|
1
|
Kalafateli M, Tourkochristou E, Tsounis EP, Aggeletopoulou I, Triantos C. New Insights into the Pathogenesis of Intestinal Fibrosis in Inflammatory Bowel Diseases: Focusing on Intestinal Smooth Muscle Cells. Inflamm Bowel Dis 2025; 31:579-592. [PMID: 39680685 DOI: 10.1093/ibd/izae292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Indexed: 12/18/2024]
Abstract
Strictures in inflammatory bowel disease, especially Crohn's disease (CD), are characterized by increased intestinal wall thickness, which, according to recent accumulating data, is mainly attributed to the expansion of the intestinal smooth muscle layers and to a lesser extent to collagen deposition. In this review, we will discuss the role of intestinal smooth muscle cells (SMCs) as crucial orchestrators of stricture formation. Activated SMCs can synthesize extracellular matrix (ECM), thus contributing to intestinal fibrosis, as well as growth factors and cytokines that can further enhance ECM production, stimulate other surrounding mesenchymal and immune cells, and increase SMC proliferation via paracrine or autocrine signaling. There is also evidence that, in stricturing CD, a phenotypic modulation of SMC toward a myofibroblast-like synthetic phenotype takes place. Moreover, the molecular mechanisms and signaling pathways that regulate SMC hyperplasia/hypertrophy will be extensively reviewed. The understanding of the cellular network and the molecular background behind stricture formation is essential for the design of effective anti-fibrotic strategies, and SMCs might be a promising therapeutic target in the future.
Collapse
Affiliation(s)
- Maria Kalafateli
- Department of Gastroenterology, General Hospital of Patras, Patras, Greece
| | - Evanthia Tourkochristou
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Efthymios P Tsounis
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Christos Triantos
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| |
Collapse
|
|
2
|
Liu S, Li J, Wang W, Zhang Y, Li S, Li T, Jiang J, Zhao F. Prenatal exposure to dibutyl phthalate contributes to erectile dysfunction in offspring male rats by activating the RhoA/ROCK signalling pathway. Toxicology 2024; 508:153925. [PMID: 39151608 DOI: 10.1016/j.tox.2024.153925] [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: 06/11/2024] [Revised: 08/01/2024] [Accepted: 08/12/2024] [Indexed: 08/19/2024]
Abstract
Prenatal exposure to dibutyl phthalate (DBP) has been reported to cause erectile dysfunction (ED) in adult offspring rats. However, its underlying mechanisms are not fully understood. Previously, we found that DBP activates the RhoA/ROCK pathway in the male reproductive system. This study investigated how prenatal exposure to DBP activates the RhoA/ROCK signalling pathway, leading to ED in male rat offspring. Pregnant rats were stratified into DBP-exposed and NC groups, with the exposed group receiving 750 milligrams per kilogram per day (mg/kg/day) of DBP through gavage from days 14-18 of gestation. DBP exposure activated the RhoA/ROCK pathway in the penile corpus cavernosum (CC) of descendants, causing smooth muscle cell contraction, fibrosis, and apoptosis, all of which contribute to ED. In vitro experiments confirmed that DBP induces apoptosis and RhoA/ROCK pathway activation in CC smooth muscle cells. Treatment of DBP-exposed offspring with the ROCK inhibitor Y-27632 for 8 weeks significantly improved smooth muscle cell condition, erectile function, and reduced fibrosis. Thus, prenatal DBP exposure induces ED in offspring through RhoA/ROCK pathway activation, and the ROCK inhibitor Y-27632 shows potential as an effective treatment for DBP-induced ED.
Collapse
Affiliation(s)
- Siyu Liu
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Jianying Li
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Wenhao Wang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Yijun Zhang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Shufeng Li
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Tiewen Li
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Juntao Jiang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
| | - Fujun Zhao
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
| |
Collapse
|
|
3
|
Saha B, Pallatt S, Banerjee A, Banerjee AG, Pathak R, Pathak S. Current Insights into Molecular Mechanisms and Potential Biomarkers for Treating Radiation-Induced Liver Damage. Cells 2024; 13:1560. [PMID: 39329744 PMCID: PMC11429644 DOI: 10.3390/cells13181560] [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: 08/07/2024] [Revised: 09/10/2024] [Accepted: 09/11/2024] [Indexed: 09/28/2024] Open
Abstract
Highly conformal delivery of radiation therapy (RT) has revolutionized the treatment landscape for primary and metastatic liver cancers, yet concerns persist regarding radiation-induced liver disease (RILD). Despite advancements, RILD remains a major dose-limiting factor due to the potential damage to normal liver tissues by therapeutic radiation. The toxicity to normal liver tissues is associated with a multitude of physiological and pathological consequences. RILD unfolds as multifaceted processes, intricately linking various responses, such as DNA damage, oxidative stress, inflammation, cellular senescence, fibrosis, and immune reactions, through multiple signaling pathways. The DNA damage caused by ionizing radiation (IR) is a major contributor to the pathogenesis of RILD. Moreover, current treatment options for RILD are limited, with no established biomarker for early detection. RILD diagnosis often occurs at advanced stages, highlighting the critical need for early biomarkers to adjust treatment strategies and prevent liver failure. This review provides an outline of the diverse molecular and cellular mechanisms responsible for the development of RILD and points out all of the available biomarkers for early detection with the aim of helping clinicians decide on advance treatment strategies from a single literature recourse.
Collapse
Affiliation(s)
- Biki Saha
- Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
| | - Sneha Pallatt
- Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
| | - Antara Banerjee
- Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
| | - Abhijit G. Banerjee
- R&D, Genomic Bio-Medicine Research and Incubation (GBMRI), Durg 491001, Chhattisgarh, India
| | - Rupak Pathak
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Surajit Pathak
- Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
| |
Collapse
|
|
4
|
Veisman I, Massey WJ, Goren I, Liu W, Chauhan G, Rieder F. Muscular hyperplasia in Crohn's disease strictures: through thick and thin. Am J Physiol Cell Physiol 2024; 327:C671-C683. [PMID: 38912732 PMCID: PMC11427014 DOI: 10.1152/ajpcell.00307.2024] [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: 05/06/2024] [Revised: 06/18/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Fibrostenosing Crohn's disease (CD) represents a challenging clinical condition characterized by the development of symptomatic strictures within the gastrointestinal tract. Despite therapeutic advancements in managing inflammation, the progression of fibrostenotic complications remains a significant concern, often necessitating surgical intervention. Recent investigations have unveiled the pivotal role of smooth muscle cell hyperplasia in driving luminal narrowing and clinical symptomatology. Drawing parallels to analogous inflammatory conditions affecting other organs, such as the airways and blood vessels, sheds light on common underlying mechanisms of muscular hyperplasia. This review synthesizes current evidence to elucidate the mechanisms underlying smooth muscle cell proliferation in CD-associated strictures, offering insights into potential therapeutic targets. By highlighting the emerging significance of muscle thickening as a novel therapeutic target, this review aims to inform future research endeavors and clinical strategies with the goal to mitigate the burden of fibrostenotic complications in CD and other conditions.
Collapse
Affiliation(s)
- Ido Veisman
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
| | - William J Massey
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
| | - Idan Goren
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
| | - Weiwei Liu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
| | - Gaurav Chauhan
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
- Cleveland Clinic Program for Global Translational Inflammatory Bowel Diseases (GRID), Cleveland, Ohio, United States
| |
Collapse
|
|
5
|
Wei JY, Ma LX, Liu WT, Dong LH, Hou X, Bao XY, Hou W. Mechanisms and protective measures for radiation-induced brachial plexus nerve injury. Brain Res Bull 2024; 210:110924. [PMID: 38460911 DOI: 10.1016/j.brainresbull.2024.110924] [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: 10/07/2023] [Revised: 02/06/2024] [Accepted: 03/06/2024] [Indexed: 03/11/2024]
Abstract
Radiation therapy is a common treatment modality for patients with malignant tumors of the head and neck, chest and axilla. However, radiotherapy inevitably causes damage to normal tissues at the irradiated site, among which damage to the brachial plexus nerve(BP) is a serious adverse effect in patients receiving radiation therapy in the scapular or axillary regions, with clinical manifestations including abnormal sensation, neuropathic pain, and dyskinesia, etc. These adverse effects seriously reduce the living quality of patients and pose obstacles to their prognosis. Therefore, it is important to elucidate the mechanism of radiation induced brachial plexus injury (RIBP) which remains unclear. Current studies have shown that the pathways of radiation-induced BP injury can be divided into two categories: direct injury and indirect injury, and the indirect injury is closely related to the inflammatory response, microvascular damage, cytokine production and other factors causing radiation-induced fibrosis. In this review, we summarize the underlying mechanisms of RIBP occurrence and possible effective methods to prevent and treat RIBP.
Collapse
Affiliation(s)
- Jia Ying Wei
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Li Xin Ma
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Wen Tong Liu
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Li Hua Dong
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Xue Hou
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Xue Ying Bao
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China
| | - Wei Hou
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China.
| |
Collapse
|
|
6
|
Zhang X, Tian B, Cong X, Ning Z. SLIT3 promotes cardiac fibrosis and differentiation of cardiac fibroblasts by RhoA/ROCK1 signaling pathway. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:832-840. [PMID: 38800023 PMCID: PMC11127076 DOI: 10.22038/ijbms.2024.73812.16044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/08/2023] [Indexed: 05/29/2024]
Abstract
Objectives Slit guidance ligand 3 (SLIT3) has been identified as a potential therapeutic regulator against fibroblast activity and fibrillary collagen production in an autocrine manner. However, this research aims to investigate the potential role of SLIT3 in cardiac fibrosis and fibroblast differentiation and its underlying mechanism. Materials and Methods C57BL/6 mice (male, 8-10 weeks, n=47) were subcutaneously infused with Ang II (2.0 mg/kg/day) for 4 weeks. One to two-day-old Sprague-Dawley (SD) rats were anesthetized by intraperitoneal injection of 1% pentobarbital sodium (60 mg/kg) and ketamine (50 mg/kg) and the cardiac fibroblast was isolated aseptically. The mRNA and protein expression were analyzed using RT-qPCR and Western blotting. Results The SLIT3 expression level was increased in Ang II-induced mice models and cardiac fibroblasts. SLIT3 significantly increased migrated cells and α-smooth muscle actin (α-SMA) expression in cardiac fibroblasts. Ang II-induced increases in mRNA expression of collagen I (COL1A1), and collagen III (COL3A1) was attenuated by SLIT3 inhibition. SLIT3 knockdown attenuated the Ang II-induced increase in mRNA expression of ACTA2 (α-SMA), Fibronectin, and CTGF. SLIT3 suppression potentially reduced DHE expression and decreased malondialdehyde (MDA) content, and the superoxide dismutase (SOD) and catalase (CAT) levels were significantly increased in cardiac fibroblasts. Additionally, SLIT3 inhibition markedly decreased RhoA and ROCK1 protein expression, whereas ROCK inhibitor Y-27632 (10 μM) markedly attenuated the migration of cardiac fibroblasts stimulated by Ang II and SLIT3. Conclusion The results speculate that SLIT3 could significantly regulate cardiac fibrosis and fibroblast differentiation via the RhoA/ROCK1 signaling pathway.
Collapse
Affiliation(s)
- Xiaogang Zhang
- Department of Cardiology, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital affiliated to Shanghai Medical College of Health), Pudong New District, Shanghai 201318, China
- These authors contributed equally to this work
| | - Bei Tian
- Department of Cardiology, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital affiliated to Shanghai Medical College of Health), Pudong New District, Shanghai 201318, China
- These authors contributed equally to this work
| | - Xinpeng Cong
- Department of Cardiology, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital affiliated to Shanghai Medical College of Health), Pudong New District, Shanghai 201318, China
| | - Zhongping Ning
- Department of Cardiology, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital affiliated to Shanghai Medical College of Health), Pudong New District, Shanghai 201318, China
| |
Collapse
|
|
7
|
Yu Z, Xu C, Song B, Zhang S, Chen C, Li C, Zhang S. Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances. J Transl Med 2023; 21:708. [PMID: 37814303 PMCID: PMC10563272 DOI: 10.1186/s12967-023-04554-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 09/22/2023] [Indexed: 10/11/2023] Open
Abstract
Cancer remains the leading cause of death around the world. In cancer treatment, over 50% of cancer patients receive radiotherapy alone or in multimodal combinations with other therapies. One of the adverse consequences after radiation exposure is the occurrence of radiation-induced tissue fibrosis (RIF), which is characterized by the abnormal activation of myofibroblasts and the excessive accumulation of extracellular matrix. This phenotype can manifest in multiple organs, such as lung, skin, liver and kidney. In-depth studies on the mechanisms of radiation-induced fibrosis have shown that a variety of extracellular signals such as immune cells and abnormal release of cytokines, and intracellular signals such as cGAS/STING, oxidative stress response, metabolic reprogramming and proteasome pathway activation are involved in the activation of myofibroblasts. Tissue fibrosis is extremely harmful to patients' health and requires early diagnosis. In addition to traditional serum markers, histologic and imaging tests, the diagnostic potential of nuclear medicine techniques is emerging. Anti-inflammatory and antioxidant therapies are the traditional treatments for radiation-induced fibrosis. Recently, some promising therapeutic strategies have emerged, such as stem cell therapy and targeted therapies. However, incomplete knowledge of the mechanisms hinders the treatment of this disease. Here, we also highlight the potential mechanistic, diagnostic and therapeutic directions of radiation-induced fibrosis.
Collapse
Affiliation(s)
- Zuxiang Yu
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Chaoyu Xu
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Bin Song
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
- NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang, 621099, China
| | - Shihao Zhang
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Chong Chen
- Department of Gastroenterology, The First People's Hospital of Xuzhou, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, 221200, China
| | - Changlong Li
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China.
- Department of Molecular Biology and Biochemistry, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.
| | - Shuyu Zhang
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China.
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China.
- NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang, 621099, China.
| |
Collapse
|
|
8
|
Sinitsky M, Asanov M, Sinitskaya A, Shishkova D, Khutornaya M, Minina V, Ponasenko A. Atorvastatin Can Modulate DNA Damage Repair in Endothelial Cells Exposed to Mitomycin C. Int J Mol Sci 2023; 24:ijms24076783. [PMID: 37047754 PMCID: PMC10094919 DOI: 10.3390/ijms24076783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/15/2023] [Accepted: 04/04/2023] [Indexed: 04/14/2023] Open
Abstract
HMG-CoA reductase inhibitors (statins) are widely used in the therapy of atherosclerosis and have a number of pleiotropic effects, including DNA repair regulation. We studied the cytogenetic damage and the expression of DNA repair genes (DDB1, ERCC4, and ERCC5) in human coronary artery (HCAEC) and internal thoracic artery endothelial cells (HITAEC) in vitro exposed to mitomycin C (MMC) (positive control), MMC and atorvastatin (MMC+Atv), MMC followed by atorvastatin treatment (MMC/Atv) and 0.9% NaCl (negative control). MMC/Atv treated HCAEC were characterized by significantly decreased micronuclei (MN) frequency compared to the MMC+Atv group and increased nucleoplasmic bridges (NPBs) frequency compared to both MMC+Atv treated cells and positive control; DDB1, ERCC4, and ERCC5 genes were upregulated in MMC+Atv and MMC/Atv treated HCAEC in comparison with the positive control. MMC+Atv treated HITAEC were characterized by reduced MN frequency compared to positive control and decreased NPBs frequency in comparison with both the positive control and MMC/Atv group. Nuclear buds (NBUDs) frequency was significantly lower in MMC/Atv treated cells than in the positive control. The DDB1 gene was downregulated in the MMC+Atv group compared to the positive control, and the ERCC5 gene was upregulated in MMC/Atv group compared to both the positive control and MMC+Atv group. We propose that atorvastatin can modulate the DNA damage repair response in primary human endothelial cells exposed to MMC in a cell line- and incubation scheme-dependent manner that can be extremely important for understanding the fundamental aspects of pleoitropic action of atorvastatin and can also be used to correct the therapy of patients with atherosclerosis characterized by a high genotoxic load.
Collapse
Affiliation(s)
- Maxim Sinitsky
- Laboratory of Genome Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo 650002, Russia
| | - Maxim Asanov
- Laboratory of Genome Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo 650002, Russia
| | - Anna Sinitskaya
- Laboratory of Genome Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo 650002, Russia
| | - Daria Shishkova
- Laboratory for Molecular, Translation and Digital Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo 650002, Russia
| | - Maria Khutornaya
- Laboratory of Genome Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo 650002, Russia
| | - Varvara Minina
- Department of Genetic and Fundamental Medicine, Kemerovo State University, Kemerovo 650000, Russia
| | - Anastasia Ponasenko
- Laboratory of Genome Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo 650002, Russia
| |
Collapse
|
|
9
|
Wang J, Han Y, Li Y, Zhang F, Cai M, Zhang X, Chen J, Ji C, Ma J, Xu F. Targeting Tumor Physical Microenvironment for Improved Radiotherapy. SMALL METHODS 2022; 6:e2200570. [PMID: 36116123 DOI: 10.1002/smtd.202200570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 08/23/2022] [Indexed: 06/15/2023]
Abstract
Radiotherapy has led to important clinical advances; existing cancer radiotherapy resistance is one remaining major challenge. Recently, biophysical cues in the tumor microenvironment (TME) have been regarded as the new hallmarks of cancer, playing pivotal roles in various cancer behaviors and treatment responses, including radiotherapy resistance. With recent advances in micro/nanotechnologies and functional biomaterials, radiotherapy exerts great influence on biophysical cues in TME, which, in turn, significantly affect the response to radiotherapy. Besides, various strategies have emerged that target biophysical cues in TME, to potentially enhance radiotherapy efficacy. Therefore, this paper reviews the four biophysical cues (i.e., extracellular matrix (ECM) microarchitecture, ECM stiffness, interstitial fluid pressure, and solid stress) that may play important roles in radiotherapy resistance, their possible mechanisms for inducing it, and their change after radiotherapy. The emerging therapeutic strategies targeting the biophysical microenvironment, to explore the mechanism of radiotherapy resistance and develop effective strategies to revert it for improved treatment efficacy are further summarized.
Collapse
Affiliation(s)
- Jin Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710061, P. R. China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P. R. China
| | - Yulong Han
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P. R. China
- State Key Laboratory of Mechanics and Control of Mechanical Structures, Nanjing University of Aeronautics and Astronautics, Nanjing, 210016, P. R. China
| | - Yuan Li
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P. R. China
- MOE Key Laboratory of Biomedical Information Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P. R. China
| | - Fengping Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710061, P. R. China
| | - Mengjiao Cai
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710061, P. R. China
| | - Xinyue Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710061, P. R. China
| | - Jie Chen
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710061, P. R. China
| | - Chao Ji
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710061, P. R. China
| | - Jinlu Ma
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710061, P. R. China
| | - Feng Xu
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P. R. China
- MOE Key Laboratory of Biomedical Information Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P. R. China
| |
Collapse
|
|
10
|
Zeng Q, Cheng J, Wu H, Liang W, Cui Y. The dynamic cellular and molecular features during the development of radiation proctitis revealed by transcriptomic profiling in mice. BMC Genomics 2022; 23:431. [PMID: 35681125 PMCID: PMC9178886 DOI: 10.1186/s12864-022-08668-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/30/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Radiation proctitis (RP) is the most common complication of radiotherapy for pelvic tumor. Currently there is a lack of effective clinical treatment and its underlying mechanism is poorly understood. In this study, we aimed to dynamically reveal the mechanism of RP progression from the perspective of RNomics using a mouse model, so as to help develop reasonable therapeutic strategies for RP. RESULTS Mice were delivered a single dose of 25 Gy rectal irradiation, and the rectal tissues were removed at 4 h, 1 day, 3 days, 2 weeks and 8 weeks post-irradiation (PI) for both histopathological assessment and RNA-seq analysis. According to the histopathological characteristics, we divided the development process of our RP animal model into three stages: acute (4 h, 1 day and 3 days PI), subacute (2 weeks PI) and chronic (8 weeks PI), which could recapitulate the features of different stages of human RP. Bioinformatics analysis of the RNA-seq data showed that in the acute injury period after radiation, the altered genes were mainly enriched in DNA damage response, p53 signaling pathway and metabolic changes; while in the subacute and chronic stages of tissue reconstruction, genes involved in the biological processes of vessel development, extracellular matrix organization, inflammatory and immune responses were dysregulated. We further identified the hub genes in the most significant biological process at each time point using protein-protein interaction analysis and verified the differential expression of these genes by quantitative real-time-PCR analysis. CONCLUSIONS Our study reveals the molecular events sequentially occurred during the course of RP development and might provide molecular basis for designing drugs targeting different stages of RP development.
Collapse
Affiliation(s)
- Qingzhi Zeng
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China
| | - Jingyang Cheng
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China
| | - Haiyong Wu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China
| | - Wenfeng Liang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China
| | - Yanmei Cui
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.
| |
Collapse
|
|
11
|
Xie L, Wang T, Lin S, Lu Z, Wang Y, Shen Z, Cheng Y, Shen A, Peng J, Chu J. Uncaria Rhynchophylla attenuates angiotensin Ⅱ-induced myocardial fibrosis via suppression of the RhoA/ROCK1 pathway. Biomed Pharmacother 2022; 146:112607. [PMID: 35062072 DOI: 10.1016/j.biopha.2021.112607] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/26/2021] [Accepted: 12/26/2021] [Indexed: 11/15/2022] Open
Abstract
Uncaria rhynchophylla (UR), a traditional Chinese medicine, has been proven effective in treating hypertensive patients in China. However, the mechanisms of action of UR in reducing hypertension and myocardial fibrosis are still unclear. The purpose of this study was to explore the role of UR in an angiotensin Ⅱ (Ang Ⅱ) induced mouse model. The mice were randomly divided into 5 groups and infused with Ang Ⅱ (500 ng/kg/min) or saline, then administered UR (0.78, 1.56 or 3.12 g/kg/d) or saline for 4 weeks. UR treatment significantly attenuated the elevation of blood pressure caused by Ang Ⅱ. It enhanced myocardial function and attenuated the increase in the heart weight index and the pathological changes in the Ang Ⅱ-induced hypertensive mice. Furthermore, UR treatment inhibited cardiac fibrosis and significantly down-regulated collagen I, collagen Ⅲ, and α-SMA protein expression in cardiac tissues. UR also attenuated the expression of RhoA, ROCK1, CTGF, and TGF-β1. In cultured cardiac fibroblasts stimulated with Ang Ⅱ, UR significantly down-regulated the expression of Collagen I, Collagen III, RhoA, ROCK1, and α-SMA. In summary, UR can significantly attenuate Ang Ⅱ-induced hypertension and cardiac fibrosis, partly via suppression of the RhoA/ROCK1 signaling pathway.
Collapse
Affiliation(s)
- Lingling Xie
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Tianyi Wang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Shan Lin
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Zhuqing Lu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Yilian Wang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Zhiqing Shen
- The People's Hospital of Fujian Traditional Medical University, No. 602, 817 Middle Road, Taijiang District, Fuzhou, Fujian 350004, China.
| | - Ying Cheng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Aling Shen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Jianfeng Chu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| |
Collapse
|
|
12
|
Therapeutic Targeting of Intestinal Fibrosis in Crohn's Disease. Cells 2022; 11:cells11030429. [PMID: 35159238 PMCID: PMC8834168 DOI: 10.3390/cells11030429] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 02/05/2023] Open
Abstract
Intestinal fibrosis is one of the most threatening complications of Crohn’s disease. It occurs in more than a third of patients with this condition, is associated with increased morbidity and mortality, and surgery often represents the only available therapeutic option. The mechanisms underlying intestinal fibrosis are partly known. Studies conducted so far have shown a relevant pathogenetic role played by mesenchymal cells (especially myofibroblasts), cytokines (e.g., transforming growth factor-β), growth factors, microRNAs, intestinal microbiome, matrix stiffness, and mesenteric adipocytes. Further studies are still necessary to elucidate all the mechanisms involved in intestinal fibrosis, so that targeted therapies can be developed. Although several pre-clinical studies have been conducted so far, no anti-fibrotic therapy is yet available to prevent or reverse intestinal fibrosis. The aim of this review is to provide an overview of the main therapeutic targets currently identified and the most promising anti-fibrotic therapies, which may be available in the near future.
Collapse
|
|
13
|
Steinhauff D, Jensen MM, Griswold E, Jedrzkiewicz J, Cappello J, Oottamasathien S, Ghandehari H. An Oligomeric Sulfated Hyaluronan and Silk-Elastinlike Polymer Combination Protects against Murine Radiation Induced Proctitis. Pharmaceutics 2022; 14:pharmaceutics14010175. [PMID: 35057068 PMCID: PMC8777937 DOI: 10.3390/pharmaceutics14010175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/30/2021] [Accepted: 01/04/2022] [Indexed: 01/23/2023] Open
Abstract
Semisynthetic glycosaminoglycan ethers (SAGEs) are short, sulfated hyaluronans which combine the natural properties of hyaluronan with chemical sulfation. In a murine model, SAGEs provide protection against radiation induced proctitis (RIP), a side effect of lower abdominal radiotherapy for cancer. The anti-inflammatory effects of SAGE have been studied in inflammatory diseases at mucosal barrier sites; however, few mechanisms have been uncovered necessitating high throughput methods. SAGEs were combined with silk-elastinlike polymers (SELPs) to enhance rectal accumulation in mice. After high radiation exposure to the lower abdominal area, mice were followed for 3 days or until they met humane endpoints, before evaluation of behavioral pain responses and histological assessment of rectal inflammation. RNA sequencing was conducted on tissues from the 3-day cohort to determine molecular mechanisms of SAGE–SELP. After 3 days, mice receiving the SAGE–SELP combination yielded significantly lowered pain responses and amelioration of radiation-induced rectal inflammation. Mice receiving the drug–polymer combination survived 60% longer than other irradiated mice, with a fraction exhibiting long term survival. Sequencing reveals varied regulation of toll like receptors, antioxidant activities, T-cell signaling, and pathways associated with pain. This investigation elucidates several molecular mechanisms of SAGEs and exhibits promising measures for prevention of RIP.
Collapse
Affiliation(s)
- Douglas Steinhauff
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA; (D.S.); (E.G.)
- Utah Center for Nanomedicine, University of Utah, Salt Lake City, UT 84112, USA
| | - Mark Martin Jensen
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (M.M.J.); (S.O.)
| | - Ethan Griswold
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA; (D.S.); (E.G.)
- Utah Center for Nanomedicine, University of Utah, Salt Lake City, UT 84112, USA
| | | | - Joseph Cappello
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA;
| | - Siam Oottamasathien
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (M.M.J.); (S.O.)
- Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Hamidreza Ghandehari
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA; (D.S.); (E.G.)
- Utah Center for Nanomedicine, University of Utah, Salt Lake City, UT 84112, USA
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA;
- Correspondence:
| |
Collapse
|
|
14
|
Molecular and Biologic Targets for Radiation Fibrosis: Implications for Rehabilitation. CURRENT PHYSICAL MEDICINE AND REHABILITATION REPORTS 2021. [DOI: 10.1007/s40141-021-00321-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
|
|
15
|
Xie J, Ning Q, Zhang H, Ni S, Ye J. RhoA/ROCK Signaling Regulates TGF-β1-Induced Fibrotic Effects in Human Pterygium Fibroblasts through MRTF-A. Curr Eye Res 2021; 47:196-205. [PMID: 34323621 DOI: 10.1080/02713683.2021.1962363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE The overexpression of transforming growth factor-beta1 (TGF-β1) after surgical excision often leads to excessive fibrosis, indicating the recurrence of pterygium. The aims of the present in vitro study were to investigate the role of RhoA/ROCK signaling in regulating fibrotic effects of primary human pterygium fibroblasts (HPFs), as well as to explore the possible mechanisms of these effects. METHODS Pterygium samples were obtained from surgery, and profibrotic activation was induced by TGF-β1. Cell proliferation was detected by CCK-8 assay; cell migration was detected by wound healing assay; quantitative real-time PCR and Western blot were used to detect the effects of TGF-β1 and the role of RhoA/ROCK signaling in the synthesis of alpha-smooth muscle actin (a-SMA), type I and III collagen (COL1 and COL3), and matrix metalloproteinase-9 (MMP9) in HPFs. The changes of signaling pathways were detected by Western blot; and pharmaceutical inhibition of RhoA/ROCK signaling and its downstream MRFT-A/SRF transcription pathway were used to assess their possible mechanism in HPFs fibrosis. RESULTS ROCK inhibitor Y-27632 decreased TGF-β1-induced cell proliferation and migration, reduced the TGF-β1-induced expression of profibrotic markers in HPFs, and suppressed TGF-β1-induced nuclear accumulation of Myocardin-related transcription factor A (MRTF-A) as well as accompanied elevation of F/G-actin ratio in HPFs. MRTF-A/Serum response factor (SRF) inhibitor CCG-100602 attenuated the TGF-β1-induced α-SMA expression and reduced myofibroblast activation in HPFs. CONCLUSIONS RhoA/ROCK signaling played a pivotal role in TGF-β1-induced fibrosis and myofibroblast activation in HPFs at least in part by inactivating the downstream MRTF-A/SRF transcriptional pathway.
Collapse
Affiliation(s)
- Jiajun Xie
- Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingyao Ning
- Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Huina Zhang
- Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shuang Ni
- Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Juan Ye
- Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
16
|
Cahill T, da Silveira WA, Renaud L, Williamson T, Wang H, Chung D, Overton I, Chan SSL, Hardiman G. Induced Torpor as a Countermeasure for Low Dose Radiation Exposure in a Zebrafish Model. Cells 2021; 10:906. [PMID: 33920039 PMCID: PMC8071006 DOI: 10.3390/cells10040906] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 04/07/2021] [Accepted: 04/11/2021] [Indexed: 12/15/2022] Open
Abstract
The development of the Artemis programme with the goal of returning to the moon is spurring technology advances that will eventually take humans to Mars and herald a new era of interplanetary space travel. However, long-term space travel poses unique challenges including exposure to ionising radiation from galactic cosmic rays and potential solar particle events, exposure to microgravity and specific nutritional challenges arising from earth independent exploration. Ionising radiation is one of the major obstacles facing future space travel as it can generate oxidative stress and directly damage cellular structures such as DNA, in turn causing genomic instability, telomere shortening, extracellular-matrix remodelling and persistent inflammation. In the gastrointestinal tract (GIT) this can lead to leaky gut syndrome, perforations and motility issues, which impact GIT functionality and affect nutritional status. While current countermeasures such as shielding from the spacecraft can attenuate harmful biological effects, they produce harmful secondary particles that contribute to radiation exposure. We hypothesised that induction of a torpor-like state would confer a radioprotective effect given the evidence that hibernation extends survival times in irradiated squirrels compared to active controls. To test this hypothesis, a torpor-like state was induced in zebrafish using melatonin treatment and reduced temperature, and radiation exposure was administered twice over the course of 10 days. The protective effects of induced-torpor were assessed via RNA sequencing and qPCR of mRNA extracted from the GIT. Pathway and network analysis were performed on the transcriptomic data to characterise the genomic signatures in radiation, torpor and torpor + radiation groups. Phenotypic analyses revealed that melatonin and reduced temperature successfully induced a torpor-like state in zebrafish as shown by decreased metabolism and activity levels. Genomic analyses indicated that low dose radiation caused DNA damage and oxidative stress triggering a stress response, including steroidal signalling and changes to metabolism, and cell cycle arrest. Torpor attenuated the stress response through an increase in pro-survival signals, reduced oxidative stress via the oxygen effect and detection and removal of misfolded proteins. This proof-of-concept model provides compelling initial evidence for utilizing an induced torpor-like state as a potential countermeasure for radiation exposure.
Collapse
Affiliation(s)
- Thomas Cahill
- School of Biological Sciences & Institute for Global Food Security, Queens University Belfast, Belfast BT9 5DL, UK; (T.C.); (W.A.d.S.); (H.W.)
| | - Willian Abraham da Silveira
- School of Biological Sciences & Institute for Global Food Security, Queens University Belfast, Belfast BT9 5DL, UK; (T.C.); (W.A.d.S.); (H.W.)
| | - Ludivine Renaud
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA;
| | - Tucker Williamson
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA; (T.W.); (S.S.L.C.)
| | - Hao Wang
- School of Biological Sciences & Institute for Global Food Security, Queens University Belfast, Belfast BT9 5DL, UK; (T.C.); (W.A.d.S.); (H.W.)
| | - Dongjun Chung
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA;
| | - Ian Overton
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK;
| | - Sherine S. L. Chan
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA; (T.W.); (S.S.L.C.)
| | - Gary Hardiman
- School of Biological Sciences & Institute for Global Food Security, Queens University Belfast, Belfast BT9 5DL, UK; (T.C.); (W.A.d.S.); (H.W.)
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA;
| |
Collapse
|
|
17
|
Feng D, Gerarduzzi C. Emerging Roles of Matricellular Proteins in Systemic Sclerosis. Int J Mol Sci 2020; 21:E4776. [PMID: 32640520 PMCID: PMC7369781 DOI: 10.3390/ijms21134776] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/11/2020] [Accepted: 06/13/2020] [Indexed: 02/07/2023] Open
Abstract
Systemic sclerosis is a rare chronic heterogenous disease that involves inflammation and vasculopathy, and converges in end-stage development of multisystem tissue fibrosis. The loss of tight spatial distribution and temporal expression of proteins in the extracellular matrix (ECM) leads to progressive organ stiffening, which is a hallmark of fibrotic disease. A group of nonstructural matrix proteins, known as matricellular proteins (MCPs) are implicated in dysregulated processes that drive fibrosis such as ECM remodeling and various cellular behaviors. Accordingly, MCPs have been described in the context of fibrosis in sclerosis (SSc) as predictive disease biomarkers and regulators of ECM synthesis, with promising therapeutic potential. In this present review, an informative summary of major MCPs is presented highlighting their clear correlations to SSc- fibrosis.
Collapse
Affiliation(s)
- Daniel Feng
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada;
- Centre de recherche de l’Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l’Université de Montréal, Montréal, QC H1T 2M4, Canada
| | - Casimiro Gerarduzzi
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada;
- Centre de recherche de l’Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l’Université de Montréal, Montréal, QC H1T 2M4, Canada
- Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada
| |
Collapse
|
|
18
|
Farhood B, Khodamoradi E, Hoseini-Ghahfarokhi M, Motevaseli E, Mirtavoos-Mahyari H, Eleojo Musa A, Najafi M. TGF-β in radiotherapy: Mechanisms of tumor resistance and normal tissues injury. Pharmacol Res 2020; 155:104745. [PMID: 32145401 DOI: 10.1016/j.phrs.2020.104745] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/25/2020] [Accepted: 03/03/2020] [Indexed: 12/20/2022]
Abstract
Emerging evidences show that changes in tumor stroma can adapt cancer cells to radiotherapy, thereby leading to a reduction in tumor response to treatment. On the other hand, radiotherapy is associated with severe reactions in normal tissues which limit the amount radiation dose received by tumor. These challenges open a window in radiobiology and radiation oncology to explore mechanisms for improving tumor response and also alleviate side effects of radiotherapy. Transforming growth factor beta (TGF-β) is a well-known and multitasking cytokine that regulates a wide range of reactions and interactions within tumor and normal tissues. Within tumor microenvironment (TME), TGF-β is the most potent suppressor of immune system activity against cancer cells. This effect is mediated through stimulation of CD4+ which differentiates to T regulatory cells (Tregs), infiltration of fibroblasts and differentiation into cancer associated fibroblasts (CAFs), and also polarization of macrophages to M2 cells. These changes lead to suppression of cytotoxic CD8 + T lymphocytes (CTLs) and natural killer (NK) cells to kill cancer cells. TGF-β also plays a key role in the angiogenesis, invasion and DNA damage responses (DDR) in cancer cells. In normal tissues, TGF-β triggers the expression of a wide range of pro-oxidant and pro-fibrosis genes, leading to fibrosis, genomic instability and some other side effects. These properties of TGF-β make it a potential target to preserve normal tissues and sensitize tumor via its inhibition. In the current review, we aim to explain the mechanisms of upregulation of TGF-β and its consequences in both tumor and normal tissues.
Collapse
Affiliation(s)
- Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Ehsan Khodamoradi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mojtaba Hoseini-Ghahfarokhi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Elahe Motevaseli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanifeh Mirtavoos-Mahyari
- Lung Transplantation Research Center (LTRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmed Eleojo Musa
- Department of Medical Physics, Tehran University of Medical Sciences (International Campus), Tehran, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| |
Collapse
|
|
19
|
Huangqi Shengmai Yin Protects against Radiation-Induced Cardiac Fibrosis Injury by Regulating the TGF- β1/Smads and MMPs. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:1358469. [PMID: 31214266 PMCID: PMC6535819 DOI: 10.1155/2019/1358469] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 03/01/2019] [Accepted: 03/04/2019] [Indexed: 12/27/2022]
Abstract
Background Radiation-induced heart damage is considered to be a progressive process of fibrosis. Emerging evidence has indicated that the Smads and matrix metalloproteinases (MMPs)/tissue inhibitors of MMPs (TIMP) may be involved in radiation-induced cardiac fibrosis (RICF) by regulating the activation of TGF-β1 signaling pathway. Based on this, the present study was undertaken to characterize the effect of Huangqi Shengmai Yin (HSY) on RICF in a rat model. Methods Precardiac region of rats was irradiated with 25 Gy X-rays, and their myocardial pathology scores in terms of injury and collagen volume fraction (CVF) and the expression levels of fibrotic molecules were detected. Results The pathology scores and CVF in myocardial tissue increased after irradiation, and the expression of TGF-β1, Col1, and Col3 increased. This change indicated that such irradiation promoted the fibrosis damage in rat hearts. The damage was accompanied by an increase in the expression of Smad 2, Smad3, Smad4, and MMP14 and a decrease in the expression of Smad 7 and TIMP1. Administration of HSY weakened the RICF by decreasing pathology score and CVF and decreased the expression of TGF-β1, Col1, and Col3 in irradiated rat hearts. In addition, Smad2, Smad3, Smad4, and MMP14 were downregulated, while Smad 7 and TIMP1 were upregulated during intervention with HSY. Conclusions The involvement of the TGF-β1/Smads and MMPs/TIMP system in RICF was confirmed. This study demonstrated, for the first time, that HSY attenuates the effects of RICF in a rat model. The effect HSY was found to be closely related to the TGF-β1/Smads signaling pathway and MMPs system. These results suggest that HSY is a prospective drug for clinical treatment of RICF.
Collapse
|
|
20
|
Henninger C, Pohlmann S, Ziegler V, Ohlig J, Schmitt J, Fritz G. Distinct contribution of Rac1 expression in cardiomyocytes to anthracycline-induced cardiac injury. Biochem Pharmacol 2019; 164:82-93. [PMID: 30936017 DOI: 10.1016/j.bcp.2019.03.038] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 03/28/2019] [Indexed: 12/16/2022]
Abstract
Cardiotoxicity is the dose limiting adverse effect of anthracycline-based anticancer therapy. Inhibitor studies point to Rac1 as therapeutic target to prevent anthracycline-induced cardiotoxicity. Yet, supporting genetic evidence is still missing and the pathophysiological relevance of different cardiac cell types is unclear. Here, we employed a tamoxifen-inducible cardiomyocyte-specific rac1 knock-out mouse model (Rac1flox/flox/MHC-MerCreMer) to investigate the impact of Rac1 expression in cardiomyocytes on cardiac injury following doxorubicin treatment. Distinctive stress responses resulting from doxorubicin treatment were observed, including upregulation of systemic markers of inflammation (IL-6, IL-1α, MCP-1), cardiac damage (ANP, BNP), DNA damage (i.e. DNA double-strand breaks (DSB)), DNA damage response (DDR) and cell death. Measuring the acute doxorubicin response, the serum level of MCP-1 was elevated, cardiac mRNA expression of Hsp70 was reduced and cardiac DDR was specifically enhanced in Rac1 deficient mice. The frequency of apoptotic heart cells remained unaffected by Rac1. Employing a subactue model, the number of doxorubicin-induced DSB was significantly reduced if Rac1 is absent. Yet, the doxorubicin-triggered increase in serum ANP and BNP levels remained unaffected by Rac1. Overall, knock-out of rac1 in cardiomyocytes confers partial protection against doxorubicin-induced cardiac injury. Hence, the data provide first genetic evidence supporting the view that pharmacological targeting of Rac1 is useful to widen the therapeutic window of anthracycline-based anticancer therapy by alleviating acute/subacute cardiomyocyte damage. Furthermore, considering published data obtained from the use of pharmacological Rac1 inhibitors, the results of our study indicate that Rac1-regulated functions of cardiac cell types others than cardiomyocytes additionally influence the adverse outcomes of anthracycline treatment on the heart.
Collapse
Affiliation(s)
- Christian Henninger
- Institute of Toxicology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
| | - Stephanie Pohlmann
- Institute of Toxicology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
| | - Verena Ziegler
- Institute of Toxicology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
| | - Jan Ohlig
- Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
| | - Joachim Schmitt
- Institute of Pharmacology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
| | - Gerhard Fritz
- Institute of Toxicology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
| |
Collapse
|
|
21
|
Bourgier C, Auperin A, Rivera S, Boisselier P, Petit B, Lang P, Lassau N, Taourel P, Tetreau R, Azria D, Bourhis J, Deutsch E, Vozenin MC. Pravastatin Reverses Established Radiation-Induced Cutaneous and Subcutaneous Fibrosis in Patients With Head and Neck Cancer: Results of the Biology-Driven Phase 2 Clinical Trial Pravacur. Int J Radiat Oncol Biol Phys 2019; 104:365-373. [PMID: 30776452 DOI: 10.1016/j.ijrobp.2019.02.024] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 01/12/2019] [Accepted: 02/08/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE The "PRAVACUR" phase 2 trial (NCT01268202) assessed the efficacy of pravastatin as an antifibrotic agent in patients with established cutaneous and subcutaneous radiation-induced fibrosis (RIF) after head and neck squamous cell carcinoma (HNSCC) radiation therapy and/or radiochemotherapy. METHODS AND MATERIALS The main inclusion criteria were: NSCC in remission, grade ≥2 cutaneous and subcutaneous neck RIF (National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0), and no current treatment with statins or fibrates. Patients received pravastatin 40 mg/d for 12 months. The primary endpoint was reduction of RIF thickness by more than 30% at 12 months, as measured by cutaneous high-frequency ultrasonography. Secondary endpoints included RIF severity reduction, pravastatin tolerance, and quality of life. RESULTS Sixty patients with grade 2 (n = 37), grade 3 (n = 22), or grade 4 (n = 1) RIF were enrolled from February 2011 to April 2016. The mean interval between RIF diagnosis and pravastatin initiation was 17.1 months. Pravastatin was stopped before 11 months of treatment in 18 patients (because of grade ≥2 adverse events related to pravastatin in 8 patients [13%]). In the 40 patients in whom pravastatin efficacy was assessed by high-frequency ultrasonography at baseline and at 12 months of treatment, a reduction of RIF thickness ≥30% was observed in 15 of 42 patients (35.7%; 95% confidence interval, 21.6%-52.0%). At the 12-month clinical evaluation, RIF severity was decreased in 50% of patients (n = 21; 95% confidence interval, 34.2%-65.8%), and the patients' self-perception, mood state, and social functioning were significantly improved. Pravastatin was well tolerated, with a very low occurrence of grade 3 toxicities (myalgia, n = 1) and grade 2 toxicities (myalgia/arthralgia or esophagitis, n = 3). CONCLUSIONS This phase 2 prospective study supports the notion of radioinduced fibrosis reversibility. It showed that pravastatin (40 mg/d for 12 months) is an efficient antifibrotic agent in patients with grade ≥2 cutaneous and subcutaneous fibrosis after HNSCC radiation therapy.
Collapse
Affiliation(s)
- Celine Bourgier
- INSERM, U1194, IRCM, Université de Montpellier, Montpellier, France; Department of Radiation Oncology, ICM-Val d'Aurelle, Université de Montpellier, Montpellier, France.
| | - Anne Auperin
- Biostatistics Department, Gustave Roussy Institute, Villejuif, France
| | - Sofia Rivera
- Department of Radiation Oncology, INSERM 1030, Université de Paris-Sud, Gustave Roussy Cancer Campus, Villejuif, France, Université de Paris-Saclay
| | - Pierre Boisselier
- Department of Radiation Oncology, ICM-Val d'Aurelle, Université de Montpellier, Montpellier, France
| | - Benoit Petit
- Radiation Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Philippe Lang
- Department of Radiation Oncology, Centre Hospitalier Universitaire, Université de Montpellier, Nîmes, France
| | - Nathalie Lassau
- Imaging Department, Gustave Roussy Institute, IR4M, Université de Paris-Sud, Villejuif, France
| | - Patrice Taourel
- Radiology Department, Centre Hospitalier Universitaire, Lapeyronie, Université de Montpellier, Montpellier, France
| | - Raphael Tetreau
- Radiology Department, ICM-Val d'Aurelle, Université de Montpellier, Montpellier, France
| | - David Azria
- INSERM, U1194, IRCM, Université de Montpellier, Montpellier, France; Department of Radiation Oncology, ICM-Val d'Aurelle, Université de Montpellier, Montpellier, France
| | - Jean Bourhis
- Radiation Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Eric Deutsch
- Department of Radiation Oncology, INSERM 1030, Université de Paris-Sud, Gustave Roussy Cancer Campus, Villejuif, France, Université de Paris-Saclay
| | - Marie-Catherine Vozenin
- Radiation Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| |
Collapse
|
|
22
|
Najafi M, Motevaseli E, Shirazi A, Geraily G, Rezaeyan A, Norouzi F, Rezapoor S, Abdollahi H. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: clinical implications. Int J Radiat Biol 2018; 94:335-356. [PMID: 29504497 DOI: 10.1080/09553002.2018.1440092] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 01/23/2018] [Accepted: 01/31/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE Cancer treatment is one of the most challenging diseases in the present era. Among a few modalities for cancer therapy, radiotherapy plays a pivotal role in more than half of all treatments alone or combined with other cancer treatment modalities. Management of normal tissue toxicity induced by radiation is one of the most important limiting factors for an appropriate radiation treatment course. The evaluation of mechanisms of normal tissue toxicity has shown that immune responses especially inflammatory responses play a key role in both early and late side effects of exposure to ionizing radiation (IR). DNA damage and cell death, as well as damage to some organelles such as mitochondria initiate several signaling pathways that result in the response of immune cells. Massive cell damage which is a common phenomenon following exposure to a high dose of IR cause secretion of a lot of inflammatory mediators including cytokines and chemokines. These mediators initiate different changes in normal tissues that may continue for a long time after irradiation. In this study, we reviewed the mechanisms of inflammatory responses to IR that are involved in normal tissue toxicity and considered as the most important limiting factors in radiotherapy. Also, we introduced some agents that have been proposed for management of these responses. CONCLUSIONS The early inflammation during the radiation treatment is often a limiting factor in radiotherapy. In addition to the limiting factors, chronic inflammatory responses may increase the risk of second primary cancers through continuous free radical production, attenuation of tumor suppressor genes, and activation of oncogenes. Moreover, these effects may influence non-irradiated tissues through a mechanism named bystander effect.
Collapse
Affiliation(s)
- Masoud Najafi
- a Radiology and Nuclear Medicine Department, School of Paramedical Sciences , Kermanshah University of Medical Science , Kermanshah , Iran
| | - Elahe Motevaseli
- b Department of Molecular Medicine, School of Advanced Technologies in Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Alireza Shirazi
- c Department of Medical Physics and Biomedical Engineering, Faculty of Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Ghazale Geraily
- c Department of Medical Physics and Biomedical Engineering, Faculty of Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Abolhasan Rezaeyan
- d Department of Medical Physics, School of Medicine , Iran University of Medical Sciences , Tehran , Iran
| | - Farzad Norouzi
- e Science and Research Branch , Azad University , Tehran , Iran
| | - Saeed Rezapoor
- f Department of Radiology, Faculty of Paramedical Sciences , Tehran University of Medical Sciences , Tehran , Iran
| | - Hamid Abdollahi
- d Department of Medical Physics, School of Medicine , Iran University of Medical Sciences , Tehran , Iran
| |
Collapse
|
|
23
|
Just F, Oster M, Büsing K, Borgelt L, Murani E, Ponsuksili S, Wolf P, Wimmers K. Lowered dietary phosphorus affects intestinal and renal gene expression to maintain mineral homeostasis with immunomodulatory implications in weaned piglets. BMC Genomics 2018; 19:207. [PMID: 29554878 PMCID: PMC5859397 DOI: 10.1186/s12864-018-4584-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 03/07/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND In monogastric animals, phosphorus (P) homeostasis is maintained by regulating intestinal absorption, bone mobilization, and renal excretion. Since P is a non-renewable resource, a shortage is imminent due to widespread over-usage in the farming and animal husbandry industries. As a consequence, P efficiency should be improved in pig production. We sought to characterize the transcriptional response in re-/absorbing and excreting tissues in pigs to diets varying in calcium: phosphorus ratios. Weaned piglets were assigned to one of three groups fed diets varying in digestible P content for a period of five weeks. Gene expression profiles were analyzed in jejunum, colon, and kidney. RESULTS Transcriptome analysis revealed that reduced dietary P intake affects gene expression in jejunum and kidney, but not in colon. The regulation of mineral homeostasis was reflected via altered mRNA abundances of CYP24A1, CYP27A1, TRPM6, SPP1, and VDR in jejunum and kidney. Moreover, lowered abundances of transcripts associated with the classical complement system pathway were observed in the jejunum. In kidney, shifted transcripts were involved in phospholipase C, calcium signaling, and NFAT signaling, which may have immunomodulatory implications. CONCLUSIONS Our results revealed local transcriptional consequences of variable P intake in intestinal and renal tissues. The adaptive responses are the result of organismal efforts to maintain systemic mineral homeostasis while modulating immune features at local tissue sites. Therefore, the deviation from the currently recommended dietary P supply must be carefully considered, as the endogenous mechanisms that respond to low P diets may impact important adaptive immune responses.
Collapse
Affiliation(s)
- Franziska Just
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Michael Oster
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Kirsten Büsing
- Faculty of Agricultural and Environmental Sciences, University Rostock, 18059, Rostock, Germany
| | - Luisa Borgelt
- Faculty of Agricultural and Environmental Sciences, University Rostock, 18059, Rostock, Germany
| | - Eduard Murani
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Siriluck Ponsuksili
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Petra Wolf
- Faculty of Agricultural and Environmental Sciences, University Rostock, 18059, Rostock, Germany
| | - Klaus Wimmers
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany. .,Faculty of Agricultural and Environmental Sciences, University Rostock, 18059, Rostock, Germany.
| |
Collapse
|
|
24
|
Riquelme-Guzmán C, Contreras O, Brandan E. Expression of CTGF/CCN2 in response to LPA is stimulated by fibrotic extracellular matrix via the integrin/FAK axis. Am J Physiol Cell Physiol 2017; 314:C415-C427. [PMID: 29351412 DOI: 10.1152/ajpcell.00013.2017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Fibrosis is a common feature of several chronic diseases and is characterized by exacerbated accumulation of ECM. An understanding of the cellular and molecular mechanisms involved in the development of this condition is crucial for designing efficient treatments for those pathologies. Connective tissue growth factor (CTGF/CCN2) is a pleiotropic protein with strong profibrotic activity. In this report, we present experimental evidence showing that ECM stimulates the synthesis of CTGF in response to lysophosphatidic acid (LPA).The integrin/focal adhesion kinase (FAK) signaling pathway mediates this effect, since CTGF expression is abolished by the use of the Arg-Gly-Asp-Ser peptide and also by an inhibitor of FAK autophosphorylation at tyrosine 397. Cilengitide, a specific inhibitor of αv integrins, inhibits the expression of CTGF mediated by LPA or transforming growth factor β1. We show that ECM obtained from decellularized myofibroblast cultures or derived from activated fibroblasts from muscles of the Duchenne muscular dystrophy mouse model ( mdx) induces the expression of CTGF. This effect is dependent on FAK phosphorylation in response to its activation by integrin. We also found that the fibrotic ECM inhibits skeletal muscle differentiation. This novel regulatory mechanism of CTGF expression could be acting as a positive profibrotic feedback between the ECM and CTGF, revealing a novel concept in the control of fibrosis under chronic damage.
Collapse
Affiliation(s)
- Camilo Riquelme-Guzmán
- Centro de Envejecimiento y Regeneración, CARE Chile UC, and Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Osvaldo Contreras
- Centro de Envejecimiento y Regeneración, CARE Chile UC, and Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Enrique Brandan
- Centro de Envejecimiento y Regeneración, CARE Chile UC, and Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile , Santiago , Chile
| |
Collapse
|
|
25
|
Patyar RR, Patyar S. Role of drugs in the prevention and amelioration of radiation induced toxic effects. Eur J Pharmacol 2017; 819:207-216. [PMID: 29221951 DOI: 10.1016/j.ejphar.2017.12.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 11/25/2017] [Accepted: 12/04/2017] [Indexed: 10/18/2022]
Abstract
As the use of radiation technology for nuclear warfare or for the benefits of mankind (e.g. in radiotherapy or radio-diagnosis) is increasing tremendously, the risk of associated side effects is becoming a cause of concern. These effects, ranging from nausea/vomiting to death, may result from accidental or deliberate exposure and begin in seconds. Through this review paper, efforts have been done to critically review different compounds which have been investigated as radioprotectors and radiation mitigators. Radioprotectors are compounds which are administered just before or at the time of irradiation so as to minimize the radiation induced damage to normal tissues. And radiation mitigators are the compounds which can even minimize or ameliorate post irradiaion-toxicity provided they are administered before the onset of toxic symptoms. A variety of agents have been investigated for their preventive and ameliorative potential against radiation induced toxic effects. This review article has focused on various aspects of the promising representative agents belonging to different classes of radioprotectors and mitigators. Many compounds have shown promising results, but till date only amifostine and palifermin are clinically approved by FDA. To fill this void in pharmacological armamentarium, focus should be shifted towards novel approaches.
Collapse
Affiliation(s)
| | - Sazal Patyar
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India.
| |
Collapse
|
|
26
|
Rho inhibition by lovastatin affects apoptosis and DSB repair of primary human lung cells in vitro and lung tissue in vivo following fractionated irradiation. Cell Death Dis 2017; 8:e2978. [PMID: 28796249 PMCID: PMC5596560 DOI: 10.1038/cddis.2017.372] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 06/22/2017] [Accepted: 07/02/2017] [Indexed: 12/12/2022]
Abstract
Thoracic radiotherapy causes damage of normal lung tissue, which limits the cumulative radiation dose and, hence, confines the anticancer efficacy of radiotherapy and impacts the quality of life of tumor patients. Ras-homologous (Rho) small GTPases regulate multiple stress responses and cell death. Therefore, we investigated whether pharmacological targeting of Rho signaling by the HMG-CoA-reductase inhibitor lovastatin influences ionizing radiation (IR)-induced toxicity in primary human lung fibroblasts, lung epithelial and lung microvascular endothelial cells in vitro and subchronic mouse lung tissue damage following hypo-fractionated irradiation (4x4 Gy). The statin improved the repair of radiation-induced DNA double-strand breaks (DSBs) in all cell types and, moreover, protected lung endothelial cells from IR-induced caspase-dependent apoptosis, likely involving p53-regulated mechanisms. Under the in vivo situation, treatment with lovastatin or the Rac1-specific small molecule inhibitor EHT1864 attenuated the IR-induced increase in breathing frequency and reduced the percentage of γH2AX and 53BP1-positive cells. This indicates that inhibition of Rac1 signaling lowers IR-induced residual DNA damage by promoting DNA repair. Moreover, lovastatin and EHT1864 protected lung tissue from IR-triggered apoptosis and mitigated the IR-stimulated increase in regenerative proliferation. Our data document beneficial anti-apoptotic and genoprotective effects of pharmacological targeting of Rho signaling following hypo-fractionated irradiation of lung cells in vitro and in vivo. Rac1-targeting drugs might be particular useful for supportive care in radiation oncology and, moreover, applicable to improve the anticancer efficacy of radiotherapy by widening the therapeutic window of thoracic radiation exposure.
Collapse
|
|
27
|
Ji X, Zhu X, Lu X. Effect of cancer-associated fibroblasts on radiosensitivity of cancer cells. Future Oncol 2017; 13:1537-1550. [PMID: 28685611 DOI: 10.2217/fon-2017-0054] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Solid tumors are composed of tumor epithelial cells and the stroma, which are seemingly separate but actually related through cell-cell and cell-matrix interactions. These interactions can promote tumor evolution. Cancer-associated fibroblasts (CAFs) are the most abundant non-neoplastic cells in the stroma and also among the most important cell types interacting with cancer cells. Particularly, cancer cells promote the formation and maintenance of CAFs by secreting various cytokines. The activated CAFs then synthesize a series of growth factors to promote tumor cell growth, invasion and metastasis. More importantly, the presence of CAFs also interferes with therapeutic efficacy, bringing severe challenges to radiotherapy. This review summarizes the effect of CAFs on the radiosensitivity of tumor cells and underscores the need for further studies on CAFs in order to improve the efficacy of antitumor therapy.
Collapse
Affiliation(s)
- Xiaoqin Ji
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China
| | - Xixu Zhu
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China
| | - Xueguan Lu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| |
Collapse
|
|
28
|
Abstract
PURPOSE OF REVIEW Intestinal fibrosis is a common complication of several enteropathies, with inflammatory bowel disease (IBD) being the major cause. Intestinal fibrosis affects both ulcerative colitis and Crohn's disease, and no specific antifibrotic therapy exists. This review highlights recent developments in this area. RECENT FINDINGS The pathophysiology of intestinal stricture formation includes inflammation-dependent and inflammation-independent mechanisms. A better understanding of the mechanisms of intestinal fibrogenesis and the availability of compounds for other nonintestinal fibrotic diseases bring clincial trials in stricturing Crohn's disease within reach. SUMMARY Improved understanding of its mechanisms and ongoing development of clinical trial endpoints for intestinal fibrosis will allow the testing of novel antifibrotic compounds in IBD.
Collapse
Affiliation(s)
- Giovanni Latella
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Florian Rieder
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Disease and Surgery Institute; Cleveland Clinic Foundation, Cleveland, USA
- Department of Pathobiology, Lerner Research Institute; Cleveland Clinic Foundation, Cleveland, USA
| |
Collapse
|
|
29
|
Rieder F, Fiocchi C, Rogler G. Mechanisms, Management, and Treatment of Fibrosis in Patients With Inflammatory Bowel Diseases. Gastroenterology 2017; 152:340-350.e6. [PMID: 27720839 PMCID: PMC5209279 DOI: 10.1053/j.gastro.2016.09.047] [Citation(s) in RCA: 354] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 09/07/2016] [Accepted: 09/12/2016] [Indexed: 02/08/2023]
Abstract
In the last 10 years, we have learned much about the pathogenesis, diagnosis, and management of intestinal fibrosis in patients with inflammatory bowel diseases. Just a decade ago, intestinal strictures were considered to be an inevitable consequence of long-term inflammation in patients who did not respond to anti-inflammatory therapies. Inflammatory bowel diseases-associated fibrosis was seen as an irreversible process that frequently led to intestinal obstructions requiring surgical intervention. This paradigm has changed rapidly, due to the antifibrotic approaches that may become available. We review the mechanisms and diagnosis of this serious complication of inflammatory bowel diseases, as well as factors that predict its progression and management strategies.
Collapse
Affiliation(s)
- Florian Rieder
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute; Cleveland Clinic, Cleveland, Ohio; Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
| | - Claudio Fiocchi
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute; Cleveland Clinic, Cleveland, Ohio; Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital, University of Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| |
Collapse
|
|
30
|
Radioprotection as a Method to Enhance the Therapeutic Ratio of Radiotherapy. CANCER DRUG DISCOVERY AND DEVELOPMENT 2017. [DOI: 10.1007/978-3-319-40854-5_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
|
|
31
|
Ippolito C, Colucci R, Segnani C, Errede M, Girolamo F, Virgintino D, Dolfi A, Tirotta E, Buccianti P, Di Candio G, Campani D, Castagna M, Bassotti G, Villanacci V, Blandizzi C, Bernardini N. Fibrotic and Vascular Remodelling of Colonic Wall in Patients with Active Ulcerative Colitis. J Crohns Colitis 2016; 10:1194-1204. [PMID: 26995183 DOI: 10.1093/ecco-jcc/jjw076] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 03/07/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Intestinal fibrosis is a complication of inflammatory bowel disease [IBD]. Although fibrostenosis is a rare event in ulcerative colitis [UC], there is evidence that a fibrotic rearrangement of the colon occurs in the later stages. This is a retrospective study aimed at examining the histopathological features of the colonic wall in both short-lasting [SL] and long-lasting [LL] UC. METHODS Surgical samples of left colon from non-stenotic SL [≤ 3 years, n = 9] and LL [≥ 10 years, n = 10] UC patients with active disease were compared with control colonic tissues from cancer patients without UC [n = 12] to assess: collagen and elastic fibres by histochemistry; vascular networks [CD31/CD105/nestin] by immunofluorescence; parameters of fibrosis [types I and III collagen, fibronectin, RhoA, alpha-smooth muscle actin [α-SMA], desmin, vimentin], and proliferation [proliferating nuclear antigen [PCNA]] by western blot and/or immunolabelling. RESULTS Colonic tissue from both SL-UC and LL-UC showed tunica muscularis thickening and transmural activated neovessels [displaying both proliferating CD105-positive endothelial cells and activated nestin-positive pericytes], as compared with controls. In LL-UC, the increased collagen deposition was associated with an up-regulation of tissue fibrotic markers [collagen I and III, fibronectin, vimentin, RhoA], an enhancement of proliferation [PCNA] and, along with a loss of elastic fibres, a rearrangement of the tunica muscularis towards a fibrotic phenotype. CONCLUSIONS A significant transmural fibrotic thickening occurs in colonic tissue from LL-UC, together with a cellular fibrotic switch in the tunica muscularis. A full-thickness angiogenesis is also evident in both SL- and LL-UC with active disease, as compared with controls.
Collapse
Affiliation(s)
| | - Rocchina Colucci
- Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Mariella Errede
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, School of Medicine, University of Bari, Bari, Italy
| | - Francesco Girolamo
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, School of Medicine, University of Bari, Bari, Italy
| | - Daniela Virgintino
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, School of Medicine, University of Bari, Bari, Italy
| | | | - Erika Tirotta
- Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | | | | | | | - Gabrio Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia, Perugia, Italy
| | | | - Corrado Blandizzi
- Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | |
Collapse
|
|
32
|
Liu LJ, Yao FJ, Lu GH, Xu CG, Xu Z, Tang K, Cheng YJ, Gao XR, Wu SH. The Role of the Rho/ROCK Pathway in Ang II and TGF-β1-Induced Atrial Remodeling. PLoS One 2016; 11:e0161625. [PMID: 27611832 PMCID: PMC5017578 DOI: 10.1371/journal.pone.0161625] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 08/09/2016] [Indexed: 02/05/2023] Open
Abstract
Objectives To study the role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling. Methods and Results A canine atrial fibrillation (AF) model was established by rapid atrial pacing (RAP) of the left atrium. The roles of TGF-β1, the RhoA/ROCK signaling pathway and connective tissue growth factor (CTGF) in atrial remodeling were studied via both in vitro and in vivo experiments. Each of the dogs that received RAP developed persistent AF within 4 weeks. The mRNA expression levels of TGF-β1 (1.32±0.38), Collagen-I(1.33±0.91), CTGF(5.83±3.71), RhoA(1.23±0.57) and ROCK-1 (1.02±0.27) in the left atrium were significantly increased following 4 weeks of RAP. Angiotensin II (Ang II) induced the proliferation of atrial fibroblasts and up-regulated the expression of both CTGF and ROCK-1 in a dose-dependent manner. Simvastatin and Y27632 reversed Ang II-induced CFs proliferation, as well as ROCK-1(0.89±0.05 and 1.27±0.03, respectively) and CTGF (0.87±0.04 and 0.91±0.02, respectively) expression. The expression mRNA of ROCK-1(1.74±0.13) and CTGF (2.28±0.11) can upregulated by TGF-β1, and down-regulated by Simvastatin (1.22±0.03 vs 2.27±0.11), Y27632 (1.01±0.04 vs 1.64±0.03), Los (1.04±0.11 vs 1.26±0.05), respectively. Losartan and Simvastatin attenuated the effects of TGF-β1, inhibited RhoA activity as opposed to RhoA protein expression. Y27632 had no effect on either the expression or the activity of RhoA. Conclusions The increased expression of profibrotic factors (CTGF, ROCK1 and Smad2/3) played an important role in our RAP-induced AF model. Increased atrial profibrotic factors involve the activation of either the TGF-β1/RhoA/ROCK-1 or the TGF-β1/Smad2/3 signaling pathway.
Collapse
Affiliation(s)
- Li-Juan Liu
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Feng-Juan Yao
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Gui-Hua Lu
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Cheng-Gui Xu
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhe Xu
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Kai Tang
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yun-Jiu Cheng
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiu-Ren Gao
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- * E-mail: (SW); (XG)
| | - Su-Hua Wu
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- * E-mail: (SW); (XG)
| |
Collapse
|
|
33
|
Kumar R, Griffin M, Adigbli G, Kalavrezos N, Butler PEM. Lipotransfer for radiation-induced skin fibrosis. Br J Surg 2016; 103:950-61. [PMID: 27169866 DOI: 10.1002/bjs.10180] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 12/21/2015] [Accepted: 03/02/2016] [Indexed: 01/04/2023]
Abstract
BACKGROUND Radiation-induced fibrosis (RIF) is a late complication of radiotherapy that results in progressive functional and cosmetic impairment. Autologous fat has emerged as an option for soft tissue reconstruction. There are also sporadic reports suggesting regression of fibrosis following regional lipotransfer. This systematic review aimed to identify cellular mechanisms driving RIF, and the potential role of lipotransfer in attenuating these processes. METHODS PubMed, OVID and Google Scholar databases were searched to identify all original articles regarding lipotransfer for RIF. All articles describing irradiated fibroblast or myofibroblast behaviour were included. Data elucidating the mechanisms of RIF, role of lipotransfer in RIF and methods to quantify fibrosis were extracted. RESULTS Ninety-eight studies met the inclusion criteria. A single, definitive model of RIF is yet to be established, but four cellular mechanisms were identified through in vitro studies. Twenty-one studies identified connective tissue growth factor and transforming growth factor β1 cytokines as drivers of fibrotic cascades. Hypoxia was demonstrated to propagate fibrogenesis in three studies. Oxidative stress from the release of reactive oxygen species and free radicals was also linked to RIF in 11 studies. Purified autologous fat grafts contain cellular and non-cellular properties that potentially interact with these processes. Six methods for quantifying fibrotic changes were evaluated including durometry, ultrasound shear wave elastography, thermography, dark field imaging, and laser Doppler and laser speckle flowmetry. CONCLUSION Understanding how lipotransfer causes regression of RIF remains unclear; there are a number of new hypotheses for future research.
Collapse
Affiliation(s)
- R Kumar
- Division of Surgery and Interventional Science, Royal Free Campus, London, UK.,Charles Wolfson Centre for Reconstructive Surgery, Royal Free Hospital, London, UK
| | - M Griffin
- Division of Surgery and Interventional Science, Royal Free Campus, London, UK.,Department of Plastic and Reconstructive Surgery, Royal Free Hospital, London, UK.,Charles Wolfson Centre for Reconstructive Surgery, Royal Free Hospital, London, UK
| | - G Adigbli
- Division of Surgery and Interventional Science, Royal Free Campus, London, UK.,Charles Wolfson Centre for Reconstructive Surgery, Royal Free Hospital, London, UK
| | - N Kalavrezos
- Head and Neck Unit, Macmillan Cancer Centre, University College London Hospital, London, UK.,Charles Wolfson Centre for Reconstructive Surgery, Royal Free Hospital, London, UK
| | - P E M Butler
- Division of Surgery and Interventional Science, Royal Free Campus, London, UK.,Head and Neck Unit, Macmillan Cancer Centre, University College London Hospital, London, UK.,Department of Plastic and Reconstructive Surgery, Royal Free Hospital, London, UK.,Charles Wolfson Centre for Reconstructive Surgery, Royal Free Hospital, London, UK
| |
Collapse
|
|
34
|
Ziegler V, Albers A, Fritz G. Lovastatin protects keratinocytes from DNA damage-related pro-apoptotic stress responses stimulated by anticancer therapeutics. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:1082-92. [PMID: 26876155 DOI: 10.1016/j.bbamcr.2016.02.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 01/29/2016] [Accepted: 02/10/2016] [Indexed: 01/14/2023]
Abstract
BACKGROUND Oral mucositis (OM) is a relevant adverse effect of anticancer therapy involving ionizing radiation (IR) and doxorubicin (Doxo). Because DNA damage of keratinocytes is causative for the pathogenesis of OM, we aim to identify pharmacological measures for geno- and cytoprotection of keratinocytes. METHODS We investigated the influence of the lipid-lowering drug lovastatin on cell death, proliferation and DNA damage response (DDR) mechanisms of human keratinocytes following treatment with IR and Doxo. RESULTS Lovastatin protected keratinocytes from the cytotoxic and genotoxic effects of IR and Doxo as shown by a diminished induction of apoptosis as well as a reduced formation and slightly improved repair of DNA damage following Doxo and IR treatment, respectively. Lovastatin selectively blocked the activation of Chk1 and ATR kinases following treatment with IR, Doxo and the ribonucleotide reductase inhibitor hydroxyurea, indicating that the statin antagonizes ATR/Chk1-regulated replicative stress responses. Part of the cytoprotective activity of lovastatin seems to rest on a delayed entry of lovastatin treated cells into S-phase. Yet, because the statin also protected non-proliferating keratinocytes from IR- and Doxo-induced cytotoxicity, cell cycle independent protective mechanisms are involved, too. CONCLUSIONS Lovastatin attenuates pro-toxic DNA damage-related responses of keratinocytes stimulated by OM-inducing anticancer therapeutics. The data encourage forthcoming in vivo and clinical studies addressing the usefulness of statins in the prevention of OM.
Collapse
Affiliation(s)
- Verena Ziegler
- Institute of Toxicology, Medical Faculty of the Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
| | - Anne Albers
- Institute of Toxicology, Medical Faculty of the Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
| | - Gerhard Fritz
- Institute of Toxicology, Medical Faculty of the Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
| |
Collapse
|
|
35
|
Zhang P, Cui W, Hankey KG, Gibbs AM, Smith CP, Taylor-Howell C, Kearney SR, MacVittie TJ. Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation. HEALTH PHYSICS 2015; 109:374-90. [PMID: 26425899 PMCID: PMC4593333 DOI: 10.1097/hp.0000000000000343] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus, and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition, respectively, suggesting possible crosstalk between spleen and other organs. These data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs.
Collapse
Affiliation(s)
- Pei Zhang
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA 21201 10 South Pine Street, MSTF Room 604, Baltimore, MD 21201
| | - Wanchang Cui
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA 21201 10 South Pine Street, MSTF Room 604, Baltimore, MD 21201
- Corresponding authors: Wanchang Cui, ; Phone: 410-706-5282; Fax: 410-706-5270. Thomas J. MacVittie, ; Phone: 410-706-5274; Fax: 410-706-5270
| | - Kim G. Hankey
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA 21201 10 South Pine Street, MSTF Room 604, Baltimore, MD 21201
| | - Allison M. Gibbs
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA 21201 10 South Pine Street, MSTF Room 604, Baltimore, MD 21201
| | - Cassandra P. Smith
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA 21201 10 South Pine Street, MSTF Room 604, Baltimore, MD 21201
| | - Cheryl Taylor-Howell
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA 21201 10 South Pine Street, MSTF Room 604, Baltimore, MD 21201
| | - Sean R. Kearney
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA 21201 10 South Pine Street, MSTF Room 604, Baltimore, MD 21201
| | - Thomas J. MacVittie
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA 21201 10 South Pine Street, MSTF Room 604, Baltimore, MD 21201
- Corresponding authors: Wanchang Cui, ; Phone: 410-706-5282; Fax: 410-706-5270. Thomas J. MacVittie, ; Phone: 410-706-5274; Fax: 410-706-5270
| |
Collapse
|
|
36
|
Rho GTPases: Novel Players in the Regulation of the DNA Damage Response? Biomolecules 2015; 5:2417-34. [PMID: 26437439 PMCID: PMC4693241 DOI: 10.3390/biom5042417] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 09/02/2015] [Accepted: 09/09/2015] [Indexed: 12/26/2022] Open
Abstract
The Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the family of Ras-homologous small GTPases. It is well characterized as a membrane-bound signal transducing molecule that is involved in the regulation of cell motility and adhesion as well as cell cycle progression, mitosis, cell death and gene expression. Rac1 also adjusts cellular responses to genotoxic stress by regulating the activity of stress kinases, including c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 kinases as well as related transcription factors. Apart from being found on the inner side of the outer cell membrane and in the cytosol, Rac1 has also been detected inside the nucleus. Different lines of evidence indicate that genotoxin-induced DNA damage is able to activate nuclear Rac1. The exact mechanisms involved and the biological consequences, however, are unclear. The data available so far indicate that Rac1 might integrate DNA damage independent and DNA damage dependent cellular stress responses following genotoxin treatment, thereby coordinating mechanisms of the DNA damage response (DDR) that are related to DNA repair, survival and cell death.
Collapse
|
|
37
|
Chang PY, Qu YQ, Wang J, Dong LH. The potential of mesenchymal stem cells in the management of radiation enteropathy. Cell Death Dis 2015; 6:e1840. [PMID: 26247725 PMCID: PMC4558492 DOI: 10.1038/cddis.2015.189] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 06/02/2015] [Accepted: 06/08/2015] [Indexed: 12/20/2022]
Abstract
Although radiotherapy is effective in managing abdominal and pelvic malignant tumors, radiation enteropathy is still unavoidable. This disease severely affects the quality of life of cancer patients due to some refractory lesions, such as intestinal ischemia, mucositis, ulcer, necrosis or even perforation. Current drugs or prevailing therapies are committed to alleviating the symptoms induced by above lesions. But the efficacies achieved by these interventions are still not satisfactory, because the milieus for tissue regeneration are not distinctly improved. In recent years, regenerative therapy for radiation enteropathy by using mesenchymal stem cells is of public interests. Relevant results of preclinical and clinical studies suggest that this regenerative therapy will become an attractive tool in managing radiation enteropathy, because mesenchymal stem cells exhibit their pro-regenerative potentials for healing the injuries in both epithelium and endothelium, minimizing inflammation and protecting irradiated intestine against fibrogenesis through activating intrinsic repair actions. In spite of these encouraging results, whether mesenchymal stem cells promote tumor growth is still an issue of debate. On this basis, we will discuss the advances in anticancer therapy by using mesenchymal stem cells in this review after analyzing the pathogenesis of radiation enteropathy, introducing the advances in managing radiation enteropathy using regenerative therapy and exploring the putative actions by which mesenchymal stem cells repair intestinal injuries. At last, insights gained from the potential risks of mesenchymal stem cell-based therapy for radiation enteropathy patients may provide clinicians with an improved awareness in carrying out their studies.
Collapse
Affiliation(s)
- P-Y Chang
- 1] Department of Radiation Oncology, The First Bethune Hospital of Jilin University, Changchun 130021, China [2] Electrochemical State Key Laboratory, Changchun Institute of Applied Chemistry Academy of Science, Changchun 130021, China
| | - Y-Q Qu
- Department of Radiation Oncology, The First Bethune Hospital of Jilin University, Changchun 130021, China
| | - J Wang
- Electrochemical State Key Laboratory, Changchun Institute of Applied Chemistry Academy of Science, Changchun 130021, China
| | - L-H Dong
- Department of Radiation Oncology, The First Bethune Hospital of Jilin University, Changchun 130021, China
| |
Collapse
|
|
38
|
Osteopontin knockout does not influence the severity of rectal damage in a preclinical model of radiation proctitis in mice. Dig Dis Sci 2015; 60:1633-44. [PMID: 25577272 DOI: 10.1007/s10620-014-3520-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 12/30/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Radiation damage to the normal gut is a dose-limiting factor in the application of radiation therapy to treat abdominal and pelvic cancers. All tissue cell types react in concert to orchestrate an acute inflammatory reaction followed by a delayed chronic scarring process. Osteopontin (OPN) is a matricellular protein known to be involved in various physiological but also pathological processes such as tissue inflammation and fibrosis. AIMS The aim of our study was to determine whether OPN knockout influences the severity of radiation proctitis and to investigate the role of OPN in the development of radiation-induced gut damage. RESULTS Here we show that human radiation proctitis is associated with increased immunostaining of the intracellular and extracellular/matrix-linked isoforms of OPN. Moreover, endothelial cells in vitro and rectal tissue in a preclinical model of radiation proctitis in mice both respond to radiation exposure by a sustained increase in OPN mRNA and protein levels. Genetic deficiency of OPN did not influence radiation-induced rectal damage and was associated with significantly decreased animal survival. The acute and late radiation injury scores were similar in OPN-null mice compared with their control littermates. CONCLUSION This study shows that in our model and given the pleiotropic actions of OPN in tissue inflammation and fibrosis, further studies are necessary to understand the precise roles of OPN in radiation-induced proctitis and to determine whether OPN is a useful therapeutic tool in prevention of radiation-induced intestinal tissue injury.
Collapse
|
|
39
|
Straub JM, New J, Hamilton CD, Lominska C, Shnayder Y, Thomas SM. Radiation-induced fibrosis: mechanisms and implications for therapy. J Cancer Res Clin Oncol 2015; 141:1985-94. [PMID: 25910988 DOI: 10.1007/s00432-015-1974-6] [Citation(s) in RCA: 422] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 04/15/2015] [Indexed: 01/01/2023]
Abstract
PURPOSE Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition. METHODS A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords "Radiation-Induced Fibrosis," "Radiotherapy Complications," "Fibrosis Therapy," and other closely related terms. RESULTS RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways. CONCLUSION Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies.
Collapse
Affiliation(s)
- Jeffrey M Straub
- Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, 3020A Wahl Hall East, Kansas City, KS, 66160, USA
| | - Jacob New
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Chase D Hamilton
- Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, 3020A Wahl Hall East, Kansas City, KS, 66160, USA
| | - Chris Lominska
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Yelizaveta Shnayder
- Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, 3020A Wahl Hall East, Kansas City, KS, 66160, USA
| | - Sufi M Thomas
- Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, 3020A Wahl Hall East, Kansas City, KS, 66160, USA. .,Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA. .,Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
| |
Collapse
|
|
40
|
Huang Y, Xiao S, Jiang Q. Role of Rho kinase signal pathway in inflammatory bowel disease. Int J Clin Exp Med 2015; 8:3089-3097. [PMID: 26064197 PMCID: PMC4443031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 02/27/2015] [Indexed: 06/04/2023]
Abstract
Inflammatory Bowel Disease (IBD) is nonspecific inflammation in the intestinal track, including Ulcerative Colitis (UC) and Crohn's disease (CD). The incidence of IBD has increased significantly, with its numerous rising up to five million globally, more than 1,700,000 in China. Pathological character of IBD is the inflammation of intestinal mucosa and intestinal fibrosis. Although the pathogenesis of the disease has not yet been fully clarified, some evidence suggests that excessive intestinal inflammation reaction, intestinal barrier impairment and abnormal immune response can initiate IBD. As research continues, some of them have provided new insights toward understanding of Rho kinase signal pathway function at the occurrence and development of IBD. This review aims to summarize the general principles of Rho kinase signal pathway in the pathological procedure of IBD.
Collapse
|
|
41
|
Malik M, Britten J, Segars J, Catherino WH. Leiomyoma cells in 3-dimensional cultures demonstrate an attenuated response to fasudil, a rho-kinase inhibitor, when compared to 2-dimensional cultures. Reprod Sci 2014; 21:1126-38. [PMID: 25084783 PMCID: PMC4212347 DOI: 10.1177/1933719114545240] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Uterine leiomyomata are common benign tumors in women of reproductive age and demonstrate an attenuated response to mechanical signaling that involves Rho and integrins. To further characterize the impairment in Rho signaling, we studied the effect of Rho-kinase inhibitor, fasudil, on extracellular matrix production, in 2-dimensional (2D) and 3-dimensional (3D) cultures of leiomyoma and myometrial cells. Leiomyoma 2D cultures demonstrated a rapid decrease in gene transcripts and protein for fibronectin, procollagen 1A, and versican. In 3D cultures, fibronectin and procollagen 1A proteins demonstrated increased levels at lower concentrations of fasudil, followed by a concentration-dependent decrease. Versican protein increased up to 3-fold, whereas fibromodulin demonstrated a significant decrease of 1.92-fold. Myometrial 2D or 3D cultures demonstrated a decrease in all proteins after 72 hours of treatment. The 3D leiomyoma cultures demonstrated a significant increase in active RhoA, followed by a concentration-dependent decrease at higher concentrations. A concentration-dependent increase in phospho-extracellular regulated signal kinase and proapoptotic protein Bax was observed in 3D leiomyoma cultures. Fasudil relaxed the contraction of the 3D collagen gels caused by myometrium and leiomyoma cell growth. These findings indicate that the altered state of Rho signaling in leiomyoma was more clearly observed in 3D cultures. The results also suggest that fasudil may have clinical applicability for treatment of uterine leiomyoma.
Collapse
Affiliation(s)
- Minnie Malik
- Department of Obstetrics and Gynecology, Uniformed Services, University of the Health Sciences, Bethesda, MD, USA
| | - Joy Britten
- Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA
| | - James Segars
- Department of Obstetrics and Gynecology, Uniformed Services, University of the Health Sciences, Bethesda, MD, USA Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA
| | - William H Catherino
- Department of Obstetrics and Gynecology, Uniformed Services, University of the Health Sciences, Bethesda, MD, USA Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA
| |
Collapse
|
|
42
|
Bitar KN, Raghavan S, Zakhem E. Tissue engineering in the gut: developments in neuromusculature. Gastroenterology 2014; 146:1614-24. [PMID: 24681129 PMCID: PMC4035447 DOI: 10.1053/j.gastro.2014.03.044] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Revised: 03/17/2014] [Accepted: 03/20/2014] [Indexed: 12/13/2022]
Abstract
The complexity of the gastrointestinal (GI) tract lies in its anatomy as well as in its physiology. Several different cell types populate the GI tract, adding to the complexity of cell sourcing for regenerative medicine. Each cell layer has a specialized function in mediating digestion, absorption, secretion, motility, and excretion. Tissue engineering and regenerative medicine aim to regenerate the specific layers mimicking architecture and recapitulating function. Gastrointestinal motility is the underlying program that mediates the diverse functions of the intestines, as an organ. Hence, the first logical step in GI regenerative medicine is the reconstruction of the tubular smooth musculature along with the drivers of their input, the enteric nervous system. Recent advances in the field of GI tissue engineering have focused on the use of scaffolding biomaterials in combination with cells and bioactive factors. The ability to innervate the bioengineered muscle is a critical step to ensure proper functionality. Finally, in vivo studies are essential to evaluate implant integration with host tissue, survival, and functionality. In this review, we focus on the tubular structure of the GI tract, tools for innervation, and, finally, evaluation of in vivo strategies for GI replacements.
Collapse
Affiliation(s)
- Khalil N. Bitar
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem NC 27101,Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Winston-Salem NC 27101
| | - Shreya Raghavan
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem NC 27101,Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Winston-Salem NC 27101
| | - Elie Zakhem
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem NC 27101,Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Winston-Salem NC 27101
| |
Collapse
|
|
43
|
Harris GM, Piroli ME, Jabbarzadeh E. Deconstructing the Effects of Matrix Elasticity and Geometry in Mesenchymal Stem Cell Lineage Commitment. ADVANCED FUNCTIONAL MATERIALS 2014; 24:2396-2403. [PMID: 25530746 PMCID: PMC4267324 DOI: 10.1002/adfm.201303400] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
A wide variety of environmental factors including physical and biochemical signals are responsible for stem cell behavior and function. In particular, matrix elasticity and cell shape have been shown to determine stem cell function, yet little is known about the interplay between how these physical cues control cell differentiation. For the first time, by using ultraviolet (UV) lithography to pattern poly(ethylene) glycol (PEG) hydrogels we are able to manufacture microenvironments capable of parsing the effects of matrix elasticity, cell shape, and cell size in order to explore the relationship between matrix elasticity and cell shape in mesenchymal stem cell (MSC) lineage commitment. Our data shows that cells cultured on 1,000 μm2 circles, squares, and rectangles were primarily adipogenic lineage regardless of matrix elasticity, while cells cultured on 2,500 and 5,000 μm2 shapes more heavily depended on shape and elasticity for lineage specification. We further went on to characterize how modifying the cell cytoskeleton through pharmacological inhibitors can modify cell behavior. By showing MSC lineage commitment relationships due to physical signals, this study highlights the importance of cell shape and matrix elasticity in further understanding stem cell behavior for future tissue engineering strategies.
Collapse
Affiliation(s)
- Greg M. Harris
- Department of Chemical Engineering, University of South Carolina, SC 29208
| | - Maria E. Piroli
- Department of Biomedical Engineering, University of South Carolina, SC 29208
| | - Ehsan Jabbarzadeh
- Department of Chemical Engineering, University of South Carolina, SC 29208
- Department of Biomedical Engineering, University of South Carolina, SC 29208
- Department of Orthopaedic Surgery, University of South Carolina, SC 29208
- Corresponding author Ehsan Jabbarzadeh Ph.D., Assistant Professor of Chemical Engineering, Assistant Professor of Biomedical Engineering, Assistant Professor of Orthopaedic Surgery, University of South Carolina, Columbia, SC 29208, Ph: (803) 777-3297, Fax: (803) 777-8265,
| |
Collapse
|
|
44
|
Monceau V, Llach A, Azria D, Bridier A, Petit B, Mazevet M, Strup-Perrot C, To THV, Calmels L, Germaini MM, Gourgou S, Fenoglietto P, Bourgier C, Gomez AM, Escoubet B, Dörr W, Haagen J, Deutsch E, Morel E, Vozenin MC. Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis. Radiother Oncol 2014; 111:63-71. [PMID: 24721545 DOI: 10.1016/j.radonc.2014.01.025] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 01/06/2014] [Accepted: 01/28/2014] [Indexed: 01/22/2023]
Abstract
BACKGROUND Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target. METHODS The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes. RESULTS In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca(2+) transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals. CONCLUSION Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart.
Collapse
Affiliation(s)
- Virginie Monceau
- INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France
| | - Anna Llach
- INSERM U769, IFR141, LabEx LERMIT, Faculté de Pharmacie, Châtenay-Malabry, France
| | - David Azria
- Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France
| | - André Bridier
- Département de radiothérapie, Institut Gustave Roussy, Villejuif, France
| | - Benoît Petit
- INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France
| | - Marianne Mazevet
- INSERM U769, IFR141, LabEx LERMIT, Faculté de Pharmacie, Châtenay-Malabry, France
| | | | - Thi-Hong-Van To
- INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France
| | - Lucie Calmels
- Département de radiothérapie, Institut Gustave Roussy, Villejuif, France
| | | | - Sophie Gourgou
- Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France
| | - Pascal Fenoglietto
- Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France
| | - Céline Bourgier
- INSERM U1030, LabEx LERMIT, Villejuif, France; Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France; Département de radiothérapie, Institut Gustave Roussy, Villejuif, France
| | - Ana-Maria Gomez
- INSERM U769, IFR141, LabEx LERMIT, Faculté de Pharmacie, Châtenay-Malabry, France
| | - Brigitte Escoubet
- Département de Physiologie, Explorations Fonctionnelles, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, France; Université Paris Diderot, France; INSERM U872, Paris, France
| | - Wolfgang Dörr
- Department of Radiotherapy and Radiation Oncology, Technical University, Dresden, Germany; Department of Radiation Oncology & Christian Doppler Laboratory for Medical Radiation Research in Radiooncology Medical University, Vienna, Austria
| | - Julia Haagen
- Department of Radiotherapy and Radiation Oncology, Technical University, Dresden, Germany
| | - Eric Deutsch
- INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France; Département de radiothérapie, Institut Gustave Roussy, Villejuif, France
| | - Eric Morel
- INSERM U769, IFR141, LabEx LERMIT, Faculté de Pharmacie, Châtenay-Malabry, France
| | - Marie Catherine Vozenin
- INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France; Laboratoire de Radio-oncologie, CHUV, Lausanne, Switzerland.
| |
Collapse
|
|
45
|
Akita S. Treatment of Radiation Injury. Adv Wound Care (New Rochelle) 2014; 3:1-11. [PMID: 24761339 DOI: 10.1089/wound.2012.0403] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 01/20/2013] [Indexed: 02/06/2023] Open
Abstract
Significance: Radiation exposure as a result of radiation treatment, accident, or terrorism may cause serious problems such as deficiency due to necrosis or loss of function, fibrosis, or intractable ulcers in the tissues and organs. When the skin, bone, oral mucous membrane, guts, or salivary glands are damaged by ionizing radiation, the management and treatment are very lengthy and difficult. Critical Issues: In severe and irreversible injuries, surgery remains the mainstay of treatment. Several surgical procedures, such as debridement, skin grafting, and local and free-vascularized flaps, are widely used. Recent Advances: In specific cases of major morbidity or in high-risk patients, a newly developed therapy using a patient's own stem cells is safe and effective. Adipose tissue, normally a rich source of mesenchymal stem cells, which are similar to those from the bone marrow, can be harvested, since the procedure is easy, and abundant tissue can be obtained with minimal invasiveness. Future Directions: Based on the molecular basis of radiation injuries, several prospective treatments are under development. Single-nucleotide polymorphisms focus on an individual's sensitivity to radiation in radiogenomics, and the pathology of radiation fibrosis or the effect of radiation on wound healing is being studied and will lead to new insight into the treatment of radiation injuries. Protectors and mitigators are being actively investigated in terms of the timing of administration or dose.
Collapse
Affiliation(s)
- Sadanori Akita
- Division of Plastic and Reconstructive Surgery, Department of Developmental and Reconstructive Medicine, Graduate School of Biomedical and Sciences, Nagasaki University, Nagasaki, Japan
| |
Collapse
|
|
46
|
Abstract
BACKGROUND Ras homolog gene family, member A (RhoA)/Rho-associated coiled-coil forming protein kinase signaling is a key pathway in multiple types of solid organ fibrosis, including intestinal fibrosis. However, the pleiotropic effects of RhoA/Rho-associated coiled-coil forming protein kinase signaling have frustrated targeted drug discovery efforts. Recent recognition of the role of Rho-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) suggest a novel locus for pharmacological intervention. METHODS Because RhoA signaling is mediated by both physical and biochemical stimuli, we examined whether pharmacological inhibition of RhoA or the downstream transcription pathway of MRTF-A/SRF could block intestinal fibrogenesis in 2 in vitro models. RESULTS In this study, we demonstrate that inhibition of RhoA signaling blocks both matrix-stiffness and transforming growth factor beta-induced fibrogenesis in human colonic myofibroblasts. Repression of alpha-smooth muscle actin and collagen expression was associated with the inhibition of MRTF-A nuclear localization. CCG-1423, a first-generation Rho/MRTF/SRF pathway inhibitor, repressed fibrogenesis in both models, yet has unacceptable cytotoxicity. Novel second-generation inhibitors (CCG-100602 and CCG-203971) repressed both matrix-stiffness and transforming growth factor beta-mediated fibrogenesis as determined by protein and gene expression in a dose-dependent manner. CONCLUSIONS Targeting the Rho/MRTF/SRF mechanism with second-generation Rho/MRTF/SRF inhibitors may represent a novel approach to antifibrotic therapeutics.
Collapse
|
|
47
|
PKCδ as a regulator for TGF-β-stimulated connective tissue growth factor production in human hepatocarcinoma (HepG2) cells. Biochem J 2013; 456:109-18. [PMID: 23988089 DOI: 10.1042/bj20130744] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
CTGF (connective tissue growth factor) is widely regarded as an important amplifier of the profibrogenic action of TGF-β (transforming growth factor β) in a variety of tissues, although the precise mechanism of how the TGF-β signalling pathways modulate CTGF expression remains unclear. In the present study, the role of PKCδ (protein kinase Cδ) in TGF-β1-mediated CTGF expression was investigated using HepG2 cells. TGF-β1 treatment specifically elevated PKCδ activation and CTGF expression. In contrast, blockade of PKCδ by the selective inhibitor Rottlerin or by siRNA knockdown significantly reduced TGF-β1-induced CTGF production. The regulatory mechanism was further demonstrated in HepG2 cells whereby TGF-β1-induced PKCδ activation negatively regulated the nuclear levels of PPM1A (protein phosphatase, Mg2+/Mn2+ dependent, 1A) through the RhoA/ROCK (Rho-associated kinase) pathway. Moreover, we showed that both Smad signalling and the PKCδ pathway appeared to be stimulated by TGF-β1 in parallel. Time course assessments indicated that PKCδ signalling may have a function in maintaining nuclear phospho-Smads at a maximal level. The collective results of the present study demonstrated that PKCδ-stimulated RhoA/ROCK activation resulted in a reduction in PPM1A, thereby up-regulating Smad-dependent gene induction for extended periods. These findings indicated that PKCδ plays a critical role in TGF-β1-induced CTGF production in HepG2 cells.
Collapse
|
|
48
|
Hamama S, Noman MZ, Gervaz P, Delanian S, Vozenin MC. MiR-210: A potential therapeutic target against radiation-induced enteropathy. Radiother Oncol 2013; 111:219-21. [PMID: 24290534 DOI: 10.1016/j.radonc.2013.10.030] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2013] [Revised: 10/01/2013] [Accepted: 10/16/2013] [Indexed: 11/30/2022]
Abstract
A previously undescribed and robust miR210 overexpression is shown in intestinal samples obtained from patients with radiation enteropathy and fibrotic cultured cells. In addition, miR-210 overexpression is repressed by antifibrotic treatment combining pentoxifylline and α-tocopherol.
Collapse
Affiliation(s)
- Saad Hamama
- INSERM U-1030 "Molecular Radiotherapy", Institut Gustave Roussy, Villejuif, France; LabEX LERMIT Villejuif, France; Université Paris Sud Paris XI, Le Kremlin Bicêtre, France.
| | - Muhammad Zaeem Noman
- INSERM, U753, Laboratoire d'immunologie des Tumeurs Humaines: Interaction Effecteurs Cytotoxiques-Système Tumoral, Institut Gustave-Roussy, Villejuif, France.
| | - Pascal Gervaz
- Geneva University Hospital and Medical School, Geneva, Switzerland.
| | - Sylvie Delanian
- Unité de Radiopathologie, Service Oncologie-Radiothérapie, Hôpital Saint-Louis, APHP, Paris, France.
| | - Marie-Catherine Vozenin
- INSERM U-1030 "Molecular Radiotherapy", Institut Gustave Roussy, Villejuif, France; LabEX LERMIT Villejuif, France; Université Paris Sud Paris XI, Le Kremlin Bicêtre, France; Laboratoire de RadioOncologie, Swiss Cancer Center of Lausanne, CHUV, Lausanne, Switzerland.
| |
Collapse
|
|
49
|
Corre I, Guillonneau M, Paris F. Membrane signaling induced by high doses of ionizing radiation in the endothelial compartment. Relevance in radiation toxicity. Int J Mol Sci 2013; 14:22678-96. [PMID: 24252908 PMCID: PMC3856084 DOI: 10.3390/ijms141122678] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 11/01/2013] [Accepted: 11/06/2013] [Indexed: 01/30/2023] Open
Abstract
Tumor areas can now be very precisely delimited thanks to technical progress in imaging and ballistics. This has also led to the development of novel radiotherapy protocols, delivering higher doses of ionizing radiation directly to cancer cells. Despite this, radiation toxicity in healthy tissue remains a major issue, particularly with dose-escalation in these new protocols. Acute and late tissue damage following irradiation have both been linked to the endothelium irrigating normal tissues. The molecular mechanisms involved in the endothelial response to high doses of radiation are associated with signaling from the plasma membrane, mainly via the acid sphingomyelinase/ceramide pathway. This review describes this signaling pathway and discusses the relevance of targeting endothelial signaling to protect healthy tissues from the deleterious effects of high doses of radiation.
Collapse
Affiliation(s)
- Isabelle Corre
- CRCNA-UMR Inserm U892-CNRS 6299-Institut de Recherche en Santé de l'Université de Nantes, Nantes 44007, France.
| | | | | |
Collapse
|
|
50
|
Bopp A, Wartlick F, Henninger C, Kaina B, Fritz G. Rac1 modulates acute and subacute genotoxin-induced hepatic stress responses, fibrosis and liver aging. Cell Death Dis 2013; 4:e558. [PMID: 23519127 PMCID: PMC3613835 DOI: 10.1038/cddis.2013.57] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
To investigate the importance of the Ras-homologous GTPase Rac1 for the hepatic response to genotoxic insults and liver aging, rac1 was deleted in liver of mice by Mx1-Cre-based recombination. Knockout of rac1 caused complex changes in basal as well as doxorubicin and ionizing radiation-induced mRNA expression of various genotoxic stress response-related genes, including hspa1b, rad51, wrn and xpc. Rac1 deletion protected the liver from acute toxicity following doxorubicin treatment. Moreover, the level of S139 phosphorylated histone H2AX (γH2AX), which is indicative of DNA damage, and mRNA expression of pro-inflammatory (IL-6) and pro-fibrotic (CTGF, TGFβ, αSMA) factors were mitigated in rac1 knockout animals. By contrast, lack of rac1 promoted subacute hepatotoxicity, which was determined 3 weeks after injection of multiple low doses of doxorubicin by assaying the γH2AX level, mitotic index and pro-fibrotic gene expression. Regarding ionizing radiation, rac1 deficiency had no major effects on DNA damage induction or acute pro-inflammatory and pro-fibrotic stress responses. Mice lacking hepatic rac1 for extended period of time (15 months) revealed increased mRNA expression of fibrosis-related factors (CTGF, TGFβ, collagen, MMP1) and fibrotic tissue remodeling. In addition, protein expression of the senescence marker p16 was enhanced in the absence of rac1. Taken together, the data provide evidence that Rac1 is required for doxorubicin-induced DNA damage induction. It is also involved in both the acute and delayed inflammatory and fibrotic stress response in the liver following doxorubicin, but not ionizing radiation, treatment and, furthermore, protects against endogenous liver aging.
Collapse
Affiliation(s)
- A Bopp
- Department of Toxicology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | | | | | | | | |
Collapse
|