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Srinivasan D, Subbarayan R, Krishnan M, Balakrishna R, Adtani P, Shrestha R, Chauhan A, Babu S, Radhakrishnan A. Radiation therapy-induced normal tissue damage: involvement of EMT pathways and role of FLASH-RT in reducing toxicities. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2025; 64:1-16. [PMID: 39760753 DOI: 10.1007/s00411-024-01102-2] [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: 01/22/2024] [Accepted: 12/20/2024] [Indexed: 01/07/2025]
Abstract
Radiation therapy (RT) is fundamental to the fight against cancer because of its exceptional ability to target and destroy cancer cells. However, conventional radiation therapy can significantly affect the adjacent normal tissues, leading to fibrosis, inflammation, and decreased organ function. This tissue damage not only reduces the quality of life but also prevents the total elimination of cancer. The transformation of epithelial cells into mesenchymal-like cells, termed epithelial-mesenchymal transition (EMT), is essential for processes such as fibrosis, embryogenesis, and wound healing. Conventional radiation therapy increases the asymmetric activation of fibrotic and inflammatory pathways, and the resulting chronic fibrotic changes and organ dysfunction are linked to radiation-induced epithelial-mesenchymal transition. Recent advances in radiation therapy, namely flash radiation therapy (FLASH-RT), have the potential to widen the therapeutic index. Radiation delivered by FLASH-RT at very high dose rates (exceeding 40 Gy/s) can protect normal tissue from radiation-induced damage, a phenomenon referred to as the "FLASH effect". Preclinical studies have demonstrated that FLASH-RT successfully inhibits processes associated with fibrosis and epithelial-mesenchymal transition, mitigates damage to normal tissue, and enhances regeneration. Three distinct types of EMT have been identified: type-1, associated with embryogenesis; Type-2, associated with injury potential; and type-3, related with cancer spread. The regulation of EMT via pathways, including TGF-β/SMAD, WNT/β-catenin, and NF-κB, is essential for radiation-induced tissue remodelling. This study examined radiation-induced EMT, TGF-β activity, multiple signalling pathways in fibrosis, and the potential of FLASH-RT to reduce tissue damage. FLASH-RT is a novel approach to treat chronic tissue injury and fibrosis post-irradiation by maintaining epithelial properties and regulating mesenchymal markers including vimentin and N-cadherin. Understanding these pathways will facilitate the development of future therapies that can alleviate fibrosis, improve the efficacy of cancer therapy, and improve the quality of life of patients.
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Affiliation(s)
- Dhasarathdev Srinivasan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India
| | - Rajasekaran Subbarayan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India.
- Centre for Herbal Pharmacology and Environmental Sustainability, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India.
| | - Madhan Krishnan
- Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India
| | - Ranjith Balakrishna
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India
| | - Pooja Adtani
- Department of Basic Medical and Dental Sciences, Gulf Medical University, Ajman, United Arab Emirates
| | - Rupendra Shrestha
- Department of Natural and Applied Sciences, Nexus Institute of Research and Innovation (NIRI), Lalitpur, Nepal.
| | - Ankush Chauhan
- Centre for Herbal Pharmacology and Environmental Sustainability, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India
| | - Shyamaladevi Babu
- Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India
| | - Arunkumar Radhakrishnan
- Department of Pharmacology, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
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Yu W, Chen S, Guan X, He G, Zhang W, Zhang H, Huang S, Ye Z, Pan H, Zhong Z. Yiqi Huayu Jiedu formula inhibits JAK2/STAT3-mediated partial EMT in treating chronic atrophic gastritis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 137:156356. [PMID: 39799895 DOI: 10.1016/j.phymed.2024.156356] [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: 05/05/2024] [Revised: 12/26/2024] [Accepted: 12/28/2024] [Indexed: 01/15/2025]
Abstract
BACKGROUND Chronic atrophic gastritis (CAG) is a precursor to gastric cancer, a leading cause of cancer-related deaths worldwide. Despite current therapeutic strategies, preventing the transition from gastritis to cancer remains a challenge. Traditional Chinese Medicine (TCM), particularly the Yiqi-Huayu-Jiedu (YQHYJD) formula, have exhibited promising results in CAG management. However, the pharmacological underpinnings of this formula remain elusive. PURPOSE The study aimed to elucidate the pharmacological mechanisms of the YQHYJD formula in treating CAG and its role in inhibiting the progression to gastric cancer through the modulation of the "inflammation-cancer" sequence. METHODS Mass spectrometric analysis of YQHYJD formula-containing serum was conducted to determine the active compounds involved in CAG treatment. A CAG rat model was induced using a combination of deoxycholic acid and ammonia, while a gastric precancerous lesion cell model was generated by exposing GES-1 cells to deoxycholic acid. Both models were treated with varying concentrations of the YQHYJD formula to assess its effects of the JAK2/STAT3 signaling-mediated epithelial-mesenchymal transition (EMT) pathway. RESULTS Mass spectrometry analysis identified 80 active compounds in the YQHYJD formula, including quercetin. Network pharmacology analysis revealed that these active compounds may exert their therapeutic effects on CAG through various mechanisms, including the JAK/STAT signaling. Using rat and cellular models of CAG, we found that the JAK/STAT pathway is activated alongside partial epithelial-mesenchymal transition (pEMT). YQHYJD treatment effectively mitigated the activation of the JAK2/STAT3 activation and pEMT. Furthermore, the therapeutic effect of the YQHYJD formula was maintained even in the presence of Colivelin or overexpressed STAT3. CONCLUSIONS The YQHYJD formula treats CAG by inhibiting the JAK2/STAT3 -mediated pEMT, thereby suppressing the gastric "inflammation-cancer" transformation. This study provides mechanistic insights into the efficacy of YQHYJD in CAG treatment and suggests new therapeutic strategies for preventing gastric cancer development.
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Affiliation(s)
- Weifeng Yu
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences/State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China; Department of Gastroenterology, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China
| | - Shuni Chen
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences/State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China; Department of Spleen and Stomach Diseases, Shenzhen Hospital of Beijing University of Chinese Medicine (Longgang), Shenzhen, China
| | - Xiuming Guan
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences/State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China
| | - Guihua He
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences/State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China
| | - Wang Zhang
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences/State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China
| | - Haiyan Zhang
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences/State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China
| | - Suiping Huang
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences/State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China
| | - Zhenhao Ye
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences/State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China.
| | - Hudan Pan
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences/State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China.
| | - Zishao Zhong
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences/State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China; Guangdong Provincial Key laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, Guangzhou, China.
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Wanjiru DK, Niyonzima YB, Kadokawa H. Lower expression of colony-stimulating factor 2, an embryokine, in the endometrial epithelium of old cows. Reprod Fertil Dev 2025; 37:RD24163. [PMID: 39951370 DOI: 10.1071/rd24163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 01/30/2025] [Indexed: 02/16/2025] Open
Abstract
Context Infertility increases with age in various animals, including cows, owing to unknown mechanisms. The glandular and luminal epithelia of the bovine uterus synthesise and secrete colony-stimulating factor 2 (CSF2), which is a well-studied embryokine. We recently reported the possibility of fibrosis in the uteri of old cows. However, the relationship between CSF2 expression and fibrosis has not yet been clarified. Aims We tested the hypothesis that the endometrial epithelia of old cows have lower CSF2 expression compared to in heifers, and that myofibroblasts [alpha-smooth muscle actin (αSMA)-positive fibroblasts] increase near the epithelium of old cows. Methods We collected caruncle and intercaruncle samples from post-pubertal, growing, nulliparous heifers (n =6; 24.7±1.3months old) and old multiparous cows (n =6; 128.5±15.4months old). We analysed mRNA and protein expression, along with fluorescent immunohistochemistry for CSF2, anti-collagen type IV, anti-Müllerian hormone type 2 receptor, and anti-αSMA. Key results Quantitative reverse transcription polymerase chain reaction and western blot analysis revealed lower CSF2 expression in the caruncle and intercaruncle of old cows than in young heifers. Fluorescence microscopy using the same antibodies and anti-collagen type IV, anti-Müllerian hormone type 2 receptor, and anti-αSMA antibodies showed increased fibroblasts and αSMA signals near the epithelium of old cows compared to young heifers. Conclusion CSF2 expression was lower in endometrial epithelia of old cows compared to those in heifers, and myofibroblasts increased near the epithelia of old cows. Implications Lower CSF2 may play an important role in age-related infertility.
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Affiliation(s)
- Denis Karani Wanjiru
- Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi-shi, Yamaguchi-ken 1677-1, Japan
| | - Yvan Bienvenu Niyonzima
- Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi-shi, Yamaguchi-ken 1677-1, Japan
| | - Hiroya Kadokawa
- Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi-shi, Yamaguchi-ken 1677-1, Japan
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Lu C, Liu Y, Ren F, Zhang H, Hou Y, Zhang H, Chen Z, Du X. HO-1: An emerging target in fibrosis. J Cell Physiol 2025; 240:e31465. [PMID: 39420552 DOI: 10.1002/jcp.31465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 09/08/2024] [Accepted: 09/30/2024] [Indexed: 10/19/2024]
Abstract
Fibrosis, an aberrant reparative response to tissue injury, involves a disruption in the equilibrium between the synthesis and degradation of the extracellular matrix, leading to its excessive accumulation within normal tissues, and culminating in organ dysfunction. Manifesting in the terminal stages of nearly all chronic ailments, fibrosis carries a high mortality rate and poses a significant threat to human health. Heme oxygenase-1 (HO-1) emerges as an endogenous protective agent, mitigating tissue damage through its antioxidant, anti-inflammatory, and antiapoptotic properties. Numerous studies have corroborated HO-1's potential as a therapeutic target in anti-fibrosis treatment. This review delves into the structural and functional attributes, and the upstream and downstream pathways of HO-1. Additionally, the regulatory networks and mechanisms of HO-1 in cells associated with fibrosis are elucidated. The role of HO-1 in various fibrosis-related diseases is also explored. Collectively, this comprehensive information serves as a foundation for future research and augments the viability of HO-1 as a therapeutic target for fibrosis.
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Affiliation(s)
- Chenxi Lu
- Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, China
| | - Yuan Liu
- Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, China
| | - Feifei Ren
- Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, China
| | - Haoran Zhang
- Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, China
| | - Yafang Hou
- Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, China
| | - Hong Zhang
- Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, China
| | - Zhiyong Chen
- Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, China
| | - Xia Du
- Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, China
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Karetnikova ES, Livanova AA, Fedorova AA, Markov AG. Early Radiation-Induced Changes in Lung Tissue and Intercellular Junctions: Implications for Tissue Repair and Fibrosis. PATHOPHYSIOLOGY 2024; 31:531-544. [PMID: 39449521 PMCID: PMC11503413 DOI: 10.3390/pathophysiology31040039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 09/13/2024] [Accepted: 09/21/2024] [Indexed: 10/26/2024] Open
Abstract
Early changes in lung tissue following ionizing radiation (IR) initiate processes that may lead to either regeneration or fibrosis. Intercellular junction proteins play a crucial role in the organization and function of epithelial tissues, both under normal conditions and after injuries. Alterations in the expression and localization of these proteins can influence the fate of epithelial cells. This study aims to investigate the effects of IR on lung tissue structure, as well as on the levels and distribution of intercellular junction proteins. Wistar rats were subjected to total X-ray irradiation at doses of 2 and 10 Gy. Lung tissue samples were collected for Western blot and histological analysis 72 h post-IR. IR at doses of 2 and 10 Gy led to structural changes in lung tissue and elevated levels of E-cadherin. The 10 Gy IR resulted in increased claudin-4 and occludin in lung parenchyma, decreased claudin-8 and claudin-12 in bronchial epithelium and endothelium, and suppression of apoptosis. Data evaluation indicated that alterations in the protein composition of intercellular junctions are essential processes in lung tissue at early stages after IR, and at least some of these alterations are associated with adaptation.
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Affiliation(s)
- Ekaterina S. Karetnikova
- Department of General Physiology, St. Petersburg State University, 199034 St. Petersburg, Russia
- Interoception Laboratory, Pavlov Institute of Physiology RAS, 199034 St. Petersburg, Russia
| | - Alexandra A. Livanova
- Department of General Physiology, St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Arina A. Fedorova
- Department of General Physiology, St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Alexander G. Markov
- Department of General Physiology, St. Petersburg State University, 199034 St. Petersburg, Russia
- Interoception Laboratory, Pavlov Institute of Physiology RAS, 199034 St. Petersburg, Russia
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Ni WJ, Li ZL, Wen XL, Ji JL, Liu H, Yin Q, Jiang LYZ, Zhang YL, Wen Y, Tang TT, Jiang W, Lv LL, Gan WH, Liu BC, Wang B. HIF-1α and adaptor protein LIM and senescent cell antigen-like domains protein 1 axis promotes tubulointerstitial fibrosis by interacting with vimentin in angiotensin II-induced hypertension. Br J Pharmacol 2024; 181:3098-3117. [PMID: 38698737 DOI: 10.1111/bph.16358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 01/03/2024] [Accepted: 02/05/2024] [Indexed: 05/05/2024] Open
Abstract
BACKGROUND AND PURPOSE Activation of the renin-angiotensin system, as a hallmark of hypertension and chronic kidney diseases (CKD) is the key pathophysiological factor contributing to the progression of tubulointerstitial fibrosis. LIM and senescent cell antigen-like domains protein 1 (LIMS1) plays an essential role in controlling of cell behaviour through the formation of complexes with other proteins. Here, the function and regulation of LIMS1 in angiotensin II (Ang II)-induced hypertension and tubulointerstitial fibrosis was investigated. EXPERIMENTAL APPROACH C57BL/6 mice were treated with Ang II to induce tubulointerstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) renal tubular-specific knockout mice or LIMS1 knockdown AAV was used to investigate their effects on Ang II-induced renal interstitial fibrosis. In vitro, HIF-1α or LIMS1 was knocked down or overexpressed in HK2 cells after exposure to Ang II. KEY RESULTS Increased expression of tubular LIMS1 was observed in human kidney with hypertensive nephropathy and in murine kidney from Ang II-induced hypertension model. Tubular-specific knockdown of LIMS1 ameliorated Ang II-induced tubulointerstitial fibrosis in mice. Furthermore, we demonstrated that LIMS1 was transcriptionally regulated by HIF-1α in tubular cells and that tubular HIF-1α knockout ameliorates LIMS1-mediated tubulointerstitial fibrosis. In addition, LIMS1 promotes Ang II-induced tubulointerstitial fibrosis by interacting with vimentin. CONCLUSION AND IMPLICATIONS We conclude that HIF-1α transcriptionally regulated LIMS1 plays a central role in Ang II-induced tubulointerstitial fibrosis through interacting with vimentin. Our finding represents a new insight into the mechanism of Ang II-induced tubulointerstitial fibrosis and provides a novel therapeutic target for progression of CKD.
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Affiliation(s)
- Wei-Jie Ni
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Zuo-Lin Li
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Xian-Li Wen
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jia-Ling Ji
- Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hong Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Qing Yin
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Liang-Yun-Zi Jiang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yi-Lin Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yi Wen
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Tao-Tao Tang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Wei Jiang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Lin-Li Lv
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Wei-Hua Gan
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Bin Wang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
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Liu F, Xu J, Li F, Ni W, Chen Z, Hou S, Ke S, Wang B. Resveratrol reinforces the therapeutic effect of mesenchymal stem cell (MSC)-derived exosomes against renal ischemia‒reperfusion injury (RIRI)-associated fibrosis by suppressing TGF-β-induced epithelial-mesenchymal transition. INTERNATIONAL JOURNAL OF CARDIOLOGY. CARDIOVASCULAR RISK AND PREVENTION 2024; 22:200242. [PMID: 39280777 PMCID: PMC11401501 DOI: 10.1016/j.ijcrp.2024.200242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 01/25/2024] [Accepted: 01/31/2024] [Indexed: 09/18/2024]
Abstract
Resveratrol (RSV) has been shown to prevent epithelial-mesenchymal transition (EMT) in different diseases by modulating several signaling pathways, and RSV can prevent EMT by modulating the signaling of the TGF-β/Smad axis. In the development of renal ischemia‒reperfusion injury (RIRI), RSV and MSC-derived exosomes could ameliorate RIRI via different signaling pathways. In this study, we aimed to investigate the effect of RSV plus MSC-derived exosomes on the prognosis of RIRI. Quantitative real-time polymerase chain reaction (PCR) was performed to measure the expression of E-CAD, SMA, COL10A1, VMT and MMP-7 mRNA in TCMK-1 cells and mice under various conditions. HE and Masson staining were used to evaluate kidney injury and fibrosis in mice under various conditions. RSV effectively maintained the TGF-β- and AA-induced upregulation of E-CAD, SMA, COL10A1, VMT and MMP-7 mRNA expression in TCMK-1 cells. Moreover, MSC-derived exosomes effectively reinforced the effect of RSV on reducing the TGF-β- and AA-induced upregulation of E-CAD, SMA, COL10A1, VMT and MMP-7 mRNA expression in TCMK-1 cells. Furthermore, MSC-derived exosomes enhanced the capability of RSV to maintain the RIRI-induced increases in Cr and BUN, as well as the upregulation of E-CAD, SMA, COL10A1, VMT and MMP-7 mRNA expression in mice. In addition, MSC-derived exosomes enhanced the capability of RSV to decrease RIRI-induced kidney injury and fibrosis in mice. Our findings showed that the administration of MSC-derived exosomes and RSV could suppress the TGF-β-induced epithelial-mesenchymal transition. This suppressive effect was promoted by the coadministration of MSC-derived exosomes and RSV.
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Affiliation(s)
- Fuhe Liu
- Pharmaceutical Department, Zhejiang Pharmaceutical College, Ningbo, Zhejiang, 315100, China
| | - Jinlong Xu
- Ningbo Yinzhou No.2 Hospital, Ningbo, Zhejiang, 315100, China
| | - Fen Li
- Huzhou Institute for Food and Drug Control, Huzhou, Zhejiang, 313000, China
| | - Wenjuan Ni
- Pharmaceutical Department, Zhejiang Pharmaceutical College, Ningbo, Zhejiang, 315100, China
| | - Ziwei Chen
- Pharmaceutical Department, Zhejiang Pharmaceutical College, Ningbo, Zhejiang, 315100, China
| | - Shanshan Hou
- Pharmaceutical Department, Zhejiang Pharmaceutical College, Ningbo, Zhejiang, 315100, China
| | - Shasha Ke
- Municipal Hospital Affiliated to Taizhou University, Taizhou, Zhejiang, 318000, China
| | - Binhui Wang
- Municipal Hospital Affiliated to Taizhou University, Taizhou, Zhejiang, 318000, China
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Solé C, Royo M, Sandoval S, Moliné T, Gabaldón A, Cortés-Hernández J. Precise Targeting of Autoantigen-Specific B Cells in Lupus Nephritis with Chimeric Autoantibody Receptor T Cells. Int J Mol Sci 2024; 25:4226. [PMID: 38673811 PMCID: PMC11050013 DOI: 10.3390/ijms25084226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/03/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Despite conventional therapy, lupus nephritis (LN) remains a significant contributor to short- and long-term morbidity and mortality. B cell abnormalities and the production of autoantibodies against nuclear complexes like anti-dsDNA are recognised as key players in the pathogenesis of LN. To address the challenges of chronic immunosuppression associated with current therapies, we have engineered T cells to express chimeric autoantibody receptors (DNA-CAART) for the precise targeting of B cells expressing anti-dsDNA autoantibodies. T cells from LN patients were transduced using six different CAAR vectors based on their antigen specificity, including alpha-actinin, histone-1, heparan sulphate, or C1q. The cytotoxicity, cytokine production, and cell-cell contact of DNA-CAART were thoroughly investigated in co-culture experiments with B cells isolated from patients, both with and without anti-dsDNA positivity. The therapeutic effects were further evaluated using an in vitro immune kidney LN organoid. Among the six proposed DNA-CAART, DNA4 and DNA6 demonstrated superior selectively cytotoxic activity against anti-dsDNA+ B cells. Notably, DNA4-CAART exhibited improvements in organoid morphology, apoptosis, and the inflammatory process in the presence of IFNα-stimulated anti-dsDNA+ B cells. Based on these findings, DNA4-CAART emerge as promising candidates for modulating autoimmunity and represent a novel approach for the treatment of LN.
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Affiliation(s)
- Cristina Solé
- Rheumatology Research Group, Lupus Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (M.R.); (S.S.); (J.C.-H.)
| | - Maria Royo
- Rheumatology Research Group, Lupus Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (M.R.); (S.S.); (J.C.-H.)
| | - Sebastian Sandoval
- Rheumatology Research Group, Lupus Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (M.R.); (S.S.); (J.C.-H.)
| | - Teresa Moliné
- Department of Pathology, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (T.M.); (A.G.)
| | - Alejandra Gabaldón
- Department of Pathology, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (T.M.); (A.G.)
| | - Josefina Cortés-Hernández
- Rheumatology Research Group, Lupus Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (M.R.); (S.S.); (J.C.-H.)
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Cantor J. Maximizing the Therapeutic Effect of Endothelin Receptor Antagonists in Pulmonary Fibrosis: A Paradigm for Treating the Disease. Int J Mol Sci 2024; 25:4184. [PMID: 38673771 PMCID: PMC11050024 DOI: 10.3390/ijms25084184] [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: 01/20/2024] [Revised: 03/12/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Using a lipopolysaccharide model of acute lung injury, we previously showed that endothelin-1 (ET-1), a potent mediator of vasoconstriction, may act as a "gatekeeper" for the influx of inflammatory cells into the lung. These studies provided a rationale for testing the effect of HJP272, an endothelin receptor antagonist (ERA), in hamster models of pulmonary fibrosis induced by intratracheal instillation of either bleomycin (BLM) or amiodarone (AM). To determine the temporal effects of blocking ET-1 activity, animals were given HJP272 either 1 h before initiation of lung injury or 24 h afterward. The results indicated that pretreatment with this agent caused significant reductions in various inflammatory parameters, whereas post-treatment was ineffective. This finding suggests that ERAs are only effective at a very early stage of pulmonary fibrosis and explains their lack of success in clinical trials involving patients with this disease. Nevertheless, ERAs could serve as prophylactic agents when combined with drugs that may induce pulmonary fibrosis. Furthermore, developing a biomarker for the initial changes in the lung extracellular matrix could increase the efficacy of ERAs and other therapeutic agents in preventing the progression of the disease. While no such biomarker currently exists, we propose the ratio of free to peptide-bound desmosine, a unique crosslink of elastin, as a potential candidate for detecting the earliest modifications in lung microarchitecture associated with pulmonary fibrosis.
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Affiliation(s)
- Jerome Cantor
- School of Pharmacy and Health Sciences, Queens, NY 11439, USA
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10
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Jimenez SA, Piera-Velazquez S. Cellular Transdifferentiation: A Crucial Mechanism of Fibrosis in Systemic Sclerosis. Curr Rheumatol Rev 2024; 20:388-404. [PMID: 37921216 DOI: 10.2174/0115733971261932231025045400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/13/2023] [Accepted: 07/27/2023] [Indexed: 11/04/2023]
Abstract
Systemic Sclerosis (SSc) is a systemic autoimmune disease of unknown etiology with a highly complex pathogenesis that despite extensive investigation is not completely understood. The clinical and pathologic manifestations of the disease result from three distinct processes: 1) Severe and frequently progressive tissue fibrosis causing exaggerated and deleterious accumulation of interstitial collagens and other extracellular matrix molecules in the skin and various internal organs; 2) extensive fibroproliferative vascular lesions affecting small arteries and arterioles causing tissue ischemic alterations; and 3) cellular and humoral immunity abnormalities with the production of numerous autoantibodies, some with very high specificity for SSc. The fibrotic process in SSc is one of the main causes of disability and high mortality of the disease. Owing to its essentially universal presence and the severity of its clinical effects, the mechanisms involved in the development and progression of tissue fibrosis have been extensively investigated, however, despite intensive investigation, the precise molecular mechanisms have not been fully elucidated. Several recent studies have suggested that cellular transdifferentiation resulting in the phenotypic conversion of various cell types into activated myofibroblasts may be one important mechanism. Here, we review the potential role that cellular transdifferentiation may play in the development of severe and often progressive tissue fibrosis in SSc.
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Affiliation(s)
- Sergio A Jimenez
- Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia 19107, USA
| | - Sonsoles Piera-Velazquez
- Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia 19107, USA
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11
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Yoshie S, Murono S, Hazama A. Approach for Elucidating the Molecular Mechanism of Epithelial to Mesenchymal Transition in Fibrosis of Asthmatic Airway Remodeling Focusing on Cl - Channels. Int J Mol Sci 2023; 25:289. [PMID: 38203460 PMCID: PMC10779031 DOI: 10.3390/ijms25010289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/15/2023] [Accepted: 12/16/2023] [Indexed: 01/12/2024] Open
Abstract
Airway remodeling caused by asthma is characterized by structural changes of subepithelial fibrosis, goblet cell metaplasia, submucosal gland hyperplasia, smooth muscle cell hyperplasia, and angiogenesis, leading to symptoms such as dyspnea, which cause marked quality of life deterioration. In particular, fibrosis exacerbated by asthma progression is reportedly mediated by epithelial-mesenchymal transition (EMT). It is well known that the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling is closely associated with several signaling pathways, including the TGF-β1/Smad, TGF-β1/non-Smad, and Wnt/β-catenin signaling pathways. However, the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling has not yet been fully clarified. Given that Cl- transport through Cl- channels causes passive water flow and consequent changes in cell volume, these channels may be considered to play a key role in EMT, which is characterized by significant morphological changes. In the present article, we highlight how EMT, which causes fibrosis and carcinogenesis in various tissues, is strongly associated with activation or inactivation of Cl- channels and discuss whether Cl- channels can lead to elucidation of the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling.
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Affiliation(s)
- Susumu Yoshie
- Department of Cellular and Integrative Physiology, Graduate School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Shigeyuki Murono
- Department of Otolaryngology Head and Neck Surgery, Graduate School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Akihiro Hazama
- Department of Cellular and Integrative Physiology, Graduate School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan
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Liu Y, Li G, Lu F, Guo Z, Cai S, Huo T. Excess iron intake induced liver injury: The role of gut-liver axis and therapeutic potential. Biomed Pharmacother 2023; 168:115728. [PMID: 37864900 DOI: 10.1016/j.biopha.2023.115728] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/10/2023] [Accepted: 10/13/2023] [Indexed: 10/23/2023] Open
Abstract
Excessive iron intake is detrimental to human health, especially to the liver, which is the main organ for iron storage. Excessive iron intake can lead to liver injury. The gut-liver axis (GLA) refers to the bidirectional relationship between the gut and its microbiota and the liver, which is a combination of signals generated by dietary, genetic and environmental factors. Excessive iron intake disrupts the GLA at multiple interconnected levels, including the gut microbiota, gut barrier function, and the liver's innate immune system. Excessive iron intake induces gut microbiota dysbiosis, destroys gut barriers, promotes liver exposure to gut microbiota and its derived metabolites, and increases the pro-inflammatory environment of the liver. There is increasing evidence that excess iron intake alters the levels of gut microbiota-derived metabolites such as secondary bile acids (BAs), short-chain fatty acids, indoles, and trimethylamine N-oxide, which play an important role in maintaining homeostasis of the GLA. In addition to iron chelators, antioxidants, and anti-inflammatory agents currently used in iron overload therapy, gut barrier intervention may be a potential target for iron overload therapy. In this paper, we review the relationship between excess iron intake and chronic liver diseases, the regulation of iron homeostasis by the GLA, and focus on the effects of excess iron intake on the GLA. It has been suggested that probiotics, fecal microbiota transfer, farnesoid X receptor agonists, and microRNA may be potential therapeutic targets for iron overload-induced liver injury by protecting gut barrier function.
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Affiliation(s)
- Yu Liu
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China
| | - Guangyan Li
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China
| | - Fayu Lu
- School of Public Health, China Medical University, Shenyang, Liaoning 110122, China
| | - Ziwei Guo
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China
| | - Shuang Cai
- The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
| | - Taoguang Huo
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning 110122, China; Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China.
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14
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Liu D, Zhang C, Zhang J, Xu GT, Zhang J. Molecular pathogenesis of subretinal fibrosis in neovascular AMD focusing on epithelial-mesenchymal transformation of retinal pigment epithelium. Neurobiol Dis 2023; 185:106250. [PMID: 37536385 DOI: 10.1016/j.nbd.2023.106250] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/11/2023] [Accepted: 07/31/2023] [Indexed: 08/05/2023] Open
Abstract
Age-related macular degeneration (AMD) is a leading cause of vision loss among elderly people in developed countries. Neovascular AMD (nAMD) accounts for more than 90% of AMD-related vision loss. At present, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is widely used as the first-line therapy to decrease the choroidal and retinal neovascularizations, and thus to improve or maintain the visual acuity of the patients with nAMD. However, about 1/3 patients still progress to irreversible visual impairment due to subretinal fibrosis even with adequate anti-VEGF treatment. Extensive literatures support the critical role of epithelial-mesenchymal transformation (EMT) of retinal pigment epithelium (RPE) in the pathogenesis of subretinal fibrosis in nAMD, but the underlying mechanisms still remain largely unknown. This review summarized the molecular pathogenesis of subretinal fibrosis in nAMD, especially focusing on the transforming growth factor-β (TGF-β)-induced EMT pathways. It was also discussed how these pathways crosstalk and respond to signals from the microenvironment to mediate EMT and contribute to the progression of nAMD-related subretinal fibrosis. Targeting EMT signaling pathways might provide a promising and effective therapeutic strategy to treat subretinal fibrosis secondary to nAMD.
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Affiliation(s)
- Dandan Liu
- Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, School of Medicine, Tongji University, Shanghai, China
| | - Chaoyang Zhang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Jingting Zhang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Guo-Tong Xu
- Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, School of Medicine, Tongji University, Shanghai, China.
| | - Jingfa Zhang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China.
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15
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Kooistra EJ, Dahm K, van Herwaarden AE, Gerretsen J, Nuesch Germano M, Mauer K, Smeets RL, van der Velde S, van den Berg MJW, van der Hoeven JG, Aschenbrenner AC, Schultze JL, Ulas T, Kox M, Pickkers P. Molecular mechanisms and treatment responses of pulmonary fibrosis in severe COVID-19. Respir Res 2023; 24:196. [PMID: 37559053 PMCID: PMC10413531 DOI: 10.1186/s12931-023-02496-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 07/21/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone (DEXA) treatment on the clinical course of PF in critically ill COVID-19 patients. METHODS We performed a pre-post design study in 191 COVID-19 patients admitted to the Intensive Care Unit (ICU) spanning two treatment cohorts: the pre-DEXA- (n = 67) and the DEXA-cohort (n = 124). PF was identified based on radiological findings, worsening of ventilatory parameters and elevated circulating PIIINP levels. Longitudinal transcriptome profiles of 52 pre-DEXA patients were determined using RNA sequencing. Effects of prednisone treatment on clinical fibrosis parameters and outcomes were analyzed between PF- and no-PF-patients within both cohorts. RESULTS Transcriptome analyses revealed upregulation of inflammatory, coagulation and neutrophil extracellular trap-related pathways in PF-patients compared to no-PF patients. Key genes involved included PADI4, PDE4D, MMP8, CRISP3, and BCL2L15. Enrichment of several identified pathways was associated with impaired survival in a external cohort of patients with idiopathic pulmonary fibrosis. Following prednisone treatment, PF-related profiles reverted towards those observed in the no-PF-group. Likewise, PIIINP levels decreased significantly following prednisone treatment. PF incidence was 28% and 25% in the pre-DEXA- and DEXA-cohort, respectively (p = 0.61). ICU length-of-stay (pre-DEXA: 42 [29-49] vs. 18 [13-27] days, p < 0.001; DEXA: 42 [28-57] vs. 13 [7-24] days, p < 0.001) and mortality (pre-DEXA: 47% vs. 15%, p = 0.009; DEXA: 61% vs. 19%, p < 0.001) were higher in the PF-groups compared to the no-PF-groups within both cohorts. Early dexamethasone therapy did not influence these outcomes. CONCLUSIONS ICU patients with COVID-19 who develop PF exhibit upregulated coagulation, inflammation, and neutrophil extracellular trap-related pathways as well as prolonged ICU length-of-stay and mortality. This study indicates that early dexamethasone treatment neither influences the incidence or clinical course of PF, nor clinical outcomes.
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Affiliation(s)
- Emma J Kooistra
- Department of Intensive Care Medicine, Radboud University Medical Center, Postbus 9101, 6500 HB, Nijmegen, The Netherlands
- Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Kilian Dahm
- Translational Pediatrics, Department of Pediatrics, University Hospital Wuerzburg, 97080, Würzburg, Bavaria, Germany
- PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases, University of Bonn, Bonn, Germany
| | - Antonius E van Herwaarden
- Radboudumc Laboratory for Diagnostics, Department of Laboratory Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Jelle Gerretsen
- Department of Intensive Care Medicine, Radboud University Medical Center, Postbus 9101, 6500 HB, Nijmegen, The Netherlands
- Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | | | - Karoline Mauer
- PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases, University of Bonn, Bonn, Germany
| | - Ruben L Smeets
- Radboudumc Laboratory for Diagnostics, Department of Laboratory Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
- Laboratory for Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Sjef van der Velde
- Department of Intensive Care Medicine, Radboud University Medical Center, Postbus 9101, 6500 HB, Nijmegen, The Netherlands
| | - Maarten J W van den Berg
- Department of Intensive Care Medicine, Radboud University Medical Center, Postbus 9101, 6500 HB, Nijmegen, The Netherlands
- Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Johannes G van der Hoeven
- Department of Intensive Care Medicine, Radboud University Medical Center, Postbus 9101, 6500 HB, Nijmegen, The Netherlands
- Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Anna C Aschenbrenner
- Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Joachim L Schultze
- PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases, University of Bonn, Bonn, Germany
- Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
- Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Thomas Ulas
- PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases, University of Bonn, Bonn, Germany
- Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
- Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Matthijs Kox
- Department of Intensive Care Medicine, Radboud University Medical Center, Postbus 9101, 6500 HB, Nijmegen, The Netherlands
- Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Peter Pickkers
- Department of Intensive Care Medicine, Radboud University Medical Center, Postbus 9101, 6500 HB, Nijmegen, The Netherlands.
- Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
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Karetnikova ES, Jarzebska N, Rodionov RN, Rubets E, Markov AG, Spieth PM. mRNA Levels of Epithelial and Mesenchymal Markers in Lung Epithelial Cell Lines. Rep Biochem Mol Biol 2023; 12:211-219. [PMID: 38317809 PMCID: PMC10838588 DOI: 10.61186/rbmb.12.2.211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 07/14/2023] [Indexed: 02/07/2024]
Abstract
Background Epithelial-mesenchymal transition (EMT) is an important physiologic process that determines the outcome of lung tissue healing after injury. Stimuli and molecular cascades inducing EMT lead to up-regulation of the mesenchymal-specific genes in the alveolar epithelial cells and to down-regulation of the genes coding for epithelial markers. Alveolar epithelial cell lines are commonly used as in vitro models to study processes occurring in the lung tissue. The aim of this study is to quantify and compare mRNA expression levels of epithelial and mesenchymal markers in a number of lung epithelial cell lines. Methods Lung epithelial cell lines L2, R3/1 and RLE-6TN were cultured. Repeated mRNA isolation, reverse transcription, and quantitative PCR with primers to epithelial (E-cadherin, occludin, and ZO-2) and mesenchymal (α-SMA, collagen III, and vimentin) markers were performed. Results First, our study revealed a higher level of epithelial transcripts in the RLE-6TN cell line compared to L2 and R3/1 cells. Secondly, we have found simultaneous mRNA expression of both epithelial (E-cadherin, occludin and ZO-2) and mesenchymal (α-SMA, collagen III and vimentin) markers in all cell lines studied. Conclusions Our data indicate that at the transcriptional level the L2, R3/1, and RLE-6TN cell lines are at one of the intermediate stages of EMT, which opens new possibilities for the study of EMT on cell lines. Determination of the direction of changes in epithelial and mesenchymal markers will make it possible to establish the factors responsible for both EMT and reverse mesenchymal-epithelial transition.
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Affiliation(s)
- Ekaterina Sergeevna Karetnikova
- Department of Anesthesiology and Critical Care Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
- Department of General Physiology, Saint-Petersburg State University, Saint-Petersburg, Russia.
| | - Natalia Jarzebska
- Department of Anesthesiology and Critical Care Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
- Division of Angiology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
| | - Roman Nikolaevich Rodionov
- Division of Angiology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
| | - Elena Rubets
- Department of General Physiology, Saint-Petersburg State University, Saint-Petersburg, Russia.
- Division of Angiology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
| | - Alexander Georgievich Markov
- Department of General Physiology, Saint-Petersburg State University, Saint-Petersburg, Russia.
- The first and the second authors contributed equally to this work.
| | - Peter Markus Spieth
- Department of Anesthesiology and Critical Care Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
- The first and the second authors contributed equally to this work.
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Zhang Z, Li H, Wang G, Zhao G, Li C, Cao Y. Thrombospondin-1 and prolyl 4-hydroxylase subunit alpha 3 as potential biomarkers of salivary gland fibrosis. J Dent Sci 2023. [DOI: 10.1016/j.jds.2023.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
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18
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Cao Y, Shi Y, Yang Y, Wu Z, Peng N, Xiao J, Dou F, Xu J, Pei W, Fu C, Chen P, Wang Y. Urinary exosomes derived circRNAs as biomarkers for chronic renal fibrosis. Ann Med 2022; 54:1966-1976. [PMID: 35819256 PMCID: PMC9291679 DOI: 10.1080/07853890.2022.2098374] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Chronic renal disease (CKD) is a common and irreversible loss of renal function. Renal fibrosis reflected the degree of renal dysfunction. However, the current biomarkers only characterize the renal function instead of indicating the fibrosis degree. The potential diagnostic value of urinary exosomes derived circRNAs for renal fibrosis needs to be further studied. METHODS Urine exosomes from 3 chronic kidney disease (CKD) patients without renal fibrosis and 3 renal fibrotic patients were collected and human circRNAs microarray analysis were performed to detect the circRNAs expression profile. 110 biopsy-proven CKD patients and 54 healthy controls were enrolled and urine exosomes derived RNA was isolated. The expression of hsa_circ_0036649 was measured and the correlation with renal function parameter and pathological indicators was performed. The receiver operating characteristic (ROC) curve for the diagnosis of renal fibrosis was calculated. RESULTS Human circRNAs microarray showed 365 circRNAs up expressed and 195 circRNAs down expressed in renal fibrotic patients compared to none fibrosis CKD patients. The expression of hsa_circ_0036649 was decreased in renal fibrotic patients according to RT-PCR and correlated with serum creatinine, blood urea nitrogen (BUN), estimated glomerular filtration rate and cystatin c. Further, the expression of hsa_circ_0036649 was correlated with the score of tubulointerstitial fibrosis (TIF) and the score of glomerular sclerosis. The ROC curve showed that hsa_circ_0036649 may predict renal fibrosis at a cut-off value of 0.597 with a sensitivity of 45.5% and specificity of 87.9%. CONCLUSION Expression of urinary exosomes derived hsa_circ_0036649 associated with the degree of renal fibrosis. Its potential role as a biomarker in CKD remained to be supported by further follow-up studies.Key MessagescircRNAs profile in urine exosomes in renal fibrosis patients was revealed.The expression of urine exosomes derived hsa_circ_0036649 was correlated to renal function and fibrosis degree.circRNAs derived from urinary exosomes may become a new research direction for biomarkers of renal fibrosis.
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Affiliation(s)
- Yuhan Cao
- Department of Nephrology, Yi Ji Shan hospital affiliated to Wan Nan Medical College, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution (Wan Nan Medical College), Wuhu, China.,Anesthesia Laboratory & Training Center of Wan Nan Medical College, Wuhu, China
| | - Yuanhui Shi
- Department of Nephrology, Yi Ji Shan hospital affiliated to Wan Nan Medical College, Wuhu, China
| | - Yanlang Yang
- Department of Nephrology, Yi Ji Shan hospital affiliated to Wan Nan Medical College, Wuhu, China
| | - Zhangli Wu
- Department of Nephrology, Yi Ji Shan hospital affiliated to Wan Nan Medical College, Wuhu, China
| | - Nana Peng
- School of Clinical Medicine, Wan Nan Medical College, Wuhu, China
| | - Jie Xiao
- School of Anesthesiology, Wan Nan Medical College, Wuhu, China
| | - Fan Dou
- Department of Nephrology, Yi Ji Shan hospital affiliated to Wan Nan Medical College, Wuhu, China
| | - Jingjing Xu
- Department of Nephrology, Yi Ji Shan hospital affiliated to Wan Nan Medical College, Wuhu, China
| | - Wenjun Pei
- Anhui Province Key Laboratory of Biological Macromolecules Research (Wan Nan Medical College), Wuhu, China
| | - Cong Fu
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution (Wan Nan Medical College), Wuhu, China.,Anesthesia Laboratory & Training Center of Wan Nan Medical College, Wuhu, China.,Department of Cardiology, Yi Ji Shan Hospital Affiliated to Wan Nan Medical College, Wuhu, China
| | - Pingsheng Chen
- Department of Pathology and Pathophysiology, Medical School, Southeast University, Dhaka, Bangladesh
| | - Yuwei Wang
- Department of Nephrology, Yi Ji Shan hospital affiliated to Wan Nan Medical College, Wuhu, China
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Lemieszek MK, Golec M, Zwoliński J, Dutkiewicz J, Milanowski J. Cathelicidin Treatment Silences Epithelial-Mesenchymal Transition Involved in Pulmonary Fibrosis in a Murine Model of Hypersensitivity Pneumonitis. Int J Mol Sci 2022; 23:13039. [PMID: 36361827 PMCID: PMC9659202 DOI: 10.3390/ijms232113039] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 03/06/2025] Open
Abstract
Pulmonary fibrosis is becoming an increasingly common pathology worldwide. Unfortunately, this disorder is characterized by a bad prognosis: no treatment is known, and the survival rate is dramatically low. One of the most frequent reasons for pulmonary fibrosis is hypersensitivity pneumonitis (HP). As the main mechanism of pulmonary fibrosis is a pathology of the repair of wounded pulmonary epithelium with a pivotal role in epithelial-mesenchymal transition (EMT), we assumed that EMT silencing could prevent disease development. Because of several biological features including wound healing promotion, an ideal candidate for use in the treatment of pulmonary fibrosis seems to be cathelicidin. The aim of the studies was to understand the influence of cathelicidin on the EMT process occurring during lung fibrosis development in the course of HP. Cathelicidin's impact on EMT was examined in a murine model of HP, wherein lung fibrosis was induced by chronic exposure to extract of Pantoea agglomerans (SE-PA) by real-time PCR and Western blotting. Studies revealed that mouse exposure to cathelicidin did not cause any side changes in the expression of investigated genes/proteins. Simultaneously, cathelicidin administered together or after SE-PA decreased the elevated level of myofibroblast markers (Acta2/α-smooth muscle actin, Cdh2/N-cadherin, Fn1/Fibronectin, Vim/vimentin) and increased the lowered level of epithelial markers (Cdh1/E-cadherin, Ocln/occludin). Cathelicidin provided with SE-PA or after cessation of SE-PA inhalations reduced the expression of EMT-associated factors (Ctnnd1/β-catenin, Nfkb1/NFκB, Snail1/Snail, Tgfb1/TGFβ1 Zeb1/ZEB1, Zeb2/ZEB2) elevated by P. agglomerans. Cathelicidin's beneficial impact on the expression of genes/proteins involved in EMT was observed during and after the HP development; however, cathelicidin was not able to completely neutralize the negative changes. Nevertheless, significant EMT silencing in response to cathelicidin suggested the possibility of its use in the prevention/treatment of pulmonary fibrosis.
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Affiliation(s)
| | - Marcin Golec
- Heidelberg Institute of Global Health (HIGH), Faculty of Medicine and University Hospital, Heidelberg University, 69117 Heidelberg, Germany
| | - Jacek Zwoliński
- Department of Biological Health Hazards and Parasitology, Institute of Rural Health, 20-090 Lublin, Poland
| | - Jacek Dutkiewicz
- Department of Biological Health Hazards and Parasitology, Institute of Rural Health, 20-090 Lublin, Poland
| | - Janusz Milanowski
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-059 Lublin, Poland
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20
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Breast Cancer Treatment Decreases Serum Levels of TGF-β1, VEGFR2, and TIMP-2 Compared to Healthy Volunteers: Significance for Therapeutic Outcomes? PATHOPHYSIOLOGY 2022; 29:537-554. [PMID: 36136069 PMCID: PMC9500649 DOI: 10.3390/pathophysiology29030042] [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: 07/28/2022] [Revised: 08/22/2022] [Accepted: 08/25/2022] [Indexed: 11/25/2022] Open
Abstract
Various complications from a breast cancer treatment, in the pathogenesis of which excessive tissue fibrosis plays a leading role, are a common pathology. In this study, the levels of TGF-β1, VEGFR-2, and TIMP-2 were determined by the immuno-enzyme serum analysis for patients during the long-term period after breast cancer treatment as potential markers of fibrosis. The single-center study enrolled 92 participants, which were divided into two age-matched groups: (1) 67 patients following breast cancer treatment, and (2) 25 healthy female volunteers. The intergroup analysis demonstrated that the patients after breast cancer treatment showed a decrease in the serum levels of TGF-β1 (U = 666, p < 0.001) and TIMP-2 (U = 637, p < 0.001) as compared to the group of healthy volunteers. The levels of VEGFR-2 in these groups were comparable (U = 1345, p = 0.082). It was also found that the type of treatment, the presence of lymphedema, shoulder joint contracture, and changes in lymphoscintigraphy did not affect the levels of TGF-β1, VEGFR-2, and TIMP-2 within the group of patients after breast cancer treatment. These results may indicate that these biomarkers do not play a leading role in the maintenance and progression of fibrosis in the long-term period after breast cancer treatment. The reduced levels of TGF-β1 and TIMP-2 may reflect endothelial dysfunction caused by the antitumor therapy.
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21
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Sun C, Zou H, Yang Z, Yang M, Chen X, Huang Y, Fan W, Yuan R. Proteomics and phosphoproteomics analysis of vitreous in idiopathic epiretinal membrane patients. Proteomics Clin Appl 2022; 16:e2100128. [PMID: 35510950 DOI: 10.1002/prca.202100128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 03/18/2022] [Accepted: 05/02/2022] [Indexed: 12/30/2022]
Abstract
PURPOSE The purpose of the present study was to characterize the idiopathic epiretinal membrane (iERM) through proteomics and phosphoproteomics analysis to facilitate the diagnosis and treatment of iERM. EXPERIMENTAL DESIGN The vitreous of 25 patients with an iERM and 15 patients with an idiopathic macular hole were analyzed by proteomic and phosphoproteomic analysis based on tandem mass tag. PRM was used to verify the differential proteins. RESULTS Proteomic analysis identified a total of 878 proteins, including 50 differential proteins. Tenascin-C, galectin-3-binding protein, glucose-6-phosphate isomerase, neuroserpin, collagen alpha-1(XI) chain, and collagen alpha-1(II) chain were verified to be upregulated in iERM by PRM. Phosphoproteomic analysis identified a total of 401 phosphorylation sites on 213 proteins, including 27 differential phosphorylation sites on 24 proteins. Mitogen-activated protein kinase-activated protein kinase (MAPKAPK)3 and MAPKAPK5 were predicted as the major kinases in the vitreous of iERM. Twenty-six of the differential proteins and phosphorylated proteins may be closely related to fibrosis in iERM. CONCLUSION AND CLINICAL RELEVANCE Our results indicated the potential biomarkers or therapeutic targets for iERM, provided key kinases that may be involved in iERM. Fibrosis plays an essential role in iERM, and further exploration of related differential proteins has important clinical significance.
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Affiliation(s)
- Chao Sun
- Department of Ophthalmology, the Second Affiliated Hospital of Army Medical University, Chongqing, PR China
| | - Huan Zou
- Department of Ophthalmology, the Second Affiliated Hospital of Army Medical University, Chongqing, PR China
| | - Zhouquan Yang
- Department of Ophthalmology, the Second Affiliated Hospital of Army Medical University, Chongqing, PR China
| | - Mei Yang
- Department of Ophthalmology, the Second Affiliated Hospital of Army Medical University, Chongqing, PR China
| | - Xiaofan Chen
- Department of Ophthalmology, the Second Affiliated Hospital of Army Medical University, Chongqing, PR China
| | - Yanming Huang
- Department of Ophthalmology, the Second Affiliated Hospital of Army Medical University, Chongqing, PR China
| | - Wei Fan
- Department of Ophthalmology, the Second Affiliated Hospital of Army Medical University, Chongqing, PR China
| | - Rongdi Yuan
- Department of Ophthalmology, the Second Affiliated Hospital of Army Medical University, Chongqing, PR China
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22
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Choi KH, Kim DK, Kim AR, Lee SR. Prevention of urethral fibrosis induced by transforming growth factor beta 1 using selective Wnt/β-catenin signaling inhibitors in a rat model. Int J Urol 2022; 29:764-771. [PMID: 35381618 DOI: 10.1111/iju.14884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 03/21/2022] [Indexed: 01/08/2023]
Abstract
OBJECTIVES To determine the anti-fibrotic effects of Wnt/β-catenin signaling inhibitors on urethral stricture. METHODS Human fibroblasts were exposed to transforming growth factor beta 1 combined with various concentrations of Wnt/β-catenin inhibitors (ICG-001, IWR-1, and PRI-724), and cell proliferation and migration were evaluated. Urethral fibrosis was induced in male Sprague-Dawley rats by urethral injection of transforming growth factor beta 1 and co-treatement with inhibitors. Urethral tissues were harvested 2 weeks after the injection. The messenger ribonucleic acid and protein expression was examined for fibrosis markers Axin-1, collagen type 1, alpha smooth muscle actin, and β-catenin. Histological analysis of fibrosis and collagen deposition was also performed. RESULTS Cell migration was ameliorated by ICG-001 and PRI-724. Protein and messenger ribonucleic acid expression of collagen type 1 and alpha smooth muscle actin in transforming growth factor beta 1-treated fibroblasts decreased in a concentration-dependent manner with the ICG-001 and PRI-724 treatments (P < 0.05). However, there were no significant changes with the IWR-1 treatment. Collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression were both significantly increased in the urethral tissues of rats with transforming growth factor beta 1-induced urethral fibrosis. Rats co-treated with ICG-001 or PRI-724 showed relatively mild fibrosis and significantly reduced collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression (P < 0.05). CONCLUSIONS ICG-001 and PRI-724 significantly ameliorated urethral fibrosis induced by transforming growth factor beta 1 in rats. These results suggest that ICG-001 and PRI-724 can be developed as therapeutics for treating urethral stricture.
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Affiliation(s)
- Kyung Hwa Choi
- Department of Urology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Dae Keun Kim
- Department of Urology, CHA Fertility Center Seoul Station, CHA University School of Medicine, Seoul, Korea
| | - A Ram Kim
- Department of Dermatology, School of Medicine, CHA University School of Medicine, Pocheon, Korea
| | - Seung-Ryeol Lee
- Department of Urology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
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Ocon A, Lokineni S, Korman B. Understanding and Therapeutically Targeting the Scleroderma Myofibroblast. CURRENT TREATMENT OPTIONS IN RHEUMATOLOGY 2022. [DOI: 10.1007/s40674-021-00189-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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24
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Morin C, Moyret-Lalle C, Mertani HC, Diaz JJ, Marcel V. Heterogeneity and dynamic of EMT through the plasticity of ribosome and mRNA translation. Biochim Biophys Acta Rev Cancer 2022; 1877:188718. [PMID: 35304296 DOI: 10.1016/j.bbcan.2022.188718] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/02/2022] [Accepted: 03/11/2022] [Indexed: 02/06/2023]
Abstract
Growing evidence exposes translation and its translational machinery as key players in establishing and maintaining physiological and pathological biological processes. Examining translation may not only provide new biological insight but also identify novel innovative therapeutic targets in several fields of biology, including that of epithelial-to-mesenchymal transition (EMT). EMT is currently considered as a dynamic and reversible transdifferentiation process sustaining the transition from an epithelial to mesenchymal phenotype, known to be mainly driven by transcriptional reprogramming. However, it seems that the characterization of EMT plasticity is challenging, relying exclusively on transcriptomic and epigenetic approaches. Indeed, heterogeneity in EMT programs was reported to depend on the biological context. Here, by reviewing the involvement of translational control, translational machinery and ribosome biogenesis characterizing the different types of EMT, from embryonic and adult physiological to pathological contexts, we discuss the added value of integrating translational control and its machinery to depict the heterogeneity and dynamics of EMT programs.
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Affiliation(s)
- Chloé Morin
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France; Institut Convergence PLAsCAN, 69373 Lyon cedex 08, France; DevWeCan Labex Laboratory, 69373 Lyon cedex 08, France
| | - Caroline Moyret-Lalle
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France; Institut Convergence PLAsCAN, 69373 Lyon cedex 08, France; DevWeCan Labex Laboratory, 69373 Lyon cedex 08, France
| | - Hichem C Mertani
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France; Institut Convergence PLAsCAN, 69373 Lyon cedex 08, France; DevWeCan Labex Laboratory, 69373 Lyon cedex 08, France
| | - Jean-Jacques Diaz
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France; Institut Convergence PLAsCAN, 69373 Lyon cedex 08, France; DevWeCan Labex Laboratory, 69373 Lyon cedex 08, France
| | - Virginie Marcel
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France; Institut Convergence PLAsCAN, 69373 Lyon cedex 08, France; DevWeCan Labex Laboratory, 69373 Lyon cedex 08, France.
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Briones-Orta MA, Delgado-Coello B, Gutiérrez-Vidal R, Sosa-Garrocho M, Macías-Silva M, Mas-Oliva J. Quantitative Expression of Key Cancer Markers in the AS-30D Hepatocarcinoma Model. Front Oncol 2021; 11:670292. [PMID: 34737944 PMCID: PMC8561839 DOI: 10.3389/fonc.2021.670292] [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: 02/20/2021] [Accepted: 09/14/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatocellular carcinoma is one of the cancers with the highest mortality rate worldwide. HCC is often diagnosed when the disease is already in an advanced stage, making the discovery and implementation of biomarkers for the disease a critical aim in cancer research. In this study, we aim to quantify the transcript levels of key signaling molecules relevant to different pathways known to participate in tumorigenesis, with special emphasis on those related to cancer hallmarks and epithelial-mesenchymal transition, using as a model the murine transplantable hepatocarcinoma AS-30D. Using qPCR to quantify the mRNA levels of genes involved in tumorigenesis, we found elevated levels for Tgfb1 and Spp1, two master regulators of EMT. A mesenchymal signature profile for AS-30D cells is also supported by the overexpression of genes encoding for molecules known to be associated to aggressiveness and metastatic phenotypes such as Foxm1, C-met, and Inppl1. This study supports the use of the AS-30D cells as an efficient and cost-effective model to study gene expression changes in HCC, especially those associated with the EMT process.
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Affiliation(s)
- Marco A Briones-Orta
- Department of Infectious Disease, Imperial College London, London, United Kingdom
| | - Blanca Delgado-Coello
- Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Roxana Gutiérrez-Vidal
- Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Marcela Sosa-Garrocho
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Marina Macías-Silva
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Jaime Mas-Oliva
- Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Liu ZZ(G, Taiyab A, West-Mays JA. MMP9 Differentially Regulates Proteins Involved in Actin Polymerization and Cell Migration during TGF-β-Induced EMT in the Lens. Int J Mol Sci 2021; 22:ijms222111988. [PMID: 34769418 PMCID: PMC8584335 DOI: 10.3390/ijms222111988] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/23/2021] [Accepted: 11/02/2021] [Indexed: 11/16/2022] Open
Abstract
Fibrotic cataracts have been attributed to transforming growth factor-beta (TGF-β)-induced epithelial-to-mesenchymal transition (EMT). Using mouse knockout (KO) models, our laboratory has identified MMP9 as a crucial protein in the TGF-β-induced EMT process. In this study, we further revealed an absence of alpha-smooth muscle actin (αSMA) and filamentous-actin (F-actin) stress fibers in MMP9KO mouse lens epithelial cell explants (LECs). Expression analysis using NanoString revealed no marked differences in αSMA (ACTA2) and beta-actin (β-actin) (ACTB) mRNA between the lenses of TGF-β-overexpressing (TGF-βtg) mice and TGF-βtg mice on a MMP9KO background. We subsequently conducted a protein array that revealed differential regulation of proteins known to be involved in actin polymerization and cell migration in TGF-β-treated MMP9KO mouse LECs when compared to untreated controls. Immunofluorescence analyses using rat LECs and the novel MMP9-specific inhibitor, JNJ0966, revealed similar differential regulation of cortactin, FAK, LIMK1 and MLC2 as observed in the array. Finally, a reduction in the nuclear localization of MRTF-A, a master regulator of cytoskeletal remodeling during EMT, was observed in rat LECs co-treated with JNJ0966 and TGF-β. In conclusion, MMP9 deficiency results in differential regulation of proteins involved in actin polymerization and cell migration, and this in turn prevents TGF-β-induced EMT in the lens.
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Affiliation(s)
| | | | - Judith A. West-Mays
- Correspondence: ; Tel.: +1-(905)-525-9140 (ext. 26237); Fax: +1-(905)-525-7400
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27
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Global gene expression analysis of systemic sclerosis myofibroblasts demonstrates a marked increase in the expression of multiple NBPF genes. Sci Rep 2021; 11:20435. [PMID: 34650102 PMCID: PMC8516909 DOI: 10.1038/s41598-021-99292-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 09/08/2021] [Indexed: 12/22/2022] Open
Abstract
Myofibroblasts are the key effector cells responsible for the exaggerated tissue fibrosis in Systemic Sclerosis (SSc). Despite their importance to SSc pathogenesis, the specific transcriptome of SSc myofibroblasts has not been described. The purpose of this study was to identify transcriptome differences between SSc myofibroblasts and non-myofibroblastic cells. Alpha smooth muscle actin (α-SMA) expressing myofibroblasts and α-SMA negative cells were isolated employing laser capture microdissection from dermal cell cultures from four patients with diffuse SSc of recent onset. Total mRNA was extracted from both cell populations, amplified and analyzed employing microarrays. Results for specific genes were validated by Western blots and by immunohistochemistry. Transcriptome analysis revealed 97 differentially expressed transcripts in SSc myofibroblasts compared with non-myofibroblasts. Annotation clustering of the SSc myofibroblast-specific transcripts failed to show a TGF-β signature. The most represented transcripts corresponded to several different genes from the Neuroblastoma Breakpoint Family (NBPF) of genes. NBPF genes are highly expanded in humans but are not present in murine or rat genomes. In vitro studies employing cultured SSc dermal fibroblasts and immunohistochemistry of affected SSc skin confirmed increased NBPF expression in SSc. These results indicate that SSc myofibroblasts represent a unique cell lineage expressing a specific transcriptome that includes very high levels of transcripts corresponding to numerous NBPF genes. Elevated expression of NBPF genes in SSc myofibroblasts suggests that NBPF gene products may play a role in SSc pathogenesis and may represent a novel therapeutic target.
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Niu D, Luo T, Wang H, Xia Y, Xie Z. Lactic acid in tumor invasion. Clin Chim Acta 2021; 522:61-69. [PMID: 34400170 DOI: 10.1016/j.cca.2021.08.011] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 08/07/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022]
Abstract
Invasion involves tumor cells altering their cell-matrix interactions and acquiring motility for metastatic spread. Invasive tumor cells exhibit dysregulated metabolism and enhanced aerobic glycolysis, leading to nutrient depletion, hypoxia, and lactic acid production. Lactic acid is a byproduct of glycolysis capable of promoting oncogenic progression, but its role in tumor invasion is unclear. A growing number of studies have demonstrated that lactic acid regulates the degradation of collagen Ⅳ, collagen Ⅶ, and glycoprotein; the synthesis of collagen Ⅰ; and multiple signaling pathways, including TGF-β/Smad, Wnt/β-catenin, IL-6/STAT3, and HGF/MET, which are associated with basement membrane (BM) remodeling and epithelial-mesenchymal transition (EMT), two hallmarks of the tumor invasive process. In the present review, we summarize BM remodeling and EMT in tumor invasion, discuss the emerging roles and molecular mechanisms of lactic acid in these processes, and provide insights for further research.
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Affiliation(s)
- Dun Niu
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang 421001, China
| | - Ting Luo
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang 421001, China
| | - Hanbin Wang
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang 421001, China
| | - Yiniu Xia
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang 421001, China
| | - Zhizhong Xie
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang 421001, China.
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29
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Meng X, Liu K, Xie H, Zhu Y, Jin W, Lu J, Wang R. Endoplasmic reticulum stress promotes epithelial‑mesenchymal transition via the PERK signaling pathway in paraquat‑induced pulmonary fibrosis. Mol Med Rep 2021; 24:525. [PMID: 34036384 PMCID: PMC8170262 DOI: 10.3892/mmr.2021.12164] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 04/26/2021] [Indexed: 12/11/2022] Open
Abstract
Pulmonary fibrosis is the primary reason for mortality in patients with paraquat (PQ) poisoning. Our previous study demonstrated that epithelial-mesenchymal transition (EMT) had a role in PQ-induced pulmonary fibrosis. However, the role of endoplasmic reticulum (ER) stress in PQ-induced EMT remains clear. The present study aimed to determine the role of ER stress in EMT in PQ-induced pulmonary fibrosis. A549 and RLE-6TN cells were incubated with LY294002 (a PI3K inhibitor) or transfected with protein kinase RNA-like ER kinase (PERK) small interfering RNA (si) for 24 h prior to being exposed to PQ. Next, the expression levels of ER stress-related proteins, PI3K/AKT/GSK-3β signaling pathway-related proteins and EMT-related markers were analyzed by performing western blotting, reverse transcription-quantitative PCR and immunofluorescence assays. The results of the present study revealed that the protein expression levels of PERK, phosphorylated (p)-PERK, p-eukaryotic initiation factor 2 (eIF2)α were significantly upregulated in the PQ group, whereas p-PI3K, p-AKT and p-GSK-3β were significantly upregulated in the sicontrol + PQ group compared with the sicontrol group. In vitro, following transfection with siPERK or treatment with the PI3K inhibitor, the protein expression levels of E-cadherin (an epithelial marker) were upregulated, whereas the protein expression levels of α-SMA (a mesenchymal marker) were downregulated. Immunofluorescence analysis revealed that the levels of E-cadherin were markedly upregulated, whereas the levels of α-SMA were notably downregulated following transfection with siPERK compared with the sicontrol group. The results of wound healing assay demonstrated that cell migration in the siPERK + PQ group was markedly decreased compared with the sicontrol + PQ group. These indicated that PQ-induced EMT was suppressed after silencing PERK. The expression levels of p-GSK-3β, p-AKT and p-PI3K were also markedly downregulated in the siPERK + PQ group compared with the sicontrol + PQ group. In conclusion, the findings of the present study suggested that ER stress may promote EMT through the PERK signaling pathway in PQ-induced pulmonary fibrosis. Thus, ER stress may represent a potential therapeutic target for PQ-induced pulmonary fibrosis.
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Affiliation(s)
- Xiaoxiao Meng
- Department of Critical Care Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, P.R. China
| | - Kan Liu
- Department of Diving Medicine, Faculty of Nautical Medicine, Second Military Medical University, Shanghai 200082, P.R. China
| | - Hui Xie
- Department of Critical Care Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, P.R. China
| | - Yong Zhu
- Department of Critical Care Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, P.R. China
| | - Wei Jin
- Department of Critical Care Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, P.R. China
| | - Jian Lu
- Department of Critical Care Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, P.R. China
| | - Ruilan Wang
- Department of Critical Care Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, P.R. China
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Beneficial impact of cathelicidin on hypersensitivity pneumonitis treatment-In vivo studies. PLoS One 2021; 16:e0251237. [PMID: 33999928 PMCID: PMC8128276 DOI: 10.1371/journal.pone.0251237] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
Cathelicidin (CRAMP) is a defence peptide with a wide range of biological responses including antimicrobial, immunomodulatory and wound healing. Due to its original properties the usefulness of CRAMP in the treatment of pulmonary fibrosis was assessed in a murine model of hypersensitivity pneumonitis (HP). The studies were conducted on mouse strain C57BL/6J exposed to a saline extract of Pantoea agglomerans cells (HP inducer). Cathelicidin was administered in the form of an aerosol during and after HP development. Changes in the composition of immune cell populations (NK cells, macrophages, lymphocytes: Tc, Th, Treg, B), were monitored in lung tissue by flow cytometry. Extracellular matrix deposition (collagens, hydroxyproline), the concentration of cytokines involved in inflammatory and the fibrosis process (IFNγ, TNFα, TGFβ1, IL1β, IL4, IL5, IL10, IL12α, IL13) were examined in lung homogenates by the ELISA method. Alterations in lung tissue morphology were examined in mouse lung sections stained with haematoxylin and eosin as well as Masson trichrome dyes. The performed studies revealed that cathelicidin did not cause any negative changes in lung morphology/structure, immune cell composition or cytokines production. At the same time, CRAMP attenuated the immune reaction induced by mice chronic exposure to P. agglomerans and inhibited hydroxyproline and collagen deposition in the lung tissue of mice treated with bacteria extract. The beneficial effect of CRAMP on HP treatment was associated with restoring the balance in quantity of immune cells, cytokines production and synthesis of extracellular matrix components. The presented study suggests the usefulness of cathelicidin in preventing lung fibrosis; however, cathelicidin was not able to reverse pathological changes completely.
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Schwerdt G, Kopf M, Gekle M. The Impact of the Nephrotoxin Ochratoxin A on Human Renal Cells Studied by a Novel Co-Culture Model Is Influenced by the Presence of Fibroblasts. Toxins (Basel) 2021; 13:toxins13030219. [PMID: 33803529 PMCID: PMC8003035 DOI: 10.3390/toxins13030219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/15/2021] [Accepted: 03/16/2021] [Indexed: 12/04/2022] Open
Abstract
The kidney is threatened by a lot of potentially toxic substances. To study the influence of the nephrotoxin ochratoxin A (OTA) we established a cell co-culture model consisting of human renal proximal tubule cells and fibroblasts. We studied the effect of OTA on cell survival, the expression of genes and/or proteins related to cell death, extracellular matrix and energy homeostasis. OTA-induced necrosis was enhanced in both cell types in the presence of the respective other cell type, whereas OTA-induced apoptosis was independent therefrom. In fibroblasts, but not in tubule cells, a co-culture effect was visible concerning the expression of the cell-cycle-related protein p21. The expression of the epithelial-to-mesenchymal transition-indicating protein vimentin was independent from the culture-condition. The expression of the OTA-induced lncRNA WISP1-AS1 was enhanced in co-culture. OTA exposure led to alterations in the expression of genes related to energy metabolism with a glucose-mobilizing effect and a reduced expression of mitochondrial proteins. Together we demonstrate that the reaction of cells can be different in the presence of cells which naturally are close-by, thus enabling a cellular cross-talk. Therefore, to evaluate the toxicity of a substance, it would be an advantage to consider the use of co-cultures instead of mono-cultures.
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Sun M, Zhou W, Yao F, Song J, Xu Y, Deng Z, Diao H, Li S. MicroRNA-302b mitigates renal fibrosis via inhibiting TGF-β/Smad pathway activation. ACTA ACUST UNITED AC 2021; 54:e9206. [PMID: 33503202 PMCID: PMC7836400 DOI: 10.1590/1414-431x20209206] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 08/31/2020] [Indexed: 11/22/2022]
Abstract
Renal fibrosis is one of the most significant pathological changes after ureteral
obstruction. Transforming growth factor-β (TGF-β) signaling pathway plays
essential roles in kidney fibrosis regulation. The aims of the present study
were to investigate effects of microRNA-302b (miR-302b) on renal fibrosis, and
interaction between miR-302b and TGF-β signaling pathway in murine unilateral
ureteral obstruction (UUO) model. Microarray dataset GSE42716 was downloaded by
retrieving Gene Expression Omnibus database. In accordance with bioinformatics
analysis results, miR-302b was significantly down-regulated in UUO mouse kidney
tissue and TGF-β1-treated HK-2 cells. Masson's trichrome staining showed that
miR-302b mimics decreased renal fibrosis induced by UUO. The increased mRNA
expression of collagen I and α-smooth muscle actin (α-SMA) and decreased
expression of E-cadherin were reversed by miR-302b mimics. In addition, miR-302b
up-regulation also inhibited TGF-β1-induced epithelial mesenchymal transition
(EMT) of HK-2 cells by restoring E-cadherin expression and decreasing α-SMA
expression. miR-302b mimics suppressed both luciferase activity and protein
expression of TGF-βR2. However, miR-302b inhibitor increased TGF-βR2 luciferase
activity and protein expression. Meanwhile, miR-302b mimics inhibited TGF-βR2
mRNA expression and decreased Smad2 and Smad3 phosphorylation in
vivo and in vitro. Furthermore, over-expression of
TGF-βR2 restored the miR-302b-induced decrease of collagen I and α-SMA
expression. In conclusion, this study demonstrated that miR-302b attenuated
renal fibrosis by targeting TGF-βR2 to suppress TGF-β/Smad signaling activation.
Our findings showed that elevating renal miR-302b levels may be a novel
therapeutic strategy for preventing renal fibrosis.
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Affiliation(s)
- Mengkui Sun
- Department of Urology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China.,Laboratory of Pelvic Floor Muscle Function, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China
| | - Wei Zhou
- Department of Urology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China.,Laboratory of Pelvic Floor Muscle Function, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China
| | - Fei Yao
- Department of Urology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China.,Laboratory of Pelvic Floor Muscle Function, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China
| | - Jianming Song
- Department of Pathology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China
| | - Yanan Xu
- Department of Urology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China.,Laboratory of Pelvic Floor Muscle Function, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China
| | - Zhimei Deng
- Department of Urology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China.,Laboratory of Pelvic Floor Muscle Function, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China
| | - Hongwang Diao
- Department of Urology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China.,Laboratory of Pelvic Floor Muscle Function, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China
| | - Shoulin Li
- Department of Urology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China.,Laboratory of Pelvic Floor Muscle Function, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China
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Forouzanfar F, Guest PC, Jamialahmadi T, Sahebkar A. Hepatoprotective Effect of Trehalose: Insight into Its Mechanisms of Action. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1328:489-500. [PMID: 34981500 DOI: 10.1007/978-3-030-73234-9_34] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Yang X, Ren H, Guo X, Hu C, Fu J. Radiation-induced skin injury: pathogenesis, treatment, and management. Aging (Albany NY) 2020; 12:23379-23393. [PMID: 33202382 PMCID: PMC7746368 DOI: 10.18632/aging.103932] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 07/30/2020] [Indexed: 12/15/2022]
Abstract
Radiation-induced skin injury (RSI) refers to a frequently occurring complication of radiation therapy. Nearly 90% of patients having received radiation therapy underwent moderate-to-severe skin reactions, severely reducing patients' quality of life and adversely affecting their disease treatment. No gold standard has been formulated for RSIs. In the present study, the mechanism of RSI and topical medications was discussed. Besides, this study can be referenced for clinicians to treat RSIs to guide subsequent clinical medicine.
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Affiliation(s)
- Xiaojing Yang
- Department of Radiation Oncology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Hanru Ren
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, Shanghai, China
| | - Xiaomao Guo
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Shanghai Medical College, Fudan University, Shanghai, China
| | - Chaosu Hu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jie Fu
- Department of Radiation Oncology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
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Li J, Huang B, Dong L, Zhong Y, Huang Z. WJ‑MSCs intervention may relieve intrauterine adhesions in female rats via TGF‑β1‑mediated Rho/ROCK signaling inhibition. Mol Med Rep 2020; 23:8. [PMID: 33179074 PMCID: PMC7673328 DOI: 10.3892/mmr.2020.11646] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 03/31/2020] [Indexed: 12/12/2022] Open
Abstract
Estrogen is a commonly used hormone in the adjuvant treatment of intrauterine adhesion (IUA), which can promote endometrial growth. Stem cell transplantation has also been reported to promote endometrial regeneration in IUA due to its potential differentiative capacity. Human Wharton's jelly mesenchymal stem cells (WJ-MSCs) are isolated from the umbilical cord, possess strong self-renewal and proliferative abilities, and are hypo-immunogenic and non-tumorigenic. Therefore, the present study aimed to investigate the therapeutic effects and underlying mechanism of WJ-MSCs transplantation with estrogen treatment, separately or as a combined therapy, on IUA. The IUA model was established using the ethanol damage method. A total of 50 Sprague-Dawley female rats were randomly divided into the control, IUA model, WJ-MSCs treatment, estrogen treatment and WJ-MSCs+ estrogen treatment groups (n=10/group). WJ-MSCs were injected three times at 5-day intervals. IUA rats in the estrogen group received 0.2 mg/kg estrogen through intragastric administration, once every 2 days for 8 weeks. Morphological changes were evaluated by hematoxylin-eosin staining. Immunohistochemical evaluations of pan-keratin, vimentin, transforming growth factor (TGF)-β1, RhoA, RhoB, RhoC, Rho-associated coiled-coil-containing protein kinase (ROCK)I, and ROCKII expression were performed in uterine tissue. After treatment, the uterine specimens were observed to have increased uterine thickness and gland numbers in all treatment groups compared with the IUA group; however, the degree of restoration in the independent WJ-MSCs and estrogen treatment groups was better than in the combined treatment group. Immunohistochemical analysis demonstrated that pan-keratin expression was increased, and RhoA, ROCKI and TGF-β1 expression was significantly inhibited in the WJ-MSCs and WJ-MSCs + estrogen treatment groups compared with the IUA group; however, the expression levels of these proteins were similar among all treatment groups. No change in vimentin expression was detected in any treatment group. The expression levels of RhoB, RhoC and ROCKII were clearly not affected by WJ-MSCs intervention alone. In conclusion, transplantation of WJ-MSCs may repair endometrial damage in IUA rats via TGF-β1-mediated inhibition of RhoA/ROCKI signaling.
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Affiliation(s)
- Jun Li
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Bo Huang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Lan Dong
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yajuan Zhong
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zhixin Huang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Qiu J, Wang Y, Guo W, Xu L, Mou Y, Cui L, Han F, Sun Y. Role of TGF-β1-mediated epithelial-mesenchymal transition in the pathogenesis of tympanosclerosis. Exp Ther Med 2020; 21:6. [PMID: 33235615 PMCID: PMC7678609 DOI: 10.3892/etm.2020.9438] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023] Open
Abstract
The present study aimed to explore the role of TGF-β1-mediated epithelial-mesenchymal transition (EMT) in the pathogenesis of tympanosclerosis. Sprague Dawley rats were injected with inactivated Streptococcus pneumoniae suspension to establish a rat model of tympanosclerosis. The rats were sacrificed 8 weeks after the model was established. H&E and von Kossa staining was used to observe the morphological changes of middle ear mucosa. Western blotting was used to detect the expression of TGF-β1 and EMT-associated proteins in the mucosa samples. Middle ear mucosal epithelial cells of rats were collected to establish a primary culture. The cultured cells were stimulated with TGF-β1 and the expression of EMT-associated proteins was detected by western blotting and immunofluorescence. In addition, the cells were treated with TGF-β receptor type I/II inhibitor and the expression level of EMT-associated proteins was detected by western blotting. Sclerotic lesions appeared on 72.4% of tympanic membranes, and marked inflammation, inflammatory cell infiltration and fibrosis were found in the middle ear mucosa of rat models of tympanosclerosis. In middle ear mucosa of rats with tympanosclerosis, the expression of mesenchymal cell markers increased and that of epithelial cell markers decreased compared with the control group. TGF-β1 stimulated the activation of the EMT pathway in middle ear mucosal epithelial cells, resulting in an increased expression of fibronectin and N-cadherin. In addition, a decreased expression level of EMT-associated proteins was observed when TGF-β1 was inhibited. In conclusion, the present study indicated that TGF-β1-mediated EMT may play an important role in the pathogenesis of tympanosclerosis.
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Affiliation(s)
- Jingjing Qiu
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Yanmei Wang
- Department of Blood Purification, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Wentao Guo
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Ling Xu
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Yakui Mou
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Limei Cui
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Fengchan Han
- Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Yan Sun
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
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Song Q, Yang L, Han Z, Wu X, Li R, Zhou L, Liu N, Sui H, Cai J, Wang Y, Ji Q, Li Q. Tanshinone IIA Inhibits Epithelial-to-Mesenchymal Transition Through Hindering β-Arrestin1 Mediated β-Catenin Signaling Pathway in Colorectal Cancer. Front Pharmacol 2020; 11:586616. [PMID: 33192529 PMCID: PMC7658606 DOI: 10.3389/fphar.2020.586616] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 09/30/2020] [Indexed: 12/24/2022] Open
Abstract
Tanshinone IIA (Tan IIA) is a major active ingredient extracted from Salvia miltiorrhiza, which has been proved to be able to inhibit metastasis of various cancers including colorectal cancer (CRC). However, the mechanisms of anti-metastatic effect of Tan IIA on CRC are not well explored. A number of studies indicate that epithelial-to-mesenchymal transition (EMT) plays an important role in CRC metastasis, and our previous studies demonstrate that β-arrestin1could regulate EMT in CRC partly through β-catenin signaling pathway. In this work, we investigate whether Tan IIA could regulate EMT in CRC through β-arrestin1-mediated β-catenin signaling pathway both in vivo and in vitro. Our results showed that Tan IIA inhibited lung metastases of CRC cells in vivo and extended the survival time of mice with CRC. In vitro, Tan IIA increased the expression of E-cadherin, decreased the expression of Snail, N-cadherin and Vimentin, thus suppressed EMT and the migratory ability of CRC cells. Further study found that the mechanism of action of Tan IIA in regulating EMT and metastasis is associated with the suppression of β-arrestin1 expression, resulting in the increase of GSK-3β expression, reduction of β-catenin nuclear localization, thereby decreased the activity of β-catenin signaling pathway. Our data revealed a new mechanism of Tan IIA on the suppression of EMT and metastasis in CRC via β-arrestin1-mediated β-catenin signaling pathway and provided support for using Tan IIA as anti-metastatic agents in CRC.
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Affiliation(s)
- Qing Song
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Medical Oncology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Liu Yang
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Oncology, Baoshan Branch, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhifen Han
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinnan Wu
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ruixiao Li
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lihong Zhou
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ningning Liu
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hua Sui
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianfeng Cai
- Department of Chemistry, University of South Florida, Tampa, FL, United States
| | - Yan Wang
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qing Ji
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qi Li
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Guo Q, Zhang N, Liu S, Pang Z, Chen Z. By targeting TRAF6, miR-140-3p inhibits TGF-β1-induced human osteosarcoma epithelial-to-mesenchymal transition, migration, and invasion. Biotechnol Lett 2020; 42:2123-2133. [PMID: 32562135 DOI: 10.1007/s10529-020-02943-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 06/13/2020] [Indexed: 11/25/2022]
Abstract
OBJECTIVES We evaluated the effects of miR-140-3p on EMT, cellular migration, and invasion in TGF-β1 treated human OS cells. Human fresh OS tissue and normal bone tissue specimens were gathered from 42 patients (29 male and 13 female, 11 to 24 years of age with a mean age of 17.5 ± 2.3 years) diagnosed with OS by pathology. By targeting TRAF6, miR-140-3p inhibits TGF-β1-induced human osteosarcoma epithelial-to-mesenchymal transition, migration, and invasion. RESULTS In this study, we found microRNA (miR)-140-3p to be down-regulated and tumor necrosis factor receptor-associated factor 6 (TRAF6) to be up-regulated in patient OS samples. Lower levels of miR-140-3p and higher levels of TRAF6 were found in the advanced Enneking stage of OS. Furthermore, both mRNA and protein levels of TRAF6 were negatively associated with miR-140-3p mRNA expression in human OS tissue. TRAF6 was verified as a direct target of miR-140-3p in TGF-β1-treated human U2OS cells. Further, a miR-140-3p mimic dramatically inhibited while a miR-140-3p inhibitor enhanced TGF-β1-induced epithelial-to-mesenchymal transition, migration, and invasion of U2OS cells. Small interfering RNA was found to silence TRAF6 and to partly reverse the effects of the miR-140-3p inhibitor on TGF-β1-treated U2OS cells in vitro. CONCLUSION These results demonstrate miR-140-3p to function as a tumor inhibitor of human OS cells by decreasing TRAF6 expression. miR-140-3p and TRAF6 may be valuable and novel biomarkers for diagnosis and treatment of OS.
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Affiliation(s)
- Qianchen Guo
- Department of Orthopaedics, General Hospital of Tianjin Medical University, 154, Anshan road, Heping district, Tianjin, 300052, China.
| | - Nai Zhang
- Department of Neurosurgery, General Hospital of Tianjin Medical University, Tianjin, 300052, China
| | - Shen Liu
- Department of Orthopaedics, General Hospital of Tianjin Medical University, 154, Anshan road, Heping district, Tianjin, 300052, China
| | - Zixuan Pang
- Department of Orthopaedics, The Seventh People's Hospital of Hebei Province, Dingzhou, 073000, Hebei, China
| | - Zhao Chen
- Department of Orthopaedics, General Hospital of Tianjin Medical University, 154, Anshan road, Heping district, Tianjin, 300052, China
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Lemieszek MK, Rzeski W, Golec M, Mackiewicz B, Zwoliński J, Dutkiewicz J, Milanowski J. Pantoea agglomerans chronic exposure induces epithelial-mesenchymal transition in human lung epithelial cells and mice lungs. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 194:110416. [PMID: 32146192 DOI: 10.1016/j.ecoenv.2020.110416] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/27/2020] [Accepted: 03/01/2020] [Indexed: 06/10/2023]
Abstract
Pantoea agglomerans is gram-negative bacteria widely distributed in nature. It predominates in inhalable dust from grain, herbs, and flax, and was identified as the most important cause of hypersensitivity pneumonitis (HP) in eastern Poland. To better understand the molecular mechanism of HP development studies focused on the interactions between P. agglomerans and alveolar epithelial cells as well as lung tissue with particular emphasis on the epithelial-mesenchymal transition (EMT). The studies were conducted on human normal lung epithelial NL20 cells and mice strain C57BL/6J. Cells and mice underwent chronic exposure to saline extract of P. agglomerans (SE-PA). Morphological changes were evaluated under light microscopy, the concentration of fibrosis markers was examined by the ELISA method, while the expression of genes involved in EMT was evaluated by RealTime PCR. During incubation with SE-PA epithelial cells underwent conversion and assumed fibroblast phenotype characterized by a decrease in epithelial cells markers (CDH1, CLDN1, JUP) and increase in mesenchymal cells markers (FN1, VIM, CDH2). Mice lungs collected after 14 days of SE-PA treatment revealed inflammation with marked lymphocytes infiltration. The intensified inflammatory process accompanied by increased proliferation of fibrous connective tissue was noted in mice lungs after 28 days of SE-PA exposure. Histological changes correlated with an increase of fibrosis markers (hydroxyproline, collagens), downregulation of epithelial markers (Cdh1, Cldn1, Jup, Ocln) and upregulation of myofibroblasts markers (Acta2, Cdh2, Fn1, Vim). Obtained results revealed SE-PA ability to induce EMT in human lung epithelial cells and mice lung tissue, with the scale of changes proportional to the time of treatment.
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Affiliation(s)
| | - Wojciech Rzeski
- Department of Medical Biology, Institute of Rural Health, Lublin, Poland; Department of Functional Anatomy and Cytobiology, Maria Curie-Skłodowska University, Lublin, Poland
| | - Marcin Golec
- Unit of Fibroproliferative Diseases, Institute of Rural Health, Lublin, Poland
| | - Barbara Mackiewicz
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| | - Jacek Zwoliński
- Department of Biological Health Hazards and Parasitology, Institute of Rural Health, Lublin, Poland
| | - Jacek Dutkiewicz
- Department of Biological Health Hazards and Parasitology, Institute of Rural Health, Lublin, Poland
| | - Janusz Milanowski
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
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Ghamari SH, Abbasi-Kangevari M, Tayebi T, Bahrami S, Niknejad H. The Bottlenecks in Translating Placenta-Derived Amniotic Epithelial and Mesenchymal Stromal Cells Into the Clinic: Current Discrepancies in Marker Reports. Front Bioeng Biotechnol 2020; 8:180. [PMID: 32232037 PMCID: PMC7083014 DOI: 10.3389/fbioe.2020.00180] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 02/24/2020] [Indexed: 12/23/2022] Open
Abstract
Placenta-derived amniotic cells have prominent features for application in regenerative medicine. However, there are still discrepancies in the characterization of human amniotic epithelial and mesenchymal stromal cells. It seems crucial that the characterization of human amniotic membrane cells be investigated to determine whether there are currently discrepancies in their characterization reports. In addition, possible causes for the witnessed discrepancies need to be addressed toward paving the way for further clinical application and safer practices. The objective of this review is to investigate the marker characterization as well as the potential causes of the discrepancies in the previous reports on placenta-derived amniotic epithelial and mesenchymal stromal cells. The current discrepancies could be potentially due to reasons including passage number and epithelial to mesenchymal transition (EMT), cell heterogeneity, isolation protocols and cross-contamination, the region of cell isolation on placental disk, measuring methods, and gestational age.
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Affiliation(s)
- Seyyed-Hadi Ghamari
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohsen Abbasi-Kangevari
- Student Research Committee, Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tahereh Tayebi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soheyl Bahrami
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, Vienna, Austria
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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41
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Advances in pathogenic mechanisms and management of radiation-induced fibrosis. Biomed Pharmacother 2020; 121:109560. [DOI: 10.1016/j.biopha.2019.109560] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 10/04/2019] [Accepted: 10/17/2019] [Indexed: 12/12/2022] Open
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Ferraz LR, Moreira BC, de Queiroz GDSR, Formigari RDF, Esquisatto MAM, Felonato M, Alves AA, Thomazini BF, de Oliveira CA. Tissue-specific transcriptional regulation of epithelial/endothelial and mesenchymal markers during renovascular hypertension. Mol Med Rep 2019; 20:4467-4476. [PMID: 31702037 PMCID: PMC6797995 DOI: 10.3892/mmr.2019.10722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 07/22/2019] [Indexed: 01/03/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition are processes that can occur under different biological conditions, including tissue healing due to hypertension and oxidative stress. The purpose of the present study was to evaluate the differences in gene expression of epithelial/endothelial and mesenchymal markers in different tissues. A two-kidney, one-clip (2K1C) renovascular hypertension rat model was used. Hypertension was induced by the clipping of the left renal artery; the rats were randomized into sham and 2K1C groups and monitored for up to 4 weeks. The gene expressions of E-cadherin (E-cad), N-cadherin (N-cad), α-smooth muscle actin (α-SMA), collagen I (COL1A1), collagen III (COL3A1) and hepatocyte growth factor (HGF) were determined by reverse transcription-PCR. The levels of the cytokines transforming growth factor-β1, tumor necrosis factor-α, interleukin (IL)-4, IL-6 and IL-10 were evaluated using ELISAs. The levels of thiobarbituric acid reactive substances and thiol groups were measured to evaluate oxidative stress. All analyses were performed on the liver, heart and kidneys tissues of sham and model rats. The 2K1C animals exhibited a higher systolic blood pressure, as well as cardiac hypertrophy and atrophy of the left kidney. Fibrotic alterations in the heart and kidneys were observed, as was an increase in the collagen fiber areas, and higher levels of inflammatory cytokines, which are associated with the increased expression of fibroproliferative and anti-fibrotic genes. Renovascular hypertension regulated epithelial/endothelial and mesenchymal markers, including E-cad, N-cad, α-SMA and COL1A1 in the kidneys and heart. EMT in the kidneys was mediated by an increased level of inflammatory and profibrotic cytokines, as well as by oxidative stress. The data in the present study suggested that the expression of epithelial/endothelial and mesenchymal markers are differentially regulated by hypertension in the liver, heart and kidneys.
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Affiliation(s)
- Leandro Ricardo Ferraz
- Graduate Program in Biomedical Sciences, University Center of the Hermínio Ometto Foundation, Araras, São Paulo 13607-339, Brazil
| | - Bianca Caruso Moreira
- Graduate Program in Biomedical Sciences, University Center of the Hermínio Ometto Foundation, Araras, São Paulo 13607-339, Brazil
| | | | - Regiane de Freitas Formigari
- Graduate Program in Biomedical Sciences, University Center of the Hermínio Ometto Foundation, Araras, São Paulo 13607-339, Brazil
| | | | - Maira Felonato
- Graduate Program in Biomedical Sciences, University Center of the Hermínio Ometto Foundation, Araras, São Paulo 13607-339, Brazil
| | - Armindo Antonio Alves
- Graduate Program in Biomedical Sciences, University Center of the Hermínio Ometto Foundation, Araras, São Paulo 13607-339, Brazil
| | - Bruna Fontana Thomazini
- Graduate Program in Biomedical Sciences, University Center of the Hermínio Ometto Foundation, Araras, São Paulo 13607-339, Brazil
| | - Camila Andréa de Oliveira
- Graduate Program in Biomedical Sciences, University Center of the Hermínio Ometto Foundation, Araras, São Paulo 13607-339, Brazil
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Presence of Stromal Cells Enhances Epithelial-to-Mesenchymal Transition (EMT) Induction in Lung Bronchial Epithelium after Protracted Exposure to Oxidative Stress of Gamma Radiation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4120379. [PMID: 31583039 PMCID: PMC6754954 DOI: 10.1155/2019/4120379] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/19/2019] [Accepted: 07/23/2019] [Indexed: 02/03/2023]
Abstract
The aim of the study was to investigate the role of a microenvironment in the induction of epithelial-to-mesenchymal transition (EMT) as a sign of early stages of carcinogenesis in human lung epithelial cell lines after protracted low-dose rate γ-radiation exposures. BEAS-2B and HBEC-3KT lung cell lines were irradiated with low-dose rate γ-rays (137Cs, 1.4 or 14 mGy/h) to 0.1 or 1 Gy with or without adding TGF-β. TGF-β-treated samples were applied as positive EMT controls and tested in parallel to find out if the radiation has a potentiating effect on the EMT induction. To evaluate the effect of the stromal component, the epithelial cells were irradiated in cocultures with stromal MRC-9 lung fibroblasts. On day 3 post treatment, the EMT markers: α-SMA, vimentin, fibronectin, and E-cadherin, were analyzed. The oxidative stress levels were evaluated by 8-oxo-dG analysis in both epithelial and fibroblast cells. The protracted exposure to low Linear Energy Transfer (LET) radiation at the total absorbed dose of 1 Gy was able to induce changes suggestive of EMT. The results show that the presence of the stromal component and its signaling (TGF-β) in the cocultures enhances the EMT. Radiation had a minor cumulative effect on the TGF-β-induced EMT with both doses. The oxidative stress levels were higher than the background in both epithelial and stromal cells post chronic irradiation (0.1 and 1 Gy); as for the BEAS-2B cell line, the increase was statistically significant. We suggest that the induction of EMT in bronchial epithelial cells by radiation requires more than single acute exposure and the presence of stromal component might enhance the effect through free radical production and accumulation.
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George B, Rivera Rolon MDM, Mohit S, Stevenson HL. Epithelial to mesenchymal transition in endomyocardial biopsies from orthotopic heart transplant recipients. BMJ Case Rep 2019; 12:12/8/e229175. [PMID: 31444257 PMCID: PMC6720799 DOI: 10.1136/bcr-2018-229175] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Epithelial to mesenchymal transition (EMT) occurs when cells lose morphological features of epithelial cells, such as cell-to-cell adhesion, and gain features of mesenchymal cells, including elongation and flattening. These cells also lose expression of epithelial immunohistochemical markers. In this report, we present a 55-year-old Caucasian male patient who underwent orthotopic heart transplant and immunosuppressant therapy with tacrolimus and mycophenolic acid. Seven and a half months later, an endomyocardial biopsy revealed a hypercellular, atypical lesion. Evaluation was negative for acute cellular rejection and post-transplant lymphoproliferative disorder. Histopathologic features and immunohistochemical stains were consistent with EMT. We subsequently identified four additional cases of EMT in patients who underwent orthotopic heart transplantation and received a similar immune suppression regimen. EMTs have been reported to occur in lung and kidney allografts; however, this is the first known report describing this entity in a heart transplant recipient.
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Affiliation(s)
- Bistees George
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | | | - Sharma Mohit
- Department of Cardiology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
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Advances in Molecular Mechanisms and Immunotherapy Involving the Immune Cell-Promoted Epithelial-to-Mesenchymal Transition in Lung Cancer. JOURNAL OF ONCOLOGY 2019; 2019:7475364. [PMID: 31531020 PMCID: PMC6721259 DOI: 10.1155/2019/7475364] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/24/2019] [Accepted: 08/04/2019] [Indexed: 12/16/2022]
Abstract
Immunotherapy has offered a new opportunity for the treatment of many malignancies. In patients with lung cancer, immune checkpoint inhibitors have significantly improved survival. However, little is known about predictive factors or primary and acquired resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is a complex of phenotypic changes involved in carcinogenesis and resistance to cancer treatments. Specifically, immune cells in the tumor microenvironment can promote EMT, and mesenchymal phenotype acquisition negatively regulates the anticancer immune response. EMT is associated with higher expression of PD-L1 and other immune checkpoints. In this review, we focused on the role of EMT in the interplay between tumor cells and the immune system, with particular emphasis on lung cancer. On the basis of our findings, we hypothesize that the effects of EMT on immune cells could be overcome in this disease by a new combination of immune checkpoint inhibitors.
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Nanofiber-expanded human CD34 + cells heal cutaneous wounds in streptozotocin-induced diabetic mice. Sci Rep 2019; 9:8415. [PMID: 31182750 PMCID: PMC6557810 DOI: 10.1038/s41598-019-44932-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 05/28/2019] [Indexed: 12/29/2022] Open
Abstract
Despite advances in diabetic wound care, the significant number of amputations that occur every year demands more effective therapeutics. Herein, we offer an aminated polyethersulfone nanofiber-expanded human umbilical cord blood-derived CD34+ cells (henceforth CD34+ cells) effective therapy, tested in cutaneous wounds developed in streptozotocin-induced diabetic NOD/SCID mice. We show that systemic administration of CD34+ cells homed to the wound site and significantly accelerated wound closure. Wound closure was associated with improved re-epithelialization and increased neovascularization; and with decreased sustained pro-inflammatory activity of NF-κB and its downstream effector molecules TNF-α, IL-1β, and IL-6 at the wound bed. This finding was further supported by the observation of a decreased number of myeloperoxidase positive neutrophils, and concomitantly increased levels of IL-10. In addition, improved granulation tissue formation was observed along with higher collagen deposition and myofibroblasts and decreased expressions of MMP-1. Mechanistically, CD34+ cells reduced the level of MMP-1 expression by inhibiting recruitment of NF-κB to the MMP-1 promoter site in dermal fibroblasts. In summary, we provide evidence of a novel nanofiber-expanded CD34+ stem cell therapeutic development for treating diabetic wounds by defining their cellular and molecular mechanisms.
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MicroRNA-34a inhibits epithelial-mesenchymal transition of lens epithelial cells by targeting Notch1. Exp Eye Res 2019; 185:107684. [PMID: 31158382 DOI: 10.1016/j.exer.2019.05.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 04/16/2019] [Accepted: 05/28/2019] [Indexed: 01/08/2023]
Abstract
Posterior capsule opacification (PCO) is a common long-term complication of modern cataract surgery. The epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a crucial process in the development of PCO. The purpose of this study is to investigate the role of microRNA-34a (miR-34a) in the regulation of EMT and its target gene. Human LECs were treated with TGFβ2 to induce EMT as a model for PCO. The mRNA levels of miR-34a and EMT markers were examined by real-time quantitative polymerase chain reaction (qPCR). The expression level of miR-34a was downregulated, whereas that of Notch1 was upregulated in TGFβ2-induced EMT of LECs. Overexpression of miR-34a by transfection with miR-34a inhibited EMT of LECs and reduced the expression of Notch1; while, inhibition of miR-34a upregulated the expression of both Notch1 and its ligand Jagged1 in LECs. Luciferase reporter assays revealed that Notch1 gene was direct target of miR-34a. Moreover, DAPT, a specific inhibitor of Notch signaling pathway, reversed LEC-EMT. In addition, the expression level of miR-34a was downregulated, whereas that of Notch1 was upregulated in capsular opacification from cataract samples. MiR-34a can negatively regulate EMT of LECs by targeting Notch1. Therefore, miR-34a/Notch1 could serve as a potential therapeutic approach for the treatment of PCO.
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Qu Y, Liu D, Jia H, Yang Z. Circular RNA rno_circ_0004002 regulates cell proliferation, apoptosis, and epithelial‐mesenchymal transition through targeting miR‐342‐5p and Wnt3a in anorectal malformations. J Cell Biochem 2019; 120:15483-15493. [PMID: 31074015 DOI: 10.1002/jcb.28814] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 02/14/2019] [Accepted: 02/27/2019] [Indexed: 01/09/2023]
Affiliation(s)
- Yuan Qu
- Department of Pediatric Surgery, Shengjing Hospital China Medical University Shenyang Liaoning China
| | - Dan Liu
- Department of Pediatric Surgery, Shengjing Hospital China Medical University Shenyang Liaoning China
| | - Huimin Jia
- Department of Pediatric Surgery, Shengjing Hospital China Medical University Shenyang Liaoning China
| | - Zhonghua Yang
- Department of Pediatric Surgery, Shengjing Hospital China Medical University Shenyang Liaoning China
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Fintha A, Gasparics Á, Rosivall L, Sebe A. Therapeutic Targeting of Fibrotic Epithelial-Mesenchymal Transition-An Outstanding Challenge. Front Pharmacol 2019; 10:388. [PMID: 31057405 PMCID: PMC6482168 DOI: 10.3389/fphar.2019.00388] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 03/29/2019] [Indexed: 12/11/2022] Open
Abstract
Back in 1995, a landmark paper was published, which shaped the fibrosis literature for many years to come. During the characterization of a fibroblast-specific marker (FSP1) in the kidneys, an observation was made, which gave rise to the hypothesis that “fibroblasts in some cases arise from the local conversion of epithelium.” In the following years, epithelial-mesenchymal transition was in the spotlight of fibrosis research, especially in the kidney. However, the hypothesis came under scrutiny following some discouraging findings from lineage tracing experiments and clinical observations. In this review, we provide a timely overview of the current position of the epithelial-mesenchymal transition hypothesis in the context of fibrosis (with a certain focus on renal fibrosis) and highlight some of the potential hurdles and pitfalls preventing therapeutic breakthroughs targeting fibrotic epithelial-mesenchymal transition.
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Affiliation(s)
- Attila Fintha
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Ákos Gasparics
- 1st Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary
| | - László Rosivall
- Department of Pathophysiology, International Nephrology Research and Training Center, Semmelweis University, Budapest, Hungary
| | - Attila Sebe
- Department of Pathophysiology, International Nephrology Research and Training Center, Semmelweis University, Budapest, Hungary.,Division of Medical Biotechnology, Paul Ehrlich Institute, Langen, Germany
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Elufioye TO, Habtemariam S. Hepatoprotective effects of rosmarinic acid: Insight into its mechanisms of action. Biomed Pharmacother 2019; 112:108600. [PMID: 30780110 DOI: 10.1016/j.biopha.2019.108600] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 01/11/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
Liver diseases such as hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma are one of the major health challenges in the world and many conditions such as inadequate nutrition, viral infection, ethanol and drug abuse, xenobiotic exposure, and metabolic diseases have been implicated in the development and progression of liver diseases. Several factors including lipid peroxidation, production of reactive oxygen species (ROS), peroxynitrite formation, complement factors and proinflammatory mediators, such as cytokines and chemokines, are involved in hepatic diseases. Rosmarinic acid (RA) is a natural phenolic compound found mainly in the family Lamiaceae consisting of several medicinal plants, herbs and spices. Several biological activities have been reported for RA and these include antioxidant properties as a ROS scavenger and lipid peroxidation inhibitor, anti-inflammatory, neuroprotective and antiangiogenic among others. This review is aimed at discussing the effects of RA on the liver, highlighting its hepatoprotective potential and the underlying mechanisms.
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Affiliation(s)
- Taiwo O Elufioye
- Department of Pharmacognosy, Faculty of Pharmacy, University of Ibadan, Nigeria.
| | - Solomon Habtemariam
- Pharmacognosy Research Laboratories & Herbal Analysis Services, University of Greenwich, Chatham, Maritime Kent, ME4 4TB, UK
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