, non‐treated HUVEC or HUVEC treated only with IL‐1β in the absence or presence of ASC‐CMed were used. Gene expression of inflammatory, endothelial, mesenchymal and extracellular matrix markers, transcription factors and cell receptors was analysed by RT‐qPCR. The protein expression of endothelial and mesenchymal markers was evaluated by immunofluorescence microscopy and immunoblotting. Endothelial cell function was measured by sprouting assay. Results IL‐1β/TGF‐β2 treatment induced EndMT, as evidenced by the change in HUVEC morphology and an increase in mesenchymal markers. ASC‐CMed blocked the EndMT‐related fibrotic processes, as observed by reduced expression of mesenchymal markers TAGLN (P = 0.0008) and CNN1 (P = 0.0573), as well as SM22α (P = 0.0501). The angiogenesis potential was impaired in HUVEC undergoing EndMT and could not be restored by ASC‐CMed. Conclusions We demonstrated that ASC‐CMed reduces IL‐1β/TGF‐β2‐induced EndMT as observed by the loss of mesenchymal markers. The present study supports the anti‐fibrotic effects of ASC‐CMed through the modulation of the EndMT process.
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Affiliation(s)
- Tácia Tavares Aquinas Liguori
- Laboratório de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Gabriel Romero Liguori
- Laboratório de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Luiz Felipe Pinho Moreira
- Laboratório de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Martin Conrad Harmsen
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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白 志, 陆 静, 杨 亦. [Role of TGF-β1/ILK/FSP1 signaling pathway in cyclosporin A-induced epithelialmesenchymal transition in cultured renal tubular epithelial cells]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2019; 39:804-809. [PMID: 31340913 PMCID: PMC6765554 DOI: 10.12122/j.issn.1673-4254.2019.07.09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To explore the role of transforming growth factor-β1/integrin-linked kinase/fibroblast-specific protein 1 (TGF- β1/ILK/FSP1) signaling pathway in cyclosporine A (CsA)-induced renal tubular epithelial cell transdifferentiation. METHODS Rat renal tubular epithelial NRK-52E cells were induced with 1 mg/L CsA, treated with TGF-β1 inhibitor (SB431542, 10 μmol/L), or transfected with the ILK-RNAi lentiviral expression vector (ILKshRNA) or a negative control vector before CsA induction. The expressions of TGF-β1, ILK and FSP-1 mRNAs and proteins in the cells were detected using real-time PCR and Western blotting. The positive cells for α-SMA expression were detected by immunohistochemistry. RESULTS Compared with the blank control cells, the cells treated with CsA showed significantly increased levels of TGF-β1, ILK and FSP-1 mRNAs and proteins (P < 0.05). The expressions of TGF-β1, ILK and FSP-1 were significantly lower in TGF-β1 inhibitor group than in CsA group (P < 0.05). The levels of ILK and FSP-1 were significantly decreased after shRNA-mediated ILK silencing (P < 0.05). The number of positive cells for α-SMA was significantly lower in cells treated with SB431542 and in cells with ILK silencing than in the cells treated with CsA alone (P < 0.05). CONCLUSIONS The activation of TGF-β1/ILK/FSP-1 signaling pathway is an important mechanism for CsA-induced transdifferentiation in rat renal tubular epithelial cells. ILK participates in CsA-induced epithelialmesenchymal transition of renal tubular epithelial cells.
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Affiliation(s)
- 志勋 白
- 遵义医科大学第二附属医院肾病风湿科，贵州 遵义 563000Department of Nephrology and Rheumatology, Second Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - 静 陆
- 遵义医药高等专科学校，贵州 遵义 563006Zunyi Medical and Pharmaceutical College, Zunyi 563006, China
| | - 亦彬 杨
- 遵义医科大学附属医院肾病风湿科，贵州 遵义 563006Department of Nephrology, Affiliated Hospital of Zunyi Medical University, Zunyi 563006, China
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Zhao S, Jiang JT, Li D, Zhu YP, Xia SJ, Han BM. Maternal exposure to di-n-butyl phthalate promotes Snail1-mediated epithelial-mesenchymal transition of renal tubular epithelial cells via upregulation of TGF-β1 during renal fibrosis in rat offspring. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 169:266-272. [PMID: 30453174 DOI: 10.1016/j.ecoenv.2018.10.073] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/17/2018] [Accepted: 10/20/2018] [Indexed: 05/26/2023]
Abstract
We previously demonstrated that maternal exposure to di-n-butyl phthalate (DBP) resulted in renal fibrosis in male offspring; however, the underlying mechanism governing this effect has not been thoroughly elucidated to date. We hypothesized that DBP exposure induces TGF-β expression and abnormal activation of epithelial-mesenchymal transition (EMT) in fibrotic kidneys. Pregnant rats received DBP orally at a dose of 850 mg/kg BW/day during gestational days 14-18. In the DBP-exposed group, immunohistochemistry (IHC) staining showed increased expression of TGF-β1 and EMT markers. In rat kidney tubular epithelial cells (NRK52E), ROS production increased expression levels of TGF-β1 and subsequently contributed to the induction of Snail1-mediated EMT. Notably, DBP exposure also promoted autophagy that downregulated TGF-β1. Taken together, our findings suggest that maternal exposure to DBP promotes EMT in tubular epithelial cells via upregulation of TGF-β1.
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Affiliation(s)
- Sheng Zhao
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Jun-Tao Jiang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Deng Li
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Yi-Ping Zhu
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Shu-Jie Xia
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Bang-Min Han
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
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Zhang G, Cui G, Tong S, Cao Q. Salvianolic acid A alleviates the renal damage in rats with chronic renal failure1. Acta Cir Bras 2019; 34:e201900204. [PMID: 30843937 PMCID: PMC6585911 DOI: 10.1590/s0102-8650201900204] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 01/11/2019] [Indexed: 01/19/2023] Open
Abstract
Purpose To investigate the protective effects of salvianolic acid A (SAA) on renal
damage in rats with chronic renal failure (CRF). Methods The five-sixth nephrectomy model of CRF was successfully established in
group CRF (10 rats) and group CRF+SAA (10 rats). Ten rats were selected as
sham-operated group (group S), in which only the capsules of both kidneys
were removed. The rats in group CRF+SAA were intragastrically administrated
with 10 mg/kg SAA for 8 weeks. The blood urine nitrogen (BUN), urine
creatinine (Ucr), creatinine clearance rate (Ccr), and serum uperoxide
dismutase (SOD) and malondialdehyde (MDA) were tested. The expressions of
transforming growth factor-β1 (TGF-β1), bone morphogenetic protein 7 (BMP-7)
and Smad6 protein in renal tissue were determined. Results After treatment, compared with group CRF, in group CRF+SAA the BUN, Scr,
serum MDA and kidney/body weight ratio were decreased, the Ccr and serum SOD
were increased, the TGF-β1 protein expression level in renal tissue was
decreased, and the BMP-7 and Smad6 protein levels were increased (all P <
0.05). Conclusion SAA can alleviate the renal damage in CRF rats through anti-oxidant stress,
down-regulation of TGF-β1 signaling pathway and up-regulation of BMP-7/Smad6
signaling pathway.
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Affiliation(s)
- Guangming Zhang
- Master, Department of Urology, Affiliated Hospital, Beihua University, China. Technical procedures, final approval
| | - Guanghua Cui
- Bachelor, Department of Urology, Affiliated Hospital of Beihua University, China. Acquisition of data, statistics analysis, final approval
| | - Shuangxi Tong
- Master, Department of Urology, Affiliated Hospital, Beihua University, China. Manuscript preparation, final approval
| | - Qingxian Cao
- Master, Department of Urology, Affiliated Hospital, Beihua University, China. Design of the study, critical revision, final approval
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Abstract
The number of individuals affected by acute kidney injury (AKI) and chronic kidney disease (CKD) is constantly rising. In light of the limited availability of treatment options and their relative inefficacy, cell based therapeutic modalities have been studied. However, not many efforts are put into safety evaluation of such applications. The aim of this study was to review the existing published literature on adverse events reported in studies with genetically modified cells for treatment of kidney disease. A systematic review was conducted by searching PubMed and EMBASE for relevant articles published until June 2018. The search results were screened and relevant articles selected using pre-defined criteria, by two researchers independently. After initial screening of 6894 abstracts, a total number of 97 preclinical studies was finally included for full assessment. Of these, 61 (63%) presented an inappropriate study design for the evaluation of safety parameters. Only 4 studies (4%) had the optimal study design, while 32 (33%) showed sub-optimal study design with either direct or indirect evidence of adverse events. The high heterogeneity of studies included regarding cell type and number, genetic modification, administration route, and kidney disease model applied, combined with the consistent lack of appropriate control groups, makes a reliable safety evaluation of kidney cell-based therapies impossible. Only a limited number of relevant studies included looked into essential safety-related outcomes, such as inflammatory (48%), tumorigenic and teratogenic potential (12%), cell biodistribution (82%), microbiological safety with respect to microorganism contamination and latent viruses' reactivation (1%), as well as overall well-being and animal survival (19%). In conclusion, for benign cell-based therapies, well-designed pre-clinical studies, including all control groups required and good manufacturing processes securing safety, need to be done early in development. Preferably, this should be performed side by side with efficacy evaluation and according to the official guidelines of leading health organizations.
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Zhuang Q, Ma R, Yin Y, Lan T, Yu M, Ming Y. Mesenchymal Stem Cells in Renal Fibrosis: The Flame of Cytotherapy. Stem Cells Int 2019; 2019:8387350. [PMID: 30766607 PMCID: PMC6350586 DOI: 10.1155/2019/8387350] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 11/27/2018] [Indexed: 12/24/2022] Open
Abstract
Renal fibrosis, as the fundamental pathological process of chronic kidney disease (CKD), is a pathologic extension of the normal wound healing process characterized by endothelium injury, myofibroblast activation, macrophage migration, inflammatory signaling stimulation, matrix deposition, and remodelling. Yet, the current method of treating renal fibrosis is fairly limited, including angiotensin-converting enzyme inhibition, angiotensin receptor blockade, optimal blood pressure control, and sodium bicarbonate for metabolic acidosis. MSCs are pluripotent adult stem cells that can differentiate into various types of tissue lineages, such as the cartilage (chondrocytes), bone (osteoblasts), fat (adipocytes), and muscle (myocytes). Because of their many advantages like ubiquitous sources, convenient procurement and collection, low immunogenicity, and low adverse effects, with their special identification markers, mesenchymal stem MSC-based therapy is getting more and more attention. Based on the mechanism of renal fibrosis, MSCs mostly participate throughout the renal fibrotic process. According to the latest and overall literature reviews, we aim to elucidate the antifibrotic mechanisms and effects of diverse sources of MSCs on renal fibrosis, assess their efficacy and safety in preliminarily clinical application, answer the controversial questions, and provide novel ideas into the MSC cellular therapy of renal fibrosis.
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Affiliation(s)
- Quan Zhuang
- Transplantation Center of The 3rd Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
- Research Center of National Health Ministry on Transplantation Medicine, Changsha, Hunan 410013, China
| | - Ruoyu Ma
- Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Yanshuang Yin
- Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Tianhao Lan
- Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Meng Yu
- Transplantation Center of The 3rd Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
- Research Center of National Health Ministry on Transplantation Medicine, Changsha, Hunan 410013, China
| | - Yingzi Ming
- Transplantation Center of The 3rd Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
- Research Center of National Health Ministry on Transplantation Medicine, Changsha, Hunan 410013, China
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Marcheque J, Bussolati B, Csete M, Perin L. Concise Reviews: Stem Cells and Kidney Regeneration: An Update. Stem Cells Transl Med 2018; 8:82-92. [PMID: 30302937 PMCID: PMC6312445 DOI: 10.1002/sctm.18-0115] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 08/03/2018] [Indexed: 02/06/2023] Open
Abstract
Significant progress has been made to advance stem cell products as potential therapies for kidney diseases: various kinds of stem cells can restore renal function in preclinical models of acute and chronic kidney injury. Nonetheless this literature contains contradictory results, and for this reason, we focus this review on reasons for apparent discrepancies in the literature, because they contribute to difficulty in translating renal regenerative therapies. Differences in methodologies used to derive and culture stem cells, even those from the same source, in addition to the lack of standardized renal disease animal models (both acute and chronic), are important considerations underlying contradictory results in the literature. We propose that harmonized rigorous protocols for characterization, handling, and delivery of stem cells in vivo could significantly advance the field, and present details of some suggested approaches to foster translation in the field of renal regeneration. Our goal is to encourage coordination of methodologies (standardization) and long‐lasting collaborations to improve protocols and models to lead to reproducible, interpretable, high‐quality preclinical data. This approach will certainly increase our chance to 1 day offer stem cell therapeutic options for patients with all‐too‐common renal diseases. Stem Cells Translational Medicine2019;8:82–92
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Affiliation(s)
- Julia Marcheque
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Children's Hospital Los Angeles, Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, California
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
| | - Marie Csete
- Medical Engineering, California Institute of Technology, Los Angeles, California.,Department of Anesthesiology, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Laura Perin
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Children's Hospital Los Angeles, Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, California
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Luo J, Zhao S, Wang J, Luo L, Li E, Zhu Z, Liu Y, Kang R, Zhao Z. Bone marrow mesenchymal stem cells reduce ureteral stricture formation in a rat model via the paracrine effect of extracellular vesicles. J Cell Mol Med 2018; 22:4449-4459. [PMID: 29993184 PMCID: PMC6111875 DOI: 10.1111/jcmm.13744] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 05/18/2018] [Indexed: 02/06/2023] Open
Abstract
With no effective therapy to prevent or treat ureteral stricture (US), a multifactorial fibrotic disease after iatrogenic injury of the ureter, the need for new therapies is urgent. Mesenchymal stem cells (MSCs) have been widely studied for treating tissue defects and excessive fibrosis, and recent studies established that one of the main therapeutic vectors of MSCs is comprised in their secretome and represented by extracellular vesicles (EVs). Thus, we have determined to explore the specific role of MSCs‐derived EVs (MSC‐EVs) treatment in a pre‐clinical model of US. The results firstly showed that either a bolus dose of MSCs or a bolus dose of MSC‐EVs (administration via renal‐arterial) significantly ameliorated ureteral fibrosis and recuperated ureter morphological development in a US rat model. We confirmed our observations through MSCs or MSC‐EVs treatment alleviated hydronephrosis, less renal dysfunction and blunted transforming growth factor‐β1 induced fibration. Due to MSC‐EVs are the equivalent dose of MSCs, and similar curative effects of transplantation of MSCs and MSC‐EVs were observed, we speculated the curative effect of MSCs in treating US might on account of the release of EVs through paracrine mechanisms. Our study demonstrated an innovative strategy to counteract ureteral stricture formation in a rat model of US.
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Affiliation(s)
- Jintai Luo
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shankun Zhao
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiamin Wang
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lianmin Luo
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ermao Li
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhiguo Zhu
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yangzhou Liu
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ran Kang
- Department of Urology, The First Affiliated Hospital of University of South China, Hengyang, China
| | - Zhigang Zhao
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Wang D, Wang W, Liang Q, He X, Xia Y, Shen S, Wang H, Gao Q, Wang Y. DHEA-induced ovarian hyperfibrosis is mediated by TGF-β signaling pathway. J Ovarian Res 2018; 11:6. [PMID: 29321035 PMCID: PMC5763573 DOI: 10.1186/s13048-017-0375-7] [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: 07/14/2017] [Accepted: 12/22/2017] [Indexed: 01/17/2023] Open
Abstract
Background The polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder with pathological mechanisms remain unclear. The following study investigates the ovarian hyperfibrosis forming via transforming growth factor-β (TGF-β) signaling pathway in Dehydroepiandrosterone (DHEA)- induced polycystic ovary syndrome (PCOS) rat model. We furthermore explored whether TGF-βRI inhibitor (SB431542) decreases ovarian fibrosis by counterbalancing the expression of fibrotic biomarkers. Methods Thirty female Sprague-Dawley rats were randomly divided into Blank group (n = 6), Oil group (n = 6), and Oil + DHEA-induced model group (n = 6 + 12). The model groups were established by subcutaneous injection of DHEA for 35 consecutive days. The 12 successful model rats were additionally divided in vehicle group (n = 6) and SB431542-treated group (n = 6). Vehicle group and SB431542-treated group, served as administration group and were intraperitoneally injected with DMSO and SB431542 for additional 14 consecutive days. Ovarian morphology, fibrin and collagen localization and expression in ovaries were detected using H&E staining, immunohistochemistry and Sirius red staining. The ovarian protein and RNA were examined using Western blot and RT-PCR. Results In DHEA-induced ovary in rat, fibrin and collagen had significantly higher levels, while the main fibrosis markers (TGF-β, CTGF, fibronectin, a-SMA) were obviously upregulated. SB431542 significantly reduced the expression of pro-fibrotic molecules (TGF-β, Smad3, Smad2, a-SMA) and increased anti-fibrotic factor MMP2. Conclusion TGF-βRI inhibitor (SB431542) inhibits the downstream signaling molecules of TGF-β and upregulates MMP2, which in turn prevent collagen deposition. Moreover, ovarian hyperfibrosis in DHEA-induced PCOS rat model could be improved by TGF-βRI inhibitor (SB431542) restraining the transcription of accelerating fibrosis genes and modulating EMT mediator. Electronic supplementary material The online version of this article (10.1186/s13048-017-0375-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Daojuan Wang
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Wenqing Wang
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Qiao Liang
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Xuan He
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Yanjie Xia
- Prenatal Diagnosis Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Shanmei Shen
- Divisions of Endocrinology, the Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210093, China
| | - Hongwei Wang
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Qian Gao
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Yong Wang
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China.
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